Conversion of Aryl Aldehydes to Benzyl Iodides and Diarylmethanes by H3PO3/I2

Article abstract of DOI:10.1021/acs.joc.0c02850

For the first time, H3PO3 was used as both the reducing reagent and the promotor in the reductive benzylation reactions with aryl aldehydes. By using a H3PO3/I2 combination, various aromatic aldehydes underwent iodination reactions and Friedel-Crafts type reactions with arenes via benzyl iodide intermediates, readily producing benzyl iodides and diarylmethanes in good yields. Intramolecular cyclization reactions also took place, giving the corresponding cyclic compounds. This new strategy features easy-handling, low-cost, and metal-free conditions.

Full text of DOI:10.1021/acs.joc.0c02850

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Note
Conversion of Aryl Aldehydes to Benzyl Iodides and Diarylmethanes
by H3PO3/I2
Fang Lv, Jing Xiao,* Junchun Xiang, Fengzhe Guo, Zi-Long Tang, and Li-Biao Han*
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ABSTRACT: For the first time, H3PO3 was used as both the reducing
reagent and the promotor in the reductive benzylation reactions with aryl
aldehydes. By using a H3PO3/I2 combination, various aromatic aldehydes
underwent iodination reactions and Friedel−Crafts type reactions with
arenes via benzyl iodide intermediates, readily producing benzyl iodides and
diarylmethanes in good yields. Intramolecular cyclization reactions also took
place, giving the corresponding cyclic compounds. This new strategy
features easy-handling, low-cost, and metal-free conditions.
Scheme 1. Synthesis of Benzyl Iodides and Diarylmethanes
from Aromatic Aldehydes
enzyl iodides are versatile building blocks in organic
synthesis due to its high reactivity in chemical trans-
B
formations. One of the general methods for preparing benzyl
iodides is the reductive iodination of aryl aldehydes using
LiAlH4, organosilicon, etc., followed by treating with sodium
iodide.1 Alternatives methods by using H2/NaI/Ru or H2/I2/
Rh, etc., were also known.2 Diarylmethanes are also important
structural units and have received considerable attention in
medicines, functional materials, and organic synthesis.3 The
Friedel−Crafts (F−C) alkylation reaction is one of the
fundamental methods for preparing diarylmethanes. A variety
of alkylating reagents such as benzyl halides,4 benzylic
alcohols,5 alkenes,6 and benzyl hydroxamates,7 etc., are used
in F−C alkylation reactions. Among the reported methods,
reductive benzylation of arenes using aromatic aldehydes is an
attractive protocol to access these compounds.8,9 Although the
reactions have been extensively studied, the following short-
comings remain: (1) expensive or hazardous reductants such as
silicohydrides,10,11 sodium borohydride,12 and hydrazine13 are
required; (2) metal Lewis acids such as Fe,10,11 Al,14 Sc,15,16
and In17 are usually required (Scheme 1b). Thus, the
development of cheap, green, and metal-free methods for the
synthesis of benzyl iodides and diarylmethanes is highly
desirable.
Phosphorus acid (H3PO3) is a cheap, low-toxic, and readily
available industrial material. It is estimated that millions of tons
of phosphorus acid were produced as byproduct from the
process of electroless nickel plating using H3PO2 and other
chemical transformations. However, a large amount of H3PO3
is disposed as waste. Recently, we are interested in the
utilization of H3PO3 in organic synthesis because of its green,
economic, and good ability in reduction reactions.18 In view of
our previous report on the reaction of aldehydes with
phosphorus compounds,18a we envisioned that, if aromatic
aldehydes can be reduced by the H3PO3/I2 system to form
benzyl iodides, which further reacted with arenes in one pot to
yield diarylmethanes via a H3PO3 promoted F−C benzylation
reaction, a cheaper, greener, and more practical approach for
preparing benzyl iodides and diarylmethanes may be realized.
Herein, we report that, by using a H3PO3/I2 combination, we
have succeeded in preparing various benzyl iodides and
diarylmethanes from aromatic aldehydes (Scheme 1a). As
Received: November 30, 2020
Published: January 13, 2021
https://dx.doi.org/10.1021/acs.joc.0c02850
© 2021 American Chemical Society
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Note
a
described below, studies carried out these reactions using
expensive reductants and metal Lewis acids, etc.
Table 2. Synthesis of Benzyl Iodides
We have reported that benzyl iodides could be reduced to
18b
the corresponding toluene by H3PO3/I2 and this reduction
is faster than the reduction of aromatic aldehydes. Therefore,
reactions shown in Scheme 1a should be difficult to achieve
under normal conditions. Fortunately, we noted that H3PO3 is
only sparingly soluble in organic solvent, and the melting point
of H3PO3 is about 74 °C. We, therefore, envisioned that, by
adjusting the concentration of H3PO3 using different solvents
or reaction temperatures, we should be able to manage the
generation of HI so that it can be released slowly from the
H3PO3/I2 combination, and thus avoid undesired reduction of
benzyl iodides as expected.
To achieve an efficient formation of benzyl iodides, we
began the work with the reaction of benzaldehyde 1a with I2.
