Iron-catalyzed friedel-crafts benzylation with benzyl TMS ethers at room temperature

Article abstract of DOI:10.1002/chem.201302862

Friedel-Crafts benzylations between unactivated arenes and benzyl alcohol derivatives are clean and straightforward processes to construct biologically useful di- and triarylmethanes. We have established an efficient iron-catalyzed Friedel-Crafts benzylation method at room temperature that uses benzyl TMS ethers as substrates, which are poorly reactive under common nucleophilic substitution conditions. The reaction seems to progress through iron-catalyzed self-condensation of the benzyl TMS ether to the corresponding dibenzylic ether. The use of excess arene relative to benzyl TMS ether produced mono-benzylated arene (diand tri-arylmethane products), whereas the use of excess benzyl TMS ether versus arene provided bis-benzylated arene (polyarylated products) in high yields and regioselectivities. In previous methods, the latter double Friedel-Crafts benzylations hardly proceed.

Full text of DOI:10.1002/chem.201302862

DOI: 10.1002/chem.201302862
Full Paper
&
Friedel–Crafts Reaction
Iron-Catalyzed Friedel–Crafts Benzylation with Benzyl TMS Ethers
at Room Temperature
Yoshinari Sawama,* Yuko Shishido, Takahiro Kawajiri, Ryota Goto, Yasunari Monguchi, and
Hironao Sajiki*[a]
Abstract: Friedel–Crafts benzylations between unactivated
arenes and benzyl alcohol derivatives are clean and straight-
forward processes to construct biologically useful di- and tri-
arylmethanes. We have established an efficient iron-cata-
lyzed Friedel–Crafts benzylation method at room tempera-
ture that uses benzyl TMS ethers as substrates, which are
poorly reactive under common nucleophilic substitution
conditions. The reaction seems to progress through iron-cat-
alyzed self-condensation of the benzyl TMS ether to the cor-
responding dibenzylic ether. The use of excess arene relative
to benzyl TMS ether produced mono-benzylated arene (di-
and tri-arylmethane products), whereas the use of excess
benzyl TMS ether versus arene provided bis-benzylated
arene (polyarylated products) in high yields and regioselec-
tivities. In previous methods, the latter double Friedel–Crafts
benzylations hardly proceed.
Introduction
reported in the literature, only electron-rich arenes could be
adopted and a large excess of arene (as the solvent) was re-
quired.[8] We now report an efficient Friedel–Crafts benzylation
between silyl ethers and a wide variety of arenes (including
halogenated arenes) at room temperature in the presence of
FeCl3. Although various catalysts were utilized in similar reac-
tions,[1–8] and cheap and versatile reagent FeCl3 has been
adopted in a Friedel–Crafts benzylation of free alcohols[3b] and
methyl ethers,[5] high temperatures and long reaction times
were required. The present reaction can provide di- and tri-ar-
ylmethanes by use of excess arene (3 equiv) relative to silyl
ether (1 equiv). Furthermore, the use of excess silyl ether
(4 equiv) relative to arene (1 equiv) gave the corresponding
bis-benzylated arenes,[16] which are quite difficult to synthesize
by previous methods.[17]
Friedel–Crafts benzylations[1–8] between unactivated arenes and
benzyl alcohol derivatives are clean and straightforward pro-
cesses to construct di- and tri-arylmethanes,[9,10] which are
useful substructures that are present in various biologically
active compounds. Reactivity is strongly dominated by the
Lewis or Brønsted acidities of the reagents and the dissociative
capacity of the activated benzyl alcohol functionality on the
substrate because the nucleophilicities of the arenes are very
low (especially, halogenated arenes are less reactive). There-
fore, the application of heat and/or the use of a significant
excess of arene is required in many cases, although many reac-
tions that use free benzyl alcohols,[2] acetates,[3] alkyl halides,[4]
methyl ethers,[5] benzyl ethers,[6] and hydroxamates[7] as the
substrates have already been reported in the literature. On the
other hand, silyl ethers are traditionally utilized for protection
of the alcohol functionality and are tolerated under the nucleo-
philic conditions due to the low dissociative capacity of the
siloxy functionality as a leaving group.[11] Very recently, we dis-
covered that silyl ethers are suitable substrates for iron-cata-
lyzed azidation reactions,[12,13] and other research groups have
also reported the reactions between silyl ethers and reactive
carbon nucleophiles, such as allylsilanes[14] and enol acetates.[15]
Although Friedel–Crafts reactions with silyl ethers have been
Results and Discussion
The Lewis acid efficiency was evaluated in the Friedel–Crafts
benzylation of 1-phenylethyl TMS ether (1a) and ortho-xylene
(3 equiv), a comparatively weak nucleophile, in (CH2Cl)2 at
room temperature (Table 1). Consequently, FeCl3, FeBr3, and
AuCl3 (5–10 mol%) were found to be the most efficient cata-
lysts to produce the desired product 2 in near quantative yield
in a short time (Table 1, entries 1–3 and 6). The Friedel–Crafts
benzylation did not proceed when other Lewis acids ([Fe-
(acac)3], FeCl2·4H2O, InCl3, BF3·Et2O, CuCl2, AgOAc; Table 1, en-
tries 4, 5, and 8–11) or Brønsted acid TFA (Table 1, entry 12)
were used. In these cases, desilylated byproduct 1-phenyletha-
nol (3) and self-condensation product bis(1-phenylethyl)ether
(4) were obtained instead of 2. Solvents (CH2Cl)2 and CH2Cl2
were found to be suitable, whereas the reactions in CHCl3, THF,
or toluene did not proceed (the effect of the solvent and other
Lewis acids are described in the Supporting Information) Fur-
[a] Dr. Y. Sawama, Y. Shishido, T. Kawajiri, R. Goto, Dr. Y. Monguchi,
Prof. Dr. H. Sajiki
Laboratory of Organic Chemistry, Gifu Pharmaceutical University
1-25-4 Daigakunishi, Gifu 501-1196 (Japan)
Fax: (+81)58-230-8109
E-mail: sawama@gifu-pu.ac.jp
sajiki@gifu-pu.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201302862.
