Disproportionation reaction of diarylmethylisopropyl ethers: a versatile access to diarylmethanes from diarylcarbinols speeded up by the use of microwave irradiation

Article abstract of DOI:10.1016/j.tet.2006.09.083

An efficient synthesis of diarylmethanes under classical thermal conditions and under microwave heating is described from diarylcarbinols via a new disproportionation reaction. The key step involves a selective hydride transfer of isopropyl ether intermed

Full text of DOI:10.1016/j.tet.2006.09.083

Tetrahedron 62 (2006) 11994–12002
Disproportionation reaction of diarylmethylisopropyl ethers:
a versatile access to diarylmethanes from diarylcarbinols
speeded up by the use of microwave irradiation
*
Nathalie L’Hermite, Anne Giraud, Olivier Provot, Jean-Franc¸ois Peyrat,
*
Mouad Alami and Jean-Daniel Brion
^
´
´
´
Laboratoire de Chimie Therapeutique, BioCIS-CNRS (UMR 8076), Universite Paris-Sud, Faculte de Pharmacie,
´
rue J.B. Clement, 92296 Cha^tenay-Malabry Cedex, France
Received 18 July 2006; revised 18 September 2006; accepted 21 September 2006
Available online 25 October 2006
Abstract—An efficient synthesis of diarylmethanes under classical thermal conditions and under microwave heating is described from diaryl-
carbinols via a new disproportionation reaction. The key step involves a selective hydride transfer of isopropyl ether intermediates. Mild
reaction conditions i.e., catalytic CBr4 or TfOH in i-PrOH and good yields render this method useful and competitive to the conventional
approaches relying on application of external reducing agents.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Ar4
Ar1
Ar2
Ar1
Ar4
Me
Ar1
Me
During our research on the synthesis of low generation
poly(arylpropargylether) dendrimers,1 we hoped to cleave a
methoxyethoxymethyl- (MEM-) protected phenol under
mild conditions as previously described by Lee.2 However,
when ether 1 was reacted with a catalytic amount of CBr4
in i-PrOH at 80 ꢀC, the expected triarylether 2 was not de-
tected. Instead, the only products isolated were the propar-
gylic alcohol 3 (92%) and the diarylmethane 5a (70%). On
the contrary, performing the reaction at a lower temperature
(55 ꢀC; 24 h) resulted in the formation of 3 and unsymmet-
rical ether 4a (90%).
CBr4
O
O
i-PrOH
Ar1
Ar4
O
80°C
Ar3
2
5a
Ar3
1
4a
Me
Me
HO
Ar3
O
3
Ar1= 4-MeOC6H4; Ar2= 4-MEMOC6H4; Ar3= 4-EtO2CC6H4; Ar4= 4-HOC6H4
Scheme 1. Plausible mechanism for the formation of 5a from 1.
The simplicity of this transformation and the interest of di-
arylmethane derivatives in organic chemistry led us to inves-
tigate this reaction.
To explain the formation of 5a from 1, we believe that the
deprotection of the MEM group occurred and subsequently,
the intermediate 2, unstable under these acidic conditions,
cleaved to give the propargylic alcohol 3 together with 5a
having a free phenolic group. The formation of the latter
compound would probably result from a selective dispropor-
tionation reaction of the unsymmetrical ether 4a via a
concerted selective hydride transfer as in the Meerwein–
Ponndorf–Verley-reduction3 (Scheme 1). The high selectiv-
ity of this dismutation requiring catalytic acidic conditions,4
could be explained by a preferable hydride transfer to the
more electrophilic bis-benzylic carbon centre.
Diarylmethane derivatives are of considerable interest as
biological and medicinal substrates,5 models for analogous
thermally robust linkages present in fuel resources such as
coal6 and components in acid- or alkali-treated lignins.7
Besides this, some diarylmethanes are frequently used as
subunits in the design of supramolecular structures.8 A num-
ber of methods have been proposed for their synthesis in-
cluding transition metal-catalyzed cross coupling between
aryl or benzyl nucleophiles with benzyl or aryl halides,
respectively.9,10 Alternative routes consist in the reduction
of diaryl ketones11 or benzhydrols12 using, in most cases,
a hydride donor agent (e.g., Et3SiH, NaBH4, H2, PMHS,
LiAlH4,.) in the presence of TFA or a Lewis acid
(BF3$Et2O, AlCl3, InCl3.).
Keywords: Disproportionation; Diarylcarbinols; Diarylmethanes; i-PrOH;
CBr4; TfOH; Microwave heating.
* Corresponding authors. Tel.: +33 1 4683 5847; fax: +33 1 4683 5828;
e-mail addresses: olivier.provot@cep.u-psud.fr; mouad.alami@cep.
u-psud.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.083

N. L’Hermite et al. / Tetrahedron 62 (2006) 11994–12002
11995
Some examples of disproportionation reactions giving ac-
cess to diarylmethane derivatives13 were mentioned in the
literature. Most of the described methods are sometimes
harsh, need strong acidic activations and are often associated
with low yields. In this letter, we report a simple and conve-
nient procedure for the synthesis of a range of substituted
diarylmethane derivatives from diarylcarbinols mediated
by CBr4 or TfOH (triflic acid) in i-PrOH.
6a was totally transformed into 5a in only 15 min with a
good yield (78%, entry 9). Under these conditions (micro-
wave heating at 140 ꢀC), 6a was reacted with the other
previously tested catalysts (TFA, HCOOH, Amberlyst 15)
and the disappearance of the ether 4a occurred in favour of
the diarylmethane 5a (compare entries 3 and 11, 5 and 13,
6 and 14). Moreover, when using CBr4, PTSA, TfOH under
microwave irradiation, the yields obtained at 140 ꢀC were
similar to or better than those observed under classical
thermal conditions (compare entries 1 and 9, 2 and 10, 4
and 12). Finally, the amount of the catalyst was then studied.
With 5 mol % of either CBr4 or PTSA, the transformation
was efficient and no starting material or intermediate ether
4a was detected (entries 15, 16). As a control experiment,
6a was heated in i-PrOH with CBr4 (5 mol %) in a sealed
tube at 140 ꢀC for 15 min. Comparison of the results ob-
tained using convectional or microwave heating indicated
clearly the efficiency of the latter method (70%, entry 15
vs 40%, entry 17).
