Benzylation of Arenes with Benzyl Halides under Promoter-Free and Additive-Free Conditions

Article abstract of DOI:10.1002/ejoc.201900590

It was found that benzyl chlorides and bromides could directly react with electron-rich arenes, which provided an example of promoter-free and additive-free benzylation of arenes. A variety of benzyl chlorides and bromides were treated with benzene rings to give the targeted products in low to high yields. The present conditions tolerated the vinyl group of the substrates. Preliminary mechanistic investigation suggests that the present reactions possibly proceed via an autocatalytic mechanism pathway.

Full text of DOI:10.1002/ejoc.201900590

A Journal of
Accepted Article
Title: Benzylation of Arenes with Benzyl Halides under Promoter-Free
and Additive-Free Condition
Authors: Xinqiang Cheng, Jiankai Shan, Xinzhe Tian, Yunlai Ren, and
Yanyan Zhu
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10.1002/ejoc.201900590
European Journal of Organic Chemistry
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Benzylation of Arenes with Benzyl Halides under Promoter-Free
and Additive-Free Condition
Xinqiang Cheng,[a] Jiankai Shan,[b] Xinzhe Tian,[a] Yun-Lai Ren*[a] and Yanyan Zhu*[b]
arenes with alkyl halides as the alkylating reagent,[18] in which
Abstract: It was found that benzyl chlorides and bromides could
directly react with electron-rich arenes, which provided an example
of promoter-free and additive-free benzylation of arenes. A variety of
benzyl chlorides and bromides were reacted with benzene rings to
give the targeted products in low to high yields. The present
condition tolerated the vinyl group of the substrates. Preliminary
mechanistic investigation suggests that the present reactions
possibly proceed via an autocatalytic mechanism pathway.
(Bu3Sn)2 was used as the radical initiator for the alkyl radical,
and the substrates were limited to several special arenes.
+
H
Ar
Promoter
a)
Ar
Ar
Substrate
R
R
Promoters: Lewis, Bronsted, solid acids or H-bond donor solvents
.
H
Ar
Oxidant
Oxidant
b)
X
R
R
R
X = B(OH), CO2R', BF3K, SO2M, HgCl, H, etc.
c) This work:
Introduction
Ar
H
- HCl
Ar
Cl
R
R
No promoter
Alkylation of arenes plays an important role in modern organic
synthesis[1-3] because it can serve as a powerful tool for the
formation of C(sp2)–C(sp3) bonds.[4a-d] As a result, a great deal of
attention has been paid to this class of reactions, and several
strategies have been developed. One is Friedel–Crafts reactions
Scheme 1. Alkylation of arenes.
Clearly, the above-mentioned processes rely on the
presence of various promoters or additive.[12-18]
By
comparison, a promoter- and additive-free process is a
more attractive goal from environmental and economic
perspectives.[19a] Thus we have attempted to actualize this
goal, and found that benzyl chlorides and bromides could
directly react with electron-rich arenes, which provided an
example of promoter-free and additive-free alkylation of
arenes (Scheme 1c).
based on the formation of
a strong electrophile with a
pronounced C+ character (Scheme 1a).[1-3] In general, Friedel–
Crafts alkylation reactions with alkyl halides, olefins and so on
require stoichiometric quantity of Lewis,[5a] Brønsted[5b,c] or solid
acids.[6] In addition, some strong hydrogen bonding donor
solvents such as hexafluoro-isopropanol, trifluoroacetic acid and
2,2,2-trifluoroethanol have been recently used to activate the C-
X bonds [7,8] and other Friedel–Crafts type reactions.[9]
Another strategy for alkylation of arenes relies on the
transition metal-catalyzed activation of the C-H bonds on the
aromatic rings.[10] For instance, arenes can be benzylated via
Ru- or Rh-catalyzed C−H activation with the assistance of
several proximal directing groups.[11]
Recently, radical oxidative couplings are emerging as an
interesting strategy for alkylation of arenes where the alkylation
reagents are required to be oxidized into the alkyl radicals
(Scheme 1b).[12,2c] For example, the radical alkylation of a variety
of arenes with alkylboronic acids[13] has been reported. At the
same time, alkanes,[12a] trifluoroborates,[14] sulfinates,[15]
alkylmercury halides,[16] carboxylic acid[12b,17] and their
derivatives have been used to form the alkyl radical coupling
partners for the alkylation. In addition, Trahanovsky and co-
workers have reported a base-promoted radical alkylation of
Results and Discussion
Our initial study aimed at the reactivity of benzyl chloride toward
mesitylene. When the reaction mixture was stirred at 140 C for
o
20 h, the targeted product was obtained in a GC yield as high as
86% (Table 1, entry 1), along with a small amount of 3,5-
dimethylbenzyl chloride by-product. In addition, the methyl in
mesitylene underwent the oxidation to give a small amount of
3,5-dimethylbenzaldehyde as the by-product, which was
possibly due to the presence of oxygen in the reaction
system.[19b-d] Indeed, a larger amount of oxidation by-product
was observed when the air in the reaction tube was replaced by
oxygen gas (Table 1, entries 2-6). Thus we performed the
reaction under argon atmosphere to inhibit the formation of the
by-product (Table 1, entry 7). As we expected, hardly any
products from the oxidation of the methyl group were observed
under the oxygen-free condition, which promoted us to carry out
all the following reactions under argon atmosphere.
