Unsymmetrical diarylmethanes by ferroceniumboronic acid catalyzed direct friedel-crafts reactions with deactivated benzylic alcohols: Enhanced reactivity due to ion-pairing effects

Article abstract of DOI:10.1021/jacs.5b05076

The development of general and more atom-economical catalytic processes for Friedel-Crafts alkylations of unactivated arenes is an important objective of interest for the production of pharmaceuticals and commodity chemicals. Ferroceniumboronic acid hexafluoroantimonate salt (1) was identified as a superior air- and moisture-tolerant catalyst for direct Friedel-Crafts alkylations of a variety of slightly activated and neutral arenes with stable and readily available primary and secondary benzylic alcohols. Compared to the use of classical metal-catalyzed alkylations with toxic benzylic halides, this methodology employs exceptionally mild conditions to provide a wide variety of unsymmetrical diarylmethanes and other 1,1-diarylalkane products in high yield with good to high regioselectivity. The optimal method, using the bench-stable ferroceniumboronic acid salt 1 in hexafluoroisopropanol as cosolvent, displays a broader scope compared to previously reported catalysts for similar Friedel-Crafts reactions of benzylic alcohols, including other boronic acids such as 2,3,4,5-tetrafluorophenylboronic acid. The efficacy of the new boronic acid catalyst was confirmed by its ability to activate primary benzylic alcohols functionalized with destabilizing electron-withdrawing groups like halides, carboxyesters, and nitro substituents. Arene benzylation was demonstrated on a gram scale at up to 1 M concentration with catalyst recovery. Mechanistic studies point toward the importance of the ionic nature of the catalyst and suggest that factors other than the Lewis acidity (pK_a) of the boronic acid are at play. A S_N1 mechanism is proposed where ion exchange within the initial boronate anion affords a more reactive carbocation paired with the non-nucleophilic hexafluoroantimonate counteranion.

Full text of DOI:10.1021/jacs.5b05076

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Journal of the American Chemical Society
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Unsymmetrical Diarylmethanes by Ferroceni-
umboronic Acid Catalyzed Direct Friedel-
Crafts Reactions with Deactivated Benzylic
Alcohols: Enhanced Reactivity due to Ion-
Pairing Effects
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Xiaobin Mo,1 Joshua Yakiwchuk,1 Julien Dansereau,1 J. Adam McCubbin,*,2 Dennis G. Hall*,1
1 Department of Chemistry, Centennial Center for Interdisciplinary Science, University of Alberta, Edmonton, Alberta,
T6G 2G2, Canada
2 Department of Chemistry, University of Winnipeg, Winnipeg, Manitoba, R3B 2E9, Canada.
ABSTRACT: The development of general and more atom-economical catalytic processes for Friedel-Crafts alkylations of
unactivated arenes is an important objective of interest for the production of pharmaceuticals and commodity chemicals.
Ferroceniumboronic acid hexafluoroantimonate salt (1) was identified as a superior air- and moisture-tolerant catalyst for
direct Friedel-Crafts alkylations of a variety of slightly activated and neutral arenes with stable and readily available primary
and secondary benzylic alcohols. Compared to the use of classical metal-catalyzed alkylations with toxic benzylic halides,
this methodology employs exceptionally mild conditions to provide a wide variety of unsymmetrical diarylmethanes and
other 1,1-diarylalkane products in high yield with good to high regioselectivity. The optimal method, using the bench-stable
ferroceniumboronic acid salt 1 in hexafluoroisopropanol as co-solvent, displays a broader scope compared to previously
reported catalysts for similar Friedel-Crafts reactions of benzylic alcohols, including other boronic acids such as 2,3,4,5-
tetrafluorophenylboronic acid. The efficacy of the new boronic acid catalyst was confirmed by its ability to activate primary
benzylic alcohols substituted with destabilizing electron-withdrawing groups like halides, carboxyesters, and nitro
substituents. Arene benzylation was demonstrated on a gram-scale at up to 1M concentration with catalyst recovery.
Mechanistic studies point toward the importance of the ionic nature of the catalyst and suggest that factors other than the
Lewis acidity (pKa) of the boronic acid are at play. A SN1 mechanism is proposed where ion-exchange within the initial
boronate anion affords a more reactive carbocation paired with the non-nucleophilic hexafluoroantimonate counteranion.
a simple and direct route to access diaryl- and triarylme-
Introduction
thane products. Both classes of diaryl- and triarylmethane
Transformations of arenes and heteroarenes are at the
core of the production of pharmaceutical agents and
commodity chemicals. The classical Friedel-Crafts proce-
dure for alkylation of arenes, as originally reported in
1877,1 employs a stoichiometric amount of strong Lewis
acid (e.g., AlCl3, FeCl3) to activate an alkyl halide and form
a reactive carbocation as the electrophile.2 Many alkyl hal-
ides, including benzylic chlorides, pose a safety hazard as
toxic lachrymator chemicals that hydrolyze readily to gen-
erate irritating haloacid gas (HX) as a by-product. These
reaction conditions, which prevailed for more than a cen-
tury, are far from ideal from the standpoint of atom-
economy and green chemistry. It is therefore not surpris-
ing that the ACS Green Chemistry Institute Pharmaceutical
Roundtable has identified Friedel-Crafts reactions as one
of the top research priorities.3 Specifically, there is a need
for more direct and atom-economical procedures employ-
ing a catalytic amount of activator with more stable and
less toxic electrophiles like alcohols.4 The use of readily
accessible benzylic alcohol derivatives in Friedel-Crafts
alkylations of arenes is of great interest for its potential as
products have found numerous applications as pharma-
ceutical and agrochemical agents (Figure 1).5
A number of cross-coupling methods exist for synthe-
sizing diarylmethane products using, for the most part,
benzylic and arene substrates that are both embedded
with activating groups. Although this C–C bond-forming
strategy can assure a high regioselectivity, it requires the
preparation of activated substrates as well as expensive
transition metal catalysts.
