Simple Method for sp2-sp3 and sp3-sp3 Carbon-Carbon Bond Activation in 2-Substituted 1,3-Diketones

Article abstract of DOI:10.1055/s-0034-1378862

Simple and efficient methods were developed for sp²-sp³ and sp³-sp³ C-C bond-activation reactions of 2-substituted 1,3-diketones. 3-Substituted 3-bromopentane-2,4-diones were deacylated in the presence of an aromatic compound and a silica gel supported Bronsted acid containing sulfonic groups. The carbocation formed by cleavage of the sp³-sp³ C-C bond of the dione alkylated the aromatic compound.

Full text of DOI:10.1055/s-0034-1378862

SYNTHESIS
0
0
3
9
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7
8
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1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2945–2956
2945
special topic
T. Aoyama et al.
Special Topic
Synthesis
Simple Method for sp2–sp3 and sp3–sp3 Carbon–Carbon Bond
Activation in 2-Substituted 1,3-Diketones
Tadashi Aoyama*a,b
Mamiko Hayakawaa
Sho Kubotaa
Sumire Ogawaa
Erika Nakajimaa
Emi Mitsuyamaa
Taku Iwabuchia
Haruki Kanekoa
Rina Obaraa
Ar
H
NaHSO4/SiO2
or
ZnCl2/SiO2
O
O
O
silica sulfuric acid
(SSA)
R1
R2
Br
Ar R2
R3
R3
R3
R1 = Br
R3 = Me, Ph
R
1 = H, Br
R2
13 examples
up to 99% yield
41 examples
up to 99% yield
Toshio Takidoa
Mitsuo Kodomaric
Akihiko Ouchia
a Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan
aoyama.tadashi@nihon-u.ac.jp
b The Center for Creative Materials Research, Research Institute of Science and Technology, College of Science and Technology, Nihon University,
Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan
c The Institute of Natural Sciences, College of Humanities and Science, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan
Received: 30.04.2015
Accepted after revision: 05.06.2015
Published online: 29.07.2015
sp3 C–C bond activation.8 Recently, 1,3-dicarbonyl com-
pounds have been used as acylating agents. For example,
Takai and co-workers reported an indium(III) triflate-cata-
lyzed acylation of alcohols or amines through sp2–sp3 C–C
bond cleavage of 1,3-diketones;9 a modified method using
iron(III) chloride has been reported by Jana and co-work-
ers.10 Additionally, a copper-catalyzed arylation of 1,3-dike-
tones with aryl halides to give α-aryl ketones was reported
by Lei and co-workers in 2010.11 Later, a method for the
synthesis of isocoumarins through copper iodide-catalyzed
tandem acylation and cyclization was developed by Fan,12
Xi,13 and Yao,14 and their respective co-workers. Wang and
co-workers recently reported syntheses of amides, α-keto
amides, and 1H-pyrrol-3(2H)-ones from amines and 1,3-
diketones, in which the cleavage of C–C bonds was mediat-
ed by peroxides.15 We have previously reported a deacyla-
tion of 1,3-dicarbonyl compounds by using a solid-support-
ed inorganic base (sodium carbonate/alumina).16 We also
reported that the sp3–sp2 C–C bond of α-bromo β-diketones
was activated by the presence of silica sulfuric acid (SSA).17
During this study, we unexpectedly found that the sp3–sp3
C–C bond of 3-(diphenylmethyl)pentane-2,4-dione was
cleaved in the presence of a Brønsted acid in benzene to
form a diphenylmethyl cation that reacted with benzene to
give triphenylmethane (Scheme 1).18
DOI: 10.1055/s-0034-1378862; Art ID: ss-2015-c0277-st
Abstract Simple and efficient methods were developed for sp2–sp3
and sp3–sp3 C–C bond-activation reactions of 2-substituted 1,3-dike-
tones. 3-Substituted 3-bromopentane-2,4-diones were deacylated in
the presence of an aromatic compound and a silica gel supported
Brønsted acid containing sulfonic groups. The carbocation formed by
cleavage of the sp3–sp3 C–C bond of the dione alkylated the aromatic
compound.
