B(C6F5)3 catalysed reduction of: Para -quinone methides and fuchsones to access unsymmetrical diaryl- and triarylmethanes: Elaboration to beclobrate

Article abstract of DOI:10.1039/c7ob02007d

A mild and efficient method for the synthesis of unsymmetrical diaryl- and triarylmethanes through a B(C₆F₅)₃ catalyzed reduction of para-quinone methides and fuchsones respectively, using the Hantzsch ester as a reducing source has been developed. Detailed mechanistic investigations revealed that the reaction actually proceeds through a Lewis acid-base pair complex derived from B(C₆F₅)₃ and the Hantzsch ester.

Full text of DOI:10.1039/c7ob02007d

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ARTICLE
B(C6F5)3 Catalysed reduction of para-Quinone Methides and
Fuchsones to Access Unsymmetrical Diaryl- and Triarylmethanes:
Elaboration to Beclobrate
Received 00th January 20xx,
Accepted 00th January 20xx
Sriram Mahesh and Ramasamy Vijaya Anand*
DOI: 10.1039/x0xx00000x
Abstract: A mild and efficient method for the synthesis of unsymmetrical diaryl- and triarylmethanes through a B(C6F5)3
catalyzed reduction of para-quinone methides and fuchsones respectively, using Hantzsch ester as a reducing source has
been developed. Detailed mechanistic investigation revealed that the reaction actually proceeds through a Lewis acid –
base pair complex derived from B(C6F5)3 and the Hantzsch ester.
www.rsc.org/
Introduction:
Quinone methides (QMs), also known as methylene quinones
and quinone methines, are considered to be one of the highly
reactive intermediates.1 These class of compounds are
classified into two types namely, 1,2-quinone methides or o-
quinone methides (o-QMs) and 1,4-quinone methides or p-
quinone methides (p-QMs).1 Aromatisation is the driving force
for their unique reactivity towards various nucleophiles, and
therefore, these compounds act as valuable synthons for
various biologically important natural and unnatural organic
molecules.2 Although the synthetic utility of o-QMs has been
explored in many organic transformations for decades,1d-1f the
potential of p-QMs as building blocks has been realised only in
recent years.3 In fact, many new metal4 or organocatalysed5
synthetic protocols for the construction of new C–C and C–
heteroatom bonds have been developed, in which, p-QMs
principally serve as an 1,6-acceptor. In addition, p-QMs have
been explored as pro-chiral substrates for the synthesis of
enantiomerically enriched diaryl- and triarylmethane
derivatives.6
O
HO
O
Cl
O
O
1
CO2H
2
------------------------------------------------------------------------------------------------
OMe
NMe2
S
MeO
O
HO
3
4
Figure 1. Some biologically active diaryl- and triarylmethanes
There are several distinct approaches11 reported in the
literature for the synthesis of diaryl- and triarylmethane
derivatives, which include through Friedal-Crafts alkylation12
and metal catalysed cross coupling reactions.13 However, we
felt that, the reduction of p-QMs and fuchsones would be an
alternative and simple protocol to access unsymmetrical
diaryl- and triarylmethanes. Recently, Berionni and co-workers
investigated the scope and mechanism of the hydrogenation
of electron-deficient olefins using a combination triaryl borane
and triethylsilane through frustrated Lewis pair complex.14
However, in that report, only a couple of examples are
reported for the reduction of p-QMs. Herein, we report a Lewis
acid catalysed reduction of p-QMs and fuchsones to access
unsymmetrical diaryl- and triarylmethane derivatives using
Hantzsch ester as a reducing source. In addition, to the best of
our knowledge, the reduction of fuchsones to access
symmetrical as well as unsymmetrical triarylmethanes with
any reducing agents under Lewis acid catalysed conditions is
not reported so far.
Diaryl- and triarylmethane units are widely found in various
biologically active compounds.7 For example, diarylmethane
derivative
Beclobrate (
triglyceride-lowering drug.9 Unsymmetrical triarylmethane
1
has been well studied as thyroid hormone analog.8
2
) is being used as a potent cholesterol and
derivatives 3 and 4 possess anti-tuberculosis and anti-breast
cancer activities respectively.7c,10
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Results and discussion:
After identifying the optimal reaction conditions (Entry 4), the
The optimisation studies were performed with a readily
15
available p-QM 5a, Hantzsch ester (6) and B(C6F5)3 as a
substrate scope was appraised using a variety of p-quinone
methides (5b-w) and the results are unveiled in Table 2. This
catalyst, and the results are shown in Table 1. To our pleasure,
our initial attempt itself gave a fruitful result as the desired
product 7a was isolated in 70% yield in 12 h, when 1 mol% of
B(C6F5)3 and 1.1 equivalents of Hantzsch were used (Entry 1).
When the number of equivalents of Hantzsch ester was
increased to 2, there was a slight improvement in the yield
(80%) of the product in CH2Cl2 (Entry 2). When the reaction
was carried out using 5 mol% of B(C6F5)3 and 1.1 and 2
equivalents of Hantzsch ester in CH2Cl2, the desired product 7a
was obtained in 87% and 93% yield respectively after 12 h
(Entry 3 and 4). Fortified by this observation, we extended the
optimisation studies in other solvents (Entries 5-9). Although
the reaction was effectively progressing in all those solvents,
the yield of 7a was found to be inferior when compared to
Entry 4. In the absence of catalyst, the desired product 7a was
observed only in trace amounts, which obviously indicates that
a catalyst is necessary to drive this transformation (Entry 10).
Other metal catalysts such as Bi(OTf)3, Sc(OTf)3, Cu(OTf)2,
AgOTf and B(C6H5)3 were also found to be suitable for this
transformation; however, the yield of 7a was found to be
moderate in all those cases (Entries 11-15).
protocol generally worked well for all the p-QMs investigated
and, in most of the cases, the desired diarylmethane
derivatives (5b
For instance, this method worked capably for the p-quinone
methides (5b 5i), derived from electron-rich aromatic
aldehydes, and the desired products (7b 7i) were isolated in
excellent yields (88-98%). However, the yields of
diarylmethane derivatives (7j ) in the cases of p-quinone
methides (5j ), bearing electron-withdrawing groups at the
aryl group, were found to be moderate (45-72%). Halo-
substituted p-QMs 5g 5h) provided the respective
diarylmethane derivatives 7g and 7h in 70 and 50% yields,
respectively. The sterically hindered p-QM precursors (5o ),
-w) were obtained in good to excellent yields.
-f,
-f,
-m
-m
(
&
-
q
derived from 4-phenyl benzaldehyde, 2-naphthaldehyde, and
9-anthracene aldehyde underwent smooth conversion to their
corresponding diarylmethane derivatives (7o-q) in the range of
73-83% yields. Furthermore, the p-quinone methide (5n),
prepared from thiophene-2-carboxaldehyde aldehyde, was
converted to its respective diarylmethane derivative (7n) in
96% yield.