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yield (68%) of 2 (Table 1, entry 15). Based on these experimen-
tal results, the dibenzyl ether generated might be transformed
into the TMS ether, which works as the main electrophile in
the present Friedel–Crafts reaction. The TMS ether 1a and di-
benzyl ether 4[22] are in equilibrium under FeCl3-catalyzed con-
ditions, and the original or regenerated 1a is rapidly converted
to the corresponding benzyl cation intermediate (A), which is
trapped by the arene to afford the desired product
(Scheme 2).[23]
Table 1. Reaction of o-xylene with 1-phenylethyl TMS ether (1).
R
Catalyst
t [h]
Yield [%][a]
1
2
3
4
1
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TES
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
3
FeCl3
FeCl3
FeBr3
[Fe(acac)3][d]
FeCl2·4H2O
AuCl3
AlCl3
InCl3
BF3·Et2O
CuCl2
AgOAc
TFA[e]
FeCl3
FeCl3
FeCl3
1
2
1
3
3
3
3
3
3
3
3
3
1.5
2.5
6
0
0
0
87
94
0
0
0
0
99
95
76
0
0
0
92[b]
97
90[b]
0
0
0
0
0
0
0
0
48
73
0
0
14
0
0
0
0
0
0
0
0
2[c]
3
Encouraged by the precise process observed for the FeCl3-
4
5
6
7
8
9
10
11
12
13
14
15
0
96
42
0
0
0
0
0
91[b]
93[b]
68[b]
0
58
26
0
0
0
0
0
0
0
TBS
H
[a] Yields were determined by 1H NMR spectroscopy with 1,4-dioxane as
an internal standard, unless otherwise noted. [b] Isolated yield. [c] FeCl3
(5 mol%) was used. [d] acac=acetylacetonate. [e] TFA=trifluoroacetic
acid.
Scheme 2. Proposed mechanism.
catalyzed reaction of 1a, we next examined the scope of vari-
ous benzylic TMS ethers in the reaction with 1,3-dimethoxy-
benzene, selected for its high nucleophilicity and utility as
a synthetic precursor to other useful skeletons (Table 2). Secon-
dary benzyl TMS ethers 1-(4-methoxyphenyl)ethyl TMS ether
and methoxy-, chloro-, or fluoro-substituted benzhydrol TMS
ethers efficiently underwent the FeCl3-catalyzed Friedel–Crafts
reaction to construct the corresponding di- or tri-arylmethane
structures with efficient yields within 1 h (Table 2, entries 1–5).
A sterically hindered, tertiary benzyl TMS ether was also ame-
nable to the present reaction and the use of TMSCl as an addi-
tive was found to effectively promote the reaction progress
(Table 2, entry 6). The progression of the Friedel–Crafts benzy-
lation of primary benzyl TMS ethers was difficult, except in the
case of the electron-rich substrate with an electron-donating
methoxy substituent on the aromatic ring of the benzyl TMS
ether (Table 2, entry 7 versus 8). Furthermore, the high reactivi-
ty of TMS ethers enabled chemoselective Friedel–Crafts benzy-
lation at the siloxy functionality (to supply the diaryl alkylchlor-
ide) without competing Friedel–Crafts alkylation of an alkyl
chloride within the same molecule (Table 2, entry 9). The addi-
tion of TMSCl also accelerated the reaction progress, as noted
previously (Table 2, entry 6). Additionally, TMS ethers derived
from allyl alcohols could be adapted to give the corresponding
di- or tri-aryl-substituted products in excellent yields (Table 2,
entries 10 and 11).
thermore, triethyl silyl (TES) and tert-butyldimethyl silyl (TBS)
ethers 1b and 1c could also undergo the iron-catalyzed Frie-
del–Crafts reaction in (CH2Cl)2 to give 2 in excellent yield
(Table 1, entries 13 and 14), whereas the reaction of the free-al-
cohol 3 resulted in lower yield (68%) and elongation of the re-
action time (Table 1, entry 15).
In the present Friedel–Crafts benzylation with TMS ethers,
the dibenzylic ether that results from self-condensation of the
substrate is obtained as a reaction intermediate. When the re-
action of 1a was interrupted after 7 min, ether 4 was isolated
in 81% yield (Scheme 1a).[18] Furthermore, after isolation, 4
was reacted with ortho-xylene in the presence of FeCl3 and
TMSCl[19] to quantitatively give the desired Friedel–Crafts prod-
uct 2 after only 10 min at room temperature.[20] Use of
TMSOTMS[21] as an additive slightly improved the reaction effi-
ciency relative to the reaction without any additives
(Scheme 1b). The FeCl3-catalyzed Friedel–Crafts benzylation of
3 required a longer reaction time (6 h) to obtain a moderate
An investigation into the scope of the reaction of 1a with
various arenes revealed that monosubstituted arenes, toluene,
anisole, and TBS-protected phenol, underwent the present
Friedel–Crafts reaction in a para-selective manner (Table 3, en-
tries 1–3) and the reactions with mesitylene and 1,2-dimethox-
ybenzene as substrates were also successful (Table 3, entries 4
and 5). Halogenated arenes are useful synthetic precursors for
the synthesis of biaryls, boronated esters, and aromatic amines
Scheme 1.
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Table 2. Friedel–Crafts reaction between various benzyl TMS ethers and
Table 3. Scope of the arene nucleophile.