As shown in Table 1, 48% yield of benzyl iodide 2a was
a
Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: a mixture of 1 (0.6 mmol), H3PO3 (2.5 equiv),
b
and I2 (0.7 equiv) was stirred in DCE (1.2 mL) at 60 °C for 13 h. 80
°C.
entry
H3PO3 (equiv)
I2 (equiv)
solvent
yield (2a) (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
2.0
2.0
2.5
2.5
2.5
2.5
2.5
2.5
3.0
2.0
2.5
2.5
2.5
0.5
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
benzene
benzene
benzene
THF
CHCl3
CH3CN
PhCl
DCE
DCE
DCE
DCE
48
64
89
31
87
9
high yields (2b−2e). 4-Biphenylcarboxaldehyde was also
applicable to this reaction, giving the desired product 2f in
85% yield. Substrates with halogen groups on the benzene ring
also reacted with I2 smoothly, furnishing the products in high
yields (2g−2i). Similarly, aldehydes bearing electron-deficient
groups such as MeOC(O) and CF3 could also afford the
products 2j and 2k with 81% and 94% yield, respectively.
Multiple substituted aldehydes could also be used in this
reaction to produce the corresponding products in good yields
(2l and 2m). However, no corresponding iodides were
obtained from aliphatic aldehydes such as 3-phenylpropanal
and 2-methylpentanal, 4-ethynylbenzaldehyde, and ketones
due to their possible polymerization under this acid condition.
Next, we turned our attention to explore this reductive
benzylation reactions. After an extensive screening of the
reaction conditions (see Supporting Information for detail),
the substrate scope of the synthesis of diarylmethanes is
summarized in Table 3. To our delight, whether 2.0 equiv or a
large excess (as solvent) of arenes was used, good to excellent
yields could be obtained. For example, when mesitylene was
used as both substrate and solvent, 93% isolated yield of the
product was obtained. Benzaldehyde reacted with 2.0 equiv of
mesitylene in DCE could also afford the same product in 74%
yield (3a). Aldehydes with electron-rich groups at the ortho or
para position on the benzene ring were also well tolerated,
furnishing the products in good to high yields (3b−3e).
Moreover, substrates bearing a phenyl group and halogens are
amenable to this transformation (3f−3i). Gratifyingly, good
yields of products were obtained when electron-poor aldehydes
were used in the reaction (3j and 3k). Multi-substituted
aldehydes could be facilely converted to the corresponding
diarylmethanes (3l and 3m). We also extended the substrate
scope to different arenes, such as benzene, toluene, and phenol,
affording the corresponding products in moderate yields (3n−
3p). However, negative results were obtained when chlor-
obenzene, fluorobenzene, and anisole were used under this
93
95
70
50
b
72
c
DCE
DCE
N.D.
N.D.
d
a
Reaction conditions: a mixture of 1a (0.6 mmol), H3PO3, and I2 was
stirred in a solvent (1.2 mL) at 60 °C for 13 h. GC yield based on 1a
using n-tridecane as an internal standard. Not detected (N.D.). 80
b
c
d
°C. 40 °C. In air.
generated by mixing 1a, H3PO3, and I2 in benzene at 60 °C for
13 h (entry 1). Further adjusting the amount of H3PO3 or I2
could improve the reaction efficiency (entries 2 and 3). We
have tested various solvents such as THF, CHCl3, CH3CN,
PhCl, and DCE. Judging from the yields of the products, it was
shown that DCE was the solvent of choice for this reaction
(entries 4−8). The amount of H3PO3 was also crucial, and
lower yields of 2a were obtained when 3.0 and 2.0 equiv of
H3PO3 was used (entries 9 and 10). Then, the effect of
temperatures was examined, and it was shown that 60 °C was
the optimal temperature because overreduction occurred at
high temperature (entry 11). A large amount of the starting
aldehyde 1a was recovered when the reaction was performed at
40 °C or in air (entries 12 and 13).
With the optimized conditions in hand, reactions of
aldehydes with I2 were conducted. As illustrated in Table 2,
various aromatic aldehydes bearing an electron-rich substituent
at the ortho or para position on the benzene ring, such as
methyl and tert-butyl, reacted well under the present reaction
conditions, producing the corresponding iodides in good to
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Note
a
Delightfully, lactone compound 3s could also be prepared
efficiently from 2-carboxybenzaldehyde under this system (eq
3).
Table 3. Synthesis of Diarylmethanes
To demonstrate the synthetic utility of the present
transformations, two gram-scale reactions were conducted
under the standard conditions. Benzaldehyde 1a was used on a
7.0 mmol scale under the H3PO3/I2 system (eq 4). As shown
in Scheme 3, the mixture was brown after reaction (Scheme 3,
Scheme 3. Scale-Up Reactions
a
Reaction conditions: a mixture of 1 (0.6 mmol), H3PO3 (2.5 equiv),
and I2 (0.7 equiv) was stirred in arenes (1.2 mL) at 60 °C for 24 h
b
c
under N2. Arenes (2.0 equiv) and DCE (1.2 mL) were used. A
mixture of 1 (0.6 mmol), H3PO3 (2.0 equiv), and I2 (0.8 equiv) was
stirred in arenes (1.2 mL) at 60 °C for 13 h; then Na2SO3(0.5 equiv)
was added and the mixture was stirred at 130 °C for another 24 h.
d
The mixture was stirred in DCE (1.2 mL) at 60 °C for 13 h; then
phenol (0.4 mL) was added and the mixture was stirred at 130 °C for
another 24 h.
picture a). Then 5.0 wt % Na2S2O3 aqueous solution was
added to the mixture to remove excess iodine. The mixture was
extracted with CH2Cl2 three times, and the combined organic
layer was further washed with water (Scheme 3, picture b).
