Bisulfate Salt-Catalyzed Friedel-Crafts Benzylation of Arenes with Benzylic Alcohols

Article abstract of DOI:10.1021/acs.joc.8b02361

We report here a method of direct Friedel-Crafts benzylation of arenes with benzylic alcohols using cheap and readily available bisulfate salt as the catalyst in hexafluoroisopropanol. The catalytic system is powerful with a quite diverse group of functionalized arenes and benzylic alcohols. These mild conditions provide a straightforward synthesis of a variety of unsymmetrical diarylmethanes in high yield with good to high regioselectivity. An S_N1 mechanism involving activation of the hydroxy group through a hydrogen bond is proposed.

Full text of DOI:10.1021/acs.joc.8b02361

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Article
Bisulfate Salt-Catalyzed Friedel-Crafts
Benzylation of Arenes with Benzylic Alcohols
Ren-Jin TANG, Thierry Milcent, and Benoit Crousse
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02361 • Publication Date (Web): 31 Oct 2018
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The Journal of Organic Chemistry
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Bisulfate Salt-Catalyzed Friedel−Crafts Benzylation of Arenes with
Benzylic Alcohols
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Ren-Jin Tang, Thierry Milcent and Benoit Crousse*
Faculty of Pharmacy, UMR 8076, BioCIS, Univ. Paris-Sud, CNRS, University Paris-Saclay, 92290, Châtenay-Malabry,
FRANCE
Supporting Information Placeholder
R2
5 equiv.
OH
R2
R1
R1
KHSO4 (10 mol%) / HFIP
R1, R2 = EDG, EWG
ABSTRACT: We reported here a method of direct Friedel−Crafts benzylation of arenes with benzylic alcohols using cheap and
readily available bisulfate salt as catalyst in hexafluoroisopropanol (HFIP). The catalytic system was powerful with large diversity
of functionalized arenes and benzylic alcohols. These mild conditions provided a straightforward synthesis of a variety of
unsymmetrical diarylmethanes in high yield with good to high regioselectivity. A SN1 mechanism involving activation of the
hydroxy group through hydrogen-bond was proposed.
report a green, cheap and readily available bisulfate salt
promoted FC benzylation of arenes with electron-rich and -
poor benzylic alcohols (Scheme 1d).
(a) Friedel-Crafts benzylation with benzylic hydroxamate
INTRODUCTION
The Friedel−Crafts (FC) benzylation of arenes is one of the
fundamental synthetic protocols for diarylmethane moiety.
Bode et al.4
This privileged structural unit has diverse applications in the
fields of pharmacologically active compounds and functional
materials.1 In its traditional form, the reaction is promoted by
strong Lewis acids (e.g., AlCl3, FeCl3),2 requiring a full
equivalent of catalyst due to product inhibition. Moreover, the
reaction uses toxic alkyl halides as starting materials, which
hydrolyze readily to generate irritating halo-acid gas (HX) as
the byproduct.3 Therefore, these reaction conditions are far
from ideal from the standpoint of atom economy and green
chemistry. Recently, different strategies for the metal-free
synthesis of diarylmethanes have been reported (Scheme 1).
For example, Bode and co-workers developed the FC
benzylation with benzyl hydroxamates mediated by an excess
of BF3·OEt2 (Scheme 1a).4 Moreover, Paquin's group5
demonstrated the FC benzylation with benzylic fluorides in the
presence of HF in situ and Stephan's group6 reported the
activation of benzylic fluorides in the presence of
organofluorophosphonium (Scheme 1b). In 2007, the ACS
Green Chemistry Pharmaceutical Roundtable designated the
development of catalytic versions starting directly from stable
and less toxic alcohols, which produce water as the only
stoichiometric byproduct, as one of the top research priorities.7
Recently, Hall and McCubbin developed an active
ferrocenium hexafluoroantimonate boronic acid catalyst in
direct FC benzylation with stable and readily available
primary and secondary benzylic alcohols.8 More recently,
Moran and co-workers reported FC benzylation with highly
electronically deactivated benzylic alcohols using super
Brønsted acid TfOH.9 Futhermore, during our submission,
Antonchick's group disclosed the used of nitrosonium salt as
catalyst for the FC benzylation (Scheme 1c).10 Herein, we
Me
N
BF3OEt2 (2.5 equiv.)
O
Ac
Ar
Ar
R
R
R
Ar-H
(b) Friedel-Crafts benzylation with benzylic fluorides
Paquin et al.5 and Stephan et al.6
HF or Phosphonium cat., Et3SiH
F
R
Ar-H
(c) Friedel-Crafts benzylation with benzylic alcohols
Hall et al.8, Moran et al.9 and Antonchick et al.10
B(OH)2
cat. :
Fe (III)
SbF6
or TfOH or NOBF4
OH
Ar
R
R
Ar-H
(d) This work: Acid salt catalyzed Friedel-Crafts benzylation with benzylic alcohols
KHSO4 (10 mol%)
OH
Ar
R
R
Ar-H
Scheme 1. Direct arene C-H transformations for biaryl
synthesis.
Our study focused on the use of acidic inorganic salts
following Hammond and Xu’s paper11 reported that KHSO4
12
can form a hydrogen bond network with multiple molecules of
HF and thus the acidity of KHSO4 can be further enhanced.
Faced with these results, we investigated the association of
bisulfate salt with HFIP in order to perform the FC
benzylation reaction. This fluorinated alcohol is very well
known to facilitate reactions through its physico-chemical
properties and in particular its ability to form strong hydrogen
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a
b
bonds.5, 13 Moreover, it was also reported that aggregation of
HFIP in particular dimers and trimers could also enhance this
property (Scheme 2).14
Reaction scale: 1.0 mmol of benzyl alcohol. Isolated yields of
c
1
2
combined regioisomers. Isomer ratios were measured by 1H
NMR. d Performed at 50 C. 200 mg of 4Å M.S. was added.
2
e
f
mol% of KHSO4 was used. n.r. = no reaction.
3
4
5
6
F3C
H
CF3
Table 2. The FC benzylation of different benzyl alcohols
K+
O
the acidity
is enhanced
by H-bond network
n = 0, 1
-
H
with m-xylene a
HO SO3
H
n
O
O
F3C
CF3
a
F3C
CF3
KHSO4 (10 mol%)
7
b
HO
R
R
8
c
HFIP (0.5 M)
9
1
(5 equiv.)
4-20
Scheme 2. Hydrogen-bonding network assisted KHSO4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
OMe
RESULTS AND DISCUSSION
We began our studies by testing the benzylation of m-xylene 1
with benzyl alcohol 2 using 10 mol% of KHSO4 in HFIP at
room temperature (table 1). To our delight, the desired
diarylmethane isomers 3 were isolated in 84% after 16 h. A
similar result was obtained using NaHSO4 (75%). No reaction
occurred without catalyst and with sulfate or phosphate salts
(entries 3-5). It was noteworthy that strong protic acid TFA
(pKa 0.23) gave trace of products 3 (entry 6). We next
investigated the effect of different solvents. Unexpectedly,
TFE led to some traces of the products 3 (entry 7). Other
several common solvents such as EtOH, DCM, THF, CH3NO2
or m-xylene did not produce detectable amounts of products
(entry 8-12). In addition, changing the reaction temperature to
50 oC was found to provide the products 3 in 86% yield within
2 h (entry 13). No reaction was observed in the presence of
molecular sieves that would promote the formation of
potassium pyrosulfate (entry 14). Moreover, the amount of
KHSO4 can be reduced to 2 mol% and the reaction time has
risen to 5 h (entry 15). So, these different experiments show
the effectiveness of the association of KHSO4 with HFIP.