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(a) Suzuki-Miyaura cross-coupling with benzylic halide6
OMe
MeO
1
Pd(PPh3)4
(10 mol%)
2
B(OH)2
OMe
Br
3
4
5
6
7
8
9
+
N
aq. Na2CO3,
DME,
reflux, 18 h
CO2Et
OMe Cl
O
Cl
Cl
papaverine
(antispasmodic, treatment
of erectile dysfunctions)
(85%)
beclobrate
(lipoprotein regulator)
(b) Suzuki-Miyaura cross-coupling with benzylic boron reagent8
O
OTf
O
BF3K
OH
O
PdCl2(dppf)
(9 mol%)
HO
N(i-Pr)2
MeO
MeO
10
11
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+
Cs2CO3,
THF/H2O,
reflux, 18 h
CO2Me
(91%)
CO2Me
O
MeO
tolterodine
(antimuscarinic, for
urinary incontinence)
podophyllotoxin
(topical agent against genital warts)
(c) Negishi cross-coupling with benzylic zinc reagent9
Br
Ni(PPh3)4
(1 mol%)
Figure 1. Examples of biologically active diarylmethane and
diarylalkane compounds.
ZnBr
+
THF/Et2O,
rt, 1 h
CN
(92%)
CN
As exemplified by the work of Georgiou and co-workers
with a benzylic bromide (Figure 2a),6 the use of benzylic
halides and pseudo-halides in the Suzuki-Miyaura cross-
coupling of arylboronic acids constitutes a viable ap-
proach.7 Molander and co-workers successfully coupled
benzylic trifluoroborate salts with aryl triflates (Figure 2b).8
The analogous Negishi coupling can also be achieved
(Figure 2c),9,10 as well as Kumada-Corriu and related
cross-coupling processes.11 Barluenga and co-workers
reported a metal-free method for the preparation of dia-
rylmethane products between hydrazones and arylboronic
acids (Figure 2d).12 More recently, efforts have been made
to eliminate activating groups. Thus, methods using the
catalytic C–H activation of arenes followed by coupling
with benzylic halides have been reported, however most of
these methods employ structurally limited substrates engi-
neered with directing groups and they tend to require high
reaction temperatures.13
(d) Metal-free coupling of boronic acids with tosylhydrazones12
B(OH)2
NNHTs
H
K2CO3,
(3 equiv)
+
dioxane,
110 °C, 5 h
OMe
(80%)
OMe
Figure 2. Examples of methods for the preparation of dia-
rylmethane products using two activated substrates.
It is only in the past decade, however, that successful
efforts to replace benzylic halides and harsh Lewis acids
have appeared, spearheaded by the report of a scandium
triflate catalyzed benzylation of activated arenes with ben-
zylic alcohols (Figure 3b).18 Subsequently, a number of
other metal-catalyzed procedures were developed for di-
4
rect Friedel-Crafts alkylations with benzylic alcohols, in-
cluding FeCl3,19 PtCl4,20 Bi(OTf)3,21 HAuCl4,22 Ca(NTf)2,23
and other catalysts and variants.24 Remarkable advances
were described by Beller and co-workers with the use of
10 mol% of iron trichloride19 or platinum (IV) chloride20 in
direct Friedel-Crafts benzylations of neutral and activated
arenes with primary benzylic alcohols, whereas Rueping
and co-workers identified bismuth triflate as a catalyst that
can be employed in lower loadings (Figure 3b).21 Most of
these procedures, however, require a large excess of
arene used essentially as a solvent, and often at high tem-
peratures. Moreover, the demonstrated scope of sub-
strates is generally limited to arene and benzylic alcohol
substrates, mostly secondary alcohols, that are functional-
ized with simple activating substituents.
The Friedel-Crafts benzylation of arenes under the clas-
sical reaction conditions using benzylic chlorides and
strong Lewis acids, typically AlCl3, has been thoroughly
studied by Olah and co-workers (Figure 3a).14 Recently, a
method for in situ activation of benzylic alcohols with a
stoichiometric amount of a fluorination reagent was re-
ported.15 A number of other attractive methods employing
various alcohol derivatives as non-halogenated substrates,
such as ether and ester derivatives, were also reported.16
For example, Bode and co-workers recently described the
use of benzylic hydroxamates and a stoichiometric
amount of boron trifluoroborate as a remarkably effective
method for the benzylation of neutral and deactivated
arenes with a wide range of compatible functional groups
on both substrates.17 Although these methods do bypass
the use of toxic benzylic halides, they often require a su-
per-stoichiometric amount of Lewis acid and generate by-
products resulting from release of the activating group.
These procedures are thus less atom-economical com-
pared to the use of alcohols, where water would be gen-
erated as the only by-product.