Finally, the organic solvent was dried with MgSO4 and
concentrated under reduced pressure to afford analytical pure
product 2a in 91% yield (Scheme 3, picture c). Diarylmethane
3a could also be prepared on a gram scale under the similar
conditions (eq 5). These results illustrated the potential
application values in industrial scale-up.
Although the detailed mechanism was not clear, based on
the results of previous literatures,18b,c,19 a reasonable
mechanism for this reductive iodination/benzylation process
was proposed. As shown in Scheme 4, initially, H3PO3 reacts
system. It is worth noting that, for some examples such as 3k
and 3l, good results could also be obtained even when a
catalytic amount of I2 (20 mmol %) was used in the reactions.
Encouraged by the above experimental results, we
envisioned that intramolecular cyclization reactions would be
realized under the similar conditions. Indeed, as shown in
Scheme 2, by using the H3PO3/I2 system, intramolecular
cyclization occurred smoothly in 2-biphenylcarboxaldehyde,
delivering 9H-fluorene 3q in moderate yield under mild
conditions (eq 1). Similarly, when 2-benzylbenzaldehyde 1r
was employed in the reaction, a new six-membered ring was
formed to afford the product 3r in 65% yield (eq 2).
Scheme 4. Plausible Mechanism
Scheme 2. Intramolecular Cyclization Reactions
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137.8, 136.3, 129.6, 128.7, 21.3, 6.2. GC-MS (EI, 70 eV) m/z = 232
(M+). This compound is known.2a
with I2 in situ to generate HI and iodophosphate A, which is
attacked by the O atom of aldehyde 1 to afford intermediate B.
The sequential dissociation of B with HI yields intermediate C
and release of orthophosphoric acid. Next, intermediate C
further reacts with H3PO3 to provide benzylic iodides 2.
Finally, in the presence of H3PO3, a Friedel−Crafts type
reaction between 2 and arene takes place to furnish the desired
product 3.
In summary, for the first time, a cheap H3PO3/I2
combination was used instead of expensive reductants and
metal Lewis acids in reductive benzylation reactions. We have
developed a green, practical, and efficient method to produce
benzyl iodides and diarylmethanes from aromatic aldehydes.
Under similar conditions, intramolecular reductive cyclization
reactions could also take place smoothly. Further studies on
the synthetic application of H3PO3/I2 combination are
currently underway.
1-(Iodomethyl)-2-methylbenzene (2c). Light yellow solid, yield
1
64% (89.1 mg); Eluent: Petroleum ether/EtOAc = 40/1. H NMR
(500 MHz CDCl3): δ 7.33−7.31 (m, 1H), 7.22−7.15 (m, 3H), 4.46
(s, 2H), 2.36 (s, 3H). 13C{1H} NMR (125 MHz CDCl3): δ 136.5,
136.2, 130.5, 128.9, 128.0, 126.1, 18.5, 4.7. GC-MS (EI, 70 eV) m/z =
232 (M+). This compound is known.21
4-(Methylthio)benzoyl Chloride (2d). White solid, yield 75%,
1
110.7 mg; Eluent: Petroleum ether/EtOAc = 40/1. H NMR (500
MHz CDCl3): δ 7.10−7.07 (m, 1H), 7.00 (d, J = 7.5 Hz, 2H), 4.46 (s,
3H), 2.35 (s, 6H). 13C{1H} NMR (125 MHz CDCl3): δ 136.4, 134.5,
128.1, 127.6, 18.9, 2.8. GC-MS (EI, 70 eV) m/z = 246 (M+). This
compound is known.22
1-(tert-Butyl)-4-(iodomethyl)benzene (2e). Light yellow oil, yield
1
82%, 134.9 mg; Eluent: Petroleum ether/EtOAc = 40/1. H NMR
(500 MHz CDCl3): δ 7.23−7.22 (m, 4H), 4.36 (s, 2H), 1.21 (s, 9H).
13C{1H} NMR (125 MHz CDCl3): δ 151.0, 136.2, 128.5, 125.9, 34.7,
31.3, 6.2. GC-MS (EI, 70 eV) m/z = 274 (M+). This compound is
known.23
4-(Iodomethyl)-1,1′-biphenyl (2f). White solid, yield 85%, 150.0
EXPERIMENTAL SECTION
1
■
mg; Eluent: Petroleum ether/EtOAc = 40/1. H NMR (500 MHz
General Information. Unless otherwise noted, all reagents were
purchased from commercial suppliers and used without purification.
