Two-component boronic acid catalysis for increased reactivity in challenging Friedel-Crafts alkylations with deactivated benzylic alcohols

Article abstract of DOI:10.1039/c9ob01043b

A general and efficient boronic acid catalyzed Friedel-Crafts alkylation of arenes with benzylic alcohols was previously developed for the construction of unsymmetrical diarylmethane products (X. Mo, J. Yakiwchuk, J. Dansereau, J. A. McCubbin and D. G. Hall, J. Am. Chem. Soc., 2015, 137, 9694). Highly electron-deficient benzylic alcohols, however, were ineffective coupling partners due to the increased difficulty of C-O bond ionization. Herein, we report the use of perfluoropinacol as an effective co-catalyst to improve the reactivity of a boronic acid catalyst in the Friedel-Crafts benzylations of electronically deactivated primary and secondary benzylic alcohols. According to spectroscopic studies, it is believed that perfluoropinacol condenses with the arylboronic acid catalyst to form a highly electrophilic and Lewis acidic boronic ester. This in situ formed species enables a more facile ionization of the benzylic alcohols likely through a mode of activation promoted by a Lewis acid assisted hydronium Br?nsted acid generated from the interactions of the transient boronic ester with hexafluoroisopropanol solvent and water.

Full text of DOI:10.1039/c9ob01043b

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DOI: 10.1039/C9OB01043B
ARTICLE
Two-Component Boronic Acid Catalysis for Increased Reactivity in
Challenging Friedel-Crafts Alkylations with Deactivated Benzylic
Alcohols
Received 00th January 20xx,
Accepted 00th January 20xx
Hwee Ting Ang, ‡a Jason P. G. Rygus ‡a and Dennis G. Hall *a
DOI: 10.1039/x0xx00000x
A general and efficient boronic acid catalyzed Friedel-Crafts alkylation of arenes with benzylic alcohols was previously
developed for the construction of unsymmetrical diarylmethane products (J. Am. Chem. Soc. 2015, 137, 9694). Highly
electron-deficient benzylic alcohols, however, were ineffective coupling partners due to the increased difficulty of C–O
bond ionization. Herein, we report the use of perfluoropinacol as an effective co-catalyst to improve the reactivity of a
boronic acid catalyst in the Friedel-Crafts benzylations of electronically deactivated primary and secondary benzylic
alcohols. According to spectroscopic studies, it is believed that perfluoropinacol condenses with the arylboronic acid
catalyst to form a highly electrophilic and Lewis acidic boronic ester. This in situ formed species enables a more facile
ionization of the benzylic alcohols likely through a mode of activation promoted by a Lewis acid assisted hydronium
Brønsted acid generated from the interactions of the transient boronic ester with hexafluoroisopropanol solvent and
water.
ferroceniumboronic acid hexafluoroantimonate salt 1a as a
highly active catalyst (Fig. 2a)7. Although many primary
benzylic alcohols containing moderately electron-withdrawing
Introduction
Unsymmetrical diarylmethanes along with diaryl- and
triarylalkanes are a common motif within the structure of
numerous pharmaceutical agents and biologically active
natural products (see examples in Fig. 1).1 Friedel-Crafts
alkylation chemistry can provide a rapid access to these
compounds from readily available arenes and benzylic
electrophiles.2 In this regard, direct benzylation of arenes using
benzylic alcohols is highly advantageous for avoiding reactive
benzylic halides traditionally employed in this reaction,3 which
pose a hazard as toxic lachrymator chemicals that can
hydrolyze readily to generate irritating haloacid gas (HX) as by-
product. In this context, boronic acid catalysis (BAC) has
emerged as a mild and ‘greener’ method for direct activation
of hydroxy groups.4 In BAC, the C–O bond of alcohols can be
activated for further chemical transformation through a
reversible interaction with a boronic acid, releasing water as
the only by-product.4 Furthermore, many arylboronic acids are
commercially available or can be prepared readily, and they
are generally shelf stable crystalline solids that are easy to
handle,5 thus making them a great candidate for catalysis.