Key words bond activation, alkylations, deacylations, heterogeneous
reactions
Selective C–C and C–H bond activation has attracted in-
creasing attention in relation to organic synthesis.1 Com-
pared with C–H bond activation, selective activation of C–C
bonds is more difficult to achieve owing to their relatively
high strength and their its weak interactions with metal
catalysts. Consequently, many researchers have examined
C–C bond activation and its applications. Commonly used
methods for activation of C–C bonds include the use of ring-
strained molecules,2 direction by chelation assistance,3 and
the use of molecules containing sp2–sp3 or sp–sp3 C–C
bonds,4 among others.5 As an example of the use of mole-
cules containing sp2–sp3, 1,3-diketones, which are readily
available, have been used as starting materials in organic
synthesis.6 In the first half of 20th century, both acidic and
basic activations of sp2–sp3 C–C bonds in 1,3-dicarbonyl
compounds was studied by Adkins and co-workers.7 How-
ever, bases are generally used in deacylations through sp2–
Li et al.19 reported that the C–C bond in a compound
containing a dibenzoylmethyl unit as a leaving group was
activated by iron(III) chloride, whereas the C–C bond in a
compound containing a diacetylmethyl group was not acti-
vated. Here, we report both sp2–sp3 and sp3–sp3 C–C bond
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956

2946
T. Aoyama et al.
Special Topic
Synthesis
of SSA in toluene was stirred at 80 °C for five hours 4-tolu-
enesulfonic acid was obtained in good yield, a result that
agreed with that reported by Hajipour et al.20 Therefore, in
the reaction of dione 1a in the presence of SSA in toluene,
the SSA was predominately consumed in the sulfonation of
toluene rather than in the activation of the C–C bond of di-
one 1a. The resulting 4-toluenesulfonic acid was ineffective
in C–C bond activation of dione 1a.
sp3–sp2 cleavage
O
O
O
R
acid
R
sp3–sp3 cleavage
Ar
Ar
R
H
Scheme 1
Table 2 sp2–sp3 C–C Bond Activation of Dione 1a in Various Solvents
activations of 3-substituted pentane-2,4-diones by using
inorganic solid-supported Lewis or Brønsted acids.
First, we examined sp2–sp3 C–C bond activation in 3-
benzyl-3-bromopentane-2,4-dione (1a) in the presence of
various acids (Table 1). SSA showed the highest activity
among the solid acids tested (Table 1, entry 1). SSA was eas-
ily recovered, but the recovered SSA could not be reused for
subsequent reactions. Other solid acids were ineffective
(entries 2–6). However, sodium bisulfate/silica gel and Am-
berlyst 15 were mildly effective in C–C bond activation of
dione 1a, and gave the deacylated product 2a in low yields
of 17% and 2%, respectively. In reactions using a homoge-
neous catalyst, sulfuric acid showed a similar catalytic ac-
tivity to SSA but gave a lower yield of 2a as a result of unde-
sirable side reactions. When hydrochloric acid or 4-tolu-
enesulfonic acid was used as the acid catalyst, 1a was
recovered quantitatively.
SSA
1a
2a
solvent
60 °C, 1 h
Entry
Solvent
Conv. (%)
Yielda (%)
79
1
2
3
4
5
benzene
toluene
PhCl
100
4
b
–
100
100
100
85
92
69
DCE
hexane
a Isolated yield.
b Not determined.
Next, we explored the deacylation of various 3-substi-
tuted 3-bromopentane-2,4-diones 1 with SSA in benzene
or 1,2-dichloroethane (Table 3). The length of alkyl groups
at the 3-position in dione 1 did not affect the deacylation in
either solvent (entries 1–4). The reaction of dione 1e, which
has a bromine atom in the ω-position, gave the correspond-
ing deacylated product 2e in 92 and 94% yield in benzene
and 1,2-dichloroethane, respectively (entry 5). The expect-
ed product 2f from the reaction of the ester-containing di-
one 1f was not obtained in either solvent (entry 6).
When the reactions of 2,4-pentanediones 1h and 1i,
which have a sec-alkyl group at the 3-position, were carried
out in 1,2-dichloroethane at 60 °C for one hour, the deacy-
lated products 2h and 2i were obtained in low to moderate
yields. Although 2h and 2i were not obtained in benzene,
1,1-diphenylethane (4ha) and triphenylmethane (4ia) were
formed quantitatively from 1h and 1i, respectively, through
cleavage of the sp3–sp3 C–C bond (entries 8, 9 and Scheme
2); the cleavage of the sp3–sp3 C–C bond is discussed below.
Table 1 sp2–sp3 C–C Bond Activation of Dione 1a with Various Acids
O
O
O
acid (x mol%)
Bn
benzene
60 °C, 1 h
Br
Bn
Br
2a
1a
Entry
Acid
x mol%
Yielda (%)
1a
2a
100
1
2
3
4
5
6
7
8
9
SSA
185
210
480
10
–
NaHSO4/SiO2
Amberlyst 15
HClO4/SiO2
PPA/SiO2
ZnCl2/SiO2
H2SO4
83
17
2
98
100
100
100
–
–
b
–
–
–
150
900
600
100
85
O
Ph
sp3–sp2 cleavage
DCE
HCl
100
100
–
–
R
O
O
R
PTSA
Br
Br
2h–i
SSA (1 g)
60 °C, 1 h
a The recovery and yield were determined from the GLC area ratio.
b 0.3 g of PPA was used.