Table 2. Substrate scope with para-quinone methidesa
Table 1. Optimisation studiesa
H
R2
R2
B(C6F5)3 (5 mol%)
tBu
O
EtO2C
CO2Et
tBu
OH
Catalyst
+
6
+
CH2Cl2 (1.5 mL)
RT
O
OH
R1
R1
Solvent (1.5 mL)
RT
R2
R1 = Alkyl, Halo; R2 = alkyl
R2
N
7b-w
5b-w
H
tBu
5a (1 equiv.)
tBu
6 (2 equiv.)
7a
OH
OH
OH
7b, R1 = 4-Et, 2 h, 98%
7c, R1 = 4-OMe, 2 h, 96%
7d, R1 = 4- tBu, 3 h, 94%
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Entry
Catalyst (mol %)
Solvent
Time (h)
Yield (%)b
7e, R1 = 2,3-dimethoxy, 3 h, 89%
7f, R1 = 3,5-dimethoxy, 4 h, 88%
1 c
B(C6F5)3 (1)
B(C6F5)3 (1)
CH2Cl2
CH2Cl2
12
12
70
80
7g, R1
= 2-F, 20 h, 70%
R1 7h, R1 = 2-Br, 24 h, 50%
N
CF3
2
7i, 5 h, 89%
7j, 24 h, 72%
3 c
4
B(C6F5)3 (5)
B(C6F5)3 (5)
B(C6F5)3 (5)
B(C6F5)3 (5)
B(C6F5)3 (5)
B(C6F5)3 (5)
B(C6F5)3 (5)
----
CH2Cl2
CH2Cl2
CHCl3
12
12
15
24
24
12
24
24
24
12
12
24
87
93
OH
OH
OH
tBu
OH
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
5
86
6
Toluene
Et2O
40
OMe
S
OCF3
NO2
O
7
Trace
86
7k, 24 h, 60%
7m, 24 h, 50%
7n, 5 h, 96%
7l, 24 h, 45%
OH
tBu
OH
tBu
OH
tBu
OH
tBu
8
DCE
tBu
tBu
9
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
77
10
11
12
13
14
Trace
85
Bi(OTf)3 (10)
Sc(OTf)3 (10)
Cu(OTf)2 (10)
Ag(OTf) (10)
Ph
Ph
79
7o, 6 h, 83%
7p, 9 h, 86%
7r, 8 h, 97%
7q, 15 h, 73%
OH
tBu
OH
tBu
OH
tBu
OH
R2
40
tBu
R2
70
OMe
OAc
7u, 10 h, 95%
15
B(C6H5)3 (10)
CH2Cl2
30
67
Fe
7v, R2 = iPr, 8 h, 95%
7w, R2 = Me, 4 h, 60 %
a Reaction conditions: All reactions were performed with 0.067
M of 5a in solvent and 2 equivalents of Hantzsch ester. RT =
room temperature (27–30 °C). Yields reported are isolated
yields. 1.1 equiv. of Hantzsch ester was used. DCE = 1,2-
dicholoroethane
7t, 4 h, 86%
7s, 7 h, 97%
a Reaction conditions: All reactions were performed with 0.067
M scale of ) in CH2Cl2. Two equivalents of with respect
to was used in all reactions. Yields reported are isolated
yields.
b
c
5
(b
-w
6
5
2 | J. Name., 2012, 00, 1-3
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Under the optimal conditions, diarylmethanes 7r
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DOI: 10.1039/C7OB02007D
ARTICLE
-
7u could be B(C6F5)3 would generate a frustrated Lewis-pair (10a) as major
synthesized in the range of 86-97% yields from their product at -20 °C along with its Lewis acid-base adduct (10b).
corresponding precursors. Finally, this protocol was also Interestingly, upon warming the reaction mixture to room
extended to other p-QMs (5v
diisopropyl phenol and 2,6-dimethyl phenol, and in both the be isolated with maximum 70% yield in 24 h (Scheme 1).
cases, the expected products (7v 7w) were obtained in 95%
, 5w), derived from 2,6- temperature, they found that 1,2-dihydropyridine (11) could
,
B(C6F5
)
3
B(C6F5
)
3
O
O
and 60% respectively. It is worth mentioning that most of the
reactive functional groups such as, nitro, ester and alkyne
were well tolerated under the reaction conditions.
EtO2
C
CO2Et EtO2C
+
EtO2C
Me
B(C6F5)3
CD2Cl2, -20 o
OEt
OEt
Me
6
C
Me
N
Me
Me
N
Me
70%
N
H
11
H
H
HB(C6F5
)
3
major (10a)
upon warming to RT
minor (10b)
The feasibility of the present methodology was also elaborated
for the synthesis of symmetrical as well as unsymmetrical Scheme 1. Previous report by Stephan and Crudden17
triarymethanes using fuchsones instead of p-QMs. In this
context, many fuchsones (8a-h) were prepared using a known
protocol16 and subjected to B(C6F5)3 catalyzed reduction with
Hantzsch ester under the optimised conditions (Table 3).
Remarkably, the optimised condition for the reduction of p-
QMs was also found to be the well-suited condition for the
reduction of fuchsones. Under this condition, a wide range of
symmetrical and unsymmetrical triarylmethane derivatives
Based on the above observation, we thought that both the
activation modes are possible in the B(C6F5)3 catalyzed
reduction of p-QMs and fuchsones. To find out the actual
mode of activation, a few experiments were performed. In one
of the experiments, the reduction of 5a was carried out at -20
oC; however, only traces of 7a was observed (by TLC) after 12
h. Interestingly, when the same reaction mixture was warmed
to room temperature, the conversion started taking place and
the concentration of 7a was gradually increasing with respect
to time. This clearly indicates that the frustrated Lewis-pair
(
9a-e) were obtained in excellent yields (90-99%) from their
respective fuchsone precursors (8a-e). Other fuchsones (8f ),
-h
derived from 2,6-disubstituted phenols such as, 2,6-
diisopropylphenol and 2,6-dimethylphenol also underwent
(
10a) does not react with p-QMs at lower temperature even if
smooth transformation, and the products (9f
-
h
) were obtained
we assume that it was formed during the progress of the
reaction. Since the reduction of p-QMs (our protocol) is carried
out at room temperature, it is less probable that the reaction
is actually proceeding through frustrated Lewis-pair complex.
In fact, the above experimental observation clearly supports
our hypothesis. Moreover, it is reported in the literature that
the frustrated Lewis-pair 10a generally forms at lower
temperature.17 Therefore, one can conclude that the reaction
is actually proceeding through a Lewis acid-base pair. To
further confirm this, an experiment was conducted in a NMR
tube at room temperature using 1:1 ratio of Hantsch ester and
B(C6F5)3, and the progress of the reaction was monitored by
11B NMR spectroscopy. In this case, a strong signal at δ -3.82
ppm was observed (Figure 2), which actually corresponds to
the Lewis acid-base adduct (10b), according to the literature
precedence.17 The peak that corresponds to the frustrated
Lewis-pair complex [10a] (at -24.4 ppm) was not observed at
all.17
in the range of 88-99% isolated yields.