1,3-dimethoxybenzene.
Arene
Product
Yield
[%]
t
[h]
TMS ether
Product
Yield
[%]
t
84
[min]
1[a]
2[a]
3
24
3
(o/p=10:90)
1[a]
92
60
95
(o/p=18:82)
2[a]
3[a]
4
R=OMe
R=H
R=Cl
R=F
95
83
94
93
15
60
5
65
0.5
(o/p=31:69)
5
15
4
5
99
74
6
80
30
6
7
8
1.5
(97)[b] (90)[b]
6[b]
7[c]
8[c]
9
R=I
R=I
75
quant
69
90
84
85[d]
70[d]
5
10.5
0.75
3
1
2
1
trace
81
24 h
5
R=Br
R=I
R=Br
R=Cl
R=F
10
11[c]
12
13[b,c]
56
24
37
24 h
9
(77)[b] (24 h)[b]
[a] Arene (30 equiv) was used. [b] Heated at 708C. [c] TMSCl (1 equiv) was
used as an additive. [d] A slight amount of the regioisomer was obtained
as a byproduct (see the Supporting Information).
10[c]
83
91
150
15
perature of 708C to provide the corresponding product
(Table 3, entry 13).
11
It is worth noting that the use of an excess of benzyl TMS
ether (4 equiv) relative to arene (1 equiv) effectively supplied
the corresponding bis-benzylated arenes,[16] which were hardly
obtained by previous methods (Table 4).[17] Various methoxy-,
chloro-, or fluoro-substituted benzhydrol derivatives could effi-
ciently undergo the FeCl3-catalyzed Friedel–Crafts bis-benzyla-
tion with 1,3-dimethoxybenzene to give the corresponding
polyaryl products in good to quantitative yields (Table 4, en-
tries 1–4). The reactions of anisole also gave the bis-benzylated
products; the third benzylation was probably inhibited due to
steric repulsion (Table 4, entries 5 and 6). Furthermore, the bis-
benzylations of meta-iodoanisole gave the desired iodinated
Friedel–Crafts products, which are well suited for further syn-
thetic modification (Table 4, entries 7–9).
[a] FeCl3 (10 mol%) was used. [b] TMSCl (1 equiv) was used as an additive.
[c] FeBr3 (5 mol%) was used.
by transition-metal-catalyzed cross-coupling reactions, there-
fore the reactions of nucleophilic halogenated arenes were
next challenged. Although the arene that bore only a halogen
substituent did not react with 1a under the present FeCl3-cata-
lyzed Friedel–Crafts benzylation conditions, the halogenated
anisole derivatives were efficient nucleophiles (Table 3, en-
tries 6–13). The reaction of ortho-iodoanisole with 1a did not
proceed at room temperature, the application of heat (708C)
or addition of TMSCl at room temperature led to high yields of
the desired Friedel–Crafts product with perfect regioselectivity
(Table 3, entries 6 and 7). Ortho-bromoanisole was also reactive
in the presence of TMSCl (Table 3, entry 8). Meta-haloanisoles
were more reactive and the reactions efficiently proceeded at
room temperature to give the desired products with high re-
gioselectivities (Table 3, entries 9–12). The reaction of para-io-
doanisole required the addition of TMSCl and a reaction tem-
Conclusion
We have established an efficient and mild Friedel–Crafts benzy-
lation reaction that uses benzyl TMS ethers, which are general-
ly stable under the nucleophilic substitution conditions. The
present reactions are catalyzed by the safe and cheap iron cat-
alyst FeCl3 and can proceed at room temperature to give ver-
satile polyaryl products with di- and tri-arylmethane skeletons.
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under argon. After an adequate reaction time, the mixture was
quenched with water and extracted with CH2Cl2. The combined or-
ganic layers were dried with Na2SO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatography with
hexane/EtOAc (20:1) as an eluent.
Table 4. Double Friedel–Crafts benzylation.
Arene
R
Product
Yield
[%]
t
[h]
Characterization
1
2
3
4
H
OMe
Cl
quant
78
65
20
48
6
1
Compound 2: H and 13C NMR spectra of the product were identi-
cal to those reported in reference [3a]. 1H NMR (400 MHz, CDCl3):
d=7.29–7.21 (m, 4H), 7.18–7.16 (m, 1H), 7.04 (d, J=7.6 Hz, 1H),
7.03–6.95 (m, 2H), 4.08 (q, J=7.2 Hz, 1H), 2.21 (s, 6H), 1.61 ppm (d,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=146.7, 143.9, 136.4,
134.1, 129.6, 129.0, 128.3, 127.5, 125.9, 124.9, 44.4, 21.9, 19.8,
19.3 ppm.
F
quant
0.25
5
6
H
F
quant
quant
6.5
24
Compound 4 (diastereomeric mixture): H and 13C NMR spectra of
1
the product were identical to those reported in reference [24].
1H NMR (400 MHz, CDCl3): d=7.37–7.34 (m, 4H), 7.30–7.27 (m,
14H), 7.24–7.20 (m, 2H), 4.53 (q, J=6.4 Hz, 2H), 4.25 (q, J=6.4 Hz,
2H), 1.46 (d, J=6.4 Hz, 6H), 1.38 ppm (d, J=6.4 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=144.2, 144.1, 128.4, 128.2, 127.4, 127.1, 126.3,
126.2, 74.6, 74.4, 24.7, 23.0 ppm.