Furthermore, the formation of water did not disturb the
reaction because HFIP has the ability to solvate it.13i
, 50 oC, 2 h, 85%
, 50 oC, 2 h, 86%
6
4
5
, rt, 1 h, 87%
b
> 95 : 5)
a
b
> 95 : 5)
(
:
a
a
b
= 77 : 23)
(
:
(
:
OMe
OMe
OEt
OMe
, 50 oC, 2 h, 77%
8
a
7
, rt, 2 h, 74%
9
, rt, 2 h, 56%
b
(
:
= 75 : 25)
a
b
> 95 : 5)
(
:
a
b
= 76 : 24)
(
:
F
F
OBn
Cl
, 80 oC, 16 h, 77%
, 80 oC, 2 h, 80%
12
11
10
, rt, 2 h, 72%
a
b
a b
( : = 77 : 23)
(
:
> 95 : 5)
a
b
(
:
= 76 : 24)
I
OCF3
, 50 oC, 16 h, 73%
, 80 oC, 16 h, 84%
, 80 oC, 16 h, 61%
15
14
13
a
b
= 91 : 9)
a
b
(
:
a b
( : = 76 : 24)
(
:
= 78 : 22)
CF3
Table 1. Optimization of the reaction conditions a
CF3
, 100 oC, 48 h, 51%
17
NO2
, 100 oC, 48 h, 15%
, 100 oC, 48 h, 75%
16
18
a
Catalyst (10 mol%)
b
HO
a
b
= 77 : 23)
(
:
a b
( : = 80 : 20)
a b
( : = 80 : 20)
Sovent (0.5 M), r.t.
1
2
3
(5 equiv.)
S
Entry
Catalyst
(10 mol%)
Solvent
(0.5 M)
t
Yield b 3a : 3b c
(h)
(%)
, 50 oC, 2 h, 82%
, 50 oC, 2 h, 71%
20
19
1
2
KHSO4
NaHSO4
Na2SO4
NaH2PO4
-
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
TFE
16
16
16
16
16
16
16
16
16
16
16
16
2
84
75
77 : 23
a
b
= 89 : 11)
(
:
75 : 25
a
Reaction scale: 1.0 mmol of benzylic alcohol. Isolated yields of
3
n.r.
n.r.
n.r.
trace
trace
n.r.
n.r.
n.r.
n.r.
n.r.
86
-
combined regioisomers. Isomer ratios were measured by 1H NMR.
For products 11 - 13, 15 - 18, <5% of the 5-substituted isomer c
was obtained.
4
-
5
-
6
TFA
-
Under the optimized conditions (Table 1, entry 13), the
substrate scope and limitation of this FC benzylation were
explored. The effect of substituents on the benzylic alcohol
moieties is listed in Table 2. Benzylic alcohols bearing
donating groups such as methyl, hydroxyl, methoxy, ethoxy,
and benzyloxy at various positions were successfully
transformed into the desired diarylmethane products 4-10 in
moderate to good yields. Furthermore, benzylic alcohols with
slightly deactivating substituents such as fluoride, chloride
iodide or trifluoromethoxy led to high yields of products 11-15.
It is remarkable that benzylic alcohols with strongly electron-
withdrawing groups such as the trifluoromethyl group were
7
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
-
8
EtOH
DCM
THF
-
9
-
10
11
12
13 d
14 d, e
15 d, f
-
CH3NO2
m-xylene
HFIP
HFIP
HFIP
-
-
76 : 24
-
2
n.r.
80
5
76 : 24
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also applicable in this reaction providing the products 16 and
in Hall and McCubbin method8 and classical FC benzylation
with benzylic halides.3a, 3b
To highlight the synthetic utility of this protocol, we
conducted the reaction on a gram scale. Under the optimized
conditions, the gram-scale benzylation of m-xylene 1 with
1
2
3
4
5
6
7
8
17 in 75% and 51% yields respectively. Unfortunately, the
reactions gave very low yield with benzylic alcohols bearing
nitro group (product 18). Treatment of the 1,4-
benzenedimethanol with p-xylene afforded the disubstituted
products 19 in 71% yield. In addition, the reaction with 3-
thiophenemethanol processed successfully to provide the
corresponding products 20 in high yields.
benzyl alcohol
2
proceeded smoothly to give the
corresponding diarylmethanes 3 in 85% yield (scheme 3).
KHSO4 (10 mol%)
a
HO
b
Table 3. The FC benzylation of different arenes with
benzyl alcohol a
HFIP (20 mL)
50 oC, 2 h
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KHSO4 (10 mol%)
3
a
1
2
HO
R
R
b
= 75 : 25)
(1.66g, 85%,
:
(50 mmol, 5.30 g) (10 mmol, 1.08 g)
HFIP (0.25 M)
(5 equiv.)
2
21-35
Scheme 3. Gram scale reaction
Other potential hydrogen-bond-accepting leaving groups
were also evaluated. Benzyl acetate and methyl ether afforded
successfully the desired diarylmethanes 3 (Table 4, entries 1-
2). Besides, we also compared the reactivity of various
benzylic halides which are weak hydrogen-bond acceptors16
(Table 4, entries 3–4). Both benzyl chloride and benzyl
bromide reacted completely probably due both to the hydrogen
bonding donor ability of HFIP/KHSO4 and to the high ionizing
power of HFIP as solvent.
a
b
50 oC, 2 h, 87%
50 oC, 2 h, 85%
50 oC, 2 h, 87%
23,
21,
22,
a
b
= 62 : 38)
(
:
b
b
b
a
a
a
t-Bu
i-Pr
octyl
50 oC, 2 h, 72%
,
25,
24 d
50 oC, 2 h, 89%
50 oC, 2 h, 85%
26,
a
b
= 62 : 38)
(
:
a
b
a b
( : = 66 : 34)
(
:
= 65 : 35)
Table 4. Comparison of different leaving groups a
a
a
b
KHSO4 (10 mol%)
a
b
X
b
HFIP (0.5 M)
50 oC, 2 h
27,
50 oC, 2 h, 87%
50 oC, 16 h, 85%
28,
80 oC, 16 h, 88%
OMe
29,
1
3
a
b
= 70 : 30)
a
b
(
:
(
:
= 54 : 46)
(5 equiv.)
Entry
X
OAc
OMe
Cl
Yield (%) b
3a: 3b c
74: 26
79: 21
78: 22
78: 22
OMe
OMe
F
b
a
a
1
2d
3
77
64
85
82
MeO
F
b
80 oC, 48 h, 55%
30,
i-Pr
31,
rt, 2 h, 81%
32 b
,
a
b
rt, 0.5 h, 78%
a
b
(
:
> 95 : 5)
(
:
= 80 : 20)
4
Br
OMe
OMe
OMe
a
b
Reaction scale: 1.0 mmol of benzylic substituent. Yield of the
b
a
S
isolated product. c Isomer ratios were measured by 1H NMR. d The
reaction time was 16 h.
PhO
Br
OMe
rt, 0.5 h, 75%
35 b
,
rt, 0.5 h, 80%
34,
(
rt, 2 h, 88%
33,
a
b
= 87 : 13)
:
Secondary benzylic alcohols such as 1-phenylethanol was
evaluated and was able to react with m-xylene at room
temperature to lead the diaryl compound 36 in 90% yield. It
was noteworthy that the secondary benzylic alcohol bearing
the nitro group worked well and afforded products 37 in 87%
yield (table 5).
a
Reaction scale: 1.0 mmol of benzylic alcohol. Isolated yields of
combined regioisomers. Isomer ratios were measured by 1H NMR.
b HFIP/DCM (9/1) was used as the solvent.
On the other hand, a series of arenes were subjected to this
benzylation conditions (table 3). The reaction was found to be
very facile with alkyl-substituted benzene derivatives such as
o-xylene, m-xylene, mesitylene, 1-phenyloctane, tert-
butylbenzene, iso-butylbenzene and toluene (products 21-27).