Table 3. Substrate scope with Fuchsonesa
OH
R1
O
R1
R1
R1
B(C6F5)3 (5 mol%)
+
6
CH2Cl2 (1.5 mL)
RT
R2 R3
R2 R3
8a-h
9a-h
i
R1 = tBu, Pr, Me; R2 & R3 = Aryl
OH
OH
OH
OH
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
OMe
Et
Cl
OMe
9d, 12 h, 99 %
9b, 12 h, 99 %
9c, 12 h, 99 %
9a, 12 h, 90%
OH
OH
OH
OH
i
i
i
tBu
tBu
Pr
Pr
Pr
iPr
Me
Me
tBu
Cl
OMe
9g, 12 h, 96 %
9f, 12 h, 99 %
9h, 12 h, 88 %
9e, 12 h, 99 %
a Reaction conditions: All reactions were carried out with 0.067
M of ) in CH2Cl2. Two equivalents of with respect to
was used in all reactions. Yields reported are isolated yields.
8
(
a-h
6
8
After investigating the substrate scope for the synthesis of
diaryl- and triarylmethanes, we shifted our attention to
understand the mechanism of this transformation in detail. In
fact, we were primarily interested in the mode of activation of
Hantzsch ester by B(C6F5)3. Recently, Stephan and Crudden Figure 2
jointly reported17 that the reaction of Hantzsch ester (
6) with
.
11B NMR of the mixture of
6
and B(C6F5)3 at RT
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Based on the above-mentioned observations, a plausible
mechanism has been proposed (Scheme 2). Initially, B(C6F5)3
activates the Hantzsch ester and forms a Lewis acid-base
Conclusions
In conclusion, we have demonstrated a simple and direct
method for the synthesis of unsymmetrical diaryl- and
triarylethanes through a B(C6F5)3 catalysed reduction of p-QMs
and fuchsones respectively, using Hantzsch ester as a reducing
agent. Detailed mechanistic investigation revealed that the
reaction does not proceed through the frustrated Lewis pair
complex between B(C6F5)3 and Hantzsch ester. In fact, B(C6F5)3
is actually acting as a Lewis acid for this transformation. This
protocol was also elaborated to the synthesis of beclobrate in
very high overall yield (49%).
complex I. Then, the hydride transfer is taking place from I to
5a, and upon protonation, the reduced product 7a is formed
along with complex III, which liberates the pyridine by-product
and regenerate the catalyst.
H
N
N
EtO2C
CO2Et
EtO2C
CO2Et
B(C6F5)3
H
6
Experimental:
H
General methods:
N
N
Most of the reagents and starting materials used were
purchased from commercial sources and used as such. p-
quinone methides4a and fuchsones16 were prepared according
to known literature procedure. 1H, 13C (proton decoupled), 19F,
and 11B spectra were recorded in CDCl3 (400, 100, 376, and 128
MHz respectively) on Brucker FT-NMR spectrometer. Chemical
shift (δ) values are reported in parts per million relative to TMS
(for 1H and 13C), BF3.Et2O (19F and 11B); and the coupling
constants (J) are reported in Hz. Trifluoromethyl benzene was
used as internal standard for 19F spectra. High resolution mass
spectra were recorded on Waters Q-TOF Premier-HAB213
spectrometer. FT-IR spectra were recorded on a Brucker FT-IR
spectrometer equipped with a PIKE MIRacle ATR. Thin layer
chromatography was performed on Merck silica gel 60 F254
TLC plates. Column chromatography was carried out through
silica gel (100-200 mesh) using EtOAc/hexane as an eluent.
EtO
EtO
CO2Et
CO2Et
III
O
H
O
I
(C6F5)3B
(C6F5)3B
Ph
Ph
Ph
H
tBu
5a
tBu
tBu
tBu
tBu
tBu
7a
O
O
II
OH
Scheme 2. Plausible reaction mechanism
Further, to portray the synthetic utility, this protocol was
elaborated to the synthesis of beclobrate, which is a potent
cholesterol- and triglyceride lowering drug and is used for the
treatment of hyperlipidemia.9 A few divergent methods are
available in the literature for the synthesis of beclobrate.18 Our
strategy for the synthesis of beclobrate is shown in Scheme 3.
The reduction of p-QM 5x using our standard reaction
condition (Table 1, Entry 4) gave the respective diarylmethane
7x in 90% yield. AlCl3 mediated de-tert-butylation of 7x
resulted the desired diarylmethane 12 in 95% yield. The
conventional alkylation reaction between 12 and 2-
bromoethylpropiolate (13) gave the beclobrate precursor 14 in
82% yield. Finally, a base mediated alkylation of 14 with
General Procedure of the B(C6F5)3-Catalysed Hydro aromatisation
of p-quinone methides:
p-Quinone methide (0.1 mmol) was added to a mixture of
B(C6F5)3 (0.05 mmol) and Hantzsch ester (0.2 mmol) in 1.5 mL
of CH2Cl2, and the resultant mixture was stirred at room
temperature (27–30 °C) until the p-quinone methide was
completely consumed (by T.L.C). The solvent was removed
under reduced pressure and the crude reaction mixture was
directly loaded on silica gel column and purified using
hexane/EtOAc mixture as an eluent to get the pure
diaryl/triarylmethane.
iodoethane provided beclobrate (2) in 70% yield (49% overall
yield from 5x).
B(C6F5)3 (5 mol%)
tBu
6 (2 equiv.), CH2Cl2
AlCl3 (5 equiv.)
Benzene
5x
RT, 5 h
RT, 3 h
Cl
OH
Cl
OH
tBu
12, 95%
7x, 90%
4-Benzyl-2,6-di-tert-butylphenol (7a): Colourless oil; yield 95%
(28 mg); Rf = 0.6 (1% EtOAc in hexane); FT-IR (ATR): 3643,
2958, 2914 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.33 – 7.29 (m,
2H), 7.24 – 7.19 (m, 3H), 7.02 (s, 2H), 5.09 (s, 1H), 3.93 (s, 2H),
1.43 (s, 18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 152.2, 141.9,
135.9, 131.7, 129.0, 128.5, 125.9, 125.6, 41.9, 34.4, 30.4 ppm.
HRMS (ESI): m/z calcd for C21H28O [M-H]: 295.2062; found:
295.2068.
K2CO3 (3 equiv.)
13 (1.2 equiv.)
LiHMDS (1.5 equiv.)
C2H5I (1.2 equiv.)
2, 70%
Overall yield 49%
O
Cl
O
THF, 2 h, rt
DMF, 5 h,
14, 82%
RT to 80 o
C
O
Scheme 3. Synthesis of Beclobrate (2)
4 | J. Name., 2012, 00, 1-3
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2,6-Di-tert-butyl-4-(4-ethylbenzyl)phenol (7b): Colourless oil; JC–F = 3.6 Hz), 115.3 (d, JC–F = 22.1 Hz), 34.7 (d, JC–F = 2.8 Hz),
yield 98% (32 mg); Rf = 0.5 (1% EtOAc in hexane); FT-IR (ATR): 34.4, 30.4 ppm. 19F NMR (376 MHz, CDCl3) δ = -118.0 ppm.
1
3642, 2959, 2911 cm−1; H NMR (400 MHz, CDCl3) δ = 7.13 (s, HRMS (ESI): m/z calcd for C21H27FO [M˗H]: 313.1968; found:
4H), 7.01 (s, 2H), 5.07 (s, 1H), 3.88 (s, 2H), 2.63 (q, J = 7.6 Hz, 313.1957.