2. Results and discussion
At the outset of this work, we evaluated the effect of a variety
of catalysts on the disproportionation of carbinol 6a chosen
as a model substrate. Table 1 summarizes the results of our
investigations.
After screening a series of catalysts, we were delighted to
find that the use of catalytic amount of CBr4, PTSA (p-tolue-
nesulfonic acid), TfOH and aqueous HBr (entries 1, 2, 4 and
7), in contrast to TFA (trifluoroacetic acid), HCO2H and
Amberlyst 15 (entries 3, 5 and 6) allowed complete conver-
sion of intermediate 4a into 5a. The best yield (83%, entry 1)
was obtained with CBr4 (20 mol %) in boiling i-PrOH
for 24 h.
Having optimized the reaction parameters, we then exam-
ined the reaction with a wide variety of benzhydrols 6,
prepared from Grignard reagents and aromatic aldehydes
(Table 2). All benzhydrols subjected to the CBr4/i-PrOH sys-
tem produced the corresponding diarylmethane derivatives
but with variable amounts of their corresponding ether inter-
mediate 4 except in the case of 5b (entry 1). Thus, when
using CBr4 (20 mol %) in i-PrOH for 15 min under micro-
wave irradiation at 140 ꢀC, 5c and 5d were obtained together
with their isopropylether precursors (entries 2 and 4). On the
contrary, replacing CBr4 by TfOH resulted in a complete
disproportionation reaction with higher yields and easier pu-
rifications (entries 3 and 5). In this way, reduced phenstatin15
Next, in the continuation of our work to develop rapid and ef-
ficient methodologies, we choose to promote and accelerate
the synthesis of 5a using microwave-assisted irradiation.14
Because heating was not foreseen to cause any serious
decomposition problems, we gradually increased the temper-
ature. We were pleased to observe that, in the presence of
CBr4 (20 mol %) and using microwave irradiation at 140 ꢀC,
Table 1. Reduction of 6a in i-PrOH
OH
O
Reactant
20 mol %
i-PrOH
T °C
HO
OMe
HO
OMe
HO
OMe
6a
4a
5a
Entry
Reactant
Temperature (ꢀC)
Conditionsa
Time (h)
4a/5ab
5 Yieldc (%)
1
2
3
4
5
6
7
8
CBr4
PTSA
TFA
TfOH
HCO2H
Amberlyst 15
Aqueous HBr
CBr4
CBr4
PTSA
80
80
80
80
80
80
80
100
140
140
140
140
140
140
140
140
140
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
C
24
24
24
24
24
24
24
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0/100
0/100
100/0d
0/100
100/0d
30/70
0/100
0/100e
0/100
0/100
22/78
0/100
50/50
0/100
0/100
0/100
0/100
83
74
—
70
—
—
57
40
78
80
—
81
—
60
70
65
40
9
10
11
12
13
14
15
16
17
TFA
TfOH
HCO2H
Amberlyst 15
CBr4
f
PTSA
CBr4
f
a
Method: A: thermal conditions; B: microwave irradiation; C: sealed tube.
Ratio determined by 1H NMR analysis (CDCl3) of the crude reaction mixtures.
Yield of isolated product after column chromatography.
b
c
d
e
f
Isolated yield of 4a: 82% (TFA); 76% (HCO2H).
The 1H NMR spectrum of the crude mixture revealed the presence of an unidentified by-product.
The reaction was carried out using 5 mol % of CBr4.

11996
N. L’Hermite et al. / Tetrahedron 62 (2006) 11994–12002
Table 2. Synthesis of diarylmethanes 5 from diarylcarbinols 6 under microwave irradiation
Entry
1
Alcohols 6
Diarylmethanes 5
Reactant (20 mol %)
CBr4
Yielda (%)
70
OH
6b
5b
5c
MeO
OMe
Me
2
3
CBr4
TfOH
61b
85
6c
MeO
MeO
4
5
CBr4
TfOH
62b
70
6d
5d
5e
5f
Me
O
OMe
OMe
MeO
Me
6
7
6e
6f
TfOH
TfOH
72
80
O
Me
OMe
OMe
MeO
Me
O
OMe
OH
OMe
OH
OMe
8
9
6g
6h
5g
5h
TfOH
TfOH
64
78
Me
10
11
6i
6j
5i
5j
TfOH
TfOH
87
64
NMe2
MeO
MeO
NMe2
NMe2
12
6k
5k
TfOH
86
MeO
OMe
O
O
13
14
15
6l
5l
TfOH
TfOH
TfOH
75c
86
6m
6n
5m
5n
S
MeO
Br
80d
OMe
16
6o
6p
5o
5p
TfOH
TfOH
51e
67
O
Me
Me
MeO
OMe
17
O
a
Yield of isolated product after column chromatography.
Unsymmetrical diarylmethylisopropyl ether (15–20%) was also isolated.
Reaction time: 1 h.
Obtained as a 1/1 mixture of double bond transposed isomers.
Obtained as a 1/4 mixture of double bond transposed isomers.
b
c
d
e

N. L’Hermite et al. / Tetrahedron 62 (2006) 11994–12002
11997
analogues 5e and 5f were prepared with 72% and 80% iso-
4. Experimental
lated yields, respectively (entries 6 and 7). As shown with
the model benzhydrol 6a (Table 1), phenolic benzhydrols
as well as amino derivatives afforded the expected diaryl-
methanes 5g–5k with good yields (entries 8–12). We have
also noticed that the disproportionation was efficient with
methylenedioxyaryl analogue, but required a prolonged
reaction time (1 h, entry 13). Because various functional
groups survived under the reaction conditions, we have ap-
plied this process to the brominated thiophene 6m and we
were pleased to observe its total transformation affording
the reduced compound 5m with an excellent yield (86%,
entry 14). The protocol was also applied to alcohols 6n,
6o. The expected diarylmethane derivatives 5n, 5o were
then obtained with fair to good yields accompanied by iso-
mers resulting in the double bond migration (entries 15
and 16). Disproportionation was also successful (67% entry
17) with compound 6p containing two benzydrol units. In
that case, we were delighted to find that this process took
place with only 10% of TfOH per hydroxyl and preserved
the allylic ether function (entry 17).