Ph
1h R = Me
1i R = Ph
Ph
Ph
sp3–sp3 cleavage
1h–i
Next, we tested several solvents for this reaction (Table
2). 1,2-Dichloroethane was the most suitable, solvent (Table
2, entry 4) whereas toluene showed no formation of 2a (en-
try 2). The absence of 2a in toluene was explained by the
sulfonation of the aromatics with SSA; when a suspension
benzene (3a)
R
4ha–ia
Scheme 2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956

2947
T. Aoyama et al.
Special Topic
Synthesis
Table 3 Deacetylation of 1 with SSA
Table 4 Debenzoylation of Diones 1 with SSA
O
O
O
O
R
O
O
R
1) SSA (2 g)
2) Na2CO3/SiO2
SSA (1 g)
R
R
Ph
Ph
Ph
solvent
60 °C, 1 h
DCE
80 °C, 1 h
Br
1a–h
Br
Br
2a–h
Br
1j–n
2j–n
Entry
R
Product
Yielda (%)
Entry
R
Product
Yielda (%)
Benzene
1
2
3
4
5
Bn
2j
98
79
44
92
99
DCE
Me
2k
2l
1
2
3
4
5
6
7
8
9
Bn
2a
2b
2c
2d
2e
2f
79
77
95
92
92
–
92
77
99
99
94
–
4-MeC6H4CH2
4-ClC6H4CH2
Me(CH2)7
Ph(CH2)2
Me(CH2)7
Me(CH2)17
Br(CH2)5
EtO2C(CH2)3
Ph
2m
2n
a Isolated yield.
dem bromination–deacylation reaction to give bromo ke-
tones 2 from the corresponding 3-substituted pentane-2,4-
diones in one pot (Table 5). All the substrates employed un-
derwent bromination and deacylation to give the expected
α-bromo ketones 2 in moderate to good yields.
2g
2h
2i
80
–
99
11b
49
PhCH(Me)
Ph2CH
–
a Isolated yield.
b Yield was determined by GLC.
Table 5 Preparation of Bromo Ketones 2 by a Tandem Reaction
O
O
O
Deacylations of 1,3-dicarbonyl compounds have gener-
ally been carried out under basic conditions.9 In contrast,
we found that SSA was more effective than bases for the
deacylation of dibenzoyl methyl derivatives. For instance,
the reaction of 2,2-dibenzyl-1,3-diphenylpropane-1,3-di-
one (1j) in the presence of SSA gave 2-bromo-1,3-diphenyl-
propan-1-one (2j) in quantitative yield after one hour at
80 °C, whereas sodium carbonate/silica gel gave ketone 2j
in 12% yield after five hours at 80 °C (Scheme 3).
CuBr2/SiO2–SSA
R
benzene
80 °C, 1 h
Br
R
2
Entry
R
Product
Yielda (%)
1
2
3
4
5
Bn
2a
2b
2c
2e
2g
74
71
96
91
62
Ph(CH2)2
Me(CH2)7
Br(CH2)5
Ph
SSA
80 °C, 1 h
98%
O
O
O
Bn
Ph
Ph
Ph
a Isolated yield
Br
Bn
Br
Na2CO3/SiO2
1j
2j
80 °C, 5 h
<12%
Acid-catalyzed deacylation of 1,3-dicarbonyl com-
pounds is generally promoted by alcohols, but our proce-
dure does not require an alcohol. We propose a tentative
pathway (Scheme 4) for the formation of bromo ketone 2 by
sp2–sp3 C–C bond activation and cleavage, on the basis of
the following results: (a) SSA cannot be reused for subse-
quent reactions, (b) the reaction proceeds only when an
acid containing a sulfonic group is used as the catalyst, and
(c) the presence of a bromine atom at the 3-position is re-
quired. In our proposed mechanism, the sulfonyl ester 1′ is
formed via a six-membered-ring transition state. The sulfo-
nyl oxygen attacks the carbonyl carbon, which is activated
both by protonation of the oxygen atom and by the induc-
tive effect of the bromine atom. Subsequently, the C–C bond
in ester 1′ is cleaved to form an enol that isomerizes to give
the bromo ketone 2.
Scheme 3 Effectiveness of SSA for the conversion of dione 1j into ke-
tone 2j
When the reactions of the 2-bromo-1,3-diphenyl-1,3-
diones 1j–n were carried out in the presence of SSA in 1,2-
dichloroethane at 80 °C for one hour (Table 4), the diones
were debenzoylated to give corresponding products 2j–n,
together with small amounts of benzoic acid. The latter was
easily removed from the reaction mixture by the addition
of sodium carbonate/silica gel.