2H), 1.42 (s, 18H), 1.23 (t, J = 7.6 Hz, 3H) ppm. 13C NMR (100
MHz, CDCl3) δ = 152.1, 141.8, 139.2, 135.9, 131.9, 128.8, 128.0, 4-(2-Bromobenzyl)-2,6-di-tert-butylphenol
(7h): Colourless
125.6, 41.6, 34.4, 30.4, 28.6, 15.8 ppm. HRMS (ESI): m/z calcd solid; yield 50% (19 mg); mp 109–111 °C; Rf = 0.5 (1% EtOAc in
1
for C23H32O [M+H]: 325.2531; found: 325.2541.
hexane); FT-IR (ATR): 3639, 2958, 2910 cm−1; H NMR (400
MHz, CDCl3) δ = 7.56 (dd, J = 7.9, 1.2 Hz, 1H), 7.22 (td, J = 7.5,
2,6-Di-tert-butyl-4-(4-methoxybenzyl)phenol (7c): Colourless 1.2 Hz, 1H), 7.12 (dd, J = 7.7, 1.7 Hz, 1H), 7.08 – 7.04 (m, 1H),
solid; yield 96% (32 mg); mp 148–150 °C; Rf = 0.4 (1% EtOAc in 7.04 (s, 2H), 5.09 (s, 1H), 4.02 (s, 2H), 1.41 (s, 18H) ppm. 13C
1
hexane); FT-IR (ATR): 3618, 2999, 2952, 1233 cm−1; H NMR NMR (100 MHz, CDCl3) δ = 152.3, 141.4, 136.0, 132.8, 131.0,
(400 MHz, CDCl3) δ = 7.12 (d, J = 8.6 Hz, 2H), 6.98 (s, 2H), 6.84 130.0, 127.7, 127.6, 125.8, 124.9, 41.7, 34.5, 30.5 ppm. HRMS
(d, J = 8.6 Hz, 2H), 5.05 (s, 1H), 3.85 (s, 2H), 3.79 (s, 3H), 1.41(s, (ESI): m/z calcd for C21H27BrO [M-H]: 373.1167; found:
18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 157.9, 152.1, 135.9, 373.1154.
134.0, 132.1, 129.9, 125.4, 113.9, 55.4, 41.0, 34.4, 30.4 ppm.
HRMS (ESI): m/z calcd for C22H30O2 [M˗H]: 325.2168; found: 2,6-Di-tert-butyl-4-[4-(pyrrolidin-1-yl)benzyl]phenol
(7i):
325.2158.
Brown solid; yield 89% (18 mg); mp 108–110 °C; Rf = 0.3 (1%
EtOAc in hexane); FT-IR (ATR): 3638, 2954, 2871 cm−1; 1H NMR
2,6-Di-tert-butyl-4-[4-(tert-butyl)benzyl]phenol
(
7d): Yellow (400 MHz, CDCl3) δ = 7.06 (d, J = 8.6 Hz, 2H), 7.01 (s, 2H), 6.52
solid; yield 94% (33 mg); mp 88–90 °C; Rf = 0.5 (1% EtOAc in (d, J = 8.6 Hz, 2H), 5.03 (s, 1H), 3.81 (s, 2H), 3.28 – 3.25 (m, 4H),
1
hexane); FT-IR (ATR): 3643, 2955, 2907 cm−1; H NMR (400 2.00 – 1.97 (m, 4H), 1.41 (s, 18H) ppm. 13C NMR (100 MHz,
MHz, CDCl3) δ = 7.34 (d, J = 8.4Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), CDCl3) δ = 151.9, 146.5, 135.7, 132.8, 129.6, 128.8, 125.4,
7.04 (s, 2H), 5.08 (s, 1H), 3.9 (s, 2H), 1.44 (s, 18H), 1.33 (s, 9H) 111.8, 47.9, 41.0, 34.4, 30.5, 25.6 ppm. HRMS (ESI): m/z calcd
ppm. 13C NMR (100 MHz, CDCl3) δ = 152.1, 148.7, 139.0, 135.9, for C25H35NO [M+H]: 366.2798; found: 366.2789.
131.7, 128.4, 125.7, 125.4, 41.4, 34.5, 34.4, 31.6, 30.4 ppm.
HRMS (ESI): m/z calcd for C25H36O [M˗H]: 351.2688; found: 2,6-Di-tert-butyl-4-[4-(trifluoromethyl)benzyl]phenol
(7j):
351.2694.
Colourless solid; yield 72% (26 mg); mp 111–113 °C; Rf = 0.5 (1
1
% EtOAc in hexane); FT-IR (ATR): 3617, 2953, 2920 cm−1; H
2,6-Di-tert-butyl-4-(2,3-dimethoxybenzyl)phenol
(
7e): NMR (400 MHz, CDCl3) δ = 7.53 (d, J = 8.0 Hz, 2H), 7.30 (d, J =
Colourless solid; yield 89% (31 mg); mp 56–58 °C; Rf = 0.5 (5% 8.0 Hz, 2H), 6.97 (s, 2H), 5.11 (s, 1H), 3.95 (s, 2H), 1.41 (s, 18H)
EtOAc in hexane); FT-IR (ATR): 3639, 2954, 2910, 1230 cm−1; 1H ppm. 13C NMR (100 MHz, CDCl3) δ = 152.5, 146.1 (q, JC–F = 1.1
NMR (400 MHz, CDCl3) δ = 7.05 (s, 2H), 6.99 (t, J = 7.9 Hz, 1H), Hz), 136.2, 130.6, 129.2, 128.3 (q, JC–F = 32 Hz), 125.6, 125.4 (q,
6.80 (dd, J = 1.44, 8.2 Hz, 1H), 6.76 (dd, J = 1.48, 7.7 Hz, 1H), JC–F = 3.8 Hz), 124.5 (q, JC–F = 270 Hz), 41.8, 34.5, 30.4 ppm. 19
F
5.05 (s, 1H), 3.93 (s, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 1.42 (s, 18H) NMR (376 MHz, CDCl3) δ = -62.2 ppm. HRMS (ESI): m/z calcd
ppm. 13C NMR (100 MHz, CDCl3) δ = 152.9, 152.0, 147.1, 136.0, for C22H27F3O [M-H]: 363.1926; found: 363.1929.
135.7, 131.6, 125.7, 123.9, 122.5, 110.4, 60.6, 55.8, 35.7, 34.4,
30.5 ppm. HRMS (ESI): m/z calcd for C23H32O3 [M-H]: 355.2273; 2,6-Di-tert-butyl-4-[4-(trifluoromethoxy)benzyl]phenol
(7k):
found: 355.2268.
Colourless oil; yield 60% (22 mg); Rf = 0.1 (1% EtOAc in
1
hexane); FT-IR (ATR): 3642, 2957, 2912, 1254 cm−1; H NMR
2,6-Di-tert-butyl-4-(3,5-dimethoxybenzyl)phenol
(
7f): (400 MHz, CDCl3) δ = 7.21 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.3 Hz,
Colourless oil; yield 88% (29 mg); Rf = 0.3 (1% EtOAc in 2H), 6.97 (s, 2H), 5.10 (s, 1H), 3.90 (s, 2H), 1.42 (s, 18H) ppm.