4.1. Materials
All glasswares were oven-dried at 140 ꢀC. THF was distilled
from sodium-benzophenone ketyl.
4.2. Instrumentation
All microwave experiments were performed using an Emrys
Optimizer in 2–5 mL Pyrex reaction vessels. Each contained
a Teflon stir bar and Teflon coated reaction vessel cap.
The compounds were all identified by usual physical
methods, i.e., 1H NMR, 13C NMR, IR and elemental analy-
sis. 1H and 13C NMR spectra were measured in CDCl3 with
a Bruker Avance 300. 1H chemical shifts are reported in parts
per million from the peak of residual chloroform (7.27 ppm).
13C chemical shifts are reported in parts per million from the
central peak of deuteriochloroform (77.14 ppm). IR spectra
were measured on a Bruker Vector 22 spectrophotometer
(neat, cmꢁ1). Elemental analyses were performed with a
Perkin–Elmer 240 analyser. Analytical TLC was performed
on Merck precoated silica gel 60F plates. Merck silica gel
60 (230–400 mesh) was used for column chromatography.
Finally, we have tested this microwave protocol (catalytic
TfOH in i-PrOH) with the hydroxyketone 6q. After stirring
for 2 h at 170 ꢀC16 using microwave heating, we were
pleased to observe that the disproportionation process oc-
curred (60%). Careful examination of the crude mixture by
1H NMR did not reveal the presence of reduced by-products
(alcohols or diarylmethanes), demonstrating in this manner
the selectivity of the present reductive method (Scheme 2).
€
Melting points (mp) were recorded on a Buchi B-450 appa-
ratus and were uncorrected.
4.3. Typical procedure for the preparation of
diarylcarbinols 6
At ꢁ40 ꢀC, a 1 M solution of Grignard reagent (1.5 mL;
1.5 mmol) was added dropwise to a solution of aldehyde
(1 mmol) in THF (10 mL). The mixture was then stirred
for 12 h at rt and then hydrolyzed with H2O (10 mL). The or-
ganic phase was separated and the water phase was extracted
with ether (2ꢂ10 mL). The combined extracts were dried
(Na2SO4) and the solvent was evaporated under reduced
pressure to give alcohols 6, which were further purified by
flash chromatography on silica gel.
O
HO
O
TfOH 20%, i-PrOH
Microwaves, 170 °C
Me
Me
Me
Me
5q 60%
6q
Scheme 2. Reduction of 6q preserving the ketone function.
To confirm the selectivity of this process, we have carried out
the following experiment. When the model 6a and benzo-
phenone (as external carbonyl compound) were reacted to-
gether for 30 min at 140 ꢀC using microwave heating, we
were pleased to observe that the disproportionation of 6a
occurred without affecting the benzophenone, which was re-
covered totally unchanged (95%). However, we have noticed
that under these conditions (TfOH 20%, i-PrOH, micro-
waves, 140 ꢀC) several benzaldehydes were partially re-
duced under these conditions even in the absence of 6a.
Alcohols 6a, 6c, 6d, 6g, 6i, 6j, 6k, 6l and 6n are known and
gave satisfactory data. All new compounds were character-
ized by 1H, 13C NMR, IR and elemental analysis.
4.3.1. (4-Methoxyphenyl)-(3-hydroxy-4-methoxy-
phenyl)-methanol 6b. Yield: 78%.
Mp: 96 ꢀC.
TLC: Rf 0.34 (cyclohexane/AcOEt 60/40, SiO2).
3. Conclusion
Anal. Calcd for 6b (C15H16O4): C, 69.22; H, 6.20. Found: C,
69.10; H, 6.33.
We have described herein a fast and efficient synthesis of
functionalized diarylmethane derivatives under classical
thermal conditions and in a faster way under microwave
irradiation.17 This process is chemoselective since several
functional groups are tolerated (hydroxy, allyl, ketone) in
contrary to some of the previously reported methods.11,12
The key step involves a highly selective disproportionation
reaction of diarylmethylisopropyl ether intermediates ob-
tained from the corresponding carbinols. Further develop-
ments will be disclosed in due course.
IR (neat) nmax/cmꢁ1: 3447, 3204, 1610, 1510, 1247, 1127,
1025.
1H NMR (300 MHz, CDCl3) d: 2.10 (d, 1H, J¼3.3 Hz), 3.78
(s, 3H), 3.86 (s, 3H), 5.59 (s, 1H), 5.71 (d, 1H, J¼3.3 Hz),
6.78–6.92 (m, 5H), 7.27 (d, 2H, J¼8.4 Hz).
13C NMR (75 MHz, CDCl3) d: 55.3 (OCH3), 55.9 (OCH3),
75.4 (CH), 110.4 (CH), 112.9 (CH), 113.8 (2CH), 118.0

11998
N. L’Hermite et al. / Tetrahedron 62 (2006) 11994–12002
(CH), 127.7 (2CH), 136.2 (C), 137.6 (C), 145.5 (C), 145.6
(C), 159.0 (C).
13C NMR (75 MHz, CDCl3) d: 21.1 (CH3), 55.9 (OCH3),
79.2 (CH), 110.4 (CH), 113.6 (CH), 118.9 (CH), 126.3
(2CH), 129.1 (2CH), 136.0 (C), 136.8 (C), 139.5 (C),
145.4 (C), 145.8 (C).
4.3.2. (3,4,5-Trimethoxyphenyl)-(4-tolyl)methanol 6e.
Yield: 76%.
4.3.5. (5-Bromothiophen-2-yl)-(4-methoxyphenyl)-
methanol 6m. Yield: 61%.
Mp: 95 ꢀC.
TLC: Rf 0.63 (cyclohexane/AcOEt 80/20, SiO2).
TLC: Rf 0.62 (cyclohexane/AcOEt 80/20, SiO2).
Anal. Calcd for 6e (C17H20O4): C, 70.81; H, 6.99. Found: C,
70.89; H, 7.13.
Anal. Calcd for 6h (C12H11BrO2S): C, 48.17; H, 3.71.
Found: C, 48.37; H, 3.68.