All aldehydes and arenes were purchased from commercial suppliers
and used without purification. Unless otherwise noted, reactions were
performed in 25 mL or 100 mL glass Schlenk tubes carried out under
a N2 atmosphere. Flash column chromatography was performed using
200−300 mesh silica gel. Visualization on TLC was achieved by the
CDCl3): δ 7.59−7.58 (m, 2H), 7.54−7.52 (m, 2H), 7.47−7.43 (m,
4H), 7.38−7.34 (m, 1H), 4.52 (s, 2H). 13C{1H} NMR (125 MHz
CDCl3): δ 140.8, 140.5, 138.3, 129.2, 128.9, 127.6, 127.5, 127.1, 5.6.
GC-MS (EI, 70 eV) m/z = 294 (M+). This compound is known.24
1-Fluoro-4-(iodomethyl)benzene (2g). Light brown oil, yield 89%,
1
126.0 mg; Eluent: Petroleum ether/EtOAc = 40/1. H NMR (500
MHz CDCl3): δ 7.38−7.33 (m, 2H), 7.01−6.96 (m, 2H), 4.44 (m,
2H). 13C{1H} NMR (125 MHz CDCl3): δ 162.1 (d, J = 246.4 Hz),
135.2 (d, J = 3.4 Hz), 130.5 (d, J = 8.3 Hz), 115.8 (d, J = 21.8 Hz),
4.6. GC-MS (EI, 70 eV) m/z = 236 (M+). This compound is
known.25
1
use of UV light (254 nm). H NMR and 13C NMR spectra were
measured on a Bruker AV-II 500 MHz NMR spectrometer (1H: 500
MHz, 13C: 125 MHz), using CDCl3 as the solvent with
tetramethylsilane (TMS) as the internal standard. Chemical shifts
are reported in ppm and referenced to residual solvent peaks (CHCl3
1-Chloro-4-(iodomethyl)benzene (2h). White solid, yield 92%,
1
in CDCl3: 7.26 ppm for H and 77.0 ppm for 13C). The coupling
1
139.4 mg; Eluent: Petroleum ether/EtOAc = 40/1. H NMR (500
constants J are given in Hz. Mass spectra were recorded by a GCMS-
QP 2010 plus spectrometer equipped with an EI ion source. The
high-resolution mass spectrum (HRMS) was recorded on a G2-
XSQTOF instrument. A FULI GC - 9790 II instrument equipped
with an FID detector was used to analyze the reaction mixture.
Typical Procedure for the Synthesis of Benzyl Iodides.
Under N2, the aldehydes 1 (0.6 mmol), I2 (106.6 mg), and H3PO3
(123.0 mg) were added into a 25 mL dried Schlenk tube, followed by
DCE (0.6 mL). The tube was heated at in an oil bath 60 °C for 13 h.
After the reaction mixture was cooled to room temperature, the
mixture was quenched with 5.0 wt % Na2S2O3 aqueous solution and
was extracted with CH2Cl2 three times. Then the combined organic
layer was dried over MgSO4 and filtrated. After evaporation of the
solvent under reduced pressure, the residue was further purified by
column chromatography on silica gel to give the product 2.
MHz CDCl3): δ 7.25−7.22 (m, 2H), 7.20−7.17 (m, 2H), 4.34 (s,
2H). 13C{1H} NMR (125 MHz CDCl3): δ 137.9, 133.6, 130.1, 129.0,
4.2. GC-MS (EI, 70 eV) m/z = 252 (M+). This compound is
known.26
1-Bromo-4-(iodomethyl)benzene (2i). Pink solid, yield 90%, 160.4
1
mg; Eluent: Petroleum ether/EtOAc = 40/1. H NMR (500 MHz
CDCl3): δ 7.36−7.33 (m, 2H), 7.19−7.17 (m, 2H), 4.33 (s, 2H).
13C{1H} NMR (125 MHz CDCl3): δ 138.4, 132.0, 130.4, 121.8, 4.2.
GC-MS (EI, 70 eV) m/z = 296 (M+). This compound is known.2a
Methyl 4-(Iodomethyl)benzoate (2j). White solid, yield 81%,
1
134.2 mg; Eluent: Petroleum ether/EtOAc = 20/1. H NMR (500
MHz CDCl3): δ 7.98−7.95 (m, 2H), 7.44−7.43 (m, 2H), 4.46 (s,
2H), 3.91 (s, 3H). 13C{1H} NMR (125 MHz CDCl3): δ 166.6, 144.4,
130.1, 129.6, 128.8, 52.2, 3.9. GC-MS (EI, 70 eV) m/z = 276 (M+).
This compound is known.1f
Procedure for the Preparation of 2a on Gram Scale. Under
N2, the aldehydes 1a (7.0 mmol), I2 (1243.7 mg), and H3PO3 (1435.0
mg) were added into a 100 mL dried Schlenk tube, followed by DCE
(13 mL). The tube was heated in an oil bath at 60 °C for 13 h. After
the reaction mixture was cooled to room temperature, the mixture was
quenched with 5.0 wt % Na2S2O3 aqueous solution. The mixture was
extracted with CH2Cl2 three times, and the combined organic layer
was further washed with water. Then the organic layer was dried over
MgSO4 and filtrated. After evaporation of the solvent under reduced
pressure, the analytically pure product 2a was obtained in 91% yield.