Meanwhile, the benzylation of benzene and naphthalene were
successfully to afford the corresponding products 28 and 29 in
88% and 87% yields respectively. With electron deficient
arenes such as fluorobenzene as substrate the diaryl product 30
was obtained in 55% yield. Gratifyingly, electron-rich arenes,
diphenyl ether and methoxybenzene derivatives which resulted
in no reaction in Moran condition9 provided the corresponding
products 31-34 in good yields. Heteroaromatic nucleophile
was also compatible in these conditions.15 The thiophene
derivative reacted to afford the product 35. It is noteworthy
that in all cases the selectivity is very similar to that obtained
Table 5. The FC benzylation of secondary benzylic
alcohols with m-xylene a
KHSO4 (10 mol%)
HFIP (0.5 M)
a
b
HO
R
R
1
(5 equiv.)
36-37
NO2
, 100 oC, 16 h, 87%
37
36
, rt, 2 h, 90%
a
b
> 95 : 5)
(
:
a
b
= 86 : 14)
(
:
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a
AVANCE300 (1H, 300 MHz; 13C, 75 MHz) and BRUKER
AMX 200 (1H, 200 MHz; 19F, 188 MHz) spectrometers.
Unless otherwise stated, NMR data were obtained under
Reaction scale: 1.0 mmol of benzylic alcohol. Isolated yields of
1
2
3
4
5
6
7
8
combined regioisomers. Isomer ratios were measured by 1H NMR.
Under standard conditions the (R)-1-Phenylethanol was
reacted with the p-xylene. The products 38 were recovered
with a loss of stereochemical information (Scheme 4, see S. I.).
This result indicates that the secondary carbenium is formed.
1
ambient temperature conditions. Chemical shifts for H NMR
spectra are reported in parts per million (ppm) from
tetramethylsilane with the solvent resonance as the internal
standard (dimethyl sulfoxide: δ 2.50 ppm, chloroform: δ 7.26
ppm, methanol: δ 3.31 ppm). Chemical shifts for 13C{1H}
NMR spectra are reported in parts per million (ppm) from
tetramethylsilane with the solvent as the internal standard
(dimethyl sulfoxide: δ 39.52 ppm, chloroform: δ 77.16 ppm,
methanol: δ 49.00 ppm). Data are reported as following:
chemical shift, multiplicity (s = singlet, d = doublet, dd =
doublet of doublets, t = triplet, q = quartet, m = multiplet, br =
broad signal), coupling constant (Hz), and integration.
Reagents: Unless otherwise noted, all commercial materials
were purchased from various commercial sources (Sigma-
Aldrich, Alfa Aesar, FluoroChem) and used as received,
without further purification. HFIP was provided by. Central
Glass Co. Ltd.
Me
Me
KHSO4 (10 mol%)
HO
9
HFIP, rt, 2 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5 equiv.)
(R)-1-phenylethanol
38
, 66%, 0% ee
Scheme 4. Stereochemical studies
A plausible SN1-type mechanism was proposed in Scheme 5.
First, the combination of HFIP17 with KHSO4 generates a
superior catalytic specie I which leads to stronger hydrogen-
bonds. Then this association with the benzylic alcohols (II)
evolves towards the intermediate III which reacted by
electrophilic aromatic substitution with Ar2-H to yield the
desired diarylmethanes after aromatization.
General procedures for FC benzylation of arenes with
benzylic alcohols
To a stirred solution of arenes (5.0 mmol, 5 equiv) and benzyl
alcohols (1.0 mmol, 1 equiv) in HFIP (2 mL) was added
KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) under air. The reaction
mixture was stirred at rt ~ 100 oC (oil bath) for 2 ~ 48 h. After
that, the reaction mixture was evaporated under reduce
pressure and the crude product was purified by column
chromatography on silica gel using petroleum ether or
cyclohexane: dichloromethane as the eluent to afford
diarylmethanes.
K+
HO SO3----(HFIP)n
K+
I
HO SO3----(HFIP)n
Ar1
OH
Ar1
OH
II
K+
+
-
K+
HO SO3----(HFIP)n
(HFIP)n---SO3--OH
Ar1
III
O
Ar1
H
H2O
Ar2H
Physical data of 3-38
Ar1
Ar2
Only the structures of the major products are shown. The ratio
Scheme 5. A plausible mechanism for the FC benzylation
1
of regioisomer mixtures (where present) was assigned by H
NMR analysis of crude reaction mixtures. Only the major
products are characterized for mixtures where the
regioisomeric ratios are > 90:10.
CONCLUSIONS
In conclusion, we have developed a mild, efficient and
environmentally friendly method catalyzed by bisulfate salt in
HFIP for direct Friedel−Crafts benzylation of arenes with
benzylic alcohols. The catalytic system was powerful with
large diversity of functionalized arenes and benzylic alcohols.
These mild conditions provided a straightforward variety of
unsymmetrical diarylmethanes in high yield with good to high
regioselectivity. The SN1 mechanism involving activation of
the hydroxy group through hydrogen-bond system was
proposed. This approach has been carried out effectively on a
large scale. Meanwhile, the green, cheap, readily availability
and easy removal in aqueous work-up of bisulfate salt should
make this protocol attractive for the synthesis of
diarylmethanes. Work on further applications for this new
efficient system is currently underway in our laboratory.
1-benzyl-2,4-dimethylbenzene (3) 8
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol) and
KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at 50
oC for 2 h and purified by petroleum ether as a colorless oil
(168 mg, 86%).
1H NMR (300 MHz, CDCl3) δ 7.36 – 7.00 (m, 8H), 4.12 (s,
0.48H, minor), 4.01 (s, 1.52H, major), 2.36 (s, 2.09H, major),
2.30 (s, 1.43H, minor), 2.26 (s, 2.16H, major); 13C{1H} NMR
(75 MHz, CDCl3) δ 140.8, 139.9, 137.3, 137.0, 136.5, 136.0,
131.25, 130.0, 128.8, 128.5, 128.3, 128.0, 126.7, 126.5, 126.0,
125.9, 39.2 (major), 35.2 (minor), 21.1 (major), 20.4 (minor),
19.7 (major).
2,4-dimethyl-1-(3-methylbenzyl)benzene (4)
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 3-methylbenzyl alcohol (122.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
50 oC for 2 h and purified by petroleum ether as a colorless oil
(180 mg, 86%).
EXPERIMENTAL SECTION
General information: Thin-layer chromatography (TLC) was
performed on silica gel, 60F-250 (0.26mm thickness) plates.
The plates were visualized with UV light (254 nm) or with a
3.5% solution of phosphomolybdic acid in ethanol or with a
solution of KMnO4 in water. High-resolution mass spectra
(HRMS) were obtained from waters LCT Premier (ESI/TOF)
and Quattro Ultima Waters® (APCI). Flash chromatography
(FC) was performed on Merck 60 silica gel (230 - 400 mesh).
Melting points were determined on a Kofler melting point
apparatus. NMR spectra were mesured on an Ultrafield
1H NMR (300 MHz, CDCl3) δ 7.26 – 6.85 (m, 7H), 4.10 (s,
0.47H, minor), 3.98 (s, 1.53H, major), 2.38 (s, 2.56, major),
2.37 (s, 1.67, major), 2.35 (s, 0.73, minor), 2.32 (s, 1.52,
minor), 2.29 (s, 2.51, major); 13C{1H} NMR (75 MHz, CDCl3)
δ 140.8, 139.9, 138.0, 137.3, 137.1, 136.5, 136.1, 135.9, 131.2,
130.0, 129.6, 128.8, 128.4 , 128.2, 126.7, 126.7, 126.4, 125.9,
125.0, 39.1 (major), 35.1 (minor), 21.6 (major), 21.1 (major),
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The Journal of Organic Chemistry
20.4 (minor), 19.8; HRMS (APCI+) calcd. for C16H18 [M]+ m/z
rt for 2 h and purified by 20 % DCM in cyclohexane as a
colorless oil (135 mg, 56%).
1
2
3
4
5
6
7
8
210.1403, found 210.1403.