1
hexane); FT-IR (ATR): 3636, 2998, 2953, 1149 cm−1; H NMR 13C NMR (100 MHz, CDCl3) δ = 152.4, 147.5 (q, JC–F = 1.7 Hz),
(400 MHz, CDCl3) δ = 7.00 (s, 2H), 6.37 (d, J = 2.1 Hz, 2H), 6.31 140.7, 136.1, 131.0, 130.1, 125.5, 121.1, 120.7 (q, JC–F = 255
(t, J = 2.2 Hz, 1H), 5.07 (s, 1H), 3.84 (s, 2H), 3.77 (s, 6H), 1.42 (s, Hz), 41.2, 34.5, 30.4 ppm. 19F NMR (376 MHz, CDCl3) δ = -57.9
18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 160.8, 152.2, 144.4, ppm. HRMS (ESI): m/z calcd for C22H27F3O2 [M-H]: 379.1885;
135.9, 131.2, 125.6, 107.1, 97.9, 55.4, 42.2, 34.4, 30.5 ppm. found: 379.1884.
HRMS (ESI): m/z calcd for C23H32O3 [M-H]: 355.2273; found:
355.2279.
Methyl 4-(3,5-di-tert-butyl-4-hydroxybenzyl)benzoate
(7l):
Colourless solid; yield 45% (16 mg); mp 120–122 °C; Rf = 0.5
2,6-Di-tert-butyl-4-(2-fluorobenzyl)phenol (7g): Colourless oil; (5% EtOAc in hexane); FT-IR (ATR): 3642, 2957, 2911, 1721
1
yield 70% (22 mg); Rf = 0.5 (1% EtOAc in hexane); FT-IR (ATR): cm−1; H NMR (400 MHz, CDCl3) δ = 7.96 (d, J = 8.4 Hz, 2H),
1
3639, 2954, 2912 cm−1; H NMR (400 MHz, CDCl3) δ = 7.20 – 7.28 – 7.26 (m, 2H), 6.96 (s, 2H), 5.10 (s, 1H), 3.95 (s, 2H), 3.90
7.13 (m, 2H), 7.07 – 7.01 (m, 2H), 7.03 (s, 2H), 5.08 (s, 1H), 3.91 (s, 3H), 1.40 (s, 18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 167.4,
(s, 2H), 1.41 (s, 18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 161.1 152.4, 147.4, 136.1, 130.8, 129.9, 129.0, 128.0, 125.6, 52.1,
(d, JC–F = 243.4 Hz), 152.3, 136.0, 131.1 (d, JC–F = 4.7 Hz), 130.4, 42.0, 34.4, 30.4 ppm. HRMS (ESI): m/z calcd for C23H30O3
129.0 (d JC–F = 15.9 Hz), 127.8 (d JC–F = 8.0 Hz), 125.5, 124.1 (d, [M˗H]: 353.2117; found: 353.2112.
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2H), 6.97 (s, 2H), 5.09 (s, 1H), 3.91 (s, 2H), 1.41 (s, 18H) ppm.
7m): Colourless 13C NMR (100 MHz, CDCl3) δ = 152.3, 142.4, 136.0, 131.8,
2,6-Di-tert-butyl-4-(4-nitrobenzyl)phenol
(
solid; yield 50% (15 mg); mp 108–110 °C; Rf = 0.5 (5% EtOAc in 131.7, 131.2, 129.1, 128.5, 128.2, 125.6, 123.6, 120.8, 89.7,
1
hexane); FT-IR (ATR): 3618, 3008, 2957, 2916 cm−1; H NMR 89.0, 41.9, 34.5, 30.4 ppm. HRMS (ESI): m/z calcd for C29H32O
(400 MHz, CDCl3) δ = 8.15 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, [M˗H]: 395.2375; found: 395.2385.
2H), 6.95 (s, 2H), 5.14 (s, 1H), 3.99 (s, 2H), 1.41 (s, 18H) ppm.
13C NMR (100 MHz, CDCl3) δ = 152.7, 149.9, 146.5, 136.4, [(3,5-Di-tert-butyl-4-hydroxybenzyl)cyclopentadienyl]
129.9, 129.7, 125.6, 123.8, 41.8, 34.5, 30.4 ppm. HRMS (ESI): cyclopentadienyliron (7s): Brown solid; yield 97% (39 mg); mp
m/z calcd for C21H27NO3 [M-H]: 340.1913; found: 340.1918.
129–131 °C; Rf = 0.4 (1% EtOAc in hexane); FT-IR (ATR): 3620,
1
2951, 2908, 2871 cm−1; H NMR (400 MHz, CDCl3) δ = 7.00 (s,
2,6-Di-tert-butyl-4-(thiophen-2-ylmethyl)phenol (7n): Yellow 2H), 5.05 (s, 1H), 4.11 (s, 5H), 4.08 – 4.07 (m, 4H), 3.59 (s, 2H),
oil; yield 96% (29 mg); Rf = 0.5 (1% EtOAc in hexane); FT-IR 1.43 (s, 18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 152.0, 135.7,
1
(ATR) 3639, 2954, 2910, 2871 cm−1; H NMR (400 MHz, CDCl3) 132.2, 125.2, 89.1, 68.7(2C), 67.5, 35.9, 34.4, 30.5 ppm. HRMS
δ = 7.15 (dd, J = 5.1, 1.2 Hz, 1H), 7.08 (s, 2H), 6.96 – 6.93 (dd, J (ESI): m/z calcd for C25H32FeO [M+H]: 405.1881; found:
= 5.1, 3.4 Hz, 1H), 6.82 – 6.80 (m, 1H), 5.12 (s, 1H), 4.10 (s, 2H), 405.1880.
1.45 (s, 18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 152.4, 145.2,
136.0, 131.0, 126.9, 125.3, 124.9, 123.7, 36.0, 34.4, 30.4 ppm. 4-[(9H-Fluoren-2-yl)methyl]-2,6-di-tert-butylphenol
(7t):
HRMS (ESI): m/z calcd for C19H26OS [M-H]: 301.1626; found: Yellow solid; yield 86% (33 mg); mp 154–156 °C; Rf = 0.5 (1%
301.1629.
EtOAc in hexane); FT-IR (ATR): 3635, 2958, 2909 cm−1; 1H NMR
(400 MHz, CDCl3) δ = 7.76 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 7.8 Hz,
(7o): 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.29 – 7.25 (m,
4-[(1,1'-Biphenyl)-4-ylmethyl]-2,6-di-tert-butylphenol
Yellow solid; yield 83% (15 mg); mp 100–102 °C; Rf = 0.4 (1% 1H), 7.24 – 7.22 (m, 1H), 7.03 (s, 2H), 5.08 (s, 1H), 3.98 (s, 2H),
EtOAc in hexane); FT-IR (ATR): 3631, 3005, 2954, 2909 cm−1; 1H 3.87 (s, 2H), 1.42 (s, 18H) ppm. 13C NMR (100 MHz, CDCl3) δ =
NMR (400 MHz, CDCl3) δ = 7.62 – 7.60 (m, 2H), 7.54 (d, J = 8.1 152.2, 143.7, 143.4, 141.9, 140.6, 139.7, 135.9, 132.0, 127.7,
Hz, 2H), 7.46 – 7.42 (m, 2H), 7.36 – 7.32 (m, 1H), 7.30 (d, J = 8.1 126.8, 126.4, 125.7, 125.6, 125.1, 119.8, 119.75, 42.1, 37.0,
Hz, 2H), 7.05 (s, 2H), 5.10 (s, 1H), 3.96 (s, 2H), 1.44 (s, 18H) 34.5, 30.5 ppm. HRMS (ESI): m/z calcd for C28H32O [M˗H]:
ppm. 13C NMR (100 MHz, CDCl3) δ = 152.2, 141.2, 141.1, 138.9, 383.2375; found: 383.2379.