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Journal of the American Chemical Society
(a) Classical Friedel-Crafts alkylation with benzylic chlorides14
boronic acids by using the highly Lewis acidic pentafluor-
1
2
3
4
5
6
7
8
ophenylboronic acid in regioselective Friedel-Crafts reac-
tions of allylic and activated benzylic alcohols with activat-
ed, electron-rich arenes or heteroarenes. Recently, we
reported the use of tetrafluorophenylboronic acid as a su-
perior catalyst in Friedel-Crafts allylations and benzylations
of neutral arenes.29 Although secondary benzylic alcohols
reacted smoothly at room temperature, the reaction of
benzyl alcohol as a prototypic primary alcohol with both
meta and ortho xylene was more difficult and afforded
moderate yields of products (Figure 3c). The preparation
of diarylmethane products by Friedel-Crafts benzylation is
particularly challenging when using neutral arenes of mod-
erate nucleophilicity and primary benzylic alcohols func-
tionalized with electronically deactivating substituents that
destabilize the benzylic carbocation intermediate. In such
cases, undesired polyalkylation or alkylation of the alcohol
substrate can become a predominant side-reaction. Here,
we demonstrate that the ionized form of ferroceneboronic
acid, the ferroceniumboronic acid hexafluoroantimonate
salt 1, is a significantly more powerful activator of electron-
ically deactivated primary benzylic alcohols and can cata-
lyze Friedel-Crafts alkylations of a wide range of neutral
arenes functionalized with various substituents that confer
synthetic usefulness to the products (Figure 3d). Studies
were also conducted to address the reaction’s mecha-
nism and the origin of the catalyst’s efficacy, which likely
functions through a novel ion-exchange mechanism that
takes advantage of the ionic nature of catalyst 1.
X
X
AlCl3
(10-100 mol%)
Cl
+
+ HCl
CH3NO2, rt
Y
Y
(o/p/m)
(5 equiv)
(b) Lewis acid catalyzed F-C alkylations with benzylic alcohols18-21
Sc(OTf)3
(10 mol%)
9
HO
+
10
11
12
13
14
15
16
17
18
19
20
21
22
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ClCH2CH2Cl
120 °C, 4 h
(1.0 mmol)
(99%)
(5 mL)
FeCl3
(10 mol%)
HO
+
80 °C, 24 h
(5 mL)
(0.5 mmol)
(99% 99:1)
Bi(OTf)3 (1 mol%)
reflux, 2 h
HO
+
(59%)
(3 mL)
(1 mmol)
(c) Boronic acid catalyzed F-C alkylation with benzylic alcohols29
2,3,4,5-F4HC6B(OH)2
(10 mol%)
HO
Ph
+
1:4 CH3NO2 :
(CF3)2CHOH
(1 equiv)
[0.5 M], 50 °C, 24 h
(5 equiv)
(60%)
Results and Discussion
Optimization of reaction condi-
tions with catalyst 1
(d) This work:
B(OH)2
SbF6
+
Fe(III)
Previous work on boronic acid catalyzed activation of
alcohols uncovered a general trend where superior activa-
tion was achieved with arylboronic acids of a lower
pKa.26j,29 This trend, however, does not always hold true
and special effects may operate depending on the nature
of the ortho substituent. For example, despite its signifi-
cantly higher pKa, tetrafluorophenylboronic acid was
found to be a superior catalyst in Friedel-Crafts allylations
compared to pentafluorophenylboronic acid.29 From this
perspective, the possibility for anomalous reactivity led us
to consider arylboronic acids of a different structural na-
ture. In particular, we surmised that charged boronic acids
could promote an ion-exchange process that would in-
crease the lifetime or the reactivity of carbocations. The
possibility of exchanging the trihydroxyboronate coun-
teranion formed in the ionization of benzylic alcohols with
normal boronic acids (eq. 1), through replacement with a
non-nucleophilic anion (X–, eq. 2), could mitigate the back-
reaction reverting the carbocation to the starting alcohol
(Figure 4a). This search led us to ferroceneboronic acid
and its oxidized Fe(III) congener, the ferrocenium boronic
acid salt 1, which can be prepared according to literature
procedures (Figure 4b).30 The hexafluoroantimonate salt
(1) is easily obtained by treating an acetone solution of
commercially available ferroceneboronic acid with AgSbF6,
HO
1 (10 mol%)
+
X
1:4 CH3NO2 :
(CF3)2CHOH
[0.5 M], 25-80 °C,
24-48 h
Y
X
Y
2 (5 equiv)
3 (1 equiv)
New catalyst class
Mild conditions
Expanded scope
X = MeO, halide, alkyl
Y = EDG, EWG, halide, alkyl
Figure 3. Friedel-Crafts reactions with primary benzylic hal-
ides and alcohols.
Boronic acid catalysis is emerging as a promising metal-
free alternative for activating free carboxylic acids and al-
cohols as substrates in a variety of reactions.25,26 Aryl-
boronic acids are stable and safe compounds that can
form covalent bonds with alcohols in a reversible manner.
The resulting transient boronates can impart a mild elec-
trophilic activation of the hydroxyl group to facilitate the
complete or partial ionization of the C–O bond leading to a
putative carbocation intermediate.27 Moreover, compared
to the use of strong Brønsted acids, boronic acids exhibit
a wider functional group tolerance due to their mildly acid-
ic character (pKa 5-9).28 McCubbin and co-workers were
first to report on the catalytic activation of alcohols with
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followed by a filtration to remove metallic silver and leave a Table 1. Optimization of Friedel-Crafts benzyla-
1
2
3
4
5
6
7
8
filtrate that provides a bench-stable dark-blue powder
after evaporation and drying. Using cyclic voltammetry,
Moore and Wayner measured the pKas of ferro-
ceneboronic acid and the corresponding ferrocenium salt
to be 10.8 and 5.8, respectively.31 The pKa of the ferroce-
nium boronic acid, thus, is close to the value of 6.0 for
2,3,4,5-tetrafluorophenylboronic acid,29 so it was deemed
a good candidate for evaluation as a catalyst for direct
Friedel-Crafts alkylations with primary benzylic alcohols.
tion with catalyst 1.