[a] X. Q. Cheng, Ms X. Z. Tian, Prof. Y. L. Ren (Corresponding author)
School of Chemical Engineering & Pharmaceutics, Henan University of
Science and Technology, Luoyang, Henan 471003, P. R. China.
Email address: renyunlai@126.com
Further studies were undertaken to obtain higher yield and
more generally practical reaction conditions, and the results
were shown in Table 1. It was found that the present reaction
was highly dependent on the reaction temperature (Table 1,
[b] Ms Yanyan Zhu, Jiankai Shan
College of Chemistry and Molecular Engineering, Zhengzhou
University, Zhengzhou 450001, Henan Province, P.R. China
Email address: zhuyan@zzu.edu.cn
o
entries 7-12). 140 C allowed the reaction to proceed smoothly
with a complete conversion, and the desired product was
obtained in 91% yield (Table 1, entry 7), while the reaction at 60
oC gave the targeted product in only 2% yield (Table 1, entry 11).
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under: https://doi.org/
1
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10.1002/ejoc.201900590
European Journal of Organic Chemistry
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Table 2. Benzylation of mesitylene with benzyl chlorides or bromides.[a]
Sometimes, the decrease of the temperature to 120, 100, or 80
oC allowed the reaction to proceed with good results (Table 1,
entries 8-10), but the reproducibility of these experimental
results was not high according to our parallel experiments, so
140 oC was ascertained as the optimum temperature. Next, the
effect of the solvent on the reaction was investigated. The
results revealed that the use of the reactant (mesitylene) as the
solvent was required (Table 1, entry 7 vs entries 13-15), and the
addition of any other solvents resulted in poor results related to
the conversion and the yield.
X
R
R'
R
R'
+
Substrate A
Substrate B
Table 1. Benzylation of mesitylene under various conditions.[a]
Entry
Solvent
Ambience[b]
T [oC]
Yield [%][c]
1
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
air
O2
140
140
140
140
140
140
140
120
100
80
86
79
67
63
65
58
91
87
80
75
2
2
[d]
3
O2
[d]
4
O2
[d]
5
O2
[d]
6
O2
7
Ar
Ar
Ar
Ar
Ar
Ar
8
9
10
11
12
60
40
trace
cyclohexane/
mesitylene[e]
13
14
15
Ar
Ar
Ar
140
140
140
5
CH3CN/
6
mesitylene[e]
CCl4/
19
mesitylene[e]
[a] Reaction conditions: 0.5 mmol benzyl chloride, 2 mL solvent, 20 h. [b]
1 atm. [c] Determined by GC. [d] The pressure of O2 was respectively 0.5
MPa (entry 3), 1 MPa (entry 4), 2 MPa (entry 5) and 4 MPa (entry 6). [e]
The volume ratio of the two was 1:1.
With the optimal conditions in hand,
a
variety of
representative benzyl halides were used to explore the scope
and limitation of the new methodology. As shown in Table 2, the
present reaction was compatible with various groups, e.g. alkyl,
alkoxy, fluoro, bromo, and chloro group (Table 2, entries 2-11).