2-(2,4-dimethylbenzyl)phenol (5) 18
1H NMR (300 MHz, CDCl3) δ 7.07 – 6.97 (m, 5H), 6.84 (d, J
= 8.5 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.92 (s, 2H), 2.34 (s,
3H), 2.24 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 157.3, 136.5, 135.9 132.7, 131.2, 129.9,
129.7, 126.7, 114.5, 63.5, 38.3, 21.1, 19.7, 15.0; HRMS
(APCI+) calcd. for C17H20O [M]+ m/z 240.1509, found
240.1497.
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 2-(hydroxymethyl)phenol (124.0 mg, 1.0
mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2
ml) at rt for 1 h and purified by 20 % DCM in cyclohexane as
a colorless oil (185 mg, 87%).
1H NMR (300 MHz, CDCl3) δ 7.18 (t, J = 7.5 Hz, 1H), 7.09 (s,
1H), 7.02 (br, 3H), 6.92 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 7.9
Hz, 1H), 4.85 (s, 1H), 3.99 (s, 2H), 2.37 (s, 3H), 2.31 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 153.9, 136.8, 136.3, 134.5,
131.4, 130.7, 129.2, 127.7, 127.0, 126.5, 121.0, 115.7, 33.6,
21.1, 19.7.
1-(4-(benzyloxy)benzyl)-2,4-dimethylbenzene (10)
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 4-benzyloxybenzyl alcohol (214.0 mg, 1.0
mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2
ml) at rt for 2 h and purified by 20 % DCM in cyclohexane as
a colorless oil (218 mg, 72%).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(2-methoxybenzyl)-2,4-dimethylbenzene (6)
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 2-methoxybenzyl alcohol (138.0 mg, 1.0
mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2
ml) at 50 oC for 2 h and purified by 10 % DCM in
cyclohexane as a colorless oil (191 mg, 85%).
1H NMR (300 MHz, CDCl3) δ 7.49 – 7.36 (m, 5H), 7.10 –
6.99 (m, 5H), 6.94 (d, J = 8.6 Hz, 2H), 5.07 (s, 2H), 3.94 (s,
2H), 2.36 (s, 3H), 2.26 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 157.2, 137.4, 136.5, 136.4, 135.9, 133.2, 131.2,
129.9, 129.7, 128.7, 128.0, 127.6, 126.7, 114.9, 70.2, 38.3,
21.1, 19.7; HRMS (ESI+) calcd. for C22H22ONa [M+Na]+ m/z
325.1568, found 325.1562.
1H NMR (300 MHz, CDCl3) δ 7.28 – 7.22 (m, 1H), 7.07 (s,
1H), 7.01 (br, 2H), 6.95 – 6.87 (m, 3H), 3.99 (s, 2H), 3.89 (s,
3H), 2.37 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 157.5, 136.7, 135.7, 135.7, 131.0, 129.9, 129.8,
129.2, 127.2, 126.7, 120.6, 110.2, 55.4, 32.8, 21.1, 19.6;
HRMS (ESI+) calcd. for C16H18ONa [M+Na]+ m/z 249.1255,
found 249.1251.
1-(2-fluorobenzyl)-2,4-dimethylbenzene (11)
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 2-fluorobenzyl alcohol (126.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
80 oC for 2 h and purified by petroleum ether as a colorless oil
(172 mg, 80%).
1-(3-methoxybenzyl)-2,4-dimethylbenzene (7)
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 3-methoxybenzyl alcohol (138.0 mg, 1.0
mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2
ml) at 50 oC for 2 h and purified by 10 % DCM in
cyclohexane as a colorless oil (175 mg, 77%).
1H NMR (300 MHz, CDCl3) δ 7.22 – 6.95 (m, 6.78H), 6.89 (s,
0.23H, minor), 6.65 (t, J = 7.0 Hz, 0.25H, minor), 4.09 (s,
0.48H, minor), 4.00 (s, 1.52H, major), 2.35 (s, 2.16H, minor),
2.28 (s, 3.82H, major); 13C{1H} NMR (75 MHz, CDCl3) δ
161.3 (d, J = 243.0 Hz), 161.1 (d, J = 243.8 Hz), 138.1, 137.5,
136.5, 136.2, 135.6, 134.6, 131.3 , 130.7 (d, J = 4.5 Hz),
129.8, 128.8 (d, J = 4.5 Hz), 128.3, 127.8, 127.7, 127.6, 127.5,
127.4, 126.8, 126.7, 124.2, 124.1, 124.1, 115.4, 115.1, 114.8,
31.7, 27.6, 21.1, 20.1, 19.5; 19F NMR (CDCl3, 188 MHz): δ -
117.6 (m, 1F); HRMS (APCI+) calcd. for C15H16F [M+H]+ m/z
215.1231, found 215.1226.
1H NMR (300 MHz, CDCl3) δ 7.11 – 7.03 (m, 1.19H), 6.96 (s,
0.72H), 6.91 – 6.84 (m, 2.22H), 6.63 – 6.58 (m, 2.33H), 6.53 –
6.48 (m, 0.60H), 3.94 (s, 0.46H, minor), 3.82 (s, 1.48H,
major), 3.65 (s, 1.93H, major), 3.64 (s, 0.85H, minor), 2.20 (s,
2.01H, major), 2.15 (s, 1.28H, minor), 2.11 (s, 2.34H, major);
13C{1H} NMR (75 MHz, CDCl3) δ 159.9, 159.8, 142.5, 141.7,
137.3, 136.8, 136.5, 136.0, 135.8, 131.2, 130.0, 129.4, 128.2,
126.7, 126.5, 121.3, 120.5, 114.8, 114.1, 111.1, 110.8, 110.0,
55.2, 55.2, 39.2 (major), 35.2 (minor), 21.1 (major), 20.3
(minor), 19.7 (major) ; HRMS (ESI+) calcd. for C16H19O
[M+H]+ m/z 227.1436, found 227.1431
1-(3,5-dimethoxybenzyl)-2,4-dimethylbenzene (8)
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 3,5-dimethoxybenzyl alcohol (168.0 mg, 1.0
mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2
ml) at rt for 2 h and purified by 20 % DCM in cyclohexane as
a colorless oil (190 mg, 74%).
1-(3-fluorobenzyl)-2,4-dimethylbenzene (12) 8
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 3-fluorobenzyl alcohol (126.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
o
80 C for 16 h and purified by petroleum ether as a colorless
oil (165 mg, 77%).
1H NMR (300 MHz, CDCl3) δ 7.29 – 7.21 (m, 1.21H), 7.16 –
7.09 (m, 0.91H), 7.04 – 7.00 (m, 2.42H), 6.96 – 6.82 (m,
3.02H), 6.73 (d, J = 10.2 Hz, 0.26H), 4.09 (s, 0.44H, minor),
3.98 (s, 1.51H, major), 2.35 (s, 2.21H, major), 2.28 (s, 1.36H,
minor), 2.23 (s, 2.51H, major); 13C{1H} NMR (75 MHz,
CDCl3) δ 163.3 (d, J = 243.8 Hz), 163.2 (d, J = 243.8 Hz),
143.6 (d, J = 6.8 Hz), 142.8 (d, J = 7.5 Hz) , 138.2, 137.2,
136.5, 136.4, 136.2, 135.2, 131.4, 130.1, 129.9, 129.8, 128.4,
128.1, 126.9, 126.7, 124.4 (d, J = 2.3 Hz), 123.7 (d, J = 2.1
Hz), 115.6 (d, J = 21.2 Hz), 114.8 (d, J = 21.5 Hz), 112.9 (d, J
= 21.2 Hz), 112.8 (d, J = 21.1 Hz), 38.9, 34.9, 21.1, 20.3, 19.7;
19F NMR (CDCl3, 188 MHz): δ -113.6 (m, 1F).