Recently, we reported an effective direct Friedel-Crafts
benzylation reaction of π-activated alcohols6 with arenes using
substituents were successful, the most highly electron-
deficient benzylic alcohols were poor substrates for this
reaction even at elevated temperature. Presumably, this
limitation is caused by an increase in the barrier to C–O bond
activation arising from destabilization of the resulting
carbocation intermediate. Because our BAC system employs
hexafluoroisopropanol (HFIP) as a co-solvent, we suspected
that ionization of the alcohol may proceed with the assistance
of a transient, highly electrophilic mono- or di(hexafluoro-
isopropoxy) boronic ester. Subsequently, Moran and
OH
N(i-Pr)2
N
O
OH
tolterodine
lasofoxifene
(antimuscarinic, for urinary
incontinence)
(selective estrogen receptor modulator,
treatment of osteoporosis)
O
F
O
O
NH
N
MeO
O
N
O
MeO
a. Department of Chemistry, Centennial Centre for Interdisciplinary Science,
University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
E-mail: dennis.hall@ualberta.ca
F
OMe
OMe
pimozide
peperomin B
(anti-inflammatory agent)
(antipsychotic, treatment of delusional disorder)
†Electronic Supplementary Information (ESI) available: General experimental
information and NMR spectra. See DOI: 10.1039/x0xx00000x
Fig. 1
Examples of biologically active compounds containing a diarylmethane or
‡ These authors contributed equally.
diarylalkane motif.
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Organic & Biomolecular Chemistry
a. Boronic acid catalyzed F-C alkylation with benzylic alcohols7
Table 1 Reaction optimization with various co-catalystsa
View Article Online
DOI: 10.1039/C9OB01043B
HO
1a (10 mol%)
B(OH)2
+
B(OH)2
Fe(III)
X
HFIP/CH3NO2 (4:1)
Y
Y
SbF6
X
Fe(III)
(5 equiv)
(1 equiv)
[0.5 M], 25-80 °C
24-48 h
1a (10 mol%)
SbF6
New catalyst class
Mild conditions
Expanded scope
HO
co-catalyst (X mol%)
1a
X = MeO, halide, alkyl
Y = EDG, EWG, halide, alkyl
+
NO2
NO2
HFIP/CH3NO2 (4:1)
80 °C, time
4a
3a
2a
co-catalyst:
F3 CF3
b. Boronic acid/oxalic acid co-catalyzed F-C benzylation8
Br
C6F5B(OH)2 (1 mol%)
HO2CCO2H (2 mol%)
Br
Br
OH
OH
F
F
O
C
HO
OH
OH
OH
OH
+
HO
HO
HO
HO
CH3NO2, rt, 15 min
OMe
OMe
F
F
F
F
F3
C
CF3
O
Br
(95%)
(3 equiv)
(1 equiv)
A4
A5
A2
A3
A1
c. This work: Boronic acid/perfluoropinacol system for F-C alkylation
B(OH)2
F
Entry
1
2
3
4
5
6
7c
8
co-catalyst
X mol%
-
10
10
10
10
10
10
10
time
24 h
24 h
24 h
24 h
24 h
24 h
24 h
yield (%)b
R
R
F
F
-
10
26
10
4
1
6
24
30
28
0
1a or 1b (10 mol%)
A1 (10 mol%)
F
HO
A1
A2
A3
A4
A5
A1
A1
A1
A1
1b
+
HFIP/CH3NO2 (4:1)
EWG
Y
Y
EWG
F3C CF3
[0.5 M], 25-80 °C,
1-24 h
(1 equiv)
OH
(5 equiv)
HO
R = H, Me, Ar
R = H, Me, Ar
F3C CF3
A1
Fig. 2
Boronic acid catalyzed Friedel-Crafts alkyllation
7 days
24 h
24 h
co-workers described the use of oxalic acid as a powerful sub-
stoichiometric co-catalyst in Friedel-Crafts chemistry (Fig. 2b).8
We recently disclosed the use of perfluoropinacol as a co-
catalyst in the boronic acid catalyzed Beckmann
rearrangement and demonstrated that its activating effect
occurs by formation of an electrophilic boronic ester.9 These
observations prompted us to re-examine our boronic acid-
catalyzed Friedel-Crafts methodology and identify a co-catalyst
9
10d
100
10
a
Reaction condition unless otherwise noted: 2a (0.50 mmol), 3a (2.50
mmol), catalyst 1a (10 mol%), co-catalyst (10 mol%) in HFIP/CH3NO2 (4:1)
solvent mixture (1 mL) were stirred at 80 °C for 24 hours. b NMR yield with
1,4-dinitrobenzene as internal standard. Reaction performed at 100 °C.