Even the highly reactive vinyl substituent was also tolerated
(Table 2, entries 8 and 25-27). Generally, all the electron-
donating group-substituted benzyl chlorides were good
substrates, and the reactions gave the targeted products in 72-
90% isolated yields (Table 2, entries 2-7). For example, a
complete coversion and 90% isolated yield were observed in the
case of 4-methoxybenzyl chloride (Table 2, entry 6). Surprisingly,
among the test benzyl chlorides with the electron-withdrawing
groups, only 4-fluorobenzyl chloride provided a satisfying result,
and the targeted product was obtained in an isolated yield as
high as 86% (Table 2, entry 9), while 4-chlorobenzyl chloride
[a] Reaction condition A: 0.5 mmol benzyl halide, 2mL Substrate B, 20 h,
140 oC, all the yields were the isolated yields. [b] Reaction condition B: 0.5
mmol benzyl halide, 2 mmol Substrate B, 1 mL cyclohexane, 20 h, 140 oC,
all the yields were the isolated yields.
Subsequently, we evaluated the reactivity of various benzene
rings under the optimized conditions, and the results were listed
in Table 2 (entries 16-27). Electron-rich benzene rings in
mesitylene, para-xylene and 4-methylanisole were reactive
toward benzyl chlorides and bromides (Table 2, entries 16-19
and 21-27), but no targeted product was observed in the case of
electron-deficient or electron-neutral benzene rings of
and 4-bromobenzyl
chloride underwent
the present
transformation in 57% and 51% yields (Table 2, entries 10 and
11), respectively. By comparison, the chloro or bromo group-
substituted benzyl bromides[20] was found to give higher yields
(Table 2, entry 13-15).
2
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10.1002/ejoc.201900590
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chlorobenzene and benzene (Table 2, entry 20). These results
indicated that the presence of the strong electron-donating
substituent group had a positive effect on the reactivity of
product (Scheme 3a). In addition, the addition of the radical
scavengers such as 2,6-ditbutyl-4-methylphenol (BHT) and
TEMPO[25] resulted in a dramatic decrease in the yield of the
benzene rings. When 4-methylanisole was used as the substrate, targeted product (Scheme 4), which revealed that the
the benzylation reaction selectively occurred at the ortho-
position with regard to the methoxy group (Table 2, entries 18
and 19), although this position had a larger steric hindrance than
the position ortho to the methyl group.[21] In addition, we tried the
benzylation of 1,4-dimethoxybenzene with benzyl chloride under
the standard condition (Condition A in Table 2), and the targeted
product was obtained in a high GC yield (83%), but it was
difficult to isolate the product due to higher boiling and melting
point of this substrate. Thus we had to reduce the used amount
of the substrate by an addition of the solvent like cyclohexane
(Condition B in Table 2). As shown as Table 2 (entries 21-25
and 27), such a condition allowed a series of benzene rings in
preferential pathway involved the radicals.
Scavenger
no
Yield
86%
7%
Mesitylene
Standard conditions
Cl
BHT
5 equiv radical scavenger
TEMPO trace
.
Scheme 4. Effect of the radical scavengers on the reaction (for the standard
conditions, see Condition A in Table 2).
Indeed, the following results from our DFT calculation
suggest that the ion-type mechanism should be excluded. (1)
Based on our calculation, the present reaction condition does
not allow more than 33.5 kcal/mol energy barrier to be overcome,
while the heterolytic cleavage energy of the C-Cl bond in benzyl
chloride is as high as 69.6 kcal/mol (Scheme 5a), revealing that
the heterolytic cleavage does not occur under our condition. (2)
The direct reaction between benzyl chloride and the benzene
ring requires a transition state (TS1) with as high as 45.7
kcal/mol energy barrier (Scheme 5b), which suggests that this
ion-type mechanism pathway is also unreasonable.
1,2,3-trimethoxybenzene,
1,4-dimethoxybenzene
and
1-
methoxynaphthalene to be smoothly benzylated to give the
products in 71-93% yields.
Standard conditions
Cl
+
Reaction tube
a) tube
b) PTFE-lined tube
Yield
91%
86%
+
×
ΔG = 69.6 kcal/mol
Cl
Cl
+ Cl-
a)
b)
Scheme 2. Effect of the reaction vessel on the reaction (for the standard
conditions, see Condition A in Table 2).
δ+
δ-
×
+ Cl-
[TS1]
ΔG‡= 45.7 kcal/mol
+
+
It was possible that the present transformation was being
induced by Lewis acid metal impurities in the reaction system.[22]
To rule out this possibility, we analysed the reaction system
using inductively coupled plasma mass spectroscopy (ICP-MS),
but no detectable amount of metal impurities was observed.