The bromine atom in dicarbonyl compounds played an
important role in the sp2–sp3 bond activation. When a mix-
ture of SSA and 3-benzylpentane-2,4-dione in benzene was
stirred at 80 °C for one hour, no deacylated products were
observed. On the basis of this result, we developed a tan-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956

2948
T. Aoyama et al.
Special Topic
Synthesis
zoylmethane and the expected products. We therefore fo-
cused our attention on developing a simple procedure for
activation of sp3–sp3 C–C bonds.
H
O
O
O
R
O
O
R
O
S
+
HO3S
O
Si
O
O
Br
Br
In the case of sp3–sp3 C–C bond activation in 2-substi-
tuted 1,3-dicarbonyl compounds, the presence of a bromine
atom was not important. For example, when a mixture of 3-
(diphenylmethyl)pentane-2,4-dione (1i) and SSA in ben-
zene was stirred at 60 °C for one hour, triphenylmethane
(4ia) was obtained in 74% yield along with pentane-2,4-di-
one (Table 6, entry 1). When similar reactions were per-
formed in the presence of sodium bisulfate/silica gel or zinc
chloride/silica gel instead of SSA, only traces of 4ia were ob-
tained (entries 2 and 3). The sp3–sp3 C–C bond activation
was facilitated by increasing the electron density in the aro-
matic reactant. When the reactions were carried out in tol-
uene using various acids, 1-(diphenylmethyl)-4-methyl-
benzene (4ib) was obtained in all cases. Although, SSA was
the most effective of the acids used, we avoided its use in
subsequent reactions because sulfonation of 3b occurred
besides activation of the sp3–sp3 C–C bonds (entry 4). Acids
such as sulfuric acid, sodium bisulfate/silica gel, Am-
berlyst15, poly(phosphoric acid)/silica gel, or zinc(II) chlo-
ride/silica gel promoted this reaction and gave triaryl 4ib in
good to excellent yield (entries 5–9). In the reactions of xy-
lene, a large excess of p-xylene in relation to 1i was needed
to obtain triaryl 4ic in excellent yield (entry 10), whereas
Si
1
H
OH
O
O
S
O
O
R
O
S
O
O
O
Br
O
+
O
O
Br
R
Si
Si
1'
O
Br
R
2
Scheme 4 Tentative pathway for sp2–sp3 C–C bond activation
In the reaction of α-bromo-1,3-diketones with SSA in
aromatic solvents, the sp3–sp3 C–C bond was cleaved in
preference to the sp2–sp3 C–C bond, resulting in the forma-
tion of the corresponding triarylmethane (Scheme 2). A
similar activation of a C–C bond in 2-substituted 1,3-diphe-
nyl-1,3-diones by using iron(III) chloride has been reported
by Li et al.,19 who mainly used a dibenzoylmethyl unit as
the leaving group to give a stoichiometric amount of diben-
Table 6 Reactions of 3-(Diphenylmethyl)pentane-2,4-dione (1i) with Aromatic Hydrocarbons in the Presence of Various Acids
O
O
R2
R1
R2
acid
+
3a: R1 = H, R2 = H
3b: R1 = H, R2 = Me
3c: R1 = Me, R2 = Me
R1
Ph
4ia–ic
Ph
Ph
Ph
1i
(1 mmol)
3a–c
(5 mL)
Entry
R1
R2
Acid
Temp (°C)
Time (h)
Yielda (%)
1
2
H
H
SSA
60
60
1
5
5
1
5
5
5
5
5
5
74
H
H
NaHSO4/SiO2
ZnCl2/SiO2
SSA
trace
trace
99
3
H
H
60
4
Me
Me
Me
Me
Me
Me
Me
H
60
5
H
H2SO4
110
110
110
110
110
110
66
6
H
NaHSO4/SiO2
Amberlyst 15
PPA/SiO2
ZnCl2/SiO2
NaHSO4/SiO2
90
7
H
85
8
H
40
9
H
90
10
Me
92
a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956

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T. Aoyama et al.
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Synthesis
the reaction of 1i with three equivalents equiv of mesity-
lene (3d) gave 2-(diphenylmethyl)-1,3,5-trimethylbenzene
(4id) in 61% yield after six hours.
the 4-position on their rings. Sodium bisulfate/silica gel and
zinc(II) chloride/silica gel both promoted the reaction of di-
one 1i with phenol (3g) to give 4ig in excellent yields. The
selectively of alkylation at the 4-position increased when
zinc(II) chloride/silica gel was used instead of sodium bisul-
fate/silica gel. The reaction of benzenethiol (3h) in the pres-
ence of sodium bisulfate/silica gel did not give the expected
product 4ih but, instead, diphenylmethyl phenyl sulfide
was obtained in excellent yield. This result can be explained
by attack of the carbocation resulting from the cleavage of
sp3–sp3 C–C bond in 1i on the sulfur atom in 3h, which has
a higher nucleophilicity than the aromatic carbons (Scheme
6).