IR (neat) nmax/cmꢁ1: 3349, 1590, 1509, 1459, 1422, 1326,
1266, 1128, 1059, 1039, 1004.
IR (neat) nmax/cmꢁ1: 1610, 1509, 1439, 1244, 1172, 1029,
966.
1H NMR (300 MHz, CDCl3) d: 2.15 (d, 1H, J¼3.3 Hz), 2.34
(s, 3H), 3.82 (s, 3H), 3.83 (s, 6H), 5.75 (d, 1H, J¼3.3 Hz),
6.61 (s, 2H), 7.16 (d, 2H, J¼7.8 Hz), 7.27 (d, 2H, J¼7.8 Hz).
1H NMR (300 MHz, CDCl3) d: 2.91 (s, 1H), 3.80 (s, 3H),
5.83 (s, 1H), 6.57 (d, 1H, J¼3.8 Hz), 6.86 (m, 3H), 7.30
(d, 2H, J¼8.4 Hz).
13C NMR (75 MHz, CDCl3) d: 21.1 (CH3), 56.0 (2OCH3),
60.7 (OCH3), 76.0 (CH), 103.4 (2CH), 126.4 (2CH), 129.1
(2CH), 137.1 (C), 137.3 (C), 139.6 (C), 140.7 (C), 153.1
(2C).
13C NMR (75 MHz, CDCl3) d: 55.3 (OCH3), 72.1 (CH),
112.1 (C), 114.0 (2CH), 124.9 (CH), 127.7 (2CH), 129.4
(CH), 134.8 (C), 150.1 (C), 159.5 (C).
We have noticed that after few days 6m was not stable in
CDCl3.
4.3.3. (3,4,5-Trimethoxyphenyl)-(4-methoxyphenyl)-
methanol 6f. Yield: 83%.
4.3.6. (2-Methyl-2H-chromenyl)-(4-tolyl)methanol 6o.
Yield: 80% (mixture of diastereoisomers).
TLC: Rf 0.44 (cyclohexane/AcOEt 60/40, SiO2).
Anal. Calcd for 6f (C17H20O5): C, 67.09; H, 6.62. Found: C,
66.65; H, 6.86.
TLC: Rf 0.61 (cyclohexane/AcOEt 70/30, SiO2).
Anal. Calcd for 6o (C18H18O2): C, 81.17; H, 6.81. Found:
C, 80.87; H, 6.95.
IR (neat) nmax/cmꢁ1: 3500, 1601, 1510, 1493, 1462, 1243,
1172, 1092, 1009.
IR (neat) nmax/cmꢁ1: 3404, 1605, 1513, 1485, 1364, 1235,
1206, 1142, 1105, 1040, 1022.
1H NMR (300 MHz, CDCl3) d: 2.86 (d, 1H, J¼5.7 Hz), 3.68
(s, 3H), 3.81 (s, 3H), 3.87 (s, 6H), 5.91 (d, 1H, J¼5.7 Hz),
6.66 (d, 1H, J¼8.7 Hz), 6.88 (d, 2H, J¼8.7 Hz), 7.00 (d,
1H, J¼8.7 Hz), 7.29 (d, 2H, J¼8.7 Hz).
13C NMR (75 MHz, CDCl3) d: 55.2 (OCH3), 55.9 (OCH3),
60.6 (2OCH3), 71.9 (CH), 106.9 (CH), 114.4 (2CH), 122.0
(CH), 128.6 (2CH), 130.1 (C), 136.2 (C), 142.1 (C), 151.2
(C), 153.3 (C), 158.7 (C).
1H NMR (300 MHz, CDCl3) d: 1.26 (d, 1.5H, J¼6.6 Hz),
1.27 (d, 1.5H, J¼6.6 Hz), 2.02–2.10 (br s, 1H), 2.36 (s,
3H), 4.69 (q, 0.5H, J¼6.6 Hz), 4.94 (q, 0.5H, J¼6.6 Hz),
5.25 (s, 0.5H), 5.32 (s, 0.5H), 6.32 (s, 0.5H), 6.58 (s,
0.5H), 6.70–7.30 (m, 8H).
13C NMR (75 MHz, CDCl3) d: (the presence of diastereo-
isomers complicates the spectrum; only the most significant
resonances are listed) 19.5 (CH3), 20.0 (CH3), 21.2 (2CH3),
71.7 (2CH), 74.0 (CH), 75.0 (CH), 116.3 (CH), 116.4 (CH),
118.1 (CH), 120.0 (CH), 121.2 (CH), 121.3 (CH), 122.2
(2C), 126.6 (2CH), 126.8 (2CH), 129.1 (2CH), 129.3
(2CH), 129.5 (2CH), 130.0 (2CH), 137.7 (C), 138.2 (2C),
138.4 (C), 140.1 (C), 140.2 (C), 153.6 (2C).
4.3.4. (3-Hydroxy-4-methoxyphenyl)-(4-tolyl)methanol
6h. Yield: 73%.
Mp: 101–102 ꢀC.
TLC: Rf 0.55 (cyclohexane/AcOEt 80/20, SiO2).
Anal. Calcd for 6h (C15H16O3): C, 73.75; H, 6.60. Found: C,
73.61; H, 6.78.
4.3.7. Compound 6p. Compound 6p was prepared from
5-allyloxy-isophthalic acid dimethyl ester in three steps as
follows.
IR (neat) nmax/cmꢁ1: 3412, 3229, 1509, 1445, 1277, 1125,
1038, 947.
4.3.7.1. 3,5-Bis(hydroxymethyl)-(1-allyloxy)-phenyl.
Under argon, were mixed LiAlH4 in 110 mL of THF
(8.7 g; 230.4 mmol) and 5-allyloxy-isophthalic acid di-
methyl ester (14.4 g; 57.6 mmol) in 80 mL of THF. The
stirred solution was then refluxed for 3 h. After cooling at
0 ꢀC, the solution was hydrolyzed dropwise with H2O
1H NMR (300 MHz, CDCl3) d: 2.07 (d, 1H, J¼3.3 Hz), 2.32
(s, 3H), 3.87 (s, 3H), 5.57 (s, 1H), 5.73 (d, 1H, J¼3.3 Hz),
6.79–6.94 (m, 3H), 7.13 (d, 2H, J¼7.8 Hz), 7.26 (d, 2H,
J¼7.8 Hz).