a
b
Br
4a (4-)
m-xylene (5 equiv)
catalyst (10 mol%)
+
+
CH3NO2 : (CF3)2CHOH
[0.5 M]
b
a
HO
9
50 °C, 24 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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60
Br
Br
(a) Ionization of alcohols with normal (eq. 1) and ionic (eq. 2) boronic acids
3a (1 equiv)
4b (2-)
–
B(OH)2
B(OH)3
+
ROH
(1)
entry
catalyst
yield
(%)
a:b
solvent
ratio
T
(°C)
+
R
1
2
3
2,3,4,5-F4HC6B(OH)2
CpFe(II)CpB(OH)2
1:4
1:4
1:4
50
50
50
0
–
+
X–
Y
B(OH)2
+
X–
Y
B(OH)3
0
+
R
87
78:22
CpFe(III)CpB(OH)3(SbF6)
(1)
+
ROH
tetra-ion
(2)
4
5a
1
1
1
1:2
1:4
1:4
50
50
rt
71
74
14
78:22
78:22
75:25
–
+
+
X–
R
+
Y
B(OH)3
6
a 1M concentration
(b) Preparation of ferroceniumboronic acid hexafluoroantimonate (1)
B(OH)2
B(OH)2
SbF6
AgSbF6
+
Fe(II)
Fe(III)
Examination of substrate scope
acetone, rt
The generality of the reaction was studied under the op-
timal conditions of Table 1 (entry 3). Using m-xylene as a
model neutral arene, we first examined the nature of the
benzylic alcohol and the reaction’s compatibility with vari-
ous substituents and functional groups (Figure 5).
1
pKa 5.8
pKa 10.8
Figure 4. (a) Concept of ion-exchange with ionic bo-
ronic acids. (b) Preparation of ferrroceniumboronic acid
salt 1.
Benzylic alcohols containing an electronically neutral
arene core or others with slightly deactivating substituents
such as fluoride or bromide led to high yields of products
4-10 at or below 50 °C. The use of bromide substituents
is particularly attractive in view of derivatizing the resulting
products (e.g., 4, 9-10) using cross-coupling chemistry.
Although 4-methoxylbenzyl alcohol reacted efficiently to
yield 11 at 40 °C, the 4-dimethylamino analogue failed to
afford product 12. A possible reason for this failure could
be protonation or H-bonding of the aniline substituent by
the HFIP solvent (pKa = 9.3), which would effectively inhib-
it the mesomeric stabilization of the benzylic carbocation
provided by the nitrogen atom. Although benzylic alcohols
with strongly electron-withdrawing substituents such as
nitro and cyano provided only a low yield of the desired
products (e.g., products 13 and 14), it is remarkable that
the catalyst was effective with other substrates bearing
highly deactivating substituents like a carboxyester (prod-
uct 15), or trifluoromethyl (products 16-17). A tempera-
ture of 80 °C was required but these conditions did not
lead to side reactions and very high yields of products
were obtained. It is noteworthy that the nature of the ben-
zylic alcohol had little effect on the regioselectivity of the
reaction. Not surprisingly, due to unfavorable steric ef-
fects, substitution between the two methyl groups of m-
xylene was discouraged thus the 4-substituted products
The initial evaluation of catalysts was performed using
the alkylation of m-xylene (2a) with 4-bromobenzyl alcohol
(3a) under previously reported conditions with a 4:1 mix-
ture of hexafluoroisopropanol and nitromethane as the
solvent at a temperature of 50 °C (Table 1).29 Our previ-
ous best catalyst, 2,3,4,5-tetrafluorophenylboronic acid,
and ferroceneboronic acid both failed to activate alcohol
3a and produce the diarylmethane isomers 4 (entries 1-2).
To our satisfaction, the ferroceniumboronic acid salt 1
provided a high yield of 4a and 4b under the same condi-
tions (entry 3). We then examined the effect of the solvent
mixture. As observed previously,29 the reaction was sensi-
tive to the proportions of hexafluoroisopropanol and nitro-
methane, with a 4:1 mixture being preferable in order to
optimize product yield (entries 3-4). A lower yield was ob-
tained when the reaction was conducted at a higher con-
centration (entry 5) or at ambient temperature (entry 6).
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Journal of the American Chemical Society
(a) were isolated preferentially over the 2-substituted erate yield of product 31 at 80 °C. The successful for-
1
2
3
4
5
6
7
8
products (b) with selectivities greater than 3:1. This level of
selectivity is very similar to that obtained in classical
Friedel-Crafts benzylations with benzylic halides,14 indicat-
ing that all of these variants are controlled mainly by the
properties of the arene substrate, and that a common
carbocation intermediate is produced regardless of the
electrophilic precursor. The use of p-xylene as a substrate
allowed us to further examine the scope of the benzylic
alcohol without the complication of forming regioisomers
(Figure 6). Thus, various benzylic alcohols substituted with
methyl or halide substituents, including multiply substitut-
ed ones, reacted successfully (products 20-28). Other
heteroatom-substituted diarylmethanes such as 29 and
30 can be produced. Remarkably, catalyst 1 is capable
of activating 4-nitrophenylbenzyl alcohol to afford a mod-
mation of product 32 further highlights the great reactivity
of catalyst 1. In this example, the benzylic alcohol substi-
tuted with a para carboxyester was successfully activated
by catalyst 1 to afford 32 under conditions where 2,3,4,5-
tetrafluorophenylboronic acid failed entirely. The scope of
this methodology is particularly attractive from the view-
point of medicinal chemistry for its applicability to benzylic
alcohols decorated with fluoride (products 21-25, 28)
and trifluoromethyl substituents (product 33). No product
34 (or 18, Figure 5) was isolated from the use of 3,5-
bis(trifluoromethyl)benzyl alcohol, thus indicating the reac-
tion’s limits with respect to carbocation stability. On the
other hand, a naphthylmethanol was a suitable reagent
(product 35).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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Figure 5. Scope of primary benzylic alcohols with m-xylene as the arene nucleophile.a
1
2
3
4
5
6
7
8
B(OH)2
+
Fe(III)
SbF6
a
1 (10 mol%)
b
HO
+
c
CH3NO2 : (CF3)2CHOH 1:4
[0.5 M], 50 °C,a 24 h
Y
Y
m-xylene
(5 equiv)
4-19
3 (1 equiv)
isomer ratio: a (4-) : b (2-) : c (5-)
a or otherwise indicated
9
Br
9 (99%, a:b = 81:19)
NO2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
F
Br
F
5 (87%, a:b = 82:18)
6 (94%, a:b = 83:17)
7 (99%, a:b = 78:22)
8 (95%, a:b = 75:25)
10 (81%, a:b = 82:18)
Br
OMe
CN
NMe2
4 (87%,a:b = 78:22)
12 (0%; 40 °C)
11 (61%; 40 °C)
13 (10% ,a:b = 79:21; 80 °C)
14 (12%, a:b = 77:23; 80 °C)
F
CF3
CF3
F
CO2Me
15 (63%, a:b = 76:24; 80 °C)
CF3
17 (99%, a:b = 81:19; 80 °C)
F
CF3
18 (0%; 80 °C)
16 (99%, a:b = 81:19; 80 °C)
19 (60%, a:b = 77:23; 80 °C)
a Reaction scale: 0.5 mmol of alcohol. Reported yields are isolated yields of combined regioisomers. Isomer ratios were meas-
ured by H NMR. For products 7, 9, 10, 13-17, 19, less than 6% of the 5-substituted isomer c was obtained. Some regioiso-
1
mers are not separable (see Supporting Information).