Reaction performed without co-catalyst 1a.
c
d
that could provide a two-component catalyst with increased co-catalyst, the reaction time or the temperature (entries 7-9).
reactivity towards challenging substrates. Herein, we report Control experiment without co-catalyst 1a (entry 10) showed
on the successful application of perfluoropinacol as a co- that co-catalyst A1 by itself does not catalyze the reaction.
catalyst leading to a significant improvement of the Friedel-
T h e s c o p e o f t h e f e r r o c e n i u m b o r o n i c a c i d
Crafts benzylation with many challenging substrates. /perfluoropinacol co-catalyzed Friedel-Crafts alkylation
Furthermore, the use of perfluoropinacol allows for the reaction was then examined (Fig. 3), particularly with respect
Friedel-Crafts benzylation of secondary benzylic alcohols (–Me
or –Ar) to be catalyzed by 2,3,4,5-tetrafluorophenylboronic
1a (10 mol%)
B(OH)2
SbF6
HO
A1 (10 mol%)
+
acid (1b) (Fig. 2c), which is commercially available and
possesses superior shelf stability compared to the
Fe(III)
HFIP/CH3NO2 (4:1)
EWG
Y
Y
EWG
[0.5 M], 80 °C,
24 h
a
2
3
4
1a
(1 equiv)
(5 equiv)
zwitterionic ferrocenium catalyst 1a.
F
F
F
F
F
F
Results and discussion
4b, 78%;
{43% without A1}
4c, 76%;
{40% without A1}
(50 °C)
4d, 80%;
{48% without A1}
To identify an effective co-catalyst that would be synergic with
boronic acid 1a, we chose as model substrates p-nitrobenzyl
alcohol (2a), a primary benzylic alcohol previously shown to be
highly challenging, and p-xylene (3a) as the nucleophilic
partner with previously optimized reaction conditions (Table
1).7 In the absence of any co-catalyst A , the desired
diarylmethane product 4a was observed in very low yield even
a f t e r 2 4 h a t 8 0 ° C ( e n t r y 1 ) . W h e n 1 0 m o l % o f
perfluoropinacol (co-catalyst A1) was employed, a notable
increase in yield occurred (entry 2). All other electron-deficient
diols and α-hydroxy carboxylic acids tested failed to
demonstrate a similar efficacy (entries 3-6). No improvement
in yield was obtained through increasing the equivalents of the
(25 °C)
CF3
Cl
Br
Cl
CF3
4e, 83%;
{40% without A1}
(50 °C, 1 h)
4f, 76%;
{38% without A1}
4g, 23%;
{0% without A1}
(50 °C)
F
F
F
F
Cl
F
Br
F
F
Cl
F
4h, 0%;
{0% without A1}
4i, 61%;
{20% without A1}
4j, 55 %;
{33% without A1}
Fig. 3
Substrate scope of primary benzyl alcohols with co-catalysts 1a and A1.
Reaction scale: 0.5 mmol of alcohol. Reported yields of 4g, 4i and 4j are isolated yields
of combined regioisomers.
2 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
to electron-deficient benzylic alcohols that proved difficult in corresponding diarylethane or triarylmethane products (4l, 4s,
View Article Online
DOI: 10.1039/C9OB01043B
the absence of the co-catalyst. Electronically deactivated 4t, and 4u) in the presence of co-catalyst A1. Substrates
benzylic alcohols and neutral arenes constitute examples of containing a carboxyester or a sulphonyl group are also
challenging substrates in Friedel-Crafts benzylation suitable in this system, affording the desired diarylethane
chemistry.7,8 Fluorinated benzylic alcohols 3b–3d showed products 4m and 4o in good yields. Highly electronically
nearly a 2-fold increase in yield for the corresponding deactivated alcohols furnished product 4p, 4q and 4v in good
diarylmethanes 4b–4d with the addition of co-catalyst A1. yields with higher reaction temperature (100 °C), longer
Bromide and chloride-substituted benzylic alcohols also reaction time (48 h), and higher loading of co-catalysts 1b and
provided a substantial improvement in the yield of the A1. Unfortunately, heteroaryl alcohols, such as pyrrole,
corresponding diarylmethane products (4e and 4f). When pyridine, thiophene and indole derivatives, are not compatible
highly electronically deactivated alcohols such as p-nitrobenzyl with this system. In most cases, complex mixtures were
alcohol and 3,5-bis(trifluoromethyl)benzyl alcohol were obtained with no sign of desired product.
employed, the yield slightly improved when co-catalytic A1
In the reaction of diarylmethanol derivatives 2r–2v under
was employed (4a and 4g). In contrast, 2,3,5,6- optimized conditions (Fig. 4), symmetrical ethers 5 were
tetrafluorobenzyl alcohol failed to produce diarylmethane 4h observed as minor side products, corresponding to
even with the use of co-catalyst A1. Other halogenated arenes, dehydrative substitution with a second equivalent of alcohol.
such as bromo- and fluorobenzene could be employed as In contrast, ethers 5 were obtained in good yield when the
nucleophilic partners in the reaction, and an improvement in reaction was conducted without A1, or with only A1 as a
the yield of the corresponding products was observed as well catalyst without boronic acid 1b (see Supporting Information).