N. L’Hermite et al. / Tetrahedron 62 (2006) 11994–12002
11999
(100 mL), filtered and concentrated under vacuo to give
10.7 g (55.1 mmol) of the diol.
13C NMR (75 MHz, CDCl3) d: 56.5 (2OCH3), 70.2 (CH2),
76.8 (2CH), 112.9 (2CH), 115.2 (4CH), 118.3 (CH), 118.9
(CH), 129.6 (4CH), 135.8 (CH), 139.5 (2C), 149.1 (2C),
160.5 (2C), 160.7 (C).
Yield: 96%.
TLC: Rf 0.52 (CH2Cl2/MeOH 90/10, SiO2).
Mp: 54–55 ꢀC.
4.3.8. {4-[(4-Tolyl)-hydroxymethyl]-phenyl}-(4-tolyl)-
methanone 6q. Compound 6q was obtained as a by-product
(22%) of the reaction between p-tolyl magnesium bromide
(1 equiv) and terephthaldicarboxaldehyde (2 equiv) as fol-
lows: to a solution of terephthaldicarboxaldehyde (2.68 g,
22 mmol) in 40 mL of THF was added dropwise at ꢁ40 ꢀC
under argon, 11 mL (11 mmol) of a 1 M solution of p-tolyl
magnesium bromide. After stirring for a night at rt, the
mixture was treated with H2O (30 mL) and extracted with
CH2Cl2 (3ꢂ25 mL). The combined organic layers were then
dried with MgSO4 and evaporated to dryness. Purification by
flash chromatography afforded 6q as a white solid.
IR (neat) nmax/cmꢁ1: 3335, 3251, 3015, 2930, 2876, 1594.
1H NMR (300 MHz, MeOD) d: 4.54 (dt, 2H, J¼5.1 Hz,
J¼1.6 Hz), 4.56 (s, 4H), 5.23 (dq, 1H, J¼10.5 Hz;
J¼1.6 Hz), 5.39 (dq, 1H, J¼17.2 Hz, J¼1.6 Hz), 6.02 (m,
1H), 6.84 (s, 2H), 6.91 (s, 1H), (OH not seen).
13C NMR (75 MHz, MeOD) d: 65.1 (CH2), 69.7 (2CH2),
113.0 (CH), 117.4 (CH2), 118.7 (2CH), 135.0 (CH), 144.4
(2C), 160.4 (C).
Yield: 22% (not optimized).
Mp: 108 ꢀC.
4.3.7.2. 5-Allyloxyisophthalaldehyde. A solution of
the diol (350 mg; 1.80 mmol) in CH2Cl2 (11 mL) was mixed
with PCC (1.24 g; 5.7 mmol) and stirred for 2 h at rt. The
mixture was then diluted in Et2O (15 mL) and filtered over
SiO2. The filtrate was concentrated under vacuo to give
5-allyloxyisophthalaldehyde (280 mg, 1.47 mmol)as awhite
solid.
TLC: Rf 0.63 (cyclohexane/AcOEt 80/20, SiO2).
Anal. Calcd for 6q (C22H20O2): C, 83.51; H, 6.37. Found:
C, 83.29; H, 6.22.
IR (neat) nmax/cmꢁ1: 3483, 2918, 1637, 1604, 1569, 1413,
1316, 1279, 1177, 1043, 1017.
Yield: 85%.
1H NMR (300 MHz, CDCl3) d: 1.75 (s, 3H), 1.84 (s, 3H),
2.40 (s, 1H, OH), 5.25 (s, 1H), 6.56 (d, 2H, J¼7.8 Hz),
6.67 (d, 4H, J¼7.8 Hz), 6.88 (d, 2H, J¼8.4 Hz), 7.10 (d,
2H, J¼7.8 Hz), 7.13 (d, 2H, J¼8.4 Hz).
TLC: Rf 0.33 (cyclohexane/AcOEt 80/20, SiO2).
Mp: (cyclohexane) 67–68 ꢀC.
IR (neat) nmax/cmꢁ1: 3000, 2832, 1681, 1592.
13C NMR (75 MHz) d: 21.1 (CH3), 21.6 (CH3), 60.4 (CH),
126.6 (2CH), 127.2 (2CH), 128.9 (2CH), 129.8 (2CH),
130.1 (2CH), 130.2 (2CH), 134.8 (C), 136.7 (C), 137.5
(C), 140.5 (C), 143.1 (C), 148.3 (C), 196.2 (C).
1H NMR (300 MHz, CDCl3) d: 4.59 (dt, 2H, J¼5.2 Hz,
J¼1.4 Hz), 5.27 (dq, 1H, J¼10.5 Hz; J¼1.4 Hz), 5.39 (dq,
1H, J¼17.2 Hz, J¼1.4 Hz), 6.00 (m, 1H), 7.59 (s, 2H),
7.89 (s, 1H), 9.98 (s, 2H).
4.4. Typical procedure for the disproportionation of
carbinols under thermal conditions
13C NMR (75 MHz, MeOD) d: 69.3 (CH2), 118.4 (CH),
120.0 (2CH), 124.1 (CH), 132.0 (CH), 138.2 (2C), 157.9
(C), 190.7 (2C).
To a flask containing 6a (1 mmol) was added CBr4 (66 mg,
0.2 mmol) in i-PrOH (8 mL). The mixture was then stirred at
80 ꢀC for 24 h. After cooling to rt, the crude mixture was
hydrolyzed with H2O (5 mL) and extracted with CH2Cl2
(3ꢂ5 mL). The combined organic layers were then dried
with MgSO4 and evaporated to dryness. Purification by flash
chromatography afforded the diarylmethane derivative 5a.
4.3.7.3. 3,5-Bis[(4-methoxyphenyl)hydroxymethyl]-1-
allyloxy-benzene 6p. Yield: 50%.
Mp: 101–103 ꢀC.
TLC: Rf 0.13 (cyclohexane/AcOEt 60/40, SiO2).
Anal. Calcd for 6p (C25H26O5): C, 73.87; H, 6.45. Found:
C, 73.71; H, 6.48.