Next, we examined the alkylation of various aromatics
with 2-substituted 1,3-diketone in the presence of sodium
bisulfate/silica gel or zinc(II) chloride/silica gel (Scheme 5).
The general procedure was as follows. A mixture of dione 1i
(1 mmol), aromatic hydrocarbon 3 (3 mmol), and sodium
bisulfate/silica gel (1 g, 2.1 mmol) in chlorobenzene (5 mL)
was stirred at 110 °C for six hours. The results are shown in
Scheme 5. Anisole (3e) and thioanisole (3f) gave the corre-
sponding triarylmethanes 4ie and 4if, respectively, in excel-
lent yields. Alkylation of 3e and 3f occurred selectively at
method A: NaHSO4/SiO2 (2.1 mmol)
O
O
or
Ph
Ar
O
O
method B: ZnCl2/SiO2 (1.5 mmol)
+
Ar
H
+
Ph
4ie–ix
chlorobenzene (5 mL)
110 °C, 6 h
3e–x
(3 mmol)
Ph
Ph
1i
(1 mmol)
(method): yield (%)
OH
OH
OMe
OH
SMe
SH
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4ie
(A): 90% (2-/4- = 1:9.5)
4if
(A): 91% (2-/4- = 1:18)
4ig
4ih
4ii
(A): 85% (2-/4- = 1:2.4)
(A): ND (84%)
(A): 89%
(A): 89%
(B): 95% (2-/4- = 1:7.6)
HO
OH
MeO
Ph
OMe
OMe
MeO
OMe
MeO
Ph
Ph
Ph
Ph
OMe
OMe
Ph
OH
4ij
Ph
OMe
4ik
(A): 86%
Ph
Ph
Ph
4il
4im
4in
(A): no reaction
(A): 99%
(A): 86%
(A): 82%
HO
Ph
HO
HO
HO
HO
Ph
Ph
Ph
Ph
OMe
Cl
NO2
CHO
Ph
Ph
Ph
Ph
Ph
4io
4ip
4iq
4ir
4is
(A): 91%
(B): 94%
(A): 90% (2-/3- = 12:1)
(B): 92% (2-/3- = 2.7:1)
(A): 84%
(A) (130 ° C, 24 h): 30% (30%)* (A) (130 °C, 24 h): trace
(B) (130 °C, 72 h): 51% (17%)* (B) (130 °C, 24 h): 26%
* yield of deacylated product 2
MeS
Ph
OMe
S
SMe
OMe
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Br
S
O
Ph
Ph
4iu
(A) (5 h): 94%
4it
4iv
4iw
4ix
(A) (5 h): 99% (4-/5- = 2.5:1)
(A) (3 h): 98% (2-/3- = 8:1)
(B) (2 h): 99% (2-/3- = 4.3:1)
(A): 82%
(B): 92%
(A): 4%
(B): 97%
Scheme 5
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O
O
Ph
Ph
Ph
Ph
Br
SH
S
Ph
Br
NaHSO4/SiO2
ZnCl2/SiO2
+
3w
+
4iw
+
chlorobenzene
r.t., 30 min
Ph
Ph
Ph
S
58%
Ph
Ph
84%
Scheme 7
Scheme 6
When the reactions of catechol (3i) and benzene-1,3,5-
triol (3j) with dione 1i were carried out under the same
conditions, 3i gave the corresponding diol 4ii in 89% yield.
In contrast 4ij was not obtained from the reaction of 3j.
1,3,5-Trimethoxybenzene (3k) and dimethoxybenzenes 3l,
3m, and 3n reacted readily with dione 1i to give the corre-
sponding triarylmethanes 4ik and 4il–in in good yields.
The reactions of several 4-substituted phenols 3o–s were
also examined. The reactions of 4-methylphenol (3o) in the
presence of sodium bisulfate/silica gel or zinc(II) chlo-
ride/silica gel gave 4io in 91% and 94%, respectively, where-
as the reaction of 4-methoxyphenol (3p) gave mixtures of
2- and 3-(diphenylmethyl)-4-methoxyphenol 4ip in total
yields of 90% and 92%, respectively; the ratio of the 2-iso-
mer to the 3-isomer was 12:1 with sodium bisulfate/silica
gel and 2.7:1 with zinc(II) chloride/silica gel. 4-Nitrophenol
(3r) required a higher reaction temperature and a longer re-
action time for complete consumption of the reactant.