Figure 6. Scope of primary benzylic alcohols with p-xylene as the arene nucleophile.a
1 (10 mol%)
HO
+
CH3NO2 : (CF3)2CHOH 1:4
[0.5 M], 50 °C,a 24 h
Y
Y
F
3 (1 equiv)
20-35
p-xylene
(5 equiv)
a or otherwise indicated
F
F
F
F
F
F
F
F
21 (77%; rt, 48 h)
{6% with C6HF4B(OH)2}
23 (77%; 80 °C)
24 (89%; 80 °C)
20 (89%)
22 (67%; 80 °C)
25 (80%; 80 °C)
Br
F
Cl
Cl
Br
OCF3
SMe
NO2
29 (93%)
27 (98%)
{0% with C6HF4B(OH)2}
28 (57%; 80 °C)
31 (46%; 80 °C, 48 h,
with 20 mol% 1)
30 (44%; 80 °C, 48 h)
26 (77%; 80 °C)
CF3
CF3
CO2Me
CF3
34 (0%; 80 °C)
32 (85%; 80 °C)
{0% with C6HF4B(OH)2}
35 (62%)
33 (97%; 80 °C)
a Reaction scale: 0.5 mmol of alcohol (1.0 mmol for 21 and 32). Reported yields are isolated products as single isomers.
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Figure 7. Scope of arenes with 4-bromobenzyl alcohol as the electrophile.a
1
2
3
B(OH)2
+
Fe(III)
SbF6
4
1 (10 mol%)
HO
+
5
6
7
8
CH3NO2 : (CF3)2CHOH 1:4
[0.5 M], 50 °C,a 24 h
X
Br
Br
X
36-55
3a (1 equiv)
2 (5 equiv)
a or otherwise indicated
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
b
a
a
b
a
Br
Br
Br
F
Br
Br
Br
b
36 (89%; 80 °C)
37 (84%,a:b = 57:43)
39 (85%; 50 °C)
40 (88%, a:b = 70:30;
41 (88%, a:b 73:27;
38 (96%,a:b = 61:39)
48 h, 0.16 M)
80 °C, 48 h)
OH
Cl
I
b
b
a
a
a
Cl
Br
Br
Br
Cl
Br
MeO
Br
Br
b
Br
42 (77%, a:b = 71:29;
43 (0%; 80 °C)
44 (83%, a:b = 71:29;
46 (91%, a:b = 95:5)
45 (52%; 2 h, 0.25 M)
80 °C, 48 h)
80 °C, 48 h)
MeO
MeO
MeO
MeO
MeO
b
PhO
47 (65%, a:b = 57:43)
a
Br
Br
Br
Br
Br
MeO2C
51 (0%; 80 °C)
CHO
MeO2C
48 (90%; 50 °C)
50 (0%; 80 °C)
49 (94%; 80 °C, 36 h)
MeO
a
a
b
BocHN
MeO2C
Br
b
F
Br
Br
Br
CF3
CO2Me
54 (0%, 80 °C)
55 (72%; a:b = 57:43)
52 (0%; 80 °C, 48 h)
53 (52%; a:b = 75:25)
a Reaction scale: 0.5 mmol of alcohol (except for preparation of 45, 46, 49, 53: 0.25 mmol). Reported yields are isolated yields
of combined regioisomers. Isomer ratios were measured by H NMR. Some regioisomers are not separable (see Supporting In-
1
formation)
tive to give the desired product 50, the corresponding
carboxyester afforded product 49 in high yield at 80 °C.
Other multiply substituted arenes were tested. Ibuprofen
methyl ester was successfully reacted to afford product
53 in moderate yield. In contrast, the expected product
54 was not observed from an attempted benzylation of
Boc-Phenylalanine methyl ester, which was recovered
unreacted probably due to inhibition of the catalyst by the
aminoester unit.32 A trisubstituted polyfunctionalized arene
was successfully reacted to give product 55.
The scope of possible arene nucleophiles was examined
by using 4-bromobenzyl alcohol as a prototypical ben-
zylating agent (Figure 7). Thus, relatively poor nucleophiles
like benzene, toluene, o-xylene, trimethylbenzene, and
naphthalene as well as halide-substituted arenes reacted
efficiently at 80 °C to afford the respective products 36-
42, 44. These o/p-directing deactivating substituents led
to the expected mixture of regiosomeric products a/b.