(4i and 4j).
When the conversion of alcohol 2r to the Friedel-Crafts
1
When expanding the substrate scope to secondary benzylic alkylation product 4r was monitored by H NMR, build-up of
alcohols (Fig. 4), it was found that 2,3,4,5-tetrafluoro- ether 5r was observed in the initial phase of the reaction along
phenylboronic acid 1b, a commercial compound with superior with slow formation of 4r. Over time, further consumption of
shelf-stability compared to 1a, can also be employed as an ether 5r was observed to ultimately form triarylmethane 4r in
effective catalyst with co-catalyst A1. In all cases, significant good yield. The dehydrative synthesis of ether 5r from alcohol
improvement in the yield were observed when co-catalyst A1 2r was recently reported by Taylor and co-workers using
was used. It is noteworthy that the co-catalytic system of 1b 2,3,4,5,6-pentafluoro-phenylboronic acid and oxalic acid as
and A1 can also promote the reaction of primary benzylic catalysts.10
alcohols; however, as shown with 4e, longer reaction times
and a higher temperature are required for these less reactive formation of ether 5r by reaction with a second equivalent of
substrates compared to using catalyst 1a. alcohol 2r is the kinetically preferred pathway due to the
This outcome suggests that upon activation of the alcohol,
As with the above primary benzylic alcohols, halogenated nucleophilicity of oxygen, particularly in the early stages of the
substrates are well tolerated, giving high yields of the reaction where the concentration of unreacted alcohol 2r
remains high. However, subsequent decay of ether 5r suggests
R
R
B(OH)2
1b (10 mol%)
A1 (10 mol%)
that it is not an off-cycle side product, but rather an
intermediate that is capable of further catalytic activation to
ultimately form the Friedel-Crafts triarylmethane product 4r
(Fig. 5). Furthermore, control experiments show that isolated
ether 5r is cleanly converted to the triarylmethane product 4r
F
HO
+
HFIP/CH3NO2 (4:1)
Y
F
F
EWG
Y
EWG
[0.5 M], 80 °C,
24 h
F
2
3
4
1b
(1 equiv)
R = Me or Ar
(5 equiv)
R = Me or Ar
Br
CO2Me
1b
A1
(10 mol%)
(10 mol%)
Br
Ph
OH
4e, 65%
(100 °C, 24 h)
4k, 89%;
{0% without A1 or 1b}
4l, 88%;
{5% without A1}
(50 °C)
4m, 88%;
+
+
O
Ph
{5% without A1}
Ph
Ph
HFIP/CH3NO2 (4:1)
[0.5 M], 80 °C
24 h
(25 °C)
Ph
Ph
Ph
Ph
OMe
3a
2r
5r
4r
(5 eq)
NO2
CF3
SO2Me
NO2
CO2Me
100
90
80
70
60
50
40
30
20
10
0
4n, 80%;
{0% without A1}
4o, 79%;
{0% without A1}
4p, 78%;
{5% without A1}
(100 °C)
4q, 60%;
{0% without A1}
(100 °C, 48 h)
F
Cl
5r
4r
2r
CF3
Br
F
Cl
CF3
4r, 80%;
{0% without A1 or 1b}a
4s, 78%;
{0% without A1}
4t, 84%;
4u, 86%;
{0% without A1}
4v, 88%;
{0% without A1}
(100 °C)
{0% without A1}
Fig. 4
Substrate scope of secondary benzylic alcohol with co-catalysts 1a and
0
200
400
A1. Reaction scale: 0.5 mmol of alcohol. Yield reported as isolated yield. 20 mol%
of co-catalysts 1a and A1 was used for substrate 4q and 4v. a Symmetrical ether
5r was observed instead (see Fig. 5).
Time (min)
Fig. 5
Reaction profile for Friedel-Crafts benzylation of alcohol 2r with p-xylene 3a.
J. Name., 2013, 00, 1-3 | 3
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Page 4 of 8
ARTICLE
Organic & Biomolecular Chemistry
F3
C
CF3
CF3
F3
C
CF3
a)
F3
C
View ArtCicF3le Online
F3
C
when subjected to the standard catalytic reaction conditions.