4.5. Typical procedure for the disproportionation of
carbinols under microwave irradiation
IR (neat) nmax/cmꢁ1: 3347, 1611, 1509, 1441, 1282, 1247,
1168, 1111, 1028.
To an Emrys Optimizer 2–5 mL Pyrex reaction vessel were
added 0.2 mL of a 1 M solution of TfOH in i-PrOH, 1 mmol
of diarylcarbinol and i-PrOH (3 mL). The reaction vessel
was then placed in the Emrys Optimizer and exposed to
microwave irradiation according to the following specifica-
tions: temperature: 140 ꢀC, time 900 s, fixed hold time: on,
sample absorption: high, pre-stirring: 60 s. After cooling to
rt, the crude mixture was treated as above.
1H NMR (300 MHz, CDCl3) d: 3.03 (s, 6H), 3.77 (d,
2H, J¼5.0 Hz), 3.88 (d, 2H, J¼4.0 Hz), 4.47 (d, 1H,
J¼10.4 Hz), 4.64 (d, 1H, J¼17.2 Hz), 4.97 (d, 2H,
J¼4.0 Hz), 5.21–5.40 (m, 1H), 6.10–6.14 (m, 6H), 6.34 (s,
1H), 6.57 (d, 4H, J¼8.4 Hz).

12000
N. L’Hermite et al. / Tetrahedron 62 (2006) 11994–12002
Diarylmethanes 5a, 5c, 5d, 5f, 5g, 5i, 5j, 5l and 5n are known
and gave satisfactory data.
13C NMR (75 MHz, CDCl3) d: 21.0 (CH3), 40.9 (CH2), 56.0
(OCH3), 110.6 (CH), 115.1 (CH), 120.1 (CH), 128.7 (2CH),
129.1 (2CH), 134.8 (C), 135.4 (C), 138.3 (C), 144.9 (C),
145.5 (C).
4.5.1. (4-Methoxyphenyl)-(3-hydroxy-4-methoxy-
phenyl)-methane 5b. Yield: 70%.
4.5.4. (4-Methoxyphenyl)-(4-N,N-dimethylamino-
phenyl)-methane 5k. Yield: 86%.
Mp: 61–62 ꢀC.
TLC: Rf 0.48 (cyclohexane/AcOEt 60/40, SiO2).
Mp: 77 ꢀC.
Anal. Calcd for 5b (C15H16O3): C, 73.75; H, 6.60. Found: C,
73.71; H, 6.67.
TLC: Rf 0.26 (cyclohexane/AcOEt 80/20, SiO2).
Anal. Calcd for 5k (C18H23NO3): C, 71.73; H, 7.69; N, 4.65.
Found: C, 71.55; H, 7.95; N, 4.50.
IR (neat) nmax/cmꢁ1: 3467, 1609, 1586, 1508, 1463, 1444,
1271, 1223, 1202, 1178, 1130, 1020.
IR (neat) nmax/cmꢁ1: 1614, 1588, 1521, 1505, 1461, 1421,
1237, 1123, 1006.
1H NMR (300 MHz, CDCl3) d: 3.78 (s, 3H), 3.83 (s, 2H),
3.85 (s, 3H), 5.56 (s, 1H), 6.66 (dd, 1H, J¼8.2 Hz,
J¼1.8 Hz), 6.76 (d, 1H, J¼1.8 Hz), 6.77 (d, 1H,
J¼8.2 Hz), 6.82 (d, 2H, J¼8.4 Hz), 7.10 (d, 2H, J¼8.4 Hz).
13C NMR (75 MHz, CDCl3) d: 40.4 (CH2) 55.2 (OCH3),
56.0 (OCH3), 110.6 (CH), 113.8 (2CH), 115.1 (CH), 120.0
(CH), 129.7 (2CH), 133.5 (C), 135.0 (C), 144.9 (C), 145.5
(C), 157.9 (C).
1H NMR (300 MHz, CDCl3) d: 2.93 (s, 6H), 3.82 (s, 9H),
3.84 (s, 2H), 6.41 (s, 2H), 6.73 (d, 2H, J¼8.7 Hz), 7.08 (d,
2H, J¼8.7 Hz).
13C NMR (75 MHz, CDCl3) d: 40.8 (2NCH3), 41.2 (CH2),
56.0 (2OCH3), 60.8 (OCH3), 105.7 (2CH), 113.0 (2CH),
129.3 (2CH), 136.1 (C), 137.7 (2C), 149.1 (C), 153.1 (2C).
4.5.2. (4-Tolyl)-(3,4,5-trimethoxyphenyl)methane 5e.
Yield: 80%.
4.5.5. 2-Bromo-5-(4-methoxybenzyl)thiophene 5m. Yield:
86%.
Mp: 53 ꢀC.
TLC: Rf 0.59 (cyclohexane/AcOEt 50/50, SiO2).
TLC: Rf 0.40 (cyclohexane/AcOEt 80/20, SiO2).
Anal. Calcd for 5m (C12H11BrOS): C, 50.90; H, 3.92; S,
11.32. Found: C, 50.20; H, 3.78; S, 11.08.
Anal. Calcd for 5e (C17H20O3): C, 74.97; H, 7.40. Found: C,
74.89; H, 7.29.
IR (neat) nmax/cmꢁ1: 1614, 1588, 1521, 1505, 1461, 1421,
1237, 1123, 1006.
IR (neat) nmax/cmꢁ1: 1588, 1506, 1465, 1421, 1324, 1240,
1120, 1001.
1H NMR (300 MHz, CDCl3) d: 3.78 (s, 3H), 3.99 (s, 2H),
6.52 (d, 1H, J¼4.0 Hz), 6.82–6.85 (m, 3H), 7.13 (d, 2H,
J¼8.4 Hz).
13C NMR (75 MHz, CDCl3) d: 35.6 (CH2), 55.2 (OCH3),
109.9 (C), 114.0 (2CH), 125.1 (CH), 129.5 (CH), 129.6
(CH), 130.9 (CH), 131.6 (C), 146.6 (C), 158.4 (C).
1H NMR (300 MHz, CDCl3) d: 2.34 (s, 3H), 3.82 (s, 6H),
3.84 (s, 3H), 3.90 (s, 2H), 6.42 (s, 2H), 7.12 (s, 4H).
