Organocatalyzed Friedel-Crafts arylation of benzylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.02.151

Electron-rich aromatic and heteroaromatic rings are functionalized directly with a variety of benzylic alcohols under mild conditions. The reaction is catalyzed by commercially available pentafluorophenylboronic acid, which is stable under ambient conditions and recoverable. The reaction itself is highly atom economical and produces water as the only byproduct. A Friedel-Crafts mechanism is proposed.

Full text of DOI:10.1016/j.tetlet.2010.02.151

Tetrahedron Letters 51 (2010) 2447–2449
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Tetrahedron Letters
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Organocatalyzed Friedel–Crafts arylation of benzylic alcohols
b
J. Adam McCubbin a, , Oleg V. Krokhin
*
a Department of Chemistry, University of Winnipeg, Winnipeg, Canada R3B 2E9
b Department of Internal Medicine, University of Manitoba, Winnipeg, Canada R3E 3P4
a r t i c l e i n f o
a b s t r a c t
Article history:
Electron-rich aromatic and heteroaromatic rings are functionalized directly with a variety of benzylic
alcohols under mild conditions. The reaction is catalyzed by commercially available penta-
fluorophenylboronic acid, which is stable under ambient conditions and recoverable. The reaction itself
is highly atom economical and produces water as the only byproduct. A Friedel–Crafts mechanism is
proposed.
Received 8 October 2009
Revised 23 February 2010
Accepted 24 February 2010
Available online 3 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Di-, tri-, and tetraarylmethanes are important substructures in a
variety of substances with biological relevance1 as well as diverse
classes of functional materials.2 They are generally prepared via
reaction of a nucleophilic aryl species (1), with an electrophilic
benzyl derivative (2, Scheme 1). Classical methods typically rely
on either the use of harshly acidic reagents, often in stoichiometric
quantities,3 or pre-activation of the nucleophile and/or electro-
phile.4,5 Both of these general approaches produce significant
amounts of waste in the form of salt byproducts, and the latter of-
ten requires non-trivial preparation of starting materials.
Direct catalytic substitution of aromatic C–H bonds via Friedel–
Crafts (FC)-type reactions is an attractive alternative, since it elim-
inates the need for pre-activation of the aromatic species and sig-
nificantly reduces the waste generated in the coupling process.
The ideal FC reaction would employ a benzylic alcohol as the
electrophile, and therefore generate water as the only byproduct.
This has recently been achieved with a variety of conventional Le-
wis acids,6 Bronsted acids,7 and transition-metal complexes.8
Although these methods have significant advantages over tradi-
tional FC reactions (i.e., the nature of the leaving group), there
are several areas in need of improvement, including a somewhat
limited substrate scope, the harsh acidity of many Bronsted and Le-
wis acid catalysts, and the often high cost and toxicity of transi-
tion-metal-based catalysts.
We have recently described the arylboronic acid-catalyzed FC
reactions of allylic alcohols with a variety of electron-rich aromat-
ics and heterocycles.12 Herein we wish to report on an extension of
this reaction to include a second class of
benzylic alcohols.
p-activated substrates,
We began by screening a variety of electron-rich aromatic het-
erocycles and carbocycles (4–10) in reactions with di- and tri-
phenyl methanol (2a and b) under conditions established
previously for related substrates (Table 1).12 We were pleased to
observe that in all cases, Diphenyl methanol underwent clean reac-
tion with aromatic substrates 4–9 in excellent to quantitative
yields to afford triaryl substitution products 4a–9a. In the case of
10, the reaction did not reach completion (starting materials recov-
ered, entry 13). However, by changing the solvent to toluene, high
conversion and yield of 10a were achieved (entry 14). We attribute
the difference in yields to the higher temperature achieved in
refluxing toluene.13 In all cases, a single isomer of the desired prod-
uct was recovered, with no evidence of the formation of other pos-
sible regioisomers.
Disappointingly, reactions of our aromatic substrates with tri-
phenyl methanol (2b) were less successful. Those that involved
five-membered heterocycles (4, 5, and 8) performed well, affording
the corresponding tetraaryl methanes (4b, 5b, and 8b) in near-
quantitative yields (entries 2, 4, and 10). However, all the six-
membered carbocyclic derivatives (6, 7, 9, and 10) failed to react
(entries 6, 8, 12, and 15) under the specified conditions, with quan-
titative recovery of the starting materials. We attribute the marked
Diversely substituted aryl boronic acids are inexpensive and
widely available, primarily due to their use as coupling partners
in the Suzuki–Miyaura reaction.9 They possess several useful prop-
erties, including air and moisture stability, high solubility in organ-
ic solvents, and a Lewis acidic of the boron atom, which can be
modulated by ring substituents.10 Despite this, there are only spo-
radic reports of their use as catalysts.11
R2 R3
R2 R3
X
Y
R1
+
R4
R1
R4
3
1
2
* Corresponding author. Tel.: +1 204 786 9362; fax: +1 204 775 2114.
E-mail address: a.mccubbin@uwinnipeg.ca (J.A. McCubbin).
Scheme 1. Benzylic coupling for the formation of diarylmethanes.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.151