When the reaction was carried out in the presence of sodi-
um bisulfate/silica gel at 130 °C for 24 hours, the desired
product 4ir was obtained in 30% yield, along with deacylat-
ed product 2i. The corresponding reaction with zinc(II)
chloride/silica gel required a longer time and gave 4ir in
51% yield. The reaction of 4-hydroxybenzaldehyde (3s) was
not promoted by sodium bisulfate/silica gel but the reaction
on zinc(II) chloride/silica gel at 130 °C for 24 hours gave 4is
in 26%. 2-(Methylsulfanyl)anisole (3t) and 3-(methylsulfa-
nyl)anisole (3u) were alkylated to give ether sulfides 4it
and 4iu, respectively, both as mixtures of the 4- and 5-al-
kylated compounds. The reaction of 1-benzothiophene (3v)
proceeded in the presence of sodium bisulfate/silica gel or
zinc(II) chloride/silica gel to give product 3iv quantitatively
after three and two hours, respectively. The regioselectivity
of the reaction using sodium bisulfate/silica gel was higher
than that of the reaction using zinc(II) chloride/silica gel, in
which alkylation at the 2-position predominated over that
at the 3-position. In the reactions of five-membered hetero-
cycles, 2-bromothiophene (3w) gave 4iw in good to excel-
lent yield on sodium bisulfate/silica gel or zinc(II) chlo-
ride/silica gel, whereas 2-methylfuran (3x) gave a poor
yield of 4ix with sodium bisulfate/silica gel but gave a quan-
titative yield on zinc(II) chloride/silica gel.
The differences of selectivity in the reaction of 3g, 3p, or
3v with dione 1i in the presence of sodium bisulfate/silica
gel compared with those in the presence of zinc(II) chlo-
ride/silica gel might be the result of interactions between
the heteroatoms and the surface of the solid-supported
acids. The reactions probably proceeded as follows. In the
reaction using sodium bisulfate/silica gel, the dicarbonyl
compound 1i approaches the solid surface and the sp3–sp3
C–C bond is cleaved to form a carbocation that reacts with
the aromatic (3g, 3p, or 3v), whereas in the case of zinc(II)
chloride/silica gel, the carbonyl oxygen chelates with the
zinc atom to generate a carbocation and the hetero atom in
the aromatic is simultaneously adsorbed on the solid sur-
face. This chelation between the hetero atom in the aromat-
ic and the zinc atom results in suppression of alkylation at
the carbon close to the heteroatom as a result of steric hin-
drance (Scheme 8).
OH
Ph
O
Ph
Ph
O
Ph
Ph
Ph
OH
OH
O
O
NaOSO2OH
SiO2
Ph
Ph
Ph
O
Ph
O
Ph
O
Ph
O
O
O
OH
ZnCl2
ZnCl2
ZnCl2
ZnCl2
SiO2
Scheme 8
We then extended the method to the alkylation of 1,2-
dimethoxybenzene (3l) with several 3-substituted pen-
tane-2,4-diones 1o–u (Table 7). The reaction of 3-(1-phenyl-
ethyl)pentane-2,4-dione (1o) with 3l at 110 °C for six hours
gave diether 4ol in 45% yield (Table 7, entry 1). The yield of
diether 4ol increased to 80% when the reaction was carried
out at 130 °C in the presence of 2 g of sodium bisulfate/sili-
ca gel (entry 2). The reaction of 3l with dione 1p under the
same conditions gave the corresponding alkylated product
in 41% yield, together with 1,1-[bis(3,4-dimethoxyphe-
nyl)]ethane (5) (entry 4).