1H NMR (300 MHz, CDCl3) δ 7.09 – 6.96 (m, 3H), 6.32 (s,
2.44H), 6.21 (s, 0.48H), 4.03 (s, 0.5H, minor), 3.91 (s, 2H,
major), 3.76 (s, 4.41H, major), 3.75 (s, 1.69H, minor), 2.33 (s,
2.33H, major), 2.28 (s, 1.39H, minor), 2.25 (s, 2.24H, major);
13C{1H} NMR (75 MHz, CDCl3) δ 160.9, 143.3, 142.6, 137.3,
136.6, 136.5, 136.0, 135.6, 131.2, 129.9, 128.2, 126.7, 126.5,
107.1, 106.3, 97.8, 97.5, 55.3, 55.3, 39.4, 35.3, 21.1, 20.3,
19.7; HRMS (ESI+) calcd. for C17H21O2 [M+H]+ m/z 257.1542,
found 257.1535.
1-(3-chlorobenzyl)-2,4-dimethylbenzene (13)
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 3-chlorobenzyl alcohol (126.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
1-(4-ethoxybenzyl)-2,4-dimethylbenzene (9)
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 4-ethoxybenzyl alcohol (152.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
o
80 C for 16 h and purified by petroleum ether as a colorless
oil (193 mg, 84%).
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1H NMR (300 MHz, CDCl3) δ 7.23 – 7.16 (m, 1.98H), 7.12 –
HFIP (2 ml) at 100 oC for 48 h and purified by petroleum ether
as a colorless oil (135 mg, 51%).
1
2
3
4
5
6
7
8
7.10 (m, 1.41H), 7.02 – 7.00 (m, 3.14H), 6.91 – 6.89 (m,
0.43H), 4.05 (s, 0.42H, minor), 3.94 (s, 1.52H, major), 2.33 (s,
2.30H, major), 2.25 (s, 1.34H, minor), 2.21 (s, 2.51H, major);
13C{1H} NMR (75 MHz, CDCl3) δ 143.0, 142.2, 137.2, 136.5,
136.4, 136.1, 135.1, 134.4, 134.3, 131.4, 130.1, 129.7, 128.9,
128.4, 128.1, 127.0, 126.9, 126.8, 126.2, 126.2, 38.9, 34.9,
21.1, 20.3, 19.7; HRMS (APCI+) calcd. for C15H15Cl [M]+ m/z
230.0857, found 230.0857.
1H NMR (300 MHz, CDCl3) δ 7.57 – 7.53 (m, 2.04H), 7.36 –
7.26 (m, 1.84H), 7.18 – 7.11 (m, 1.15H), 7.06 – 7.04 (m,
2.23H), 4.16 (s, 0.40H, minor), 4.05 (s, 1.61H, major), 2.37 (s,
2.51H, major), 2.28 (s, 1.19H, minor), 2.24 (s, 2.36H, major);
13C{1H} NMR (75 MHz, CDCl3) δ 145.1, 144.3, 138.3, 137.2,
136.5 (d, J = 3.0Hz), 136.0, 134.9, 131.5, 130.1, 129.3, 129.0,
128.6, 128.5, 128.3, 127.0, 126.9, 125.5 (q, J = 3.8Hz), 124.5
(q, J = 270.0Hz), 39.1, 35.1, 21.1, 20.3, 19.7; 19F NMR
(CDCl3, 188 MHz): δ -62.3 (s, 3F).
1-(2-iodobenzyl)-2,4-dimethylbenzene (14)
9
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 2-iodobenzyl alcohol (234.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
2,4-dimethyl-1-(4-nitrobenzyl)benzene (18) 8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 4-nitrobenzyl alcohol (153.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
100 oC for 48 h and purified by 10 % DCM in cyclohexane as
a light-yellow solid (36 mg, 15%).
o
50 C for 16 h and purified by petroleum ether as a colorless
oil (236 mg, 73%).
1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.7 Hz, 1H), 7.24 (t,
J = 7.3 Hz, 0.92H), 7.20 – 7.10 (m, 0.83H), 7.07 (s, 0.81H),
6.99 (t, J = 7.9 Hz, 1H), 6.95 – 6.86 (m, 2.37H), 6.56 (d, J =
7.6 Hz, 0.18H, minor), 4.07 (s, 0.17H, minor), 4.02 (s, 1.80H,
major), 2.36 (s, 2.21H, major), 2.33 (s, 0.45H, minor), 2.23 (d,
J = 3.5 Hz, 3.23H, major); 13C{1H} NMR (75 MHz, CDCl3) δ
143.3, 142.0, 139.5, 139.3, 138.1, 137.4, 136.7, 136.6, 136.2,
134.8, 131.3, 130.4, 129.7, 128.5, 128.4, 128.3, 128.1, 128.0,
127.9, 127.8, 127.1, 126.9, 126.8, 102.0, 101.7, 44.5, 41.5,
21.1, 20.2, 19.7; HRMS (APCI+) calcd. for C15H16I [M+H]+
m/z 323.0290, found 323.0276.
o
1
M.p.: 90 - 92 C; H NMR (300 MHz, CDCl3) δ 8.15 (d, J =
8.5 Hz, 2H), 7.37 (d, J = 8.3 Hz, 0.18H), 7.29 (d, J = 8.2 Hz,
1.61H), 7.22 – 7.11 (m, 1H), 7.05 – 7.02 (m, 2H), 4.18 (s,
0.40H, minor), 4.07 (s, 1.57H, major), 2.35 (s, 2.42H, major),
2.25 (s, 1.13H, minor), 2.20 (s, 2.31H, major); 13C{1H} NMR
(75 MHz, CDCl3) δ 148.8, 148.1, 137.1, 136.9, 136.5, 135.3,
134.2, 131.6, 130.1, 129.8, 129.5, 128.7, 128.6, 128.5, 127.1,
127.1, 126.9, 123.8, 123.8, 39.1, 35.2, 21.1, 20.3, 19.7.
1,4-bis(2,5-dimethylbenzyl)benzene (19)
2,4-dimethyl-1-(3-(trifluoromethoxy)benzyl)benzene (15)
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 3-trifluoromethoxybenzyl alcohol (192.0 mg,
1.0 mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in
HFIP (2 ml) at 80 oC for 16 h and purified by petroleum ether
as a colorless oil (170 mg, 61%).
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 1,4-phenylenedimethanol (138.0 mg, 1.0
mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2
ml) at 50 oC for 2 h and purified by 10 % DCM in
cyclohexane as a white solid (223 mg, 71%).
o
1
M.p.: 88 - 90 C; H NMR (300 MHz, CDCl3) δ 7.12 – 7.09
(m, 6H), 7.03 (s, 1H), 7.00 (s, 3H), 3.98 (s, 4H), 2.35 (s, 6H),
2.26 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 139.0, 138.1,
135.4, 133.5, 130.9, 130.3, 128.8, 127.2, 39.1, 21.1, 19.3;
HRMS (APCI+) calcd. for C24H26 [M]+ m/z 314.2029, found
314.2028.
1H NMR (300 MHz, CDCl3) δ 7.34 – 7.26 (m, 1.09H), 7.16 –
6.92 (m, 5.90H), 4.11 (s, 0.47H, minor), 4.00 (s, 1.51H,
major), 2.36 (s, 2.17H, major), 2.28 (s, 1.41H, minor), 2.23 (s,
2.27H, major); 13C{1H} NMR (75 MHz, CDCl3) δ 149.6,
143.3, 142.5, 136.5, 136.0, 135.0, 131.4, 130.0, 130.0, 129.7,
128.4, 127.1, 126.9, 126.8, 126.3, 121.34 , 120.6, 120.6 (q, J =
255.0 Hz), 118.4 118.3, 38.9, 34.9, 21.1, 20.3, 19.6; 19F NMR
(CDCl3, 188 MHz): δ -57.7 (s, 2.3F, major), δ -57.8 (s, 0.7F,
minor); HRMS (APCI+) calcd. for C16H15F3O [M]+ m/z
280.1070, found 280.1071.