7
H
Cl
F
76
24
24
18
8[a]
9
36[b]
70
1,3-Dimethoxy-4-[1-(4-methoxyphenyl)ethyl]benzene
(Table 2,
entry 1): H and 13C NMR spectra of the product were identical to
those reported in references [2e] and [25]. 1H NMR (400 MHz,
CDCl3): d=7.14 (d, J=8.8 Hz, 2H), 7.00 (d, J=9.2 Hz, 1H), 6.82–6.79
(m, 2H), 6.43–6.41 (m, 2H), 4.42 (q, J=7.2 Hz, 1H), 3.77 (s, 3H),
3.76 (s, 3H), 3.75 (s, 3H), 1.52 ppm (d, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=159.0, 157.7, 157.5, 138.8, 128.5, 127.8, 113.4,
103.9, 98.6, 55.4, 55.3, 55.2, 36.1, 21.2 ppm.
1
[a] TMSCl (1 equiv) was used as an additive. [b] 37% of the monosubsti-
tuted product was obtained as an intermediate (see the Supporting Infor-
mation).
4-Bis(4-methoxyphenyl)methyl-1,3-dimethoxybenzene (Table 2,
1
entry 2): Colorless oil; H NMR (400 MHz, CDCl3): d=7.00–6.96 (m,
4H), 6.81–6.77 (m, 4H), 6.73 (d, J=8.4 Hz, 1H), 6.45 (d, J=2.4 Hz,
1H), 6.38 (dd, J=8.4, 2.4 Hz, 1H), 5.72 (s, 1H), 3.77 (s, 3H), 3.76 (s,
6H), 3.69 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=159.3, 157.9,
157.7, 136.7, 130.5, 130.1, 125.8, 113.4, 103.7, 98.6, 55.6, 55.2, 55.1,
47.4 ppm; IR (ATR): n˜ =2998, 2932, 2834, 1607, 1503, 1460, 1291,
1240, 1206, 1174, 1113, 1031, 820, 731, 567 cmÀ1; HRMS (ESI): m/z:
calcd for C23H25O4: 365.1747 [M+H]+; found: 365.1751.
1-Benzhydryl-2,4-dimethoxybenzene (Table 2, entry 3): 1H and
13C NMR spectra of the product were identical to those reported in
reference [2k]. 1H NMR (400 MHz, CDCl3): d=7.27–7.23 (m, 4H),
7.19–7.15 (m, 2H), 7.09–7.07 (m, 4H), 6.73 (d, J=8.4 Hz, 1H), 6.46
(d, J=2.4 Hz, 1H), 6.38 (dd, J=8.4, 2.4 Hz, 1H), 5.83 (s, 1H), 3.77 (s,
3H), 3.68 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=159.4, 158.0,
144.2, 130.7, 129.4, 128.0, 125.9, 125.2, 103.7, 98.6, 55.5, 55.3,
49.1 ppm.
TMSCl, generated during the reaction process, efficiently facili-
tated the reaction. Synthetically useful halogenated arenes
could be used as nucleophiles, and the present reaction can
be applied to a benzylic TMS ether that also bears an alkyl
chloride, which is commonly reactive under Lewis acid cata-
lyzed Friedel–Crafts alkylation conditions, without the occur-
rence of competing alkylation.
Experimental Section
Typical procedure for Friedel–Crafts monobenzylation
(Tables 1–3)
4-Bis(4-chlorophenyl)methyl-1,3-dimethoxybenzene
(Table 2,
Arene (0.6 mmol, 3 equiv) and FeCl3 (0.01 mmol, 5 mol%) were
added to a solution of a benzyl silyl ether (0.2 mmol, 1 equiv) in
(CH2Cl)2 (0.2m). The mixture was stirred at room temperature
under argon. After an adequate reaction time, the mixture was
quenched with water and extracted with CH2Cl2. The combined or-
ganic layers were dried with Na2SO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatography with
hexane/EtOAc (30:1) as an eluent.
1
entry 4): Colorless oil; H NMR (400 MHz, CDCl3): d=7.24–7.20 (m,
4H), 6.99–6.96 (m, 4H), 6.66 (d, J=8.4 Hz, 1H), 6.46 (d, J=2.8 Hz,
1H), 6.39 (dd, J=8.4, 2.8 Hz, 1H), 5.73 (s, 1H), 3.78 (s, 3H),
3.68 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=159.7, 157.8, 142.2,
131.9, 130.6, 130.4, 128.3, 124.1, 103.8, 98.7, 55.5, 55.3, 48.0 ppm;
IR (ATR): n˜ =3001, 2958, 2934, 2836, 1610, 1585, 1488, 1260, 1207,
1088, 1013, 907, 807, 731, 574, 520 cmÀ1; HRMS (ESI): m/z: calcd for
C21H18O2Cl2: 372.0678 [M]+; found: 372.0680.
4-Bis(4-fluorophenyl)methyl-1,3-dimethoxybenzene
(Table 2,
Typical procedure for Friedel–Crafts bis-benzylation
(Table 4)
entry 5): H and 13C NMR spectra of the product were identical to
those reported in reference [26]. 1H NMR (400 MHz, CDCl3): d=
7.04–7.01 (m, 4H), 6.98–6.93 (m, 4H), 6.69 (d, J=8.4 Hz, 1H), 6.48
(d, J=2.4 Hz, 1H), 6.41 (dd, J=8.4, 2.4 Hz, 1H), 5.78 (s, 1H), 3.80 (s,
3H), 3.70 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=162.5, 160.0,
1
Arene (0.2 mmol, 1 equiv) and FeCl3 (0.02 mmol, 10 mol%) were
added to a solution of a benzyl silyl ether (0.8 mmol, 4 equiv) in
(CH2Cl)2 (0.2m). The mixture was stirred at room temperature
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159.6, 157.8, 139.7, 139.6, 130.6, 130.5, 130.4, 124.8, 115.0, 114.8,
103.7, 98.6, 55.5, 55.3, 47.7 ppm.