(Iodomethyl)benzene (2a). Light yellow solid, yield 94% (123.0
1-(Iodomethyl)-4-(trifluoromethyl)benzene (2k). White solid,
yield 94%, 161.3 mg; Eluent: Petroleum ether/EtOAc = 40/1. H
1
NMR (500 MHz CDCl3): δ 7.56−7.55 (m, 2H), 7.49−7.47 (m, 2H),
4.46 (s, 2H). 13C{1H} NMR (125 MHz CDCl3): δ 143.3 (q, 3JC‑F
=
1.0 Hz), 130.2 (q, 2JC‑F = 32.6 Hz), 129.1, 126.1 (q, 1JC‑F = 270.3
Hz), 125.8 (q, 3JC‑F = 3.9 Hz), 3.2. GC-MS (EI, 70 eV) m/z = 286
(M+). This compound is known.27
1,2-Dichloro-4-(iodomethyl)benzene (2l). White solid, yield 87%,
1
149.8 mg; Eluent: Petroleum ether/EtOAc = 40/1. H NMR (500
MHz CDCl3): δ 7.46 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.20 (d, J =
8.0 Hz, 1H), 4.36 (s, 2H). 13C{1H} NMR (125 MHz CDCl3): δ
139.5, 132.7, 131.9, 130.8, 130.6, 128.1, 2.6. GC-MS (EI, 70 eV) m/z
= 286 (M+). This compound is known.28
1-Fluoro-4-(iodomethyl)-2-methylbenzene (2m). Light brown
solid, yield 83%, 124.5 mg; Eluent: Petroleum ether/EtOAc = 40/1.
1H NMR (500 MHz CDCl3): δ 7.22−7.15 (m, 2H), 6.92 (t, J = 9.0
Hz, 1H), 4.41 (s, 2H), 2.26 (s, 3H). 13C{1H} NMR (125 MHz
CDCl3): δ 160.8 (d, J = 244.9 Hz), 134.9 (d, J = 3.8 Hz), 131.9 (d, J
= 5.4 Hz), 127.7 (d, J = 8.4 Hz), 125.4 (d, J = 17.5 Hz), 115.4 (d, J =
1
mg); Eluent: Petroleum ether/EtOAc = 40/1. H NMR (500 MHz
CDCl3): δ 7.43−7.41 (m, 2H), 7.36−7.27 (m, 2H), 4.50 (m, 2H).
13C {1H} NMR (125 MHz CDCl3): δ 138.8, 128.4, 128.3, 127.5, 5.4.
GC-MS (EI, 70 eV) m/z = 218 (M+). This compound is known.20
1-(Iodomethyl)-4-methylbenzene (2b). Light yellow oil, yield 84%
1
(116.9 mg); Eluent: Petroleum ether/EtOAc = 40/1. H NMR (500
MHz CDCl3): δ 7.28 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H),
4.46 (s, 2H), 2.32 (s, 3H). 13C {1H} NMR (125 MHz CDCl3): δ
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Note
22.8 Hz), 14.5, 5.1. GC-MS (EI, 70 eV) m/z = 250 (M+). This
compound is known.29
2-(4-Fluorobenzyl)-1,3,5-trimethylbenzene (3g). Colorless oil,
yield 89% (121.9 mg); 77% (105.5 mg); Eluent: Petroleum ether/
1
Typical Procedure for the Synthesis of Diarylmethanes.
Under N2, the aldehydes 1 (0.6 mmol), I2 (106.6 mg), and H3PO3
(123.0 mg) were added into a 25 mL dried Schlenk tube, followed by
arenes (1.2 mL or 2.0 equiv) or DCE (1.2 mL). The tube was heated
in an oil bath at 60 °C for 13 h. After the reaction mixture was cooled
to room temperature, the mixture was quenched with 5.0 wt %
Na2S2O3 aqueous solution and was extracted with EtOAc three times.
Then the combined organic layer was dried over MgSO4 and filtrated.
After evaporation of the solvent under reduced pressure, the residue
was further purified by column chromatography on silica gel to give
the product 3.
Procedure for the Preparation of 3a on Gram Scale. Under
N2, the aldehydes 1a (7.0 mmol), mesitylene (14.0 mmol), I2 (1243.7
mg), and H3PO3 (1435.0 mg) were added into a 100 mL dried
Schlenk tube, followed by DCE (13 mL). The tube was heated in an
oil bath at 60 °C for 24 h. After the reaction mixture was cooled to
room temperature, the mixture was quenched with 5.0 wt % Na2S2O3
aqueous solution and was extracted with EtOAc three times. Then the
combined organic layer was dried over MgSO4 and filtrated. After
evaporation of the solvent under reduced pressure, the residue was
further purified by column chromatography on silica gel to give the
product 3a in 84% yield.