136.0, 131.5, 129.3, 128.8, 127.2, 127.14, 127.12, 125.6, 41.6,
34.5, 30.5 ppm. HRMS (ESI): m/z calcd for C27H32O [M-H]: 4-(3,5-Di-tert-butyl-4-hydroxybenzyl)-2-methoxyphenyl
371.2375; found: 371.2369.
acetate (7u): Colourless solid; yield 95% (36 mg); mp 88–90 °C;
Rf = 0.5 (1% EtOAc in hexane); FT-IR (ATR): 3634, 2954, 2910,
1
2,6-Di-tert-butyl-4-(naphthalen-2-ylmethyl)phenol
(
7p): 1762, 1195 cm−1; H NMR (400 MHz, CDCl3) δ = 7.01 (s, 2H),
Colourless solid; Yield 86% (29 mg); mp 93–95 °C; Rf = 0.5 (1% 6.95 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H), 6.77 (dd, J = 8.0,
EtOAc in hexane); FT-IR (ATR): 3622, 2952, 2913 cm−1; 1H NMR 1.9 Hz, 1H), 5.1 (s, 1H), 3.90 (s, 2H), 3.80 (s, 3H), 2.32 (s, 3H),
(400 MHz, CDCl3) δ = 8.13 – 8.09 (m, 1H), 7.89 – 7.85 (m, 1H), 1.43 (s, 18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 169.4, 152.3,
7.74 (d, J = 8.2 Hz, 1H), 7.52 – 7.46 (m, 2H), 7.41 (dd, J = 8.1, 150.8, 140.9, 137.9, 136.0, 131.1, 125.6, 122.5, 121.0, 113.1,
7.1 Hz, 1H), 7.26 – 7.23 (m, 1H), 7.04 (s, 2H), 5.06 (s, 1H), 4.38 55.9, 41.7, 34.4, 30.4, 20.8 ppm. HRMS (ESI): m/z calcd for
(s, 2H), 1.39 (s, 18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 152.2, C24H32O4 [M-H]: 383.2223; found: 383.2229.
137.8, 135.9, 133.9, 132.3, 130.9, 128.7, 126.9, 126.89, 125.9,
125.7, 125.69, 125.6, 124.4, 38.7, 34.4, 30.4 ppm. HRMS (ESI): 4-Benzyl-2,6-diisopropylphenol (7v): Yellow oil; yield 95% (22
m/z calcd for C25H30O [M˗H]: 345.2219; found: 345.2228.
mg); Rf = 0.5 (5% EtOAc in hexane); FT-IR (ATR): 3576, 2962,
1
2914 cm−1; H NMR (400 MHz, CDCl3) δ = 7.32 – 7.26 (m, 2H),
4-(Anthracen-9-ylmethyl)-2,6-di-tert-butylphenol (7q): Yellow 7.21 – 7.18 (m, 3H), 6.89 (s, 2H), 4.68 (s, 1H), 3.93 (s, 2H), 3.13
solid; yield 73% (22 mg); mp 152–154 °C; Rf = 0.3 (1% EtOAc in (septet, J = 6.8 Hz, 2H), 1.25 (d, J = 6.9 Hz, 12H) ppm. 13C NMR
1
hexane); FT-IR (ATR): 3632, 2955, 2911 cm−1; H NMR (400 (100 MHz, CDCl3) δ = 148.4, 142.0, 133.7, 132.9, 128.9, 128.5,
MHz, CDCl3) δ = 8.41 (s, 1H), 8.33 – 8.29 (m, 2H), 8.03 – 8.00 125.9, 124.2, 41.8, 27.4, 22.9 ppm. HRMS (ESI): m/z calcd for
(m, 2H), 7.50 – 7.43 (m, 4H), 6.99 (s, 2H), 4.99 (s, 1H), 4.91 (s, C19H24O [M+H]: 269.1905; found: 269.1911.
2H), 1.28 (s, 18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 152.0,
135.8, 133.0, 131.8, 131.3, 130.6, 129.1, 126.3, 125.7, 125.3, 4-Benzyl-2,6-dimethylphenol (7w):19 Yellow oil; yield 60% (6
124.9, 124.89, 34.4, 33.4, 30.3 ppm. HRMS (ESI): m/z calcd for mg); Rf = 0.5 (5% EtOAc in hexane); FT-IR (ATR): 3471, 2967,
1
C29H32O [M+H]: 397.2531; found: 397.2518.
2919 cm−1; H NMR (400 MHz, CDCl3) δ = 7.30 – 7.26 (m, 2H),
7.20 – 7.17 (m, 3H), 6.80 (s, 2H), 4.49 (s, 1H), 3.85 (s, 2H), 2.20
7r): (s, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ = 150.6, 141.9, 132.9,
2,6-Di-tert-butyl-4-[4-(phenylethynyl)benzyl]phenol
(
Colourless solid; yield 97% (38 mg); mp 139–141 °C; Rf = 0.3 129.2, 128.9, 128.5, 126.0, 123.1, 41.2, 16.1 ppm.
(1% EtOAc in hexane); FT-IR (ATR): 3630, 3009, 2954, 2910,
1
2360 cm−1; H NMR (400 MHz, CDCl3) δ = 7.54 – 7.50 (m, 2H), 4-Benzhydryl-2,6-di-tert-butylphenol (9a): Colourless solid;
7.46 (d, J = 8.2 Hz, 2H), 7.37 – 7.31 (m, 3H), 7.18 (d, J = 8.4 Hz, yield 90% (14 mg); mp 140–142 °C; Rf = 0.4 (1% EtOAc in
6 | J. Name., 2012, 00, 1-3
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hexane); FT-IR (ATR): 3579, 3021, 2952 cm−1; H NMR (400 128.4, 126.3, 122.9, 56.2, 16.2 ppm. HRMS (ESI): m/z calcd for
MHz, CDCl3) δ = 7.30 – 7.26 (m, 4H), 7.22 – 7.17 (m, 2H), 7.14 – C21H20O [M-H]: 287.1436; found: 287.1428.