2H), 4.08 (q, J=7.2 Hz, 1H), 1.60 (d, J=7.2 Hz, 3H), 0.97 (s, 9H),
0.17 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=153.7, 146.9, 138.9,
128.4, 128.3, 127.6, 125.9, 119.7, 44.0, 25.7, 22.1, 18.2, À4.4 ppm; IR
(ATR): n˜ =3028, 2957, 2929, 2857, 1607, 1508, 1463, 1252, 1172,
1013, 913, 835, 778, 697 cmÀ1; HRMS (ESI): m/z: calcd for C20H29OSi:
313.1982 [M+H]+; found: 313.2011.
1,3-Dimethoxy-4-(1-methyl-1-phenylethyl)benzene
(Table 2,
1
entry 6): H and 13C NMR spectra of the product were identical to
1
those reported in reference [2j]. H NMR (400 MHz, CDCl3): d=7.34
(d, J=8.4 Hz, 1H), 7.23–7.15 (m, 4H), 7.11–7.07 (m, 1H), 6.49 (dd,
J=8.4, 2.4 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 3.80 (s, 3H), 3.33 (s, 3H),
1.64 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=159.4, 151.7, 131.2,
127.5, 127.0, 125.6, 125.5, 124.7, 103.5, 100.6, 55.2, 55.1, 41.4, 29.8,
29.7 ppm.
1
1-Mesityl-1-phenylethane (Table 3, entry 4): H and 13C NMR spec-
tra of the product were identical to those reported in refer-
ence [29]. 1H NMR (400 MHz, CDCl3): d=7.27–7.23 (m, 2H), 7.18–
7.13 (m, 3H), 6.82 (s, 2H), 4.63 (q, J=7.6 Hz, 1H), 2.26 (s, 3H), 2.11
(s, 6H), 1.65 ppm (d, J=7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
145.4, 140.0, 136.5, 135.4, 129.9, 128.1, 126.8, 125.2, 37.8, 21.0, 20.7,
16.8 ppm.
1,3-Dimethoxy-4-(4-methoxybenzyl)benzene (Table 2, entry 8):
1H and 13C NMR spectra of the product were identical to those re-
1
ported in reference [27]. H NMR (500 MHz, CDCl3): d=7.11 (d, J=
1,2-Dimethoxy-4-(1-phenylethyl)benzene (Table 3, entry 5): 1H
and 13C NMR spectra of the product were identical to those report-
ed in reference [30]. 1H NMR (400 MHz, CDCl3): d=7.30–7.26 (m,
2H), 7.22–7.16 (m, 3H), 6.79–6.78 (m, 2H), 6.72 (d, J=1.6 Hz, 1H),
4.10 (q, J=7.2 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 1.62 ppm (d, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=148.8, 147.3, 146.6,
139.0, 128.3, 127.5, 126.0, 119.3, 111.2, 111.0, 55.9, 55.8, 44.3,
22.1 ppm.
8.0 Hz, 2H), 6.94 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 2H), 6.45 (d,
J=2.0 Hz, 1H), 6.40 (dd, J=8.0, 2.0 Hz, 1H), 3.83 (s, 2H), 3.79 (s,
3H), 3.78 (s, 3H), 3.76 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
159.0, 157.8, 157.4, 133.2, 130.1, 129.5, 129.2, 122.3, 113.4, 113.1,
103.6, 103.5, 98.2, 55.1, 54.9, 34.0 ppm.
4-(3-Chloro-1-phenylpropyl)-1,3-dimethoxybenzene
(Table 2,
1
entry 9): Colorless oil; H NMR (400 MHz, CDCl3): d=7.26–7.23 (m,
4H), 7.19–7.15 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.46–6.42 (m, 2H),
4.50 (t, J=7.6 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.50–3.39 (m, 2H),
2.50–2.41 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=159.4, 158.1,
143.8, 128.3, 128.1, 128.0, 126.1, 124.5, 104.2, 98.8, 55.4, 55.3, 43.4,
40.6, 37.7 ppm; IR (ATR): n˜ =3026, 2999, 2935, 2835, 1610, 1503,
1452, 1289, 1206, 1156, 1033, 935, 698 cmÀ1; HRMS (ESI): m/z: calcd
for C17H20O2Cl: 291.1146 [M+H]+; found: 291.1136.
2-Iodo-1-methoxy-4-(1-phenylethyl)benzene (Table 3, entries 6
1
and 7): H and 13C NMR spectra of the product were identical to
those reported in reference [31]. 1H NMR (400 MHz, CDCl3): d=
7.63–7.62 (m, 1H), 7.30–7.26 (m, 2H), 7.19–7.16 (m, 3H), 7.12 (dd,
J=8.4, 2.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 4.05 (q, J=7.6 Hz, 1H),
3.82 (s, 3H), 1.59 ppm (d, J=7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=156.4, 146.0, 140.7, 138.4, 128.6, 128.4, 127.4, 126.1,
110.8, 86.0, 56.3, 43.5, 21.9 ppm.
1,3-Dimethoxy-4-[(E)-1-phenylbut-1-en-3-yl]benzene
(Table 2,
1
entry 10): H and 13C NMR spectra of the product were identical to
1
those reported in reference [2j]. H NMR (400 MHz, CDCl3): d=7.35
2-Bromo-1-methoxy-4-(1-phenylethyl)benzene (Table 3, entry 8):
1
(d, J=7.6 Hz, 2H), 7.29–7.24 (m, 2H), 7.20–7.15 (m, 1H), 7.10 (d, J=
8.0 Hz, 1H), 6.47–6.39 (m, 4H), 4.02–3.96 (m, 1H), 3.82 (s, 3H), 3.79
(s, 3H), 1.38 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
159.1, 157.7, 138.0, 135.3, 128.4, 127.9, 127.8, 126.8, 126.6, 126.1,
104.1, 98.7, 55.4, 55.3, 34.7, 20.1 ppm.