13C NMR (75 MHz, CDCl3) d: 20.9 (CH3), 41.7 (CH2), 56.0
(2OCH3), 60.8 (OCH3), 105.8 (2CH), 128.6 (2CH), 129.1
(2CH), 135.6 (C), 136.2 (C), 136.9 (C), 137.8 (C), 153.1
(2C).
4.5.6. 2-Methyl-3-(4-methylbenzyl)-2H-chromene 5o.
Yield: 51%.
4.5.3. (4-Tolyl)-(3-hydroxy-4-methoxyphenyl)methane
5h. Yield: 64%.
TLC: Rf 0.40 (cyclohexane/AcOEt 80/20, SiO2).
Mp: 80–81 ꢀC.
IR (neat) nmax/cmꢁ1: (mixture of isomers) 2922, 1766, 1657,
1607, 1578, 1514, 1487, 1456, 1370, 1236, 1207, 1108,
1039.
TLC: Rf 0.20 (cyclohexane/AcOEt 70/30, SiO2).
Anal. Calcd for 5h (C15H16O2): C, 78.92; H, 7.06. Found:
C, 78.87; H, 7.05.
1H NMR (300 MHz, CDCl3) (obtained as an inseparable
mixture (4/1) with its minor double bond transposed isomer)
major isomer 5o d: 1.33 (d, 3H, J¼6.6 Hz), 2.35 (s, 3H), 3.36
(d, 1H, J¼15.9 Hz), 3.46 (d, 1H, J¼15.9 Hz), 4.79 (q, 1H,
J¼6.6 Hz), 6.07 (s, 1H), 6.78 (d, 1H, J¼8.1 Hz), 6.84 (t,
1H, J¼16.0 Hz), 6.93 (dd, 1H, J¼6.0 Hz, J¼1.3 Hz),
7.05–7.13 (m, 5H). 2-Methyl-3-(4-methylbenzylidene)chro-
mane (minor isomer): (only the most significant resonances
are listed) d: 1.50 (d, 3H, J¼6.6 Hz), 2.36 (s, 3H), 3.38
IR (neat) nmax/cmꢁ1: 3435, 1587, 1502, 1468, 1446, 1351,
1302, 1238, 1127, 1020.
1H NMR (300 MHz, CDCl3) d: 2.32 (s, 3H), 3.86 (s, 5H),
5.56 (s, 1H, OH), 6.67 (dd, 1H, J¼10.0 Hz, J¼2.1 Hz),
6.76–6.80 (m, 2H), 7.09 (s, 4H).

N. L’Hermite et al. / Tetrahedron 62 (2006) 11994–12002
12001
2. Lee, A. S.-Y.; Hu, Y.-J.; Chu, S.-F. Tetrahedron 2001, 57, 2121.
3. (a) Meerwein, H.; Schmidt, R. Justus Liebigs Ann. Chem. 1925,
444, 221; (b) Ponndorf, W. Angew. Chem. 1926, 39, 138; (c)
Verley, M. P. Bull. Soc. Chim. Fr. 1925, 37, 871.
4. After stirring 4a in boiling i-PrOH for 24 h without any acidic
sources, no reaction occurred and 4a was recovered totally
unchanged.
5. (a) Rische, T.; Eilbracht, P. Tetrahedron 1999, 55, 1915; (b) de
Lang, R.-J.; van Hooijdonk, M. J. C. M.; Brandsma, L.;
Kramer, H.; Seinen, W. Tetrahedron 1998, 54, 2953; (c) Prat,
(d, 1H, J¼19.0 Hz), 3.87 (d, 1H, J¼19.0 Hz), 5.37 (d, 1H,
J¼6.6 Hz), 6.56 (s, 1H), 6.89 (d, 2H, J¼7.2 Hz).
13C NMR (75 MHz, CDCl3) major isomer 5o d: 18.9 (CH3),
29.9 (CH3), 39.3 (CH2), 73.7 (CH), 115.9 (CH), 119.6 (CH),
120.9 (CH), 122.5 (C), 125.9 (CH), 128.4 (CH), 129.0
(2CH), 129.2 (2CH), 134.8 (C), 136.0 (C), 138.5 (C),
151.5 (C). 13C NMR (75 MHz, CDCl3) minor isomer:
(only the most significant resonances are listed) d: 21.1
(CH3), 29.6 (CH3), 31.6 (CH2), 70.1 (C), 117.1 (CH),
120.3 (CH), 125.4 (CH), 127.4 (CH), 128.5 (CH), 153.0 (C).
ꢀ
L.; Mojovic, L.; Levacher, V.; Dupas, G.; Queguiner, G.;
Bourguignon, J. Tetrahedron: Asymmetry 1998, 9, 2509; (d)
Ku, Y.-Y.; Patel, R. P.; Sawick, D. P. Tetrahedron Lett. 1996,
37, 1949.
4.5.7. 3,5-Bis(4-methoxybenzyl)-1-allyloxybenzene 5p.
Yield: 67%.
6. Buchanan, A. C., III; Britt, P. F.; Koran, L. J. Energy Fuels
2002, 16, 517 and references therein.
TLC: Rf 0.47 (cyclohexane/AcOEt 90/10, SiO2).
7. Lai, Y. -Z.; Xu, H.; Yang, R. Lignin: Historical, Biological, and
Materials Perspectives; Glasser, W. G., Northey, R. A., Schultz,
T. P., Eds.; American Chemical Society: Washington, DC,
2000; pp 239–249.
Anal. Calcd for 5p (C25H26O3): C, 80.18; H, 7.00. Found:
C, 80.12; H, 6.98.
IR (neat) nmax/cmꢁ1: 1592, 1509, 1453, 1241, 1175, 1107,
1034.
8. (a) Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303; (b)
€
€
Jafer, R.; Vogtle, F. Angew. Chem., Int. Ed. 1997, 36, 930.
9. For recent examples see: (a) Park, S. Y.; Kang, M.; Yie, J. E.;
Kim, J. M.; Lee, I.-M. Tetrahedron Lett. 2005, 46, 2849; (b)
Park, C.-M.; Sun, C.; Olejniczak, E. T.; Wilson, A. E.;
Meadows, R. P.; Betz, S. F.; Elmore, S. W.; Fesik, S. W.