The reaction conditions tolerate a free phenol (product
45). Although fluorobenzene was successful in affording
product 41, strongly deactivated arenes such as dichloro-
benzene, methyl benzoate, and trifluoromethylbenzene
failed to afford the respective products 43, 51, 52. The
catalyst’s efficiency is probably not at fault in these difficult
examples resulting in complicated mixtures where the al-
cohol was consumed. It is more likely that the nucleo-
philicity of the arene has reached a threshold where the
benzylic alcohol reacts as a nucleophile with its own car-
bocation intermediate to form undesired oligomeric prod-
ucts. Although 4-methoxybenzaldehyde was too unreac-
As exemplified by the formation of products 56-61, it is
not surprising that secondary alcohols are suitable ben-
zylating reagents (Figure 8). The additional stabilization
provided by a secondary carbocation permits the use of
strongly deactivated arene units such as 3,5-
bis(trifluoromethyl)phenyl units that failed when employed
as part of a primary benzylic alcohol (cf. 34, Figure 6).
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Figure 8. Scope of secondary benzylic alcohols with p-
xylene as the arene nucleophile.a
Figure 9. Preparation of unsymmetrical 1,1-diarylmethanes
using alternate disconnections.
1
2
3
4
5
6
7
8
Cl
R
R
HO
+
(1)
1 (10 mol%)
HO
+
Cl
Br
CH3NO2
:
X
Y
X
(1 equiv)
(5 equiv)
Y
(CF3)2CHOH 1:4
[0.5 M] ,rt, 24 h
2 (5 equiv)
3 (1 equiv)
1 (10 mol%)
a
(0%) Figure 6
Cl
Cl
1:4 CH3NO2
:
b
9
(CF3)2CHOH
[0.5 M],
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
(73%, a:b = 58:42)
43
80 °C, 24 h
Cl
F
CN
Cl
Cl
OH
+
56 (74%)
57 (72%)
58 (54%; 80 °C)
(2)
Br
(1 equiv)
(5 equiv)
CF3
NO2
Br
CF3
59 (74%; 50 °C,
60 (78%; 80 °C)
61 (80%)
HO
+
92%; 80 °C)
(3)
CF3
a
Reaction scale: 0.5 mmol of alcohol. Reported yields are
(1 equiv)
(5 equiv)
isolated yields of single isomers.
1 (10 mol%)
(0%)
1:4 CH3NO2
:
There are two possible disconnections that can be de-
vised towards planning the synthesis of an unsymmetrical
1,1-diarylmethane product using a Friedel-Crafts benzyla-
tion. If one approach fails as a result of challenging elec-
tronic considerations, such as the need to use a poorly
nucleophilic arene, there is a possibility that the alternate
disconnection is more favorable. This complementarity can
help to increase the scope of potentially accessible prod-
ucts. For example, whereas product 43 could not be
made by combining 1,2-dichlorobenzene with 4-
bromobenzyl alcohol (cf. Figure 7), the alternate discon-
nection using bromobenzene and 3,4-dichlorobenzyl alco-
hol does produce 43 in good yield, albeit with moderate
regioselectivity (Eqs. 1-2, Figure 9). Likewise, trifluoro-
methylbenzene is too poorly nucleophilic to react with the
carbocation of 2,5-dimethylbenzyl alcohol but the alternate
combination smoothly afforded the desired product 33 in
97% yield (Eqs. 3-4, Figure 9).
(CF3)2CHOH
[0.5 M],
(97%) Figure 5
CF3
80 °C, 24 h
33
OH
+
(4)
CF3
(1 equiv)
(5 equiv)
Figure 10. Gram-scale reaction (eq. 1) and beclobrate prep-
aration (eq. 2).
p-xylene
(26.8 mmol)
1 (10 mol%)
+
(1)
1:4 CH3NO2
:
Br
HO
(CF3)2CHOH,
50 °C, 24 h
Additional experiments were designed to address the
practicality of this method and the robustness of catalyst
1. Satisfactorily, a gram-scale reaction with a 3-month old
batch of catalyst 1 provided a near-quantitative yield of
product 62 with 60% recovery of the catalyst (Eq. 1, Fig.
10). Cognizant of the relatively high cost of HFIP as a co-
solvent, we were glad to find that the same reaction can
be achieved in high yield under conditions that favor sol-
vent savings at a high concentration of 1.0 M (Eq. 1, Fig.
10). This new method was applied to the preparation of a
pharmaceutical agent, beclobrate, which was obtained in
high yield from the direct alkylation of an alkoxybenzene
derivative with 4-chlorobenzyl alcohol (Eq. 2, Figure 10).
62
Br
(1.00 g, 5.35 mmol)
[0.5 M], 3-months 1
[1.0 M], fresh 1
95% (60% recov. 1)
87% (60% recov. 1)
(2)
CO2Et
OH
O
a
b
1 (10 mol%)
+
1:4 CH3NO2
:
CO2Et
Cl
O
beclobrate
(CF3)2CHOH,
[0.5 M]
(89%, a:b = 63:37)
80 °C, 24 h
Cl
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Study of the nature and reactivity
of catalyst 1
m-xylene
1
2
3
4
5
6
7
8
(5 equiv)
+
a
catalyst (10 mol%)
b
The special structure and ionic nature of ferroceni-
umboronic acid catalyst 1 along with its surprising effi-
ciency raise many questions. Although it is characterized
by a pKa of 5.8 that is similar to that of 2,3,4,5-
tetrafluorophenylboronic acid, catalyst 1 is clearly much
more reactive and it sustains a broader scope of arenes
CH3NO2 : (CF3)2CHOH 1:4
[0.5 M], 50 °C, 24 h
Br
HO
4a (4-) + 4b (2-)
(a:b = 78:22)
Br
3a (1 equiv)
catalyst
yield
87
[CpFe(III)CpB(OH)2]+ SbF6 (1)
–
and
benzylic
alcohols
compared
to
2,3,4,5-
9
tetrafluorophenylboronic acid and other methods using
catalysts such as FeCl3 and Bi(OTf)3.19,21 For example, not
only is 2,3,4,5-tetrafluorophenylboronic acid impotent in
promoting the formation of product 4 (Table 1, entry 1), it
also fails to yield 27 and 32 (Figure 6) under the same
conditions that led ferroceniumboronic acid hexafluoroan-
timonate (1) to afford these products in high yields.