Colorless oil; H NMR (400 MHz, CDCl3): d=7.40 (d, J=2.4 Hz, 1H),
7.31–7.26 (m, 2H), 7.20–7.17 (m, 3H), 7.10 (dd, J=8.8, 2.4 Hz, 1H),
6.81 (d, J=8.8 Hz, 1H), 4.07 (q, J=7.2 Hz, 1H), 3.86 (s, 3H),
1.60 ppm (d, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=154.1,
146.0, 140.1, 132.4, 128.4, 127.5, 127.4, 126.2, 111.8, 111.5, 56.2,
43.7, 21.9 ppm; IR (ATR): n˜ =3026, 2965, 2931, 2837, 1603, 1494,
1452, 1285, 1259, 1054, 814, 700 cmÀ1; HRMS (ESI): m/z: calcd for
C15H15OBr: 290.0301 [M]+; found: 290.0307.
1,3-Dimethoxy-4-[(E)-1,3-diphenylallyl]benzene
(Table 2,
1
entry 11): H and 13C NMR spectra of the product were identical to
1
those reported in reference [2k]. H NMR (400 MHz, CDCl3): d=7.35
(d, J=7.6 Hz, 2H), 7.29–7.16 (m, 8H), 7.06 (d, J=7.6 Hz, 1H), 6.66
(dd, J=16.0, 7.2 Hz, 1H), 6.47–6.44 (m, 2H), 6.26 (d, J=16.0 Hz,
1H), 5.22 (d, J=7.2 Hz, 1H), 3.78 (s, 3H), 3.74 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=159.5, 157.9, 143.7, 137.6, 132.8, 130.8, 129.8,
128.6, 128.4, 128.1, 127.0, 126.2, 126.0, 124.5, 104.1, 98.9, 55.5, 55.3,
46.4 ppm.
1-Methyl-4-(1-phenylethyl)benzene (Table 3, entry 1): 1H and
13C NMR spectra of the product were identical to those reported in
reference [2f]. Mixture of regioisomers: 1H NMR (400 MHz, CDCl3):
d=7.29–7.25 (m, 2H), 7.23–7.20 (m, 2H), 7.18–7.14 (m, 1H), 7.12–
7.07 (m, 4H), 4.31 (q, J=7.2 Hz, 0.09H), 4.11 (q, J=7.2 Hz, 0.91H),
2.30 (s, 2.73H), 2.23 (s, 0.27H), 1.62 (d, J=7.2 Hz, 2.73H), 1.60 ppm
(d, J=7.2 Hz, 0.27H); 13C NMR (100 MHz, CDCl3): d=146.6, 143.4,
135.5, 129.0, 128.3, 127.5, 127.4, 125.9, 44.3, 21.9, 21.0 ppm.
1-Methoxy-4-(1-phenylethyl)benzene (Table 3, entry 2): 1H and
13C NMR spectra of the product were identical to those reported in
reference [28]. 1H NMR (400 MHz, CDCl3): d=7.29–7.23 (m, 2H),
7.21–7.12 (m, 5H), 6.82 (d, J=8.8 Hz, 2H), 4.10 (q, J=7.6 Hz, 1H),
3.77 (s, 3H), 1.61 ppm (d, J=7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=157.8, 146.7, 138.5, 128.5, 128.3, 127.5, 125.9, 113.7,
55.2, 43.9, 22.0 ppm.
3-Iodo-1-methoxy-4-(1-phenylethyl)benzene (Table 3, entry 9):
Pale-yellow oil; 1H NMR (400 MHz, CDCl3): d=7.38 (d, J=2.8 Hz,
1H), 7.30–7.25 (m, 2H), 7.22–7.17 (m, 3H), 7.03 (d, J=8.8 Hz, 1H),
6.85 (dd, J=8.8, 2.8 Hz, 1H), 4.43 (q, J=6.8 Hz, 1H), 3.76 (s, 3H),
1.56 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=158.0,
145.4, 140.7, 128.3, 128.2, 127.8, 126.0, 124.4, 114.7, 101.3, 55.5,
47.5, 21.8 ppm; IR (ATR): n˜ =3024, 2963, 2929, 2833, 1595, 1484,
1283, 1228, 1016, 843, 772, 697, 554 cmÀ1; HRMS (ESI): m/z: calcd
for C15H15OI: 338.0162 [M]+; found: 338.0162.
3-Bromo-1-methoxy-4-(1-phenylethyl)benzene
(Table 3,
1
entry 10): Colorless oil; H NMR (400 MHz, CDCl3): d=7.30–7.26 (m,
2H), 7.22–7.16 (m, 3H), 7.10–7.08 (m, 2H), 6.81 (dd, J=8.4, 2.4 Hz,
1H), 4.56 (q, J=7.6 Hz, 1H), 3.77 (s, 3H), 1.58 ppm (d, J=7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=158.2, 145.4, 137.4, 129.0,
128.3, 127.7, 126.0, 124.7, 117.9, 113.8, 55.5, 42.7, 21.5 ppm; IR
(ATR): n˜ =3060, 3025, 2965, 2931, 2835, 1603, 1488, 1284, 1229,
1028, 857, 774, 697, 556 cmÀ1; HRMS (ESI): m/z: calcd for C15H14OBr:
289.0233 [MÀH]À; found: 289.0236.