The role of perfluoropinacol as a co-catalyst in boronic acid
catalysis has previously been studied extensively in the
Beckmann rearrangement.9 It was demonstrated that
perfluoropinacol reacts with the boronic acid catalyst to form a
five-membered boronic ester in situ, resulting in a more
electrophilic Lewis acidic boron center.9 We suspect that
perfluoropinacol (A1) plays a similar role in the current Friedel-
Crafts BAC system. To demonstrate the formation of an
activated boronic ester, a series of 11B NMR studies with
boronic acid catalyst 1b and co-catalyst A1 were performed.
Upon addition of co-catalyst A1 to a solution of catalyst 1a or
1b in HFIP/CH3NO2 (4:1), new 11B signals were detected in the
8 to 14 ppm region corresponding to a tetracoordinate boron
species, rather than the expected three coordinate boronic
ester (see Supporting Information). This result suggests that
upon boronic ester formation the boron centre becomes
sufficiently Lewis acidic to promote coordination by either
HFIP or adventitious water, generating a neutral or anionic
boronate species in solution.
F3
F3
C
C
O
O
HO
OH
O
O
DOI: 10.1039/C9OB01043B
B
B
B
O
HO
F3
C
CF3
HFIP/CH3NO2 (4:1)
[0.05 M], rt, 24 h
F
F
F
F
OH
+
+
HO
F3
C
CF3
F
F
F
F
F
F
F
F
A1
B
C
11B: 9.3 ppm
1b
11B: 8.5 ppm
m/z: 508.98 calculated
509.0 observed
11B: 27.0 ppm
m/z: 658.98 calculated
659.0 observed
b)
F3
C
B
CF3
F3
F3
C
F3
O
C
B
CF3
F3C
F3
O
C
B
CF3
HO
OH
HO
B
O
O
C
O
F3
F3
C
HO
HO
F
F
HFIP/CH3NO2 (4:1)
[0.05 M], rt, 24 h
C
O
F
F
F
F
F
F
F
F3
C
F
F
F
F
F
F
F
1b
m/z: 361.01 calculated; 511.00 calculated; 660.99 calculated
All complexes not observed
11B: 27.0 ppm
c)
HO
OH
B
O
O
F3
F3
C
C
O
O
B
F
F
F
B
F
O
HFIP/CH3NO2 (4:1)
[0.05 M], rt, 24 h
OH
HO
F
F
F
F
+
F
F
F
F
pinacol
1b
m/z: 443.09 calculated
not observed
11B: 29.6 ppm
11B: 27.0 ppm
Scheme 1.
Control experiments to assess a potential role for co-catalyst A1.
To further study this hypothesis, we envisioned that
anionic tetracoordinate boronates could be detected with ESI
mass spectrometry in the negative mode. Therefore, a series
of experiments were conducted (Scheme 1). In the presence of
co-catalyst A1 (Scheme 1a), the anionic complex B was indeed
detected. To further support that this tetracoordinate species
is only observed due to the formation of the highly Lewis acidic
perfluoropinacolate boronic ester, two control experiments
were planned. In the absence of co-catalyst A1, the
corresponding anionic complexes were not observed (Scheme
1b). Similarly, in the presence of pinacol, the non-fluorinated
analog of co-catalyst A1, 11B NMR showed formation of the
pinacolato-boronic ester with a slight downfield shift (29.6
ppm) relative to the free boronic acid (27.0 ppm), however,
the corresponding anionic complex was not observed (Scheme
1c).