[CpFe(III)Cp]+ SbF6
–
15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[CpFe(III)CpBpin]+ SbF6
–
45
[CpFe(III)CpBpin]+ SbF6 + 4A m.s.
27
0
–
1 + 4A m.s.
–
Ag+ SbF6
0
Our first line of investigation was directed at identifying
which features of catalyst 1 that are responsible for its
exceptional reactivity. In light of the known ability of Fe(III)
salts such as FeCl3 to catalyze Friedel-Crafts reactions of
benzylic alcohols, we designed a number of control exper-
iments to assess the relative roles of the Fe(III) metal and
the free boronic acid in the catalytic reactivity of catalyst 1
(Scheme 1). Thus, compared to the reference yield of 87%
obtained with 1, the ferrocenium salt devoid of a boronic
acid group provided a low yield of 15%. The pinacolate
derivative of catalyst 1 also led to a lower yield. As shown
with a control run using molecular sieves, it is likely that
adventitious partial hydrolysis to the boronic acid is re-
sponsible for this low activity. Catalyst 1 is inactive in the
presence of molecular sieves that would promote the for-
mation of boronic anhydrides. Clearly, a free boronic acid
is much preferred for promoting the exchange with alcohol
substrates and form a transient hemiboronate. On the
other hand, as shown in Table 1, the corresponding ferro-
cene precursor of 1, CpFe(II)CpB(OH)2, is not an active
catalyst. Thus, from all these results it is apparent that
both the Fe(III) ion and a free boronic acid are critical com-
ponents of catalyst 1. Because AgSbF6 is inactive
(Scheme 1), a solitary role for the antimonate anion as well
as the adventitious formation of HF can both be ruled out.
As mentioned above, the cationic Fe(III) ion with its con-
siderable electron-withdrawing effect lowers the pKa of
boronic acid 1 by five units compared to the neutral fer-
rroceneboronic acid. The possibility that catalyst 1 acts
merely as a Brønsted acid can be ruled out by the lack of
activity of boronic acids of similar pKa (c.f., 2,3,4,5-
F4HC6B(OH)2, Table 1) and also by the absence of reaction
with strong protic acids such as trifluoroacetic acid (pKa –
0.3), with or without water (Scheme 1).
CF3CO2H
trace
trace
CF3CO2H + H2O (20 mol%)
Scheme 1. Control experiments examining the im-
portance and the role of the boronyl unit of catalyst 1.
The substrate scope of the reaction provides strong
support for an SN1 reaction mechanism over an SN2 sub-
stitution mechanism. For example, whereas the primary
alcohol bis-3,5-bis(trifluomethyl)benzyl alcohol cannot form
product 34 (cf. Figure 6), a secondary benzylic analogue
that provides better stabilization of a carbocation interme-
diate successfully led to product 59 (cf. Figure 8). This
hypothesis is further supported by a study on the stereo-
chemical fate of optically enriched deuterated primary
benzylic alcohol 63 (Scheme 2). When activated with a
stoichiometric amount of catalyst 1 in the absence of an
arene nucleophile, the optical activity of 63 was found to
fade with time (according to 1H NMR analysis of the result-
ing Mosher ester, see Supporting Information). This result
indicates that a primary carbocation is formed, and that it
is formed reversibly. Not surprisingly, 2,3,4,5-
tetrafluorophenylboronic acid, which is not a very effective
activator for the arylation of primary benzylic alcohols (cf.
Table 1), was unable to epimerize alcohol 63 under the
same reaction conditions at 50 °C.
D
H
D
catalyst (1 equiv)
HO
HO
CH3NO2 : (CF3)2CHOH 1:4
[0.05 M]
63 (92% ee)
50 °C, time (see below)
F
F
B(OH)2
F
B(OH)2
SbF6
+
Fe(III)
catalyst
F
1
75% ee
63% ee
92% ee
92% ee
time: 15 min
30 min
Scheme 2. Ionization of optically enriched, deuterated
alcohol 63.
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Altogether, these results indicate that catalyst 1 is a 1,1-diarylalkane products in high yield with good to high
1
powerful activator of primary benzylic alcohols and does
so by full ionization to provide a solvated primary carbo-
cation. Although the role of HFIP is likely that of a highly
polar co-solvent that facilitates the formation and solvation
of carbocations,33 the possibility of generating a highly
acidic hexafluoroisopropoxyboronic ester cannot be ex-
cluded (R = CH2CH(CF3)2) in Scheme 3). Because the pKa
of 1 is similar to that of 2,3,4,5-tetrafluorophenylboronic
acid, its structure surely provides additional benefits. We
suggest that the ionic nature of catalyst 1 and the non-
coordinating hexafluoroantimonate counteranion lead to a
ion-exchange process where the expected tetra-ionic
species A breaks down to form two intimate ion pairs, B
and C (Scheme 3). The non-nucleophilic antimonate anion
is conducive to favor a solvent separated ion pair (D) that
leaves a more reactive carbocation intermediate. The ob-
vious influence of the arene nucleophile, as seen from the
substrate scope of Figure 7, is consistent with electrophilic
substitution as being the rate-determining step (i.e., for-
mation of the π or σ complex)34 requiring the appropriate
reactivity matching of the carbocation’s electrophilicity with
an arene of sufficient nucleophilicity.35 In this scenario, the
hexafluoroantimonate counteranion facilitates the reaction
by raising the energy of the carbocation compared to a
boronate counteranion (i.e., A in Scheme 3).