3-Chloro-1-methoxy-4-(1-phenylethyl)benzene
(Table 3,
1
entry 11): Colorless oil; H NMR (400 MHz, CDCl3): d=7.29–7.25 (m,
2H), 7.22–7.15 (m, 3H), 7.11 (d, J=8.8 Hz, 1H), 6.91 (d, J=2.8 Hz,
1H), 6.77 (dd, J=8.8, 2.8 Hz, 1H), 4.57 (q, J=7.2 Hz, 1H), 3.77 (s,
3H), 1.58 ppm (d, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
158.3, 145.4, 135.8, 134.2, 129.0, 128.3, 127.6, 126.0, 114.7, 113.1,
1-Tert-butyldimethylsiloxy-4-(1-phenylethyl)benzene
entry 3): Colorless oil; H NMR (400 MHz, CDCl3): d=7.29–7.25 (m,
2H), 7.21–7.14 (m, 3H), 7.06 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz,
(Table 3,
1
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55.5, 40.2, 21.3 ppm; IR (ATR): n˜ =3026, 2966, 2932, 2835, 1605,
1491, 1285, 1232, 1041, 880, 698 cmÀ1; HRMS (ESI): m/z: calcd for
C15H15OCl: 246.0806 [M]+; found: 246.0840.
CDCl3): d=6.95–6.87 (m, 17H), 6.78 (d, J=8.5 Hz, 1H), 6.47 (d, J=
1.5 Hz, 1H), 5.80 (s, 1H), 5.34 (s, 1H), 3.68 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=162.3, 162.2, 160.4, 160.3, 155.5, 155.4, 139.8,
139.7, 139.6, 139.1, 139.0, 135.3, 132.2, 131.2, 130.5, 130.4, 128.2,
115.1, 115.0, 114.9, 114.8, 110.4, 55.5, 54.3, 48.1 ppm; IR (ATR): n˜ =
3041, 2943, 2838, 1601, 1501, 1221, 1157, 1109, 1097, 1031, 1016,
821, 565 cmÀ1; HRMS (ESI): m/z: calcd for C33H24OF4: 512.1758 [M]+;
found: 512.1757.
3-Fluoro-1-methoxy-4-(1-phenylethyl)benzene
(Table 3,
1
entry 12): Colorless oil; H NMR (400 MHz, CDCl3): d=7.30–7.22 (m,
4H), 7.20–7.16 (m, 1H), 7.09 (t, J=8.8 Hz, 1H), 6.63 (dd, J=8.0,
2.4 Hz, 1H), 6.57 (dd, J=12.0, 2.4 Hz, 1H), 4.39 (q, J=7.2 Hz, 1H),
3.76 (s, 3H), 1.60 ppm (d, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=145.5, 128.8, 128.7, 128.3, 127.4, 126.1, 109.7, 109.6,
101.7, 101.5, 55.5, 37.1, 20.9 ppm; IR (ATR): n˜ =3027, 2966, 2930,
2853, 1625, 1506, 1304, 1155, 1107, 1027, 949, 698 cmÀ1; HRMS
(ESI) m/z: calcd for C15H15OF: 230.1101 [M]+; found: 230.1077.
4,6-Dibenzhydryl-3-iodo-1-methoxybenzene (Table 4, entry 7):
Colorless solid; m.p. 133–1368C; 1H NMR (400 MHz, CDCl3): d=
7.37–7.30 (m, 1H), 7.24–7.09 (m, 12H), 6.90–6.89 (m, 8H), 6.43 (s,
1H), 5.72 (s, 1H), 5.66 (s, 1H), 3.67 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=155.7, 143.0, 138.1, 132.9, 132.7, 129.3, 129.0, 128.2,
128.0, 127.2, 126.2, 126.0, 121.5, 99.4, 59.8, 55.9, 49.4 ppm; IR (ATR):
n˜ =3059, 3024, 2934, 2836, 1598, 1482, 1449, 1255, 1126, 1029,
907, 731, 696 cmÀ1; HRMS (ESI): m/z: calcd for C33H27NaOI: 589.0999
[M+Na]+; found: 589.1017.
4-Iodo-1-methoxy-2-(1-phenylethyl)benzene (Table 3, entry 13):
1
Colorless oil; H NMR (400 MHz, CDCl3): d=7.46 (dd, J=8.8, 2.4 Hz,
1H), 7.41 (d, J=2.4 Hz, 1H), 7.29–7.25 (m, 2H), 7.22–7.17 (m, 3H),
6.60 (d, J=8.8 Hz, 1H), 4.48 (q, J=7.2 Hz, 1H), 3.73 (s, 3H),
1.54 ppm (d, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=156.8,
145.5, 137.6, 136.3, 135.9, 128.2, 127.6, 125.9, 113.0, 83.2, 55.5, 37.3,
20.8 ppm; IR (ATR): n˜ =3025, 2962, 2928, 2852, 1584, 1484, 1283,
1243, 1133, 1029, 805, 699 cmÀ1; HRMS (ESI): m/z: calcd for
C15H16OI: 339.0240 [M+H]+; found: 339.0224.
4,6-Dibenzhydryl-1,3-dimethoxybenzene (Table 4, entry 1): 1H
and 13C NMR spectra of the product were identical to those report-
ed in reference [2k]. 1H NMR (400 MHz, CDCl3): d=7.26–7.10 (m,
12H), 6.96–6.94 (m, 8H), 6.46 (s, 1H), 6.40 (s, 1H), 5.76 (s, 2H),
3.65 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=156.3, 144.1, 132.7,
129.1, 127.9, 125.7, 123.9, 95.4, 55.8, 49.0 ppm.