EtOAc = 40/1. H NMR (500 MHz CDCl3): δ 6.98−6.90 (m, 6H),
3.98 (s, 2H), 2.30 (s, 3H), 2.20 (s, 6H). 13C{1H} NMR (125 MHz
CDCl3): δ 161.2 (d, 1JC‑F = 242 Hz), 136.9, 135.9, 135.6 (d, 3JC‑F
=
2.9 Hz), 133.7, 129.1 (d, 3JC‑F = 7.6 Hz), 129.0, 115.1 (d, 2JC‑F = 20.9
Hz), 33.9, 20.9, 20.1. GC-MS (EI, 70 eV) m/z = 228 (M+). This
compound is known.30
2-(4-Chlorobenzyl)-1,3,5-trimethylbenzene (3h). White solid,
yield 80% (117.5 mg); 75% (110.1 mg); Eluent: Petroleum ether/
1
EtOAc = 40/1. H NMR (500 MHz CDCl3): δ 7.21−7.18 (m, 2H),
6.94 (d, J = 8.5 Hz, 2H), 6.90 (s, 2H), 3.98 (s, 2H), 2.30 (s, 3H), 2.19
(s, 6H). 13C{1H} NMR (125 MHz CDCl3): δ 138.6, 136.9, 136.0,
133.3, 131.4, 129.2, 129.0, 128.5, 34.1, 20.9, 20.1. GC-MS (EI, 70 eV)
m/z = 244 (M+). This compound is known.30
2-(4-Bromobenzyl)-1,3,5-trimethylbenzene (3i). White solid, yield
85% (147.5 mg); 80% (138.8 mg); Eluent: Petroleum ether/EtOAc =
40/1. 1H NMR (500 MHz CDCl3): δ 7.36−7.35 (m, 2H), 6.91−6.89
(m, 4H), 3.97 (s, 2H), 2.31 (s, 3H), 2.20 (s, 6H). 13C{1H} NMR
(125 MHz CDCl3): δ 139.2, 137.0, 136.0, 133.2, 131.4, 129.6, 129.0,
119.4, 34.2, 20.9, 20.1. GC-MS (EI, 70 eV) m/z = 289 (M+). This
compound is known.30
Methyl 4-(2,4,6-Trimethylbenzyl)benzoate (3j). White solid, yield
1
64%, 103.1 mg; Eluent: Petroleum ether/EtOAc = 20/1. H NMR
2-Benzyl-1,3,5-trimethylbenzene (3a). Colorless oil, yield 93%
(117.4 mg); 74% (93.4 mg); Eluent: Petroleum ether/EtOAc = 40/1.
1H NMR (500 MHz CDCl3): δ 7.16−7.13 (m, 2H), 7.08−7.05 (m,
1H), 6.93 (d, J = 7.5 Hz, 2H), 6.81 (s, 2H), 3.94 (s, 2H), 2.21 (s,
3H), 2.12 (s, 6H). 13C{1H} NMR (125 MHz CDCl3): δ 140.2, 137.1,
135.7, 133.8, 128.9, 128.4, 127.9, 125.7, 34.8, 21.0, 20.2. GC-MS (EI,
70 eV) m/z = 210 (M+). This compound is known.30
(500 MHz CDCl3): δ 7.92−7.89 (m, 2H), 7.08 (d, J = 8.5 Hz, 2H),
6.91 (s, 2H), 4.06 (s, 2H), 3.89 (s, 3H), 2.30 (s, 3H), 2.19 (s, 6H).
13C{1H} NMR (125 MHz CDCl3): δ 167.2, 145.9, 137.0, 136.1,
132.9, 129.7, 129.0, 127.9, 127.8, 52.0, 34.9, 20.9, 20.1. GC-MS (EI,
70 eV) m/z = 268 (M+). This compound is known.33
1,3,5-Trimethyl-2-(4-(trifluoromethyl)benzyl)benzene (3k). White
solid, yield 99% (165.3 mg); 94% (157.0 mg); Eluent: Petroleum
ether/EtOAc = 40/1. 1H NMR (400 MHz CDCl3): δ 7.61 (d, J = 8.0
Hz, 2H), 7.25 (d, J = 7.6 Hz, 2H), 7.06 (s, 2H), 4.20 (s, 2H), 2.44 (s,
3H), 2.33 (s, 6H). 13C{1H} NMR (125 MHz CDCl3): δ 144.6, 137.1,
136.3, 132.9, 129.2, 128.3 (q, 2JC‑F = 32.0 Hz), 128.2, 125.4 (q, 3JC‑F
= 3.7 Hz), 124.5 (q, 1JC‑F = 270.0 Hz), 34.7, 21.0, 20.2. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C17H18F3: 279.1361, Found:
279.1366.
1,3,5-Trimethyl-2-(4-methylbenzyl)benzene (3b). Colorless oil,
yield 91% (122.5 mg); 73% (98.3 mg); Eluent: Petroleum ether/
1
EtOAc = 40/1. H NMR (500 MHz CDCl3): δ 7.08 (d, J = 7.5 Hz,
2H), 6.95−6.93 (m, 4H), 4.02 (s, 2H), 2.33 (s, 6H), 2.24 (s, 6H).