Maybe the inner wall of the reaction tube played the role of the
promoter for the reaction, but this possibility was also ruled out
based on our experimental results: a change of the reaction tube
from glassware to a new polytetrafluoroethylene (PTFE)-lined
tube had no significant effect on the reaction (Scheme 2a vs 2b).
By all appearance, all the experimental results above confirmed
the reliability of our conclusion that the present reaction was
promoter-free.
.
+
.
[TS2]
c)
ΔG‡= 28.8 kcal/mol
Scheme 5. Results from our DFT calculation (for TS1 and TS1, see Scheme
S4 and S5 in the supporting information).
It is noteworthy that the alkyl radicals are a kind of weakly
nucleophilic radicals (Scheme 5c),[13] thus the radical-type
mechanism[26] is not consistent with our experimental results that
electron-rich arenes were preferentially benzylated over
electron-deficient arenes. However, this can be rationalized by
assuming that the homolytic cleavage of the C-Cl bond is
incomplete in the present reaction, and the resulting benzyl
radical (see Transition state I in Scheme 6) has a cationic and
electrophilic characteristic due to an electron-withdrawing
inductive effect of the Cl atom.
If O2 was added
Ar CHO
.
.
.
.
.
(Observed
by-products)
Bn
Cl
Cl Bn
Ar CH2
Ar CH3
a)
b)
Ar CH2Cl
δ-
δ+
Bn
×
No oxidant
Ar CH3 +
Cl
Ar CH2Cl
+
.
.
.
δ
-
.
δ
(Suggesting the formation of
Cl Bn
)
Cl
Δ
Cl
I
Scheme 3. Possible mechanism pathways for the chlorination.
Scheme 6. The benzylation via the incomplete homolytic cleavage of the C-Cl
bond.
Afterwards, our attention was turned to the investigation on
the reaction mechanism. In any case, it was observed that
methyl group of mesitylene underwent the chlorination[23,24] to
give 3,5-dimethyl-benzyl chloride by-product (Scheme 3).
Obviously, this by-product should be formed via one of the two
kinds of pathways based on previous literatures:[23,24] One
involved the chlorine radical (Scheme 3a),[23] and the other
required the presence of strong oxidants (Scheme 3b).[24]
Actually, the latter mechanistic pathway should be excluded
because there was no any strong oxidant in our reaction system.
Thus it was reasonable that the chlorine radical was formed in
our reaction system based on the observed chlorination by-
Subsequently, a radical clock experiment with the benzyl
chloride bearing a cyclopropyl group was performed to confirm
the existence of the benzylic radical[26d] (Scheme 7). Strangely,
the substrate bearing a cyclopropyl group was less reactive,
which could not confirm the existence of the benzylic radical.
Standard conditions
Cl
+
No coupling product
Scheme 7. Radical clock experiment (for the standard conditions, see
Condition A in Table 2).
3
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10.1002/ejoc.201900590
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FULL PAPER
mm). GC-MS spectra were recorded on an Agilent 7890/5973N gas
chromatography-mass spectrometry instrument. Data are reported as
follows: m/z, % relative intensity, and possible fragment.
The benzylation with benzyl chloride would give HCl as the
by-product. Presumably the resulting HCl played a role of the
catalyst for the continuing Friedel–Crafts reaction based on
previous literatures.[5,6] Indeed, the reaction displayed an
induction period and a sigmoid kinetic profile characteristic of
autocatalytic systems (Scheme 8),[3a,7] which suggests that the
Typical procedure for the benzylation of arenes with benzyl halides:
Reaction condition A: To a dried about 40 mL tube equipped with a
magnetic stirring, 0.5 mmol benzyl halide and 2 mL substituted benzene
were added under Ar atmosphere. The reaction tube was sealed with a
septum and placed in a constant-temperature oil bath set at 140 oC to
perform the reaction for 20 h. Once the reaction time was reached, the
mixture was cooled to room temperature. The products were purified by
silica gel column chromatography on silica gel (200-300 mesh) using
EtOAc/petroleum ether as the eluent, and identified by 1H-NMR and
13C-NMR.
reaction is an autocatalytic process
.
100
80
60
40
20
0
0
2
4
6
8
10 12
Time/h
14 16 18
20
Reaction condition B: To a dried about 40 mL tube equipped with a
magnetic stirring, 0.5 mmol benzyl halide, 2 mmol substituted benzene
and 1 mL cyclohexane were added under Ar atmosphere. The reaction
tube was sealed with a septum and placed in a constant-temperature oil
bath set at 140 oC to perform the reaction for 20 h. Once the reaction
time was reached, the mixture was cooled to room temperature. The
products were purified by silica gel column chromatography on silica
gel (200-300 mesh) using EtOAc/petroleum ether as the eluent, and
identified by 1H-NMR and 13C-NMR.