3-(2,4-dimethylbenzyl)thiophene (20)
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 3-thiophenemethanol (114.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
50 oC for 2 h and purified by petroleum ether as a colorless oil
(166 mg, 82%).
2,4-dimethyl-1-(3-(trifluoromethyl)benzyl)benzene (16) 8
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 3-trifluoromethylbenzyl alcohol (176.0 mg,
1.0 mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in
1H NMR (300 MHz, CDCl3) δ 7.29 – 7.26 (m, 1H), 7.11 –
6.99 (m, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.85 (s, 0.90H, major),
6.67 (s, 0.11H, minor), 4.04 (s, 0.22H, minor), 3.97 (s, 1.74H,
major), 2.35 (s, 2.51H, major), 2.32 (s, 0.72H, minor), 2.28 (s,
2.80H, major); 13C{1H} NMR (75 MHz, CDCl3) δ 141.3,
140.4, 137.2, 136.8, 136.3, 136.0, 135.8, 131.2, 129.6, 128.5,
128.3, 128.2, 126.8, 126.4, 125.5, 121.1, 120.4, 34.0, 30.5,
21.1, 20.2, 19.5; HRMS (APCI+) calcd. for C13H14S [M]+ m/z
202.0811, found 202.0806.
o
HFIP (2 ml) at 100 C (oil bath) for 48 h and purified by
petroleum ether as a colorless oil (198 mg, 75%).
1H NMR (300 MHz, CDCl3) δ 7.50 – 7.42 (m, 1.72H), 7.40 –
7.33 (m, 1.26H), 7.33 – 7.30 (m, 0.86H), 7.18 – 7.11 (m,
1.03H), 7.05 – 7.03 (m, 2.07H), 4.15 (s, 0.43H, minor), 4.04
(s, 1.40H, major), 2.36 (s, 2.51H, major), 2.28 (s, 1.28H,
minor), 2.24 (s, 2.18H, major); 13C{1H} NMR (75 MHz,
CDCl3) δ 141.9, 141.1, 137.2, 136.5, 136.5, 135.9, 134.9,
132.1, 131.5, 131.1, 130.0, 129.0, 128.9, 128.5, 127.2 (q, J =
154.5 Hz) , 127.0, 126.9, 125.5 (q, J = 3.8 Hz), 124.9 (q, J =
4.5 Hz), 123.0, 122.9 (q, J = 3.8 Hz), 39.0 (major), 35.0
(minor), 21.1 (major), 20.3 (minor), 19.7 (major); 19F NMR
(CDCl3, 188 MHz): δ -62.5 (s, 3F).
4-benzyl-1,2-dimethylbenzene (21) 20
The title compound was prepared between o-xylene (530.0
mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol) and
KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at 50
oC for 2 h and purified by petroleum ether as a colorless oil
(170 mg, 87%).
1H NMR (300 MHz, CDCl3) δ 7.42 – 7.02 (m, 8H), 4.13 (s,
0.76H, minor), 4.03 (s, 1.22H, major), 2.40 (s, 1.19H, minor),
2.33 (s, 3.45H, major), 2.25 (s, 1.32H, minor); 13C{1H} NMR
(75 MHz, CDCl3) δ 141.7 140.9, 138.8, 138.7, 137.1, 136.7,
135.3, 134.3, 130.4, 129.8, 129.0, 128.8, 128.5, 128.5, 128.4,
2,4-dimethyl-1-(4-(trifluoromethyl)benzyl)benzene (17) 8
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 4-trifluoromethylbenzyl alcohol (176.0 mg,
1.0 mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in
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128.2, 126.4, 126.1, 125.9, 125.5, 41.7, 40.2, 20.8, 19.9, 19.4,
130.7, 129.1, 128.9, 128.8, 128.6, 128.5, 127.4, 127.0, 126.6,
126.1, 126.0, 125.8, 125.7, 124.2, 41.7, 39.0, 33.8, 29.1, 24.2,
23.9;
1
2
3
4
5
6
7
8
15.5.
2-benzyl-1,4-dimethylbenzene (22) 20
The title compound was prepared between p-xylene (530.0
mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol) and
KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at 50
oC for 2 h and purified by petroleum ether as a colorless oil
(166 mg, 85%).
1-benzyl-4-methylbenzene (27) 20
The title compound was prepared between toluene (460.0 mg,
5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol) and KHSO4
(13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at 50 oC for 16
h and purified by petroleum ether as a colorless oil (155 mg,
85%).
1H NMR (300 MHz, CDCl3) δ 7.33 (t, J = 7.2 Hz, 2H), 7.25
(d, J = 7.1 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.6
Hz, 1H), 7.08 – 6.97 (m, 2H), 4.02 (s, 2H), 2.36 (s, 3H), 2.26
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 140.7, 138.8,
135.5, 133.6, 130.9, 130.3, 128.8, 128.5, 127.2, 126.0, 39.6,
21.1, 19.3.
1H NMR (300 MHz, CDCl3) δ 7.36 – 7.31 (m, 2H), 7.26 –
7.14 (m, 7H), 4.05 (s, 0.91H, minor), 4.00 (s, 1.08H, major),
2.37 (s, 1.60H, major), 2.30 (s, 1.37H, minor); 13C{1H} NMR
(75 MHz, CDCl3) δ 141.5, 140.5, 139.1, 138.2, 136.8, 135.7,
130.4, 130.1, 129.3, 129.0, 128.9, 128.9, 128.6, 128.5, 127.0,
126.6, 126.1, 126.0, 41.7, 39.6, 21.1, 19.8.
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2-benzyl-1,3,5-trimethylbenzene (23) 20
The title compound was prepared between mesitylene (600.0
mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol) and
KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at 50
oC for 2 h and purified by petroleum ether as a colorless oil
(183 mg, 87%).
diphenylmethane (28) 20
The title compound was prepared between benzene (390.0 mg,
5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol) and KHSO4
(13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at 80 oC for 16
h and purified by petroleum ether as a colorless oil (148 mg,
88%).
1H NMR (300 MHz, CDCl3) δ 7.30 (t, J = 7.2 Hz, 2H), 7.22 (t,
J = 7.1 Hz, 1H), 7.09 (d, J = 7.2 Hz, 2H), 6.97 (s, 2H), 4.10 (s,
2H), 2.37 (s, 3H), 2.28 (s, 6H); 13C{1H} NMR (75 MHz,
CDCl3) δ 140.3, 137.2, 135.8, 133.9, 129.0, 128.5, 128.0,
125.8, 34.9, 21.1, 20.3.
1H NMR (300 MHz, CDCl3) δ 7.42 – 7.33 (m, 4H), 7.32 –
7.24 (m, 6H), 4.07 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ
141.2, 129.1, 128.6, 126.2, 42.1.
1-benzylnaphthalene (29) 20
1-benzyl-4-octylbenzene (24)
The title compound was prepared between naphthalene (640.0
mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol) and
KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at 50
oC for 2 h and purified by petroleum ether as a colorless oil
(189 mg, 87%).
The title compound was prepared between 1-phenyloctane
(950.0 mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP/DCM
(9/1, 2 ml) at 50 oC for 2 h and purified by petroleum ether as
a colorless oil (202 mg, 72%).
1H NMR (300 MHz, CDCl3) δ 7.88 – 7.85 (m, 0.73H), 7.79 –
7.69 (m, 0.73H), 7.63 (d, J = 7.8 Hz, 1.46H), 7.50 (s, 0.34H),
7.33 – 7.26 (m, 2.68H), 7.17 – 7.06 (m, 5.73H), 4.32 (s,
1.41H, major), 4.01 (s, 0.59H, minor); 13C{1H} NMR (75
MHz, CDCl3) δ 141.1, 140.8, 138.7, 136.8, 134.1, 133.8,
132.3, 132.2, 129.2, 128.9, 128.8, 128.6, 128.6, 128.2, 127.8,
127.7, 127.5, 127.3, 127.2, 126.3, 126.2, 126.1, 126.0, 125.7,
125.5, 124.4, 42.2, 39.2.