2448
J. A. McCubbin, O. V. Krokhin / Tetrahedron Letters 51 (2010) 2447–2449
Table 1
Table 2
Synthesis of aryl diphenyl- and aryl triphenylmethanes
Scope of reaction with benzylic alcohols
Ar1
R1
OH
Ar
R
C6F5B(OH)2
(10 mol%)
OH
C6F5B(OH)2
(10 mol%)
+
Ar-H
Ph
Ph
Ar2
R2
Ph
Ph
Ar -H
Ar2
R2
1
+
R
o
R1
2
o
DCE 4A M.S.
2a: R = H
PhMe, 4A M.S.
reflux, 16h
2b: R = Ph
reflux, 16h
Product (X): yield (%)a
Run
Ar–H
2
Product
Yield (%)a
Run
ArH
X
R
Ph
Ph
H
N
Ph
Ph
OMe
N
H
HO
OMe
74
N
H
1
2
5
5
2c
5c:
Ph
1
2
4
4
2a
2b
4a: R = H
4b: R = Ph
93
99
Cl
Cl
HO
Ph
R
N
H
N
H
2d
0
Ph
Me
Me
3
4
5
5
2a
2b
5a: R = H
5b: R = Ph
85
90
HO
OMe
Ph
OMe
R
HN
X
X
Ph
OMe
3
4
6
4
2e (X = H)
2f (X = OH)
0
76
4f:
MeO
OMe
MeO
Me
OMe Me
5
6
6
6
2a
2b
6a: R = H
6b: R = Ph
99
0
HO
OMe
OMe
Ph
R
Ph
MeO
OMe
5
6
2g
6g:
95
MeO
7
7
MeO
7a: R = H
7b: R = Ph
X1
X1
X2
76b
0
O
7
8
2a
2b
HO
Me
X2
O
Ph
Me
2h (X1 = OMe, X2 = OH)
2i (X1 = H, X2 = OH)
2j (X1 = H, X2 = OMe)
8h:
8i:
8j:
94
67
81
O
R
6
7
8
8
8
8
Me
Ph
9
10
8
8
2a
2b
8a: R = H
8b: R = Ph
94
98
OH
HO
OH
OH
OMe
89
OMe
R
Ph
Ph
Ph
OMe
Br
OMe
Br
9
10
8
2k
10k:
11
12
9
9
2a
2b
9a: R = H
9b: R = Ph
87
0
Br
Br
O
HO
Me
OH
R
Ph
HO
HO
10
2l
8l:
54
48
OH
Me
Me
NH2
O
O
Me
HO
13
10
10
10
2a
2a
2b
10a: R = H
10a: R = H
10b: R = Ph
60
82
0
14c
15
NH2
11
8
2m
8m:
R1 R2
R1 R2
a
b
c
Isolated yield.
12% of disubstituted product was isolated in addition.
Reaction run in refluxing PhMe.
Me
Ph
HO
Ph
12
13
8
8
2n (R1 = R2 = Me)
8n:
8o:
72b
55c
2o (R1–R2 = (CH2)5)
difference in reactivity between the 5- and 6-membered nucleo-
philes to differences in steric bulk. The presumed carbocation (vide
infra) formed from the departure of the hydroxide-leaving group in
2b is crowded significantly by the three phenyl groups, which may
be difficult for the bulkier substituted six-membered ring nucleo-
philes to access. Electronic factors may be a contributing factor
in some cases: The triphenyl methane carbocation is also signifi-
cantly more stable than the corresponding diphenyl methane car-
bocation, which may render it unreactive to poorer nucleophiles.
Having established the scope of the reaction of various aromatic
nucleophiles with simple di- and tri-arylmethanes, we turned our
attention to the reaction of these nucleophiles with a selection of
functionalized mono- and diaryl-methanols (Table 2). Reaction of
pyrrole 5 with electron-rich methoxy diaryl methane 2c afforded
a
b
c
Isolated yields.
23% of 1-methylstyrene was isolated in addition.
36% of 1-phenylcyclohexene was isolated in addition.
triarylmethane 5c in good yield (entry 1). In contrast, electron-
poor diarylmethanol 2d failed to react with furan 8 under the same
conditions. This suggests that the stability of the diarylcarbocation
is critical to the success of this reaction and the presence of even
moderately electron-withdrawing groups is sufficiently destabiliz-
ing to prevent the reaction from occurring.
Similarly, 1-phenylethanol 2e failed to react under the specified
conditions (entry 3), which suggests that a single unsubstituted

