2
T. Das et al. / Tetrahedron Letters xxx (2014) xxx–xxx
L
L
These results clearly indicate that solvent composition controls
OAc
Pd
OAc
the product diversity. Therefore, we adopted the solvent composi-
tion of dioxane/water (5:1) and TfOH as an additive in all cases to
prepare the desired carbinols from the addition reaction of boronic
acids to aldehydes. A range of the substituted benzaldehydes affor-
ded 1,2-addition product in good to excellent yields by this condi-
tion (Table 1). Steric factor appears to influence the yield to some
extent. For example, 1-naphthyl or 2-naphthyl-aldehyde required
more time to produce carbinols in good yields (entries 8 and 9;
Table 1). Also, addition of 1-naphthylboronic acid and mesitylbo-
ronic acid to 4-nitrobenzaldehyde resulted in lower yield com-
pared to phenylboronic acid (compare entries-3 and 4 with
entry-2, Table 1). No perceptible product formation was observed
if the ligand L is omitted from the reaction mixture.
TfOH
OH
Ar
L
L
L
L
OTf
OTf
Ar'
-OTf
Pd
A
Pd OTf
H
B
A
r
B
(
O
H
)
2
L
L
Solv
Pd
Ar
L
Pd
Ar
Pd
L
L
Ar'-CHO
O
O
H
L
OTf
Ar' Ar
H
D
Ar'
C
E
Scheme 2. Tentative mechanism for the formation of carbinol.
A tentative reaction mechanism is illustrated in Scheme 2. It has
been suggested earlier8 that transmetalation of an electrophilic
Pd(II) intermediate such as B can lead to intermediate C. Coordina-
tion of the aldehyde to the electrophilic metal center followed by
migration of the aryl group to the activated aldehyde then leads
to intermediate E from which the carbinol is released and the cat-
alyst is regenerated.
In the absence of dioxane in the solvent these carbinols were
easily converted to symmetric ethers in situ. A few substituted
benzaldehydes were tested under this reaction condition and all
of them furnished corresponding symmetrical ethers in excellent
yields (Table 2).
Formation of symmetrical ethers from this reaction is indicative
of the intermediacy of a benzylic carbocation (Scheme 3).
Above hypothesis is supported by an independent experiment
(Scheme 4). Compound 3a was synthesized by the Grignard
method, and heated with TfOH (2 equiv) in water at 60 °C in the
absence of metal and ligand. The product obtained was character-
ized from NMR spectroscopy and found to be identical with com-
pound 4a as shown in Table 2.
Table 2
Formation of symmetrical ethera
Ar CHO
Pd(OAc)2, L
Ar
O
Ph
1
Ph Ar
TfOH, H2O, 60 °C
PhB(OH)2
2a
4
Entry
Ar
Time (h)
Product
Yieldb (%)
1
2
3
4
4-Me-Ph
4-iPr-Ph
4-F-Ph
8
6
8
8
4a
4b
4c
4d
90
80
85
82
3-OMe-Ph
a
Reaction condition: ArB(OH)2 (1.2 mmol), RCHO (1.0 mmol), TfOH (2 mmol),
H2O (2 mL), Pd(OAc)2 and L (4 mol %).
b
Isolated yield.
OH2
Ar'
Although not explicitly stated, a similar benzylic carbocation is
probably the putative intermediate in the formation of triarylme-
thanes as reported by Lin and Lu.5f Nitromethane was used as a sol-
vent and the catalyst was a Pd(II) cation. Water was clearly
detrimental to the reaction. In our case, on the other hand, water
is the best solvent when benzylic carbocation is formed leading
to the formation of the ether as the only product. We, therefore,
added 1,3,5-trimethoxybenzene to the reaction mixture from the
OH
Ar'
H
O
-H2O
Ar'
Ar
Ar
Ar
Ar
OH
Ar'
Ar
Ar'
Ar'
Ar
Ar
Ar'
Scheme 3.
Table 1
beginning and the reaction was conducted in water alone
(Scheme 5). Instead of the symmetrical ether an unsymmetrical tri-
arylmethane was the only isolable product (60%) in this reaction
further confirming the intermediacy of a carbocation.
We sought to utilize the benzylic carbocation in the synthesis of
the fluorene nucleus, an important structural motif in polycyclic
aromatic hydrocarbons that are useful advanced materials with
remarkable photonic and electronic properties, such as light-emit-
ting diodes (OLEDs), solar cells, thin film transistors, etc.9 Some flu-
orene derivatives are useful precursors for the synthesis of ligand
in organometallic chemistry10 and some of them exhibit bioactivi-
ties11 as well.
The reported methods for the synthesis of substituted fluorenes
include Friedel–Crafts ring closure of biarylalcohols promoted by
Lewis or Bronsted acid,9h,i,12 Pd-catalyzed coupling reaction,13
annulation reaction,14 and some other methods.15 Metal catalyzed
synthesis of fluorene suffers from harsh reaction condition and/or
use of phosphine ligands. In case of Friedel–Crafts ring closure,
biaryl alcohols had to be first synthesized and isolated from 2-
formylbiphenyl derivatives by air and moisture sensitive Grignard
reagents.12a,b
Addition of arylboronic acid to arylaldehydesa
OH
Pd(OAc)2, L
Ar1CHO
Ar2B(OH)2
Ar1
Ar2
H2O/dioxane
80°C
1
2
3
Entry
Ar1
Ar2
Time (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
4-CH3-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
3-NO2-4-Cl-C6H3
4-F-C6H4
Ph
Ph
1-Naph
Mesityl
Ph
Ph
7
2
2
9
2
4
4
8
8
5
7
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
81
98
88
61
92
80
94
76
79
84
78
—
4-CF3-C6H4
1-Naph
Ph
Ph
2-Naph
Ph
10
11
12c
3,4-Di-Cl-C6H3
4-iPr-C6H4
4-NO2-C6H4
Ph
Ph
Ph
3j
3k
3b
a
Reaction condition: aldehyde (1 mmol), boronic acid (1.2 mmol), Pd(OAc)2
(4 mol %), L (4 mol %), TfOH (2 mmol), dioxane/H2O (2 mL/0.4 mL).
b
Isolated yield.
No L was used.
c