Scheme 8. Benzylation of mesitylene with benzyl chloride (for the reaction
conditions, see Condition A in Table 2).
According to the above-mentioned observations,
a
autocatalytic mechanism pathway is proposed and shown in
Scheme 9. At the present stage, the mechanism of the initiation
step can not be clarified. Perhaps the initiation step involves an
incomplete homolytic cleavage of the C-Cl bond shown in
Scheme 6,[27,28] or an ion-type mechanism.[5,6]
Computational details: Using the Gaussian 09 program, all theoretical
calculations were carried out at the M06-2X/6-31G (d) level in mesitylene
with the SMD continuum model at 413.15 K. And the corresponding
vibrational frequencies were calculated at the same level to take account
of free energy contributions. What has been confirmed is that all the
reactants, intermediates, and products have no imaginary frequencies
whereas each transition state has only one imaginary frequency.
Furthermore, the intrinsic reaction coordinate (IRC) calculations were
also performed at the same level to ensure that the transition states led
to the expected reactants and products. The single-point energies of the
optimized structures were then refined at the M06-2X/6-311++G (2df,
2pd) level of theory in the solvent (mesitylene) with the SMD continuum
model at 413.15 K. And all energies reported in this article include the
zero-point vibrational energy (ZPVE) correction.
Cl
+ HCl
+ H+
Initiation:
Ion-type or radical-type mechanism
+
H+
HCl
Mesitylene
Cl
Catalysis of HCl:
Scheme 9. Proposed mechanism pathways for the benzylation.
Conclusions
In conclusion, a promoter-free and additive-free method was
developed for the benzylation of benzenes with benzyl halides.
A variety of benzyl chlorides and bromides were reacted with
benzene rings to afford the targeted products in low to high
yields. This provides a method for the synthesis of many 1,1-
diarylmethanes and 1,1,1-triarylmethanes that often occur as the
useful structural motifs in natural products or bioactive
molecules.[4] Interestingly, the present condition tolerated the
vinyl group of the substrates. Preliminary mechanistic
investigation suggests that the present reactions possibly
proceed via an autocatalytic mechanism pathway where the
resulting HCl plays a role of the catalyst for the continuing
reaction. These findings may be helpful for chemists to develop
new, economical and green methods for the alkylation or
functionalization of arenes under catalyst-free, promoter-free
and additive-free condition.
The spectroscopic data of the isolated products:
Phenyl-(2,4,6-trimethylphenyl)methane[29a] (Table 2, entries 1 and
1
12): Colorless oil; H NMR (500 MHz, CDCl3): δ (ppm) = 7.32 (t, J = 7.5
Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 6.99 (s, 2H),
4.12 (s, 2H), 2.39 (s, 3H), 2.30 (s, 6H); 13C NMR (125 MHz, CDCl3): δ
(ppm) = 140.2, 137.1, 135.7, 133.9, 129.0, 128.4, 127.9, 125.7, 34.8,
21.0, 20.2.
(2-Methylphenyl)-(2,4,6-trimethylphenyl)methane[29b] (Table 2, entry
2): White solid; 1H NMR (500 MHz, CDCl3): δ (ppm) = 7.17 (d, J = 7.4 Hz,
1H), 7.07 (t, J = 7.4 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.90 (s, 2H), 6.50 (d,
J = 7.7 Hz, 2H), 3.86 (s, 2H), 2.41 (s, 3H), 2.30 (s, 3H), 2.14 (s, 6H);
13C NMR (125 MHz, CDCl3): δ (ppm) = 140.0, 137.2, 136.3, 135.6, 133.6,
129.7, 128.9, 126.3, 126.1, 125.7, 32.0, 21.0, 19.9, 19.8.
(3-Methylphenyl)-(2,4,6-trimethylphenyl)methane[29b] (Table 2, entry
3): Colorless oil; 1H NMR (500 MHz, CDCl3): δ (ppm) = 7.10 (t, J = 7.6 Hz,
1H), 6.95 (d, J = 7.5 Hz, 1H), 6.88 (s, 2H), 6.85 (s, 1H), 6.78 (d, J = 7.3
Hz, 1H), 3.97 (s, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 2.20 (s, 6H); 13C NMR
(125 MHz, CDCl3): δ (ppm) = 140.1, 137.9, 137.1, 135.6, 133.9, 128.9,
128.7, 128.3, 126.5, 124.9, 34.7, 21.5, 21.0, 20.2.