7.11 (m, 4H), 6.91 (s, 2H), 5.45 (s, 1H), 5.09 (s, 1H), 1.36 (s,
18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 152.2, 144.9, 135.5, 4-Benzhydryl-2,6-diisopropylphenol (9g): Light yellow solid;
134.2, 129.5, 128.2, 126.2, 126.1, 56.9, 34.5, 30.1 ppm. HRMS 96% (26 mg); Rf = 0.3 (5% EtOAc in hexane); FT-IR (ATR): 3586,
(ESI): m/z calcd for C27H32O [M-H]: 371.2375; found: 371.2380. 2962, 2870 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.30 – 7.26 (m,
4H), 7.22 – 7.19 (m, 2H), 7.14 – 7.12 (m, 4H), 6.81 (s, 2H), 5.49
2,6-Di-tert-butyl-4-[(4-methoxyphenyl)(phenyl)methyl]phenol
(s, 1H), 4.70 (s, 1H), 3.1 (septet, J = 6.9 Hz, 2H), 1.19 (d, J = 6.9
(
9b): Yellow solid; yield 99% (39 mg); mp 105–108 °C; Rf = 0.3 Hz, 12H) ppm. 13C NMR (100 MHz, CDCl3) δ = 148.5, 144.8,
(1% EtOAc in hexane); FT-IR (ATR): 3637, 2998, 2954, 1245 135.7, 133.4, 129.5, 128.3, 126.2, 124.7, 56.8, 27.5, 22.8 ppm.
cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.31 – 7.26 (m, 2H), 7.22 – HRMS (ESI): m/z calcd for C25H28O [M-H]: 343.2062; found:
7.18 (m, 1H), 7.15 – 7.13 (m, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.93 343.2049.
(s, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.42 (s, 1H), 5.1 (s 1H), 3.80 (s,
3H), 1.39 (s, 18H) ppm. 13C NMR (100 MHz, CDCl3) δ = 157.9, 4-[(4-Chlorophenyl)(4-methoxyphenyl)methyl]-2,6-
152.1, 145.3, 137.2, 135.5, 134.6, 130.4, 129.4, 128.2, 126.1, diisopropylphenol (9h): Yellow oil; yield 88% (36 mg); Rf = 0.2
126.06, 113.6, 56.1, 55.3, 34.5, 30.5 ppm. HRMS (ESI): m/z (5% EtOAc in hexane); FT-IR (ATR): 3497, 2962, 2902, 1250
1
calcd for C28H34O2 [M-H]: 401.2481; found: 401.2470.
cm−1; H NMR (400 MHz, CDCl3) δ = 7.23 (d, J = 8.4 Hz, 2H),
7.03 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.7
2,6-Di-tert-butyl-4-[(4-ethylphenyl)(phenyl)methyl]phenol (9c): Hz, 2H), 6.75 (s, 2H), 5.38 (s, 1H), 4.71 (s, 1H), 3.80 (s, 3H), 3.10
Colourless solid; yield 99% (40 mg); mp 94–96 °C; Rf = 0.4 (1% (septet, J = 6.9 Hz, 2H), 1.18 (d, J = 6.9 Hz, 12H) ppm. 13C NMR
EtOAc in hexane); FT-IR (ATR): 3640, 3001, 2958 cm−1; 1H NMR (100 MHz, CDCl3) δ = 158.1, 148.6, 143.8, 136.4, 135.5, 133.5,
(400 MHz, CDCl3) δ = 7.32 – 7.26 (m, 2H), 7.21 – 7.17 (m, 1H), 131.8, 130.8, 130.3, 128.4, 124.5, 113.7, 55.4, 55.3, 27.4, 22.8
7.14 – 7.10 (m, 4H), 7.05 – 7.03 (m, 2H), 6.93 (s, 2H), 5.42 (s, ppm. HRMS (ESI): m/z calcd for C26H29ClO2 [M+H]: 409.1934;
1H), 5.08 (s, 1H), 2.64 (q, J = 7.6 Hz, 2H), 1.38 (s, 18 H), 1.23 (t, found: 409.1940.
J = 7.6 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 152.2,
145.2, 142.2, 141.9, 135.5, 134.4, 129.5, 129.4, 128.2, 127.7, Synthesis of beclobrate (2):
126.2, 126.0, 56.6, 34.5, 30.5, 28.5, 15.7 ppm. HRMS (ESI): m/z
calcd for C29H36O [M-H]: 399.2688; found: 399.2683.
2,6-Di-tert-butyl-4-(4-chlorobenzyl)phenol (7x): p-Quinone
methide 5x (164 mg, 0.5 mmol) was added to a mixture of
2,6-Di-tert-butyl-4-[(4-chlorophenyl)(4-methoxyphenyl)
B(C6F5)3 (13 mg, 0.025 mmol) and Hantzsch ester (253 mg, 1.0
methyl]phenol (9d): Yellow oil; yield 99% (46 mg); Rf = 0.5 (1%
mmol) in 5 mL of CH2Cl2, and the resultant mixture was stirred
EtOAc in hexane); FT-IR (ATR): 3635, 3002, 2958, 1249 cm−1; 1H
at room temperature (27–30 °C) until 5x was completely
NMR (400 MHz, CDCl3) δ = 7.25 (d, J = 8.6 Hz, 2H), 7.06 (d, J =
consumed (by T.L.C). The solvent was removed under reduced
8.4 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H), 6.89 (s, 2H), 6.84 (d, J = 8.7
pressure and the crude reaction mixture was directly loaded
Hz, 2H), 5.38 (s, 1H), 5.12 (s, 1H), 3.80 (s, 3H), 1.38 (s. 18H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 158.0, 152.3, 143.9, 136.6,
on silica gel column and purified using hexane/EtOAc mixture
as an eluent to get the pure product 7x. White solid; yield 90%
135.7, 134.1, 131.8, 130.8, 130.3, 128.3, 126.0, 113.7, 55.5,
(149 mg); mp 108-110 °C; Rf = 0.6 (3% EtOAc in hexane); FT-IR
55.3, 34.5, 30.4 ppm. HRMS (ESI): m/z calcd for C28H33ClO2 [M-
(ATR): 3634, 2961, 1434, 1237 cm−1; 1H NMR (400 MHz, CDCl3)
H]: 435.2091; found: 435.2093.
δ = 7.27 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.98 (s, 2H),
5.11 (s, 1H), 3.89 (s, 2H), 1.44 (s, 18H) ppm. 13C NMR (100
2,6-Di-tert-butyl-4-[(4-tert-butyl-
phenyl)(phenyl)methyl]phenol (9e): Yellow solid; yield 99% (43 MHz, CDCl3) δ = 152.3, 140.4, 136.1, 131.7, 131.2, 130.3, 128.6,
mg); mp 158–160 °C; Rf = 0.5 (1% EtOAc in hexane); FT-IR
1
125.5, 41.3, 34.4, 30.4 ppm. HRMS (ESI): m/z calcd for
C21H28ClO [M+H]: 331.1828; found: 331.1835.
(ATR): 3641, 2956, 2904 cm−1; H NMR (400 MHz, CDCl3) δ =
7.30 – 7.25 (m, 4H), 7.20 – 7.16 (m, 1H), 7.14 – 7.12 (m, 2H),
7.04 (d, J = 8.2 Hz, 2H), 6.92 (s, 2H), 5.40 (s, 1H), 5.07 (s, 1H),
1.36 (s, 18H), 1.30 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3) δ =
152.1, 148.8, 145.3, 141.8, 135.5, 134.4, 129.5, 129.0, 128.2,
126.2, 126.0, 125.1, 56.6, 34.5, 34.47, 31.5, 30.5 ppm. HRMS
(ESI): m/z calcd for C31H40O [M-H]: 427.3001; found: 427.3013.