1H NMR (300 MHz, CDCl3) δ 7.36 – 7.10 (m, 9H), 4.06 (s,
0.76H, minor), 3.99 (s, 1.24H, major), 2.64 – 2.57 (m, 2H),
1.65 – 1.50 (m, 2H), 1.31 (m, 10H), 0.92 (t, J = 6.5 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 141.5, 141.5, 141.2, 140.8,
138.4, 138.4, 130.5, 129.5, 129.1, 128.9, 128.6, 128.6, 128.5,
128.3, 126.6, 126.1, 126.0, 126.0, 42.1, 41.7, 39.0, 36.2, 35.7,
33.1, 32.1, 31.7, 31.1, 29.9, 29.6, 29.5, 29.4, 22.8, 14.3;
HRMS (APCI+) calcd. for C21H28 [M]+ m/z 280.2186, found
280.2175.
1-benzyl-4-fluorobenzene (30)
The title compound was prepared between fluorobenzene
(480.0 mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
1-benzyl-4-(tert-butyl)benzene (25) 5
The title compound was prepared between tert-butylbenzene
(670.0 mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
50 oC for 2 h and purified by petroleum ether as a colorless oil
(200 mg, 89%).
o
80 C for 16 h and purified by petroleum ether as a colorless
oil (102 mg, 55%).
1H NMR (300 MHz, CDCl3) δ 7.36 – 7.07 (m, 7H), 7.01 (t, J =
8.6 Hz, 2H), 4.05 (s, 0.41H, minor), 3.99 (s, 1.61H, major);
13C{1H} NMR (75 MHz, CDCl3) δ 161.6 (d, J = 242.3Hz),
141.1, 140.0, 136.9 (d, J = 3.8Hz), 131.2 (d, J = 4.5Hz), 130.4
(d, J = 8.3Hz), 129.0, 128.7, 128.1, 128.0 126.3, 124.2 (d, J =
3.0Hz), 115.4 (d, J = 22.5Hz), 115.3 (d, J = 21.0Hz), 41.2,
35.0; 19F NMR (CDCl3, 188 MHz): δ -117.4 (m, 0.8F), -117.9
(m, 0.2F); HRMS (APCI+) calcd. for C13H11F [M]+ m/z
186.0839, found 186.0838.
1H NMR (300 MHz, CDCl3) δ 7.40 – 7.26 (m, 7H), 7.20 (d, J
= 8.3 Hz, 1.57H), 7.06 (d, J = 6.0 Hz, 0.43H), 4.07 (s, 0.69H,
minor), 4.03 (s, 1.29H, major), 1.38 (s, 9H); 13C{1H} NMR (75
MHz, CDCl3) δ 151.4, 149.0, 141.4, 140.8, 138.2, 129.1,
129.1, 128.7, 128.6, 128.3, 126.2, 126.1, 125.5, 123.2, 42.3,
41.6, 34.8, 34.5, 31.5.
1-benzyl-4-isopropylbenzene (26) 21
The title compound was prepared between iso-propylbenzene
(600.0 mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
50 oC for 2 h and purified by petroleum ether as a colorless oil
(178 mg, 85%).
2-fluoro-1-methoxy-4-(2-methoxybenzyl)benzene (31)
The title compound was prepared between 2-fluoroanisol
(630.0 mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
rt for 2 h and purified by 20 % DCM in cyclohexane as a
colorless oil (200 mg, 81%).
1H NMR (300 MHz, CDCl3) δ 7.38 – 7.16 (m, 9H), 4.15 (s,
0.69H, minor), 4.04 (s, 1.30H, major), 3.27 – 3.18 (m, 0.34H,
minor), 3.00 – 2.91 (m, 0.65H, major), 1.32 (d, J = 6.9 Hz,
3.88H, major), 1.22 (d, J = 6.8 Hz, 2.24H, minor); 13C{1H}
NMR (75 MHz, CDCl3) δ 147.3, 146.7, 141.5, 138.6, 137.4,
1H NMR (300 MHz, CDCl3) δ 7.23 (t, J = 6.6, 1H), 7.10 (d, J
= 7.1 Hz, 1H), 6.99 – 6.84 (m, 5H), 3.92 (s, 2H), 3.87 (s, 3H),
3.84 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 157.4, 154.0,
150.8, 145.8 (d, J = 10.5 Hz), 134.4 (d, J = 6.0 Hz), 130.3,
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129.4, 127.7, 124.4 (d, J = 3.0 Hz), 120.6, 116.7 (d, J = 18.0
KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at rt for
2 h and purified by petroleum ether as a colorless oil (189 mg,
90%).
Hz), 113.5, 110.6, 56.5, 55.4, 35.1; 19F NMR (CDCl3, 188
MHz): δ -135.8 (dd, J = 13.2 Hz, 1F); HRMS (APCI+) calcd.
for C15H15O2F [M]+ m/z 246.1056, found 246.1044.
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1H NMR (300 MHz, CDCl3) δ 7.36 – 7.27 (m, 2H), 7.23 –
7.21 (m, 4H), 7.08 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 4.35 (q, J
= 7.1 Hz, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 1.66 (d, J = 7.2 Hz,
3H); 13C{1H} NMR (75 MHz, Chloroform-d) δ 146.6, 141.1,
136.0, 135.6, 131.4, 128.4, 127.8, 126.8, 125.9, 40.8, 22.3,
21.0, 19.8.
4-isopropyl-1-methoxy-2-(2-methoxybenzyl)benzene (32)
The title compound was prepared between 4-isopropylanisol
(750.0 mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP/DCM
(9/1, 2 ml) at rt for 0.5 h and purified by 20 % DCM in
cyclohexane as a white solid (210 mg, 78%).
(S)-2,4-dimethyl-1-(1-(4-nitrophenyl)ethyl)benzene (37) 18
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 1-(4-nitrophenyl)ethanol (167.0 mg, 1.0
mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2
ml) at 100 oC for 16 h and purified by 10 % DCM in
cyclohexane as a light yellow solid (221 mg, 87%).
9
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M.p.: 64 - 66 C; H NMR (300 MHz, CDCl3) δ 7.22 (t, J =
7.0 Hz, 1H), 7.07 (t, J = 6.6 Hz, 2H), 7.01 (s, 1H), 6.90 (d, J =
7.8 Hz, 2H), 6.84 (d, J = 8.3 Hz, 1H), 4.00 (s, 2H), 3.87 (s,
3H), 3.82 (s, 3H), 2.89 – 2.80 (m, 1H), 1.23 (d, J = 6.9 Hz,
6H); 13C{1H} NMR (75 MHz, CDCl3) δ 157.7, 155.9, 140.8,
130.3, 129.5, 129.0, 128.8, 127.1, 124.7, 120.4, 110.3, 110.3,
55.6, 55.4, 33.4, 30.2, 24.4; HRMS (ESI+) calcd. for
C18H22O2Na [M+Na]+ m/z 293.1517, found 293.1520.
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M.p.: 92 - 94 C; H NMR (300 MHz, CDCl3) δ 8.12 (d, J =
8.5 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 7.8 Hz, 1H),
7.05 (d, J = 8.1 Hz, 1H), 6.99 (s, 1H), 4.38 (q, J = 7.1 Hz, 1H),
2.32 (s, 3H), 2.17 (s, 3H), 1.63 (d, J = 7.2 Hz, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 154.5, 139.4, 136.4, 135.9, 131.7,
128.5, 127.1, 126.7, 123.8, 40.9, 22.0, 21.0, 19.8;
2-methoxy-1-(2-methoxybenzyl)naphthalene (33)
The title compound was prepared between 2-
methoxylnaphthalene (790.0 mg, 5.0 mmol), benzyl alcohol
(108.0 mg, 1.0 mmol) and KHSO4 (13.6 mg, 0.1 mmol, 0.1
equiv) in HFIP (2 ml) at rt for 0.5 h and purified by 20 %
DCM in cyclohexane as a white solid (208 mg, 75%).