Functional group compatibility studies via additive
experiments (see Supporting Information) revealed that the
reaction is moderately tolerant to carboxylic acid, terminal
alkyne, aliphatic alcohols and both unactivated and conjugated
alkene moieties. However, complete inhibition was observed
upon addition of 2,6-di-tert-butylpyridine or other basic
amines. Unless the pyridine additive plays another inhibitory
A. Proposed Reaction Mechanism
B. Plausible Modes of Alcohol Activation
OH
OH
R
B
i) Lewis Acid Catalysis (B-O bond formation)
B
OH
OH
Fe(III)
catalyst 1
SbF6
Ar1
CF3
H
B
CF3
CF3
CF3
CF3
(F3C)2HCO
R
O
O
Ar1CH2OH
HFIP, H2O
CF3
O
HO
O
O
O
O
1a
B
R
R
B
F3C CF3
CF3
Ar1CH2
OH
CF3
CF3
CF3
CF3
OH
F
HO
F
H3O+
OH
F3C CF3
A1
CF3
B
H2O
HO
F3C
CF3
HFIP
B
C
F
F
1b
CF3
ii) Brønsted Acid Catalysis (water-mediated protonation)
(F3C)2HCO
R
O
O
CF3
B
CF3
CF3
Ar1CH2OH
ROH
CF3
CF3
(F3C)2HCO
R
O
O
CF3
H3O+
CF3
(F3C)2HCO
O
CF3
CF3
CF3
(F3C)2HCO
R
2
O
O
B
Ar1CH2OH
H2O
CF3
R
B
B
CF3
CF3
B
H2O + HFIP
O
HOH
CF3
Ar1CH2
H
Ar1
O
H3O+
CF3
H
D
CF3
B
CF3
CF3
RO
O
O
R
O
O
CF3
R
B
RO
H
B
CF3
CF3
CF3
CF3
Ar1CH2
iii) Lewis Acid Assisted Brønsted Acid Catalysis (protonation)
F
C, R = H
D, R = CH(CF3)2
CF3
CF3
H
CF3
(F3C)2HCO
R
O
O
CF3
(F3C)2HCO
R
(F3C)2HCO
R
O
O
CF3
CF3
Ar1
CF3
O
O
B
Ar1CH2OH
B
R
O
CF3
CF3
CF3
B
CF3
RO
B
HOH
CF3
H
H
Ar1CH2
CF3
CF3
Ar1
O
H
Y
O
CF3
H
4
CF3
Ar1
Y
3
D
G
Y
E
Fig. 6
Proposed reaction mechanism and plausible modes of alcohol activation.
role, such as deprotonating the solvent to produce deleterious
4 | J. Name., 2012, 00, 1-3
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Page 5 of 8
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
1a (10 mol%)
A1 (10 mol%)
species, or through impacting the boronic acid–boroxine
equilibrium, inhibition by 2,6-di-tert-butylpyridine is a strong
evidence for a protic acid dependence in the reaction
mechanism as this highly sterically hindered base is unlikely to
coordinate to boron Lewis acids.11 Furthermore, the recent
study from Taylor and coworkers proposed that the
dehydrative substitution of benzylic alcohols using 2,3,4,5,6-
pentafluorophenylboronic acid and oxalic acid as catalysts
proceeds via a Brønsted acid alcohol activation mechanism,
where the Brønsted acid likely originates from the formation
of hydronium boronate species.10
View Article Online
OH
OH
DOI: 10.1039/C9OB01043B
+
+
Br
dry HFIP/CH3NO2 (4:1)
3 Å mol. sieves
50 °C, 1 h
Br
Br
2e
4e
0%
3a
(5 eq)
2e
98% recovery
Ph
1b (10 mol%)
A1 (10 mol%)
OH
O
Ph
+
+
dry HFIP/CH3NO2 (4:1)
3 Å mol. sieves
80 °C, 24 h
2r
3a
(5 eq)
4r
0%
5r
89%
Scheme 3
Effect of anhydrous solvents and molecular sieves on the reaction of 4-
Based on these preliminary results, possible mechanisms
for this reaction are outlined in Figure 6. In line with Taylor’s
study, we propose that catalyst 1 reacts with co-catalyst A1
and HFIP solvent in equilibrium to form hydronium boronate
complex B as the active catalyst species. Boronate B is
sufficiently activated by the electron-deficient diol to promote
ionization of the alcohol substrate, resulting in carbocation
ion-pair C or D. The activation of alcohols by active catalyst
species B may occur through either a Lewis acid, Brønsted acid
or Lewis acid assisted Brønsted acid12 catalyzed mechanism
(Fig. 6b). Then, Friedel-Crafts alkylation by nucleophilic attack
of the arene onto complex C or D results in complex E, a
Wheland intermediate stabilized by the weakly coordinating
boronate counteranion. Subsequent re-aromatization via
deprotonation with the boronate ion furnishes the benzylated
product and regenerates boronate B in the presence of HFIP
and water through a zwitterionic intermediate F, along with
the release of water or HFIP as a by-product. (Fig. 6a).
To further examine the plausible mode of alcohol
activation, the influence of 2,6-di-tert-butylpyridine on the
two-component catalyst was examined by 11B NMR to
elucidate its inhibitory effect on the Friedel-Crafts reaction
(Fig. 7). In the absence of 2,6-di-tert-butylpyridine, reaction of
equimolar boronic acid 1b with A1 gave a mixture of free
boronic acid and a tetracoordinate boron species tentatively
assigned as complex B (see Figure 6a). Upon addition of 1.5
bromobenzyl alcohol 2e and diphenylmethanol 2r with p-xylene 3a.
equivalents of 2,6-di-tert-butylpyridine, the boronic acid –
boronate equilibrium was significantly altered and complete
conversion to the four-coordinate boronate species with a
pyridinium countercation (H) was observed (Figure 7).