4,6-Bis(4,4’-dichlorobenzhydryl)-3-iodo-1-methoxybenzene
(Table 4, entry 8): Colorless solid; m.p. 183–1878C; 1H NMR
(400 MHz, CDCl3): d=7.29 (s, 1H), 7.19–7.14 (m, 8H), 6.78 (dd, J=
8.8, 2.8 Hz, 8H), 6.12 (s, 1H), 5.61 (s, 1H), 5.56 (s, 1H), 3.69 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=155.8, 140.9, 140.8, 137.3,
132.5, 132.3, 132.2, 131.9, 130.5, 130.2, 128.5, 128.4, 121.8, 99.8,
58.5, 55.9, 48.5 ppm; IR (ATR): n˜ =3024, 2935, 2838, 1486, 1254,
1089, 1014, 906, 804, 731, 520 cmÀ1; HRMS (ESI): m/z: calcd for
C33H22OCl4I: 700.9475 [MÀH]À; found: 700.9494.
4,6-Bis(4,4’-difluorobenzhydryl)-3-iodo-1-methoxybenzene
(Table 4, entry 9): Colorless solid; m.p. 138–1408C; 1H NMR
(500 MHz, CDCl3): d=7.29 (s, 1H), 6.90–6.80 (m, 16H), 6.14 (s, 1H),
5.65 (s, 1H), 5.59 (s, 1H), 3.69 ppm (s, 3H); 13C NMR (125 MHz,
CDCl3): d=162.4, 162.3, 160.4, 160.3, 155.7, 138.5, 138.4, 138.3,
138.2, 137.9, 132.5, 132.3, 130.7, 130.6, 130.3, 130.2, 121.6, 115.2,
115.1, 115.0, 114.9, 99.6, 58.2, 55.8, 48.1 ppm; IR (ATR): n˜ =3042,
4,6-Bis(4,4’-dimethoxybenzhydryl)-1,3-dimethoxybenzene
(Table 4, entry 2): Colorless solid; m.p. 157–1598C, 1H NMR
(400 MHz, CDCl3): d=6.84 (d, J=8.4 Hz, 8H), 6.69 (d, J=8.8 Hz,
8H), 6.43 (s, 1H), 6.31 (s, 1H), 5.62 (s, 2H), 3.75 (s, 12H), 3.71 ppm
(s, 6H); 13C NMR (100 MHz, CDCl3): d=157.5, 156.1, 136.6, 132.4,
129.9, 124.5, 113.2, 95.5, 55.8, 55.1, 47.4 ppm; ; IR (ATR): n˜ =2998,
2937, 2840, 1601, 1505, 1483, 1225, 1158, 1126, 838, 579 cmÀ1
;
2932, 2834, 1608, 1506, 1241, 1173, 1095, 1031, 807, 729, 541 cmÀ1
;
HRMS (ESI): m/z: calcd for C33H23OF4I: 638.0724 [M]+; found:
HRMS (ESI): m/z: calcd for C38H38NaO6: 613.2561 [M+Na]+; found:
638.0726.
613.2558.
4,6-Bis(4,4’-dichlorobenzhydryl)-1,3-dimethoxybenzene (Table 4,
entry 3): Colorless solid; m.p. 240–2428C; 1H NMR (400 MHz,
CDCl3): d=7.17–7.13 (m, 8H), 6.81 (d, J=8.4 Hz, 8H), 6.43 (s, 1H),
6.08 (s, 1H), 5.63 (s, 2H), 3.72 ppm (s, 6H); 13C NMR (100 MHz,
CDCl3): d=156.5, 142.0, 132.0, 131.9, 130.3, 128.2, 123.0, 95.2, 55.7,
48.1 ppm; IR (ATR): n˜ =2925, 2852, 1612, 1506, 1400, 1300, 1203,
1091, 1015, 806, 518 cmÀ1; HRMS (ESI): m/z: calcd for C34H26O2Cl4:
606.068 [M]+; found: 606.0686.
Acknowledgements
This work was partially supported by Grant-in-Aid for Young
Scientists (B) from the Japan Society for the Promotion of Sci-
ence (JSPS).
4,6-Bis(4,4’-difluorobenzhydryl)-1,3-dimethoxybenzene (Table 4,
entry 4): Colorless solid; m.p. 193–1968C; 1H NMR (400 MHz,
CDCl3): d=6.89–6.82 (m, 16H), 6.44 (s, 1H), 6.10 (s, 1H), 5.67 (s,
2H), 3.72 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=162.4, 160.0,
156.4, 139.5, 139.4, 132.0, 130.4, 130.3, 123.5, 114.9, 114.7, 95.1,
55.7, 47.7 ppm; IR (ATR): n˜ =3070, 2924, 2854, 1600, 1503, 1301,
1223, 1203, 1155, 1030, 823, 724, 532 cmÀ1; HRMS (ESI): m/z: calcd
for C34H25O2F4: 541.1796 [MÀH]À; found: 541.1794.
Keywords: benzylation
reaction · iron · silyl ethers
·
biarylmethanes
·
Friedel–Crafts
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2,4-Dibenzhydryl-1-methoxybenzene (Table 4, entry 5): 1H and
13C NMR spectra reported in product were identical to those in ref-
erence [32]. 1H NMR (400 MHz, CDCl3): d=7.24–7.12 (m, 12H),
7.01–7.00 (m, 8H), 6.90 (dd, J=8.4, 2.4 Hz, 1H), 6.77 (d, J=8.4 Hz,
1H), 6.68 (d, J=2.4 Hz, 1H), 5.87 (s, 1H), 5.37 (s, 1H), 3.68 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=155.5, 144.4, 143.7, 135.4,
132.3, 131.8, 129.3, 129.2, 128.1, 128.0, 126.0, 125.9, 110.4, 55.9,
55.6, 49.4 ppm.
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2,4-Bis(4,4’-difluorobenzhydryl)-1-methoxybenzene
(Table 4,
entry 6): Colorless solid; m.p. 163–1668C; 1H NMR (500 MHz,
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Received: July 22, 2013
Published online on December 2, 2013
Chem. Eur. J. 2014, 20, 510 – 516
www.chemeurj.org
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