1,4-dimethyl-2-(1-phenylethyl)benzene (38) 22
The title compound was prepared between p-xylene (530.0
mg, 5.0 mmol), (R)-1-phenylethanol (122.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
rt for 2 h and purified by petroleum ether as a colorless oil.
(139 mg, 66%).
M.p.: 128 - 130 oC; 1H NMR (300 MHz, CDCl3) δ 7.86 – 7.82
(m, 3H), 7.42 – 7.32 (m, 3H), 7.16 (t, J = 7.5 Hz, 1H), 6.94 (d,
J = 8.1 Hz, 1H), 6.71 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 7.3 Hz,
1H), 4.49 (s, 2H), 4.00 (s, 3H), 3.94 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 157.3, 155.4, 133.8, 129.4, 129.4, 128.7,
128.4, 128.3, 126.7, 126.5, 124.2, 123.4, 121.5, 120.5, 113.8,
109.9, 56.9, 55.6, 24.4; HRMS (ESI+) calcd. for C19H19O2
[M+H]+ m/z 279.1385, found 249.1394.
1H NMR (300 MHz, CDCl3) δ 7.35 – 7.27 (m, 2H), 7.24 –
7.21 (m, 3H), 7.14 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.00 (d, J
= 7.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 1H), 2.38 (s, 3H), 2.25 (s,
3H), 1.66 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 146.5, 143.8, 135.4, 133.0, 130.4, 128.4, 127.8,
127.6, 126.9, 125.9, 41.1, 22.2, 21.4, 19.4.
1-methoxy-2-(4-phenoxybenzyl)benzene (34)
The title compound was prepared between diphenyl ether
(850.0 mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP (2 ml) at
rt for 0.5 h and purified by 20 % DCM in cyclohexane as a
white solid (255 mg, 88%).
Gram Scale Reaction. To a stirred solution of m-xylene 1 (50
mmol, 5.3 g) and benzyl alcohol 2 (10 mmol, 1.08 g) in HFIP
(20 mL) was added KHSO4 (136 mg, 1.0 mmol) under air. The
o
reaction mixture was stirred at 50 C for 2 h. After that, the
mixture was transferred into a 250-mL separatory funnel. 50
mL DCM were added into the funnel and the mixture was
washed by 100 mL brine. Then, the organic layer was dried by
using anhydrous Na2SO4 and filtration. The mixture was
evaporated under reduce pressure and the crude product was
purified by column chromatography on silica gel using
petroleum ether as the eluent to give 3 as a colorless oil (1.66
g, 85%).
o
1
M.p.: 70 - 72 C; H NMR (300 MHz, CDCl3) δ 7.35 (t, J =
7.7 Hz, 2H), 7.27 – 7.21 (m, 3.09H), 7.18 – 7.01 (m, 4.20H),
7.01 – 6.84 (m, 4.31H), 4.06 (s, 0.25H, minor), 4.00 (s, 1.74H,
major), 3.86 (s, 2.63H, major), 3.80 (s, 0.33H, minor); 13C{1H}
NMR (75 MHz, CDCl3) δ 158.1, 157.6, 136.2, 132.8, 131.1,
130.7, 130.4, 130.3, 129.9, 129.8, 129.7, 127.6, 127.4, 123.9,
123.0, 122.6, 120.6, 120.5, 119.5, 119.0, 118.7, 118.0, 110.6,
110.4, 110.1, 55.5, 35.3 30.0; HRMS (ESI+) calcd. for
C20H18O2Na [M+Na]+ m/z 313.1204, found 313.1212.
2-bromo-5-(2-methoxybenzyl)thiophene (35)
ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at
http://pubs.acs.org.
The title compound was prepared between 2-bromothiophene
(810.0 mg, 5.0 mmol), benzyl alcohol (108.0 mg, 1.0 mmol)
and KHSO4 (13.6 mg, 0.1 mmol, 0.1 equiv) in HFIP/DCM
(9/1, 2 ml) at rt for 0.5 h and purified by 20 % DCM in
cyclohexane as a colorless oil (226 mg, 80%).
Copies of the 1H and 13C NMR spectra (PDF).
1H NMR (300 MHz, CDCl3) δ 7.26 (t, J = 7.7 Hz, 1H), 7.18
(d, J = 7.1 Hz, 1H), 6.98 – 6.88 (m, 2H), 6.86 (d, J = 3.6 Hz,
1H), 6.59 (d, J = 3.5 Hz, 1H), 4.09 (s, 2H), 3.87 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 157.1, 145.9, 130.1, 129.4,
128.3, 128.3, 125.3, 120.7, 110.6, 109.6, 55.4, 31.0; HRMS
(APCI+) calcd. for C12H12BrOS [M+H]+ m/z 282.9787, found
282.9776.
AUTHOR INFORMATION
Corresponding Author
* E-mail: benoit.crousse@u-psud.fr
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Central Glass Co. Ltd. is gratefully acknowledged for kindly
providing HFIP. R.-J. T. want to thanks the China Scholarship
(S)-2,4-dimethyl-1-(1-phenylethyl)benzene (36) 19
The title compound was prepared between m-xylene (530.0
mg, 5.0 mmol), 1-phenylethanol (167.0 mg, 1.0 mmol) and
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The Journal of Organic Chemistry
Nat. Rev. Chem. 2017, 1, 0088.10.1038/s41570-017-0088; (b) Li, G.
Council for a doctoral fellowship and in particular, Miss. Can
PENG for the patiently waiting and support over the years.
X.; Qu, J. Friedel–Crafts alkylation of arenes with epoxides promoted
by fluorinated alcohols or water. Chem. Commun. 2010, 46, 2653-
2655; (c) Motiwala, H. F.; Vekariya, R. H.; Aube, J. Org. Lett. 2015,
17, 5484-5487; (d) Vekariya, R. H.; Aube, J. Intramolecular Friedel–
Crafts Acylation Reaction Promoted by 1,1,1,3,3,3-Hexafluoro-2-
propanol. Org. Lett. 2016, 18, 3534-3537; (e) Weisner, N.; Khaledi,
M. G. Organic synthesis in fluoroalcohol-water two-phase systems.
Green Chem. 2016, 18, 681-685; (f) Gaster, E.; Kozuch, S.; Pappo, D.
Selective Aerobic Oxidation of Methylarenes to Benzaldehydes
Catalyzed by N‐Hydroxyphthalimide and Cobalt(II) Acetate in
Hexafluoropropan‐2‐ol. Angew. Chem. Int. Ed. 2017, 21, 5912-5915;
(g) Luan, Y.-X.; Zhang, T.; Yao, W.-W.; Lu, K.; Kong, L.-Y.; Lin,
Y.-T.; Ye, M. Amide-Ligand-Controlled Highly para-Selective
Arylation of Monosubstituted Simple Arenes with Arylboronic Acids.
J. Am. Chem. Soc. 2017, 139, 1786-1789; (h) Tang, R.-J.; Milcent, T.;
Crousse, B. Hexafluoro‐2‐propanol Promotes para‐Selective C–H
Amination of Free Anilines with Azodicarboxylates. Eur. J. Org.
Chem. 2017, 4, 4753-4757. (i) Bégué, J. P.; Bonnet-Delpon, D.;
Crousse, B. Fluorinated Alcohols: A New Medium for Selective and
Clean Reaction. Synlett, 2004, 18-28. (j) Berrien, J. F.; Ourevitch, M.;
Morgant, G.; Ghermani, N. E.; Crousse, B.; Bonnet-Delpon, D. J.
Fluorine Chem. 2007, 128, 839-843.
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