Furthermore, inhibition of the Friedel-Crafts reaction by 2,6-di-
tert-butylpyridine suggests that pyridinium complex H is an
ineffective catalyst. Complexes H and B differ only in their
countercation, suggesting that the countercation might be a
key component in the reaction.
To further probe the possibility of a hydronium boronate
catalytic species B, the efficiency of the Friedel-Crafts reaction
of alcohol 2e and 2r were examined under anhydrous
conditions using carefully dried solvents and glassware, along
with the addition of activated 3 Å molecular sieves as a
desiccant. Under these conditions, formation of the Friedel-
Crafts product 4e and 4r was completely suppressed. While
alcohol 2e was fully recovered, alcohol 2r was not observed
but ether 5r was obtained in good yield (Scheme 3). Control
experiments showed that the addition of molecular sieves
alters the equilibrium between boronic acid 1b and boronate
complex B towards a greater proportion of complex B but does
not appear to generate any previously unidentified catalytic
species (see Supporting Information). Furthermore, addition of
37 mol% water to the Friedel-Crafts reaction of 2r in dried
solvents and glassware restored catalytic activity and 4r was
formed in 71% yield.
These results demonstrate that while free alcohol 2r can
undergo C–O bond activation under anhydrous conditions,
further activation of ether 5r does not proceed without trace
water remaining in the solvents or released in boronic ester
formation by condensation of 1b and A1. This suggests that
water is necessary to form a hydronium boronate catalytic
species B (Figure 6) that is sufficiently acidic to activate the
hindered C–O bonds of benzylic ether 5r. Along these lines, the
BF3–OEt2-promoted Friedel-Crafts benzylation reaction with
benzyl ethers was previously reported by Yang and
coworkers,13 where they found that residual water was
necessary to generate BF3–H2O as the active Brønsted acid
promoter. Thus, in the absence of water, alcohol 2r may be
activated by a weaker acid via an alternative mechanism, such
as HFIP-coordinated boronic ester G. However, at this stage
the other activation modes proposed in Fig. 6b cannot be ruled
out.
F3
C
C
CF3
CF3
F3
HO
OH
B
t-Bu
N
t-Bu
F3
F3
C
C
O
O
F
F
F3
C
CF3
B
F
O
(0 or 1.5 equiv)
OH
+
F
F
HO
t-Bu
N
H
t-Bu
F
HFIP/CH3NO2 (4:1)
[0.1 M], 50 °C, 2 h
F3
C
CF3
F
F
H
1b
A1
(1 equiv)
(9.3 ppm)
(27.0 ppm)
a) 0 equiv
1b
2
B
b) 1.5 equiv
H
1
150 140 130 120 110 100 90 80 70 60 50 40 30 20 10
0
-10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150
f1 (ppm)
Fig. 7
Effect of 2,6-di-tert-butylpyridine on the catalytic species.
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
Page 6 of 8
ARTICLE
Organic & Biomolecular Chemistry
Table 2 Comparison with other Brønsted acid catalystsa
General Procedure for Friedel-Crafts Benzylation
View Article Online
DOI: 10.1039/C9OB01043B
To a vial equipped with a stir bar, containing the benzyl alcohol
(0.50 mmol) and the arene (1.00–2.50 mmol) dissolved in a
solvent mixture of 4:1 hexafluoroisopropanol and
nitromethane (1 mL), was added the ferrocenium boronic acid
catalyst 1 (10 mol%) and/or without the co-catalyst A1 (10
mol%). The vial was then capped and stirred at the indicated
temperature and time. Upon completion, the reaction mixture
was concentrated and purified by flash column
chromatography with hexanes/ EtOAc to afford the product.