J. A. McCubbin, O. V. Krokhin / Tetrahedron Letters 51 (2010) 2447–2449
2449
HO OH
B
try, and the Natural Sciences and Engineering Research Council of
Canada (O.V.K) is gratefully acknowledged.
Ar3
R1
Ar3-H
-H+
Ar2B(OH)2
Ar1
H
-Ar2B(OH)3
Ar2
Ar1
OH
O
Ar1
R2
R2
R1
Ar1
R2
R2
Supplementary data
R1
R1
12
11
2
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.151.
Scheme 2. Proposed mechanism.
References and notes
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phenyl ring affords insufficient stabilization of the carbocation
intermediate. However, increasing the electron density by incorpo-
ration of a free phenol in 2f allows the reaction with indole 4 to
proceed smoothly to completion to afford 4f in good yield (entry
4). Naphthyl derivative 2g was also an effective electrophile, and
afforded 6g in high yield upon reaction with 6 (entry 5). We attri-
bute the success of this substrate (cf. 2e, entry 3) to the increased
electron density of naphthalene relative to benzene. Electron-rich
benzylic alcohols, including methoxy phenol 2h, phenol 2i, and
methoxy benzene 2j all performed well in the reaction with 8 (en-
tries 6–8). They afforded furan derivatives 8h, 8i, and 8j, respec-
tively, in good yields. The success of the reaction in the presence
of free phenols (entries 4, 6, and 7) demonstrates the further
advantage that protecting groups are not required.
We next tested brominated derivatives 2k and 2l in combina-
tion with 10 and 8, respectively, with some success (entries 9
and 10). High yield of the coupled product 10k and moderate yield
of 8l were obtained. We attribute the somewhat reduced yields in
these cases (cf. entries 6 and 7) to a decrease in electron density
due to the electronegative bromine atoms. These products have
the advantage of allowing for further derivatization of the aryl bro-
mides. Similarly to phenols, free amines are well tolerated under
these conditions (entry 11).
Finally, we tested the coupling of tertiary alcohols 2n and 2o with
8, to afford 8n and 8o, respectively, in modest yields, with some for-
mation of the elimination products observed (entries 12 and 13).
Our results for this reaction are consistent with the mechanistic
proposals reported previously for a similar process.12 The de-
creased reactivity (or lack thereof) of alcohol substrates leading
to relatively unstabilized carbocations suggests that the formation
of such intermediates is integral to the reaction. We therefore pro-
pose
a Friedel–Crafts mechanism, involving SN1 substitution
(Scheme 2). Complexation of the arylboronic acid to benzylic alco-
hol 2 results in the formation of ate species 11. This enhances the
leaving group ability of the hydroxide, resulting in a heterolytic
cleavage to form resonance-stabilized carbocation 12. This under-
goes nucleophilic attack by the aromatic nucleophile, followed by a
conventional Friedel–Crafts mechanism to afford the product. The
resulting arylborate is in equilibrium with the arylboronic acid and
water, which is removed in situ by the molecular sieves, regener-
ating the active catalytic species.
In summary, we have developed a mild, organocatalyzed meth-
od for the synthesis of a variety of tetra- and tri-aryl methanes. The
reaction is also amenable to the preparation of electron-rich diary-
lmethanes with potential medicinal applications. The process is
highly atom economical, employing a recoverable catalyst and pro-
ducing water as the only byproduct. Preliminary results are consis-
tent with those of an SN1/Friedel–Crafts mechanism. Extension of
the scope of this reaction, as well as detailed mechanistic studies
is ongoing in our laboratory.
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Acknowledgments
We thank the University of Winnipeg for financial support of
this work in the form of a Major Research Grant (J.A.M). Additional
support from The University of Winnipeg, Department of Chemis-