13C{1H} NMR (125 MHz CDCl3): δ 137.0, 137.0, 135.6, 135.1,
134.0, 129.1, 128.9, 127.8, 34.3, 21.0, 21.0, 20.2. GC-MS (EI, 70 eV)
m/z = 224 (M+). This compound is known.30
1,3,5-Trimethyl-2-(2-methylbenzyl)benzene (3c). White solid,
2-(2,4-Dichlorobenzyl)-1,3,5-trimethylbenzene (3l). Colorless oil,
yield 87% (117.1 mg); 64% (86.2 mg); Eluent: Petroleum ether/
yield 81% (135.7 mg); 75% (125.6 mg); Eluent: Petroleum ether/
1
1
EtOAc = 40/1. H NMR (500 MHz CDCl3): δ 7.20 (d, J = 7.5 Hz,
EtOAc = 40/1. H NMR (500 MHz CDCl3): δ 7.30 (d, J = 8.0 Hz,
1H), 7.10 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.94 (s, 2H),
6.53 (d, J = 8.0 Hz, 1H), 3.89 (s, 2H), 2.45 (s, 3H), 2.34 (s, 3H), 2.17
(s, 6H). 13C{1H} NMR (125 MHz CDCl3): δ 138.0, 137.2, 136.3,
135.6, 133.6, 129.7, 128.9, 126.2, 126.1, 125.7, 32.0, 21.0, 19.9, 19.8.
GC-MS (EI, 70 eV) m/z = 224 (M+). This compound is known.30
2-(2,6-Dimethylbenzyl)-1,3,5-trimethylbenzene (3d). White solid,
yield 63%, 90.1 mg; Eluent: Petroleum ether/EtOAc = 40/1. 1H
NMR (500 MHz CDCl3): δ 7.06−7.03 (m, 1H), 7.00−6.98 (m, 2H),
6.83 (s, 2H), 4.07 (s, 2H), 2.28 (s, 3H), 2.16 (s, 6H), 2.11 (s, 6H).
13C{1H} NMR (125 MHz CDCl3): δ 138.1, 136.9, 136.7, 135.0,
134.6, 129.4, 128.6, 125.7, 31.4, 21.0, 20.9, 20.8. GC-MS (EI, 70 eV)
m/z = 238 (M+). This compound is known.31
1H), 7.11 (s, 1H), 6.92 (s, 2H), 6.85 (d, J = 8.0 Hz, 1H), 3.98 (s,
2H), 2.32 (s, 3H), 2.20 (s, 6H). 13C{1H} NMR (125 MHz CDCl3): δ
140.6, 136.9, 136.3, 132.5, 132.4, 130.3, 129.8, 129.7, 129.2, 127.3,
33.9, 21.0, 20.1. GC-MS (EI, 70 eV) m/z = 279 (M+). This
compound is known.34
2-(4-Fluoro-2-methylbenzyl)-1,3,5-trimethylbenzene (3m). Col-
orless oil, yield 80% (116.3 mg); 67% (97.4 mg); Eluent: Petroleum
1
ether/EtOAc = 40/1. H NMR (400 MHz CDCl3): δ 7.07 (s, 2H),
7.03−6.99 (m, 2H), 6.93−6.92 (m, 1H), 4.12 (s, 2H), 2.47 (s, 3H),
2.39−2.37 (m, 9H). 13C{1H} NMR (100 MHz CDCl3): δ 159.9 (d,
1JC‑F = 240.7 Hz), 137.1, 135.9, 135.5 (d, 4JC‑F = 3.4 Hz), 133.9,
130.9 (d, 3JC‑F = 4.8 Hz), 129.2, 126.5 (d, 3JC‑F = 7.7 Hz), 124.6 (d,
2JC‑F = 17.1 Hz), 114.9 (d, 2JC‑F = 22.0 Hz), 34.1, 21.1, 20.3, 14.7 (d,
3JC‑F = 3.5 Hz). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H20F: 243.1549, Found: 243.1553.
2-(4-(tert-Butyl)benzyl)-1,3,5-trimethylbenzene (3e). White solid,
yield 89% (142.3 mg); 66% (105.5 mg); Eluent: Petroleum ether/
1
EtOAc = 40/1. H NMR (500 MHz CDCl3): δ 7.28−7.26 (m, 2H),
Diphenylmethane (3n). Colorless oil, yield 40%, 40.4 mg; Eluent:
Petroleum ether/EtOAc = 40/1. 1H NMR (500 MHz CDCl3): δ
7.32−7.29 (m, 4H), 7.23−7.21 (m, 6H), 4.01 (s, 2H). 13C{1H} NMR
(125 MHz CDCl3): δ 141.2, 129.0, 128.5, 126.1, 42.0. GC-MS (EI, 70
eV) m/z = 168 (M+). This compound is known.18b
6.97 (d, J = 8.0 Hz, 2H), 6.91 (s, 2H), 4.01 (s, 2H), 2.31 (s, 3H), 2.24
(s, 6H), 1.31 (s, 9H). 13C{1H} NMR (125 MHz CDCl3): δ 148.4,
137.0, 137.0, 135.5, 134.1, 128.9, 127.5, 125.2, 34.3, 34.2, 31.4, 20.9,
20.2. GC-MS (EI, 70 eV) m/z = 266 (M+). This compound is
known.30
1-Benzyl-4-methylbenzene (3o, isomer). Colorless oil, yield 51%,
55.8 mg; Eluent: Petroleum ether/EtOAc = 40/1. H NMR (500
4-(2,4,6-Trimethylbenzyl)-1,1′-biphenyl (3f). White solid, yield
1
93% (159.8 mg); 94% (161.5 mg); Eluent: Petroleum ether/EtOAc =
1
MHz CDCl3): δ 7.19−7.15 (m, 4.47H), 7.09−6.97 (m, 15.22H), 3.89
(s, 2H), 3.84 (s, 2.59H), 2.21 (s, 3.93H), 2.14 (s, 3H). 13C{1H} NMR
(125 MHz CDCl3): δ 141.5, 140.5, 139.0, 138.2, 136.7, 135.6, 130.4,
130.1, 129.3, 129.0, 128.9, 128.8, 128.5, 128.5, 126.6, 126.1, 126.1,
126.0, 41.6, 39.6, 21.1, 19.8. GC-MS (EI, 70 eV) m/z = 182 (M+).