Experimental Section
1
General: H-NMR and 13C-NMR spectra were recorded on a Bruker 500
or 400 MHz instrument with chemical shifts reported in ppm relative to
the internal standard tetramethylsilane. Gas chromatography analyses
were performed on a Varian CP-3800 instrument with a FID detector and
a CP-WAX 57CB FS capillary chromatographic column (25 m × 0.32
(4-Methylphenyl)-(2,4,6-trimethylphenyl)methane[29a] (Table 2, entry
1
4): Colorless oil; H NMR (500 MHz, CDCl3): δ (ppm) = 7.02 (d, 2H, J =
4
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10.1002/ejoc.201900590
European Journal of Organic Chemistry
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7.9 Hz), 6.89 (d, 2H, J = 7.9 Hz), 6.87 (s, 2H), 3.97 (s, 2H), 2.28 (s, 6H),
2.19 (s, 6H); 13C NMR (125 MHz, CDCl3): δ (ppm) = 137.1, 137.0, 135.6,
135.1, 134.1, 129.1, 128.9, 127.8, 34.3, 21.0, 20.96, 20.2.
1H), 5.94 (s, 1H), 3.70 (s, 3H), 3.69 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ (ppm) = 153.4, 151.6, 143.7, 134.1, 129.5, 128.2, 126.1, 117.5,
111.9, 111.1, 56.4, 55.6, 49.8.
(4-tButylphenyl)-(2,4,6-trimethylphenyl)methane[29a] (Table 2, entry
5): White solid; 1H NMR (500 MHz, CDCl3): δ (ppm) = 7.32 (d, J = 8.3 Hz,
2H), 7.02 (d, J = 8.3 Hz, 2H), 6.96 (s, 2H), 4.05 (s, 2H), 2.36 (s, 3H), 2.29
(s, 6H), 1.36 (s, 9H); 13C NMR (125 MHz, CDCl3): δ (ppm) = 148.4, 137.0,
135.6, 134.2, 128.9, 127.6, 125.2, 34.3, 34.26, 31.5, 21.0, 20.2.
1,2,3-Trimethoxy-4-benzylbenzene[29g] (Table 2, entry 22): White solid;
1H NMR (400 MHz, CDCl3): δ (ppm) = 7.19–7.33 (m, 5 H), 6.83 (d, J =
8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 3.97 (s, 2H), 3.91 (s, 3H), 3.87 (s,
3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 152.4, 151.9,
142.4, 141.5, 128.8, 128.3, 127.4, 125.9, 124.5, 107.2, 60.8, 56.0, 35.8.
(4-Methoxyphenyl)-(2,4,6-trimethylphenyl)methane[8] (Table 2, entry
6): White solid; 1H NMR (500 MHz, CDCl3): δ (ppm) = 6.98 (d, J = 8.4 Hz,
2H), 6.94 (s, 2H), 6.83–6.85 (m, 2H), 4.01 (s, 2H), 3.81 (s, 3H), 2.35 (s,
3H), 2.27 (s, 6H); 13C NMR (125 MHz, CDCl3): δ (ppm) = 157.7, 137.0,
135.6, 134.2, 132.1, 128.9, 128.8, 113.8, 55.3, 33.8, 20.9, 20.1.
1,2,3-Trimethoxy-4-benzhydrylbenzene[29f] (Table 2, entry 23): White
solid; 1H NMR (500 MHz, CDCl3): δ (ppm) = 7.37 (t, J = 7.5 Hz, 4H),
7.26–7.31 (m, 6H), 6.78 (dd, J1 = 15.0 Hz, J2= 9.0 Hz, 2H), 6.03 (s, 1H),
3.99 (s, 3H), 3.89 (s, 3H), 3.65 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
(ppm) = 152.5, 151.9, 144.2, 142.5, 130.8, 129.6, 128.4, 126.3, 124.6,
106.9, 60.7, 60.6, 55.9, 50.2.