To demonstrate that this alkylation is complementary to
the classical Friedel–Crafts alkylation, we carried out the
reaction of 3w with bromo(diphenyl)methane using zinc(II)
chloride/silica gel as a Lewis acid. The product 4iw was ob-
tained in 58% yield, along with its regioisomer and various
polyalkylated products (Scheme 7).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956

2951
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Special Topic
Synthesis
Table 7 Alkylation of 1,2-Dimethoxybenzene (3l) with Various Diketones
OMe
OMe
O
O
OMe
NaHSO4/SiO2
(2.1 mmol/g)
OMe
+
chlorobenzene
6 h
R1
R2
R1
R2
1o–u
(1 mmol)
3l
4ol–ul
(3 mmol)
Entry
R1
Ph
R2
Temp (°C)
Acid (g)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
Me
110
130
110
130
130
110
130
110
130
1.0
2.0
1.0
2.0
3.5
1.0
2.0
1.0
1.0
4ol
4ol
4pl
4pl
4ql
4rl
45
80
71
41
75
80
96
94
97
Ph
Me
Me
Me
Me
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
Ph
4-MeOC6H4
4-ClC6H4
4sl
4tl
4-MeOC6H4
4-ClC6H4
Ph
4ul
When a mixture of dione 4pl, catechol (3lb), and sodi-
um bisulfate/silica gel in chlorobenzene was stirred at
130 °C for six hours, tetraether 5 was observed in the reac-
tion mixture (Scheme 9). To avoid further conversion of 4pl
into 5, the reaction was carried out under milder condition
to give 4pl in 71% yield (entry 3). The presence of electron-
donating substituents on the aromatic ring increased the
reactivity of 1. For example, 1r, containing methoxy sub-
stituent on the ring, reacted with dione 3l at 110 °C to give
4rl in 80% yield, whereas 1s containing a chlorine atom on
the ring required a large excess of sodium bisulfate/silica
gel and a higher reaction to give diether 4sl in excellent
yield (entries 6 and 7).
activation to give the corresponding ketone 2 as the main
product, together with 2-hydroxyphenyl acetate (entries 1
and 3).
On the basis of these results, we propose a plausible re-
action pathway (Scheme 10). Activation of the sp2–sp3 C–C
bond is triggered by a nucleophilic attack by a hydroxy oxy-
gen in 3i on the carbonyl carbon activated by the acid. Simi-
lar reactions using iron(III) chloride or iron(III) triflate have
recently been reported.10 In the case of activation of the
sp3–sp3 C–C bond, the carbonyl oxygen of diketone 1 is pro-
tonated, and subsequently an enol and a diphenylmethyl
cation are formed. The resulting carbocation reacts with ar-
omatic 3 to afford the triarylmethane 4. The ratio of cleav-
age of sp2–sp3 to sp3–sp3 C–C bonds might be dependent on
the stability of the resulting carbocation. The reactions of 1
containing benzhydryl groups gave the expected triaryl-
methanes 4 as the main products.
OMe
OMe
OMe
OMe
3l
NaHSO4/SiO2
To compare the applicability of Brønsted and Lewis
acids, we examined the reactions of 4-(2-haloethyl)phenols
6a and 6b with dione 1i in the presence of sodium bisul-
fate/silica gel or zinc(II) chloride/silica gel (Scheme 11). In
the reaction of 4-(2-chloroethyl)phenol (6a) with dione 1i
in the presence of sodium bisulfate/silica gel, the 2-alkylat-
ed product 7ia was formed quantitatively, whereas a lower
yield of 7ia was obtained with zinc(II) chloride/silica gel.
The reaction of 2-(2-bromoethyl)phenol (6b) with 1i in the
presence of sodium bisulfate/silica gel gave product 7ib in
75% yield as the sole alkylation product, whereas a mixture
of 7ib and 7ia was obtained with zinc(II) chloride/silica gel,
probably by a halogen-exchange reaction.
chlorobenzene
130 °C, 6 h
MeO
MeO
4pl
5
OMe
Scheme 9
In contrast to the efficient alkylation of 1,2-dimethoxy-
benzene (3l) with diketones 1o–u (Table 7), alkylation of
catechol (3i) did not give the corresponding triarylmethane
in satisfactory yields under similar conditions (Table 8). In
some reactions, deacylation occurred by a sp2–sp3 C–C bond
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956

2952
T. Aoyama et al.
Special Topic
Synthesis
Table 8 Alkylation of Catechol with Various Diketones
OH
OH
NaHSO4/SiO2
(2.1 mmol/g)
O
O
OH
O
OH
+
+
chlorobenzene
6 h
R1
R2
R1
R2
R1
R2
1o–u
(1 mmol)
3i
4oi–ui
2o–u
(3 mmol)
Entry
R1
Ph
R2
Me
Temp (°C)
Acid (g)
Product
Yield (%)
Product
Yield (%)
1
2
3
4
5
6
7
130
110
130
110
130
110
130
2.0
1.0
2.0
1.0
2.0
1.0
1.0
4oi
4pi
4qi
4ri
4si
4ti
20
37
10
67
57
66
70
2o
2p
2q
2r
66
–
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
Ph
Me
Me
51
–
4-MeOC6H4
4-ClC6H4
2s
2t
17
–
4-MeOC6H4
4-ClC6H4
Ph
4ui
2u
8
To investigate the competition between dehydrobromi-
nation and alkylation under harsh reaction conditions, we
examined the reactions of 2-(2-bromoethyl)phenol (6b)
with diones 1o, 1q, and 1s in the presence of sodium bisul-
fate/silica gel. In the reactions of 1o and 1q, normal alkyla-
tion took place, but a higher temperature and larger
amounts of sodium bisulfate/silica gel were needed for the
complete consumption of the starting materials (Figure 1).