regioselectivity. The optimal reaction conditions, using the
bench-stable ferroceniumboronic acid salt 1 in hex-
afluoropropanol as co-solvent, provide a broader scope of
substrates compared to previously reported catalysts for
similar Friedel-Crafts procedures with benzylic alcohols,
including FeCl3, Bi(OTf)3, and other boronic acids such as
2,3,4,5-tetrafluorophenylboronic acid. The efficacy of the
new boronic acid catalyst was confirmed by its ability to
activate primary benzylic alcohols substituted with destabi-
lizing electron-withdrawing groups like halides, carboxyes-
ters, and nitro substituents. Arene benzylations were
demonstrated on a gram-scale at up to 1 M concentration
with recovery of the catalyst. Mechanistic studies point
toward the importance of the oxidized cationic nature of
catalyst 1 and suggest that factors other than the Lewis
acidity (pKa) of the boronic acid are at play. A SN1 mecha-
nism is proposed where ion-exchange takes place with
the boronate anion to afford a more reactive carbocation
paired with the non-coordinating hexafluoroantimonate
counteranion.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Boronic acid catalysis is emerging as a new strategy to
effect direct catalytic transformations of functional groups
that are otherwise difficult to achieve with current ap-
proaches. This work on a novel class of metalocene bo-
ronic acid catalysts, with a new mode of activation taking
avantage of ion-pairing, opens up new possibilities for
achieving direct transformations of alcohols.
B(OR)2
Ar1CH2Ar2
+
Ar1CH2OH
Fe(III)
SbF6
+ H2O
ASSOCIATED CONTENT
1 (R = H, CH2CH(CF3)2)
SUPPORTING INFORMATION.
Ar2–H
B(OR)3
Experimental details, analytical and spectral reproductions for
the prepared compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
B(OR)3
+
Fe(III)
+
SbF6
Fe(III)
+
Ar1CH2
+
Ar1CH2
A (tetra-ion)
B (zwitterion)
AUTHOR INFORMATION
Corresponding Author
SbF6
* dennis.hall@ualberta.ca
D (solvated
ion-pair)
+
Ar1CH2
SbF6
Author Contributions
= solvent
The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of
the manuscript.
C (contact ion-pair)
Scheme 3. Proposed catalytic cycle and mode of activa-
tion for catalyst 1.
ACKNOWLEDGMENT
This research was generously funded by the Natural Science
and Engineering Research Council of Canada (Discovery
Grant to DGH), the University of Alberta, and the University of
Winnipeg. Acknowledgment is made to the Donors of the
American Chemical Society Petroleum Research Fund for
partial support of this research (grant 52231-URI to JAM). XM
thanks the Alberta Ingenuity – Health Solutions Foundation for
a Graduate Studentship. JAM thanks the University of Alberta
Faculty of Science for support through the Visiting Scholar
Program.
Conclusion
We have disclosed a new boronic acid catalyst, ferroce-
niumboronic acid hexafluoroantimonate salt (1), as a supe-
rior air- and moisture-tolerant catalyst for direct Friedel-
Crafts alkylations of a diverse selection of slightly activated
and neutral arenes with readily available primary and sec-
ondary benzylic alcohols. Compared to the use of classical
metal-catalyzed alkylations with toxic benzylic halides, this
method employs exceptionally mild conditions to provide a
wide variety of unsymmetrical diarylmethanes and other
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Journal of the American Chemical Society
ava, K. P. Chem. Commun. 2013, 49, 7623-7625; (d) Robbins,
ABBREVIATIONS
Cp, cyclopentadienyl; NMR, nuclear magnetic resonance;
THF, tetrahydrofuran.
1
2
3
4
5
6
7
8
D. W.; Hartwig, J. F. Angew. Chem. Int. Ed. 2013, 52, 933-937.
(14) (a) Olah, G. A.; Kuhn, S. J.; Flood, S. H. J. Am. Chem.
Soc. 1962, 84, 1688-1695; (b) Olah, G. A.; Kobayash.S; Ta-
shiro, M. J. Am. Chem. Soc. 1972, 94, 7448-7461.
(15) Desroches, J.; Champagne, P. A.; Benhassine, Y.;
Paquin, J.-F. Org. Biomol. Chem. 2015, 13, 2243-2246.
(16) Examples: (a) Shiina, I.; Suzuki, M. Tetrahedron Lett.
2002, 43, 6391-6394; (b) Wang, B. Q.; Xiang, S. K.; Sun, Z. P.;
Guan, B. T.; Hu, P.; Zhao, K. Q.; Shi, Z. J. Tetrahedron Lett.
2008, 49, 4310-4312; (c) Sawama, Y.; Shishido, Y.; Kawajiri, T.;
Goto, R.; Monguchi, Y.; Sajiki, H. Chem. Eur. J. 2014, 20, 510-
516.
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Ar1
OH
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non-coordinating
counteranion
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B(OH)2
SbF6
B(OH)3
+
Fe(III)
SbF6
Mild conditions
Broad scope of
Ar1 and Ar2
+
+
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Fe(III)
Ar1CH2
+
1
solvated ion pair
Ar2
H
Ar1
Ar2
+ H2O
13
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