(3,4-Dimethoxyphenyl)-(2,4,6-trimethylphenyl)methane[8] (Table 2,
entry 7): White solid; 1H NMR (500 MHz, CDCl3): δ (ppm) = 6.93 (s, 2H),
6.75 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H), 6.50 (td, J1 = 8.2 Hz, J2
= 1.0 Hz, 1H), 4.00 (s, 2H), 3.86 (d, J = 9.1 Hz, 6H), 2.33 (s, 3H), 2.26 (s,
6H); 13C NMR (125 MHz, CDCl3): δ (ppm) = 1148.9, 147.1, 137.0, 135.6,
133.9, 132.7, 128.9, 119.4, 111.5, 111.2, 55.9, 55.8, 34.2, 20.9, 20.1.
1-Methoxy-4-benzylnaphthalene[29a] (Table 2, entry 24): White solid;
1H NMR (500 MHz, CDCl3): δ (ppm) = 8.42–8.44 (m, 1H), 8.00–8.02 (m,
1H), 7.54-7.56 (m, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.29 (dd, J1 = 7.5 Hz, J2=
4.5 Hz, 4H), 6.84 (d, J = 8.0 Hz, 1H), 4.47 (s, 2H), 4.07 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ (ppm) = 154.6, 141.2, 133.0, 128.8, 128.6, 128.5,
127.3, 126.6, 126.1, 126.0, 125.0, 124.3, 122.6, 103.4, 55.5, 38.72.
(4-Vinylphenyl)-(2,4,6-trimethylphenyl)methane[8] (Table 2, entry 8):
1
Colorless oil; H NMR (500 MHz, CDCl3): δ (ppm) = 7.35 (d, J = 8.2 Hz,
1,2,3-Trimethoxy-4-(4-vinylbenzyl)benzene[29g] (Table 2, entry 25):
White solid; 1H NMR (500 MHz, CDCl3): δ (ppm) = 7.38 (d, J = 8.5 Hz,
2H), 7.22 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.5 Hz, 1H), 6.74 (dd, J1 = 17.5
Hz, J2= 11.0 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.76 (d, J = 17.5 Hz, 1H),
5.24 (d, J = 11 Hz, 1H), 3.97 (s, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.81(s,
3H); 13C NMR (125 MHz, CDCl3): δ (ppm) = 152.5, 151.9, 142.5, 141.3,
136.7, 135.3, 129.0, 127.2, 126.3, 124.5, 113.0, 107.2, 60.77, 60.75,
56.0, 35.6.
2H), 7.05 (d, J = 8.1 Hz, 2H), 6.97 (s, 2H), 6.74 (dd, J1 = 17.6 Hz, J2=
10.9 Hz, 1H), 5.75 (d, J = 17.6 Hz, 1H), 5.25 (d, J = 10.9 Hz, 1H), 4.08 (s,
2H), 2.37 (s, 3H), 2.28 (s, 6H); 13C NMR (125 MHz, CDCl3): δ (ppm) =
139.9, 137.0, 136.7, 135.8, 135.2, 133.7, 129.0, 128.1, 126.3, 113.0,
34.5, 21.0, 20.2.
(4-Fluorophenyl)-(2,4,6-trimethylphenyl)methane[29a] (Table 2, entries
9 and 13): Colorless oil; 1H NMR (500 MHz, CDCl3): δ (ppm) = 7.03–7.06
(m, 2H), 6.98–7.02 (m, 4H), 4.06 (s, 2H), 2.38 (s, 3H), 2.28 (s, 6H);
13C NMR (125 MHz, CDCl3): δ (ppm) = 162.2, 160.3, 137.0, 135.9, 135.7,
135.68, 133.7, 129.2, 129.15, 129.1, 115.2, 115.1, 33.9, 20.96, 20.1.
[29g]
3-(4-Vinylbenzyl)-4-methoxytoluene
(Table 2, entry 26): Pale
yellow solid; 1H NMR (500 MHz, CDCl3): δ (ppm) = 7.31 (d, J = 8.1 Hz,
2H), 7.16 (d, J = 8.1 Hz, 2H), 6.98 (dd, J1 = 8.3 Hz, J2 = 1.8 Hz, 1H), 6.87
(d, J = 1.9 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.68 (dd, J1 = 17.6 Hz, J2 =
10.9 Hz, 1H), 5.68 (dd, J1 = 17.6 Hz, J2 = 1.0 Hz, 1H), 5.17 (dd, J1 = 10.9
Hz, J2 = 0.9 Hz, 1H), 3.92 (s, 2H), 3.77 (s, 3H), 2.22 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ (ppm) = 155.3, 141.0, 136.8, 135.2, 131.1, 129.7,
129.3, 129.1, 127.7, 126.2, 112.9, 110.5, 55.6, 35.6, 20.5.