This compound is known.18b
40/1. H NMR (500 MHz CDCl3): δ 7.60 (d, J = 8.0 Hz, 2H), 7.51
(d, J = 8.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.37−7.34 (m, 1H), 7.13
(d, J = 7.5 Hz, 2H), 6.96 (s, 2H), 4.11 (s, 2H), 2.35 (s, 3H), 2.29 (s,
6H). 13C{1H} NMR (125 MHz CDCl3): δ 141.1, 139.3, 138.7, 137.1,
135.8, 133.8, 129.0, 128.8, 128.3, 127.1, 127.0, 127.0, 34.4, 21.0, 20.2.
GC-MS (EI, 70 eV) m/z = 286 (M+). This compound is known.32
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J. Org. Chem. 2021, 86, 3081−3088

The Journal of Organic Chemistry
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Note
4-Benzylphenol (3p). Light yellow oil, yield 45%, 49.7 mg; Eluent:
Petroleum ether/EtOAc = 10/1. H NMR (500 MHz CDCl3): δ
7.34−7.30 (m, 2H), 7.27−7.23 (m, 3H), 7.17−7.13 (m, 2H), 6.94−
6.90 (m, 1H), 6.81−6.79 (m, 1H), 4.02 (s, 2H). 13C{1H} NMR (125
MHz CDCl3): δ 153.8, 140.0, 131.0, 128.8, 128.7, 127.9, 127.1, 126.4,
121.0, 115.7, 36.4. GC-MS (EI, 70 eV) m/z = 184 (M+). This
compound is known.18b
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02850
1
Notes
The authors declare no competing financial interest.
9H-Fluorene (3q). White solid, yield 40%, 39.9 mg; Eluent:
Petroleum ether/EtOAc = 40/1. 1H NMR (500 MHz CDCl3): δ 7.80
(d, J = 7.5 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.40−7.37 (m, 2H),
7.32−7.29 (m, 2H), 3.91 (s, 2H). 13C{1H} NMR (125 MHz CDCl3):
δ 143.2, 141.7, 126.7, 126.7, 125.0, 119.9, 36.9. GC-MS (EI, 70 eV)
m/z = 166 (M+). This compound is known.35
ACKNOWLEDGMENTS
■
J.X. thanks the National Natural Science Foundation of China
(21703061).
REFERENCES
■
9,10-Dihydroanthracene (3r). White solid, yield 65%, 70.3 mg;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02850.
■
sı
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Optimization of the reaction conditions and copies of
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Jing Xiao − Key Laboratory of Theoretical Organic Chemistry
and Functional Molecule of Ministry of Education, School of
Chemistry and Chemical Engineering, Hunan University of
Science and Technology, Xiangtan 411201, China;
orcid.org/0000-0002-7523-2303; Email: XiaoJing@
hnust.edu.cn
Li-Biao Han − National Institute of Advanced Industrial
Science and Technology (AIST), Tsukuba, Ibaraki 305-8565,
Japan; orcid.org/0000-0001-5566-9017; Email: libiao-
han@aist.go.jp
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Authors
Fang Lv − Key Laboratory of Theoretical Organic Chemistry
and Functional Molecule of Ministry of Education, School of
Chemistry and Chemical Engineering, Hunan University of
Science and Technology, Xiangtan 411201, China
Junchun Xiang − Key Laboratory of Theoretical Organic
Chemistry and Functional Molecule of Ministry of Education,
School of Chemistry and Chemical Engineering, Hunan
University of Science and Technology, Xiangtan 411201,
China
Fengzhe Guo − Key Laboratory of Theoretical Organic
Chemistry and Functional Molecule of Ministry of Education,
School of Chemistry and Chemical Engineering, Hunan
University of Science and Technology, Xiangtan 411201,
China
Zi-Long Tang − Key Laboratory of Theoretical Organic
Chemistry and Functional Molecule of Ministry of Education,
School of Chemistry and Chemical Engineering, Hunan
University of Science and Technology, Xiangtan 411201,
China
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J. Org. Chem. 2021, 86, 3081−3088

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pubs.acs.org/joc
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