4-(4-Chlorobenzyl)phenol (12):18b AlCl3 (200 mg, 1.5 mmol) was
added to a solution of 7x (100 mg, 0.3 mmol) in 5 mL of
benzene, and the resultant mixture was stirred at room
temperature (27–30 °C) until 7x was completely consumed (by
T.L.C). The reaction mixture was quenched with water and
extracted with ethyl acetate (3 x 15 mL). The combined organic
layers were evaporated using rotary evaporator. The crude
reaction mixture was loaded on silica gel column and purified
using hexane/EtOAc mixture as an eluent to get the pure
product 12. White solid; yield 95% (63 mg); Rf = 0.3 (10%
EtOAc in hexane); mp 91-93 °C; FT-IR (ATR): 3541, 1613, 1513,
4-Benzhydryl-2,6-dimethylphenol (9f): Light yellow solid; yield
99% (29 mg); mp 136–138 °C; Rf = 0.2 (5% EtOAc in hexane);
1
FT-IR (ATR): 3573, 3025, 2958 cm−1; H NMR (400 MHz, CDCl3)
δ = 7.30 – 7.26 (m, 4H), 7.22 – 7.18 (m, 2H), 7.12 – 7.10 (m,
4H), 6.72 (s, 2H), 5.42 (s, 1H), 4.50 (s, 1H), 2.18 (s, 6H) ppm. 13
C
1
1233 cm−1; H NMR (400 MHz, CDCl3) δ = 7.27 (d, J = 7.8 Hz,
NMR (100 MHz, CDCl3) δ = 150.7, 144.5, 135.6, 129.7, 129.5,
This journal is © The Royal Society of Chemistry 20xx
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2H), 7.12 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.79 (d, J = We gratefully acknowledge the IISER Mohali for the financial
8.0 Hz, 2H), 5.57 (s, 1H), 3.89 (s, 2H) ppm. 13C NMR (100 MHz, support and also for providing infrastructure. S.M. thanks the
CDCl3) δ = 153.9, 140.1, 133.0, 131.8, 130.2, 130.1, 128.6, UGC, New Delhi for a research fellowship. The NMR and HRMS
115.5, 40.4 ppm. HRMS (ESI): m/z calcd for C13H10ClO [M-H]: facilities at IISER Mohali are gratefully acknowledged.
217.0420; found: 217.0410.
Notes and references
Ethyl 2-[4-(4-chlorobenzyl)phenoxy]propanoate (14): Ethyl 2-
bromopropanoate 13 (16 μL, 0.12 mmol) was added to a
mixture of K2CO3 (41 mg, 0.3 mmol) and 4-(4-
Chlorobenzyl)phenol 12 (22 mg, 0.1 mmol) in 1.0 mL of DMF at
room temperature (27–30 °C), and the resultant mixture was
stirred at 80 oC until 4-(4-Chlorobenzyl)phenol 12 was
completely consumed (by T.L.C). The reaction mixture was
quenched with water and extracted with diethylether (2 x 5
mL) and the combined organic layers were washed with brine
(3 x 5 mL). Solvent was evaporated under reduced pressure.
The crude reaction mixture was loaded on silica gel column
and purified using hexane/EtOAc mixture as an eluent to get
the pure product 14. Yellow oil; yield 82% (26 mg); Rf = 0.5
(10% EtOAc in hexane); FT-IR (ATR): 2987, 1754, 1510, 1241
1
2
3
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7.08 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4
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2H), 1.60 (d, J = 6.8 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H) ppm. 13C
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130.3, 130.0, 128.6, 115.3, 72.8, 61.4, 40.4, 18.7, 14.3 ppm.
HRMS (ESI): m/z calcd for C18H19ClO3Na [M+Na]: 341.0923;
found: 341.0908.
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Synthesis of Beclobrate (
was added to
2
):18b LiHMDS (150 μL, 0.15 mmol)
solution of Ethyl 2-[4-(4-
a
chlorobenzyl)phenoxy]propanoate 14 (32 mg, 0.1 mmol) in 1.5
mL of dry THF under N2, and the resultant mixture was stirred
at room temperature (27–30 °C) for 5 minutes. Ethyl iodide (10
μL, 0.12 mmol) was added to the reaction mixture and the
stirring was continued until 14 was completely consumed (by
T.L.C). The reaction mixture was quenched with water and
extracted with ethyl acetate (3 x 5 mL). Combined organic
layers were evaporated using rotary evaporator. The crude
reaction mixture was loaded on silica gel column and purified
using hexane/EtOAc mixture as an eluent to get the pure
4
For selected recent examples: (a) A. Lopez, A. Parra, C. Jarava
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product 2. Yellow oil; yield 70% (24 mg); Rf = 0.5 (10% EtOAc in
5
For selected recent examples: (a) B. T. Ramanjaneyulu, S.
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1
hexane); FT-IR (ATR): 2980, 1732, 1508, 1233 cm−1; H NMR
(400 MHz, CDCl3) δ = 7.24 (d, J = 7.7 Hz, 2H), 7.09 (d, J = 7.9 Hz,
2H), 7.01 (d, J = 8.1 Hz, 2H), 6.78 (d, J = 8.0 Hz, 2H), 4.24 (q, J =
7.1 Hz, 2H), 3.87 (s, 2H), 2.07 – 1.89 (m, 2H), 1.48 (s, 3H), 1.25
(t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (100
MHz, CDCl3) δ = 174.2, 154.0, 139.9, 134.2, 131.9, 130.3, 129.6,
128.6, 119.4, 82.0, 61.4, 40.5, 32.7, 20.9, 14.3, 8.0 ppm. HRMS
(ESI): m/z calcd for C20H23ClO3Na [M+Na]: 369.1236; found:
369.1253.
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8 | J. Name., 2012, 00, 1-3
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ARTICLE
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02007D
B(C6F5)3 Catalysed reduction of para-Quinone Methides and Fuchsones to
Access Unsymmetrical Diaryl- and Triarylmethanes: Elaboration to Beclobrate
Sriram Mahesh and Ramasamy Vijaya Anand*
H
EtO2C
CO2Et
N
R1
R1
H
H
R2
O
R2
(2 equiv.)
X
X
Cl
O
CO2Et
B(C6F5)3 (5 mol%)
OH
CH2Cl2 (1.5 mL), RT
R2
R2
R1 = H, aryl
X = alkyl, aryl, alkoxy, halo, etc.
R2 = tBu, iPr, Me
R1 = H; 24 examples;
45-98% yields
R1 = Ar; 8 examples;
88-99% yields
Beclobrate; 4 steps,
49% overall yield
An effective method for the synthesis of diaryl- and triarylmethane derivatives through a Lewis acid
catalyzed reduction of para-quinone methides and fuchsones, respectively, using Hantzsch ester as a
hydride surrogate is described. This protocol was also elaborated to the synthesis of beclobrate.