(4-Chlorophenyl)-(2,4,6-trimethylphenyl)methane[29a]
(Table
2,
entries 10 and 14): Colorless oil; 1H NMR (500 MHz, CDCl3): δ (ppm) =
7.23 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.94 (s, 2H), 4.0 (s, 2H),
2.34 (s, 3H), 2.23 (s, 6H); 13C NMR (125 MHz, CDCl3): δ (ppm) = 138.6,
136.9, 136.0, 133.3, 131.4, 130.4, 129.2, 129.0, 128.5, 34.1, 20.9, 20.1.
1-Methoxy-4-(4-vinylbenzyl)naphthalene[29a] (Table 2, entry 27):
(4-Bromophenyl)-(2,4,6-trimethylphenyl)methane[29c]
(Table
2,
Pale yellow solid; 1H NMR (500 MHz, CDCl3): δ (ppm) = 8.36-8.38 (m,
1H), 7.94-7.96 (m, 1H), 7.50-7.52 (m, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.25
(d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 6.81 (d, J = 7.8 Hz, 1H), 6.73
(dd, J1 = 17.6 Hz, J2 = 10.9 Hz, 1H), 5.74 (d, J = 17.6 Hz, 1H), 5.24 (d, J
= 10.9 Hz, 1H), 4.41 (s, 2H), 4.04 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
(ppm) = 154.6, 140.9, 136.7, 135.4, 132.9, 128.9, 128.4, 127.2, 126.6,
126.3, 126.1, 125.0, 124.2, 122.6, 113.1, 103.4, 55.5, 38.5
entries 11 and 15): Colorless oil; 1H NMR (500 MHz, CDCl3): δ (ppm) =
7.39 (d, J = 8.4 Hz, 2H), 6.92–6.95 (m, 4H), 4.0 (s, 2H), 2.35 (s, 3H), 2.23
(s, 6H); 13C NMR (125 MHz, CDCl3): δ (ppm) = 139.2, 137.0, 136.0,
133.2, 131.4, 129.6, 129.0, 119.5, 34.2, 21.0, 20.1.
Phenyl-(2,5-dimethylphenyl)methane[29d] (Table 2, entries 16 and 17):
Colorless oil; 1H NMR (500 MHz, CDCl3): δ (ppm) = 7.37 (t, J = 7.4 Hz,
2H), 7.28 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 7.6 Hz,
1H), 7.07 (d, J = 7.6 Hz, 1H), 7.04 (s, 1H), 4.06 (s, 2H), 2.39 (s, 3H), 2.30
(s, 3H); 13C NMR (125 MHz, CDCl3): δ (ppm) = 140.7, 138.8, 135.4,
133.5, 130.9, 130.3, 128.8, 128.4, 127.2, 126.0, 39.5, 21.1, 19.3.
Acknowledgments
(4-Methoxyphenyl)-(2-methoxy-5-methylphenyl)methane[29e] (Table 2,
entries 18 and 19): Pale yellow solid; 1H NMR (500 MHz, CDCl3): δ
(ppm) = 7.19 (d, J = 8.7 Hz, 2H), 7.03 (dd, J1 = 8.2 Hz, J2 = 1.8 Hz, 1H),
6.93 (d, J = 1.9 Hz, 1H), 6.88 (d, J = 9.6 Hz, 2H), 6.82 (d, J = 8.3 Hz, 1H),
3.94 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 2.29 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ (ppm) = 157.8, 155.3, 133.3, 131.0, 129.9, 129.86, 129.7,
127.6, 113.7, 110.5, 55.6, 55.3, 35.0, 20.5.
The authors would like to thank the financial supports from
the National Natural Science Foundation of China (Grant
No. 21603060).
Keywords: alkylation · benzylation · benzyl halide · arenes
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10.1002/ejoc.201900590
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
C-C bond formation
Ar'
No any promoter or additive
X
X = Cl, Br
Ar
Ar
Ar'
Xinqiang Cheng, Jiankai Shan, Xinzhe
Tian, Yun-Lai Ren* and Yanyan Zhu*
It was found that benzyl chlorides and bromides could directly react with electron-
rich arenes, which provided an example of promoter- and additive-free benzylation
of arenes.
Page No.1 – Page No.6
Benzylation of Arenes with Benzyl
Halides under Promoter-Free and
Additive-Free Condition
8
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