Bioorg. Med. Chem. Lett. 2005, 15, 771; (c) Itami, K.;
Mineno, M.; Kamei, T.; Yoshida, J.-I. Org. Lett. 2002, 4,
1H NMR (300 MHz, CDCl3) d: 3.80 (s, 6H), 3.86 (s, 4H),
4.44 (dt, 2H, J¼5.7 Hz, J¼1.5 Hz), 5.28 (dq, 1H,
J¼10.5 Hz, J¼1.5 Hz), 5.36 (dq, 1H, J¼17.4 Hz,
J¼1.5 Hz), 5.95–6.08 (m, 1H), 6.56 (s, 2H), 6.65 (s, 1H),
6.83 (d, 4H, J¼8.7 Hz), 7.10 (d, 4H, J¼8.7 Hz).
13C NMR (75 MHz, CDCl3) d: 41.0 (2CH2), 55.2 (2OCH3),
68.6 (CH2), 112.9 (2CH), 113.8 (4CH), 117.6 (CH2), 122.1
(CH), 129.8 (4CH), 133.0 (2C), 133.3 (CH), 143.0 (2C),
157.9 (2C), 158.9 (C).
´
´
´
3635; (d) Garcıa Martınez, A.; Osıo Barcina, J.; Colorado
Heras, M.; de Fresno Cerazo, A. Org. Lett. 2000, 2, 1377.
10. For recent examples see: (a) Nobre, S. M.; Monteiro, A. L.
Tetrahedron Lett. 2004, 45, 8225; (b) Langle, S.; Abarbri,
^
M.; Duchene, A. Tetrahedron Lett. 2003, 44, 9255; (c)
Pirrung, M. C.; Wedel, M.; Zhao, Y. Synlett 2002, 143; (d)
Frisch, A. C.; Shaikh, N.; Zapf, A.; Beller, M. Angew. Chem.,
Int. Ed. 2002, 41, 4056; (e) Hossain, K. M.; Takagi, K.
Chem. Lett. 1999, 1241.
4.5.8. [4-(4-Methylbenzyl)-phenyl]-(4-tolyl)methanone
5q. Yield: 61%.
11. For reduction of diarylketones see: (a) Zaccheria, F.; Ravasio,
N.; Ercoli, M.; Allegrini, P. Tetrahedron Lett. 2005, 46, 7743;
(b) Tremont, S. J.; Lee, L. F.; Huang, H.-C.; Keller, B. T.;
Banerjee, S. C.; Both, S. R.; Carpenter, A. J.; Wang, C.-C.;
Garland, D. J.; Huang, W.; Jones, C.; Koeller, K. J.;
Kolodziej, S. A.; Li, J.; Manning, R. E.; Mahoney, M. W.;
Miller, R. E.; Mischke, D. A.; Rath, N. P.; Fletcher, T.;
Reinhard, E. J.; Tollefson, M. B.; Vernier, W. F.; Wagner,
G. M.; Rapp, S. R.; Beaudry, J.; Glenn, K.; Regina, K.;
Schuh, J. R.; Smith, M. E.; Trivedi, J. S.; Reitz, D. B. J.
Med. Chem. 2005, 48, 5837; (c) Hatano, B.; Tagaya, H.
Tetrahedron Lett. 2003, 44, 6331; (d) Mahmoodi, N. O.;
Salehpour, M. J. Heterocycl. Chem. 2003, 40, 875; (e)
TLC: Rf 0.55 (cyclohexane/AcOEt 90/10, SiO2).
Anal. Calcd for 5q (C22H20O): C, 87.96; H, 6.71. Found:
C, 87.94; H, 6.66.
IR (neat) nmax/cmꢁ1: 1652, 1605, 1312, 1276, 1177, 1114.
1H NMR (300 MHz, CDCl3) d: 2.43 (s, 3H), 2.53 (s, 3H),
4.11 (s, 2H), 7.21 (s, 4H), 7.35–7.40 (m, 4H), 7.79–7.83
(m, 4H).
13C NMR (75 MHz, CDCl3) d: 21.0 (CH3), 21.6 (CH3), 41.5
(CH2), 120.1 (2CH), 129.3 (4CH), 130.1 (2CH), 130.2
(2CH), 130.3 (2CH), 135.1 (C), 135.7 (C), 135.8 (C),
137.1 (C), 143.0 (C), 146.1 (C), 196.1 (C).
˜
Toyota, S.; Nakagawa, T.; Kotani, M.; Oki, M.; Uekusa, H.;
Ohashi, Y. Tetrahedron 2002, 58, 10345; (f) Chandrasekhar,
S.; Reddy, C. R.; Babu, B. N. J. Org. Chem. 2002, 67, 9080;
(g) Studer, M.; Burkhardt, S.; Indolese, A. F.; Blaser, H.-U.
Chem. Commun. 2000, 1327; (h) Hicks, L. D.; Han, J. K.;
Fry, A. J. Tetrahedron Lett. 2000, 41, 7817; (i) Gadhwal, S.;
Baruah, M.; Sandhu, J. S. Synlett 1999, 1573; (j) Lee, W. Y.;
Park, C. H.; Kim, H. J.; Kim, S. J. J. Org. Chem. 1994, 59,
878; (k) Lee, W. Y.; Park, W. Y.; Kim, Y. D. J. Org. Chem.
1992, 57, 4074; (l) Popielarz, R.; Arnold, D. R. J. Am. Chem.
Soc. 1990, 112, 3068.
Acknowledgements
The CNRS is gratefully acknowledged for support of this
research and the MNSER for doctoral fellowships to N.L.
and A.G.
References and notes
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12. For reduction of benzhydrols see: (a) Wu, X.; Mahalingam,
A. K.; Alterman, M. Tetrahedron Lett. 2005, 46, 1501;

12002
N. L’Hermite et al. / Tetrahedron 62 (2006) 11994–12002
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16. At 140 ꢀC, the disproportionation was incomplete (30% of 4q
was observed in the crude mixture).
Waidelich, M.; Towler, M.; White, R.; Albrecht, M.;
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17. The experimental microwave experiments described in this let-
ter are well established and controlled and can be safely and
beneficially reproduced.