OH
catalyst (10 mol%)
+
solvent
[0.5 M], 80 °C
24 h
OAc
AcO
2w
2a
4w
Catalyst
(10 mol%)
1b and A1
p-TsOHH2O
CSA
Conversion
(%)b
NMR
Entry
Solvent
yield (%)b
1
2
3
4:1 HFIP/CH3NO2
4:1 HFIP/CH3NO2
4:1 HFIP/CH3NO2
>98
>98
>98
80
0
35
HCl (4.0 M in
dioxane)
TFA
Oxalic acid
TfOH
p-TsOHH2O
CSA
TFA
Oxalic acid
Conclusions
4
4:1 HFIP/CH3NO2
>98
50
In summary, this article described preliminary results on the
use of perfluoropinacol (A1) as a co-catalyst to increase the
reactivity of a boronic acid catalyst in Friedel-Crafts alkylation
with electronically deactivated benzylic alcohols. The co-
catalyst A1 is presumed to form a highly Lewis acidic boronic
ester that results in an active hydronium boronate species B,
which promotes a more facile ionization of benzylic alcohols
into the corresponding carbocations. This process likely occurs
through a Brønsted acid dependent mechanism, though the
exact mode of activation still requires further study.
Alkylations with halogenated benzylic alcohols were generally
improved, providing yields of diarylmethane products, which,
in some cases doubled the yields of reactions performed in the
absence of the co-catalyst. Other electron-withdrawing
functionalities are well-tolerated under these conditions, with
higher yields obtained when co-catalyst A1 was used.
Furthermore, acid-sensitive functional groups were well-
tolerated with this dual-catalytic system compared to
conventional Brønsted acids, which may be attributable to the
non-nucleophilic, weakly coordinating boronate counteranion
E. The co-catalytic boronic acid–diol system described herein
provides a mild synthetic method for the preparation of di-
and triarylalkanes. This system could potentially be employed
in other Bronsted acid catalyzed reactions to provide cleaner
and more effective methods.
5
6
7
8
9
4:1 HFIP/CH3NO2
4:1 HFIP/CH3NO2
>98
>98
>98
>98
>98
28
56
52
0
0
0
HFIP
DCE
DCE
DCE
DCE
10
11
0
0
81
a
Reaction condition: 2w (0.50 mmol), 3a (2.50 mmol), catalyst (10 mol%) in
b
solvent mixture (1 mL) were stirred at 80 °C for 24 hours. Conversion and NMR
yield determined by 1H NMR analysis with 1,4-dinitrobenzene as internal
standard.
To demonstrate the efficiency and chemoselectivity of our
system in comparison with common Brønsted acid catalysts,
substrate 2w, which contains an acid- and hydrolytically labile
acetate substituent was employed in the benzylation of p-
xylene (Table 2). In all cases, the alcohol 2w was fully
consumed. The highest yield of the desired product 4w was
obtained with the co-catalytic system of 1b and A1 (entry 1).
When p-toluenesulfonic acid (p-TsOHH2O) was used as the
catalyst, a complex mixture with no product formation was
observed (entry 2). The use of other strong Brønsted acids as
catalysts resulted in lower yield of the desired product 4w (35–
56%) accompanied by a mixture of by-products (entries 3–6).
When using the conditions from Moran’s work for highly
deactivated systems (entry 7),3j an intractable mixture was
observed with no desired product 4w. Furthermore, no
desired product was detected when dichloroethane (DCE), a
common solvent for these classical Brønsted acid catalysts,14
was employed (entries 8–11). These results mirror previous
claims concerning the mild reaction conditions provided by
boronic acid catalysis.15 The nature of the counteranion in a
Brønsted acid catalyst exerts an important influence on the
chemoselectivity of the reaction process. Hence, it is possible
that a large and stable boronate counteranion, such as species
E (cf., Figure 6a), displays a low level of nucleophilicity and
basicity that helps minimize side- reactions. In the same line,
such a weakly coordinating counteranion would effectively
help provide an increase of reactivity to its associated
carbocation.7
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was generously funded by the Natural Sciences and
Engineering Research Council (NSERC) of Canada (Discovery
Grant to D.G.H., CGS-D Scholarship for J.P.G.R.) and the
University of Alberta.
Notes and references
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Experimental
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Page 8 of 8
View Article Online
DOI: 10.1039/C9OB01043B
TOC Abstract
R
R
boronic acid (10 mol%)
perfluoropinacol (10 mol%)
HO
+
HFIP/CH3NO2 (4:1)
Y
EWG
Y
EWG
R = H, Me, Ar
[0.5 M], 25-80 °C,
1-24 h
- Increased reactivity
- Mild conditions
B(OH)2
F3C CF3
B(OH)2
F
OH
Fe(III)
or
HO
F3C CF3
perfluoropinacol
SbF6
F
F
F
boronic acid
The combination of a boronic acid catalyst with perfluoropinacol as a co-catalyst improves the
scope of Friedel-Crafts benzylations of arenes with electronically deactivated primary and
secondary benzylic alcohols.