In the presence of sodium bisulfate/silica gel, the reac-
tion of dione 1i with 1-(2-bromopropyl)-4-methoxyben-
zene (6c), which has secondary alkyl bromide moiety on
the ring, gave the alkylation product 7ic in 72% yield. In
contrast, when the reaction was carried out in the presence
of zinc(II) chloride/silica gel, the indane derivative 8 was
obtained in low yield instead of 7ic (Scheme 12).
A plausible pathway for the formation of 8 is shown in
Scheme 13. The zinc(II) chloride has two functions. First, it
catalyzes the enolization of dione 1i to give complex 1′. Sec-
ondly, it eliminates bromine from bromide 6c to form car-
bocation 6′, which leads to olefin 6′′. The diphenylmethyl
cation 1′ adds to olefin 6′′ to give 8′, which undergoes intra-
molecular cyclization to give the final product 8.
O
O
OH
R1
O
OH
R1
O
sp3–sp3 bond
cleavage
OH
O
O
O
NaHSO4/SiO2
+
R2
R2
R1
R2
1
R2
R1
sp2–sp3 bond
cleavage
H
OH
O
Ar
H
OH
H
O
O
OH
O
3
OH
R1
R2
Ar
R1
R2
R2
R1
OH
R2
O
OH
4
O
+
O
R2
R1
R1
2
Scheme 10
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956

2953
T. Aoyama et al.
Special Topic
Synthesis
NaHSO4/SiO2 (2.1 mmol)
or
RX
RX
Br
Ph
Ph
NaHSO4/SiO2
(2.1 mmol)
ZnCl2/SiO2 (1.5 mmol)
+
1i
Ph
(1 mmol)
chlorobenzene (5 mL)
110 °C, 6 h
Br
OH
OH
7ia–ib
Ph
OMe
6a–b
(3 mmol)
7ic: 72%
+
1i
Br
Cl
OMe
ZnCl2/SiO2
(1.5 mmol)
Ph
Ph
Ph
Ph
6c
Ph
OH
OMe
OH
7ia
7ib
8: 21%*
NaHSO4/SiO2: 93%
ZnCl2/SiO2: 36%
NaHSO4/SiO2: 75%
* determined by NMR
ZnCl2/SiO2: 20% (18%*)
Scheme 12
* yield of 7ia
Scheme 11
alkylation of the aromatic compound occurred. A signifi-
cant advantage of our method is that aromatics having ω-
bromoalkyl groups can be alkylated without elimination of
bromine atoms.
In conclusion, we have developed a convenient and effi-
cient method for activating sp2–sp3 and sp3–sp3 C–C bond in
2-substituted 1,3-diketones. Both deacetylation and deben-
zoylation of 2-substituted 2-bromo-1,3-diketones readily
occurred through cleavage of an sp2–sp3 C–C bond in the
presence of SSA. This deacylation of 2-substituted 2-bro-
mo-1,3-diketones was used in one-pot tandem bromina-
tion/deacylation reactions. On the other hand, when an
sp3–sp3 C–C bond was activated in the presence of an aro-
matic compound with the aid of a Lewis or Brønstead acid,
Melting points were determined on a Yanako micro-melting point ap-
paratus or on a Büchi Melting Point B-540. NMR spectra were record-
ed on a JEOL JNM-GX400 or JNM-ECX400 spectrometer; TMS (δ = 0)
and CDCl3 (δ = 77.0) were used as internal standards for 1H and 13C
NMR, respectively. Mass analyses were performed on a Shimazu
Cl
Cl
O
Cl
Cl
O
Zn
Zn
O
O
O
O
ZnCl2/SiO2
+
Ph
Ph
Ph
Ph
1i
Ph
Ph
1'
H
Br
OMe
6c
OMe
ZnCl/SiO2
6"
Ph
– H
OMe
8'
H
Ph
H
OMe
OMe
6'
8
Scheme 13
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956

2954
T. Aoyama et al.
Special Topic
Synthesis
3-Bromo-5-phenylpentan-2-one (2b)
Colorless oil; yield: 0.186 g (77%).
IR (neat): 1716 cm–1
Cl
Br
Br
.
1H NMR (400 MHz, CDCl3): δ = 2.20–2.36 (m, 2 H), 2.34 (s, 3 H), 2.68–
2.75 (m, 1 H), 2.80–2.87 (m, 1 H), 4.17 (dd, J = 8.6, 5.7 Hz, 1 H), 7.19–
7.32 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 26.6, 33.2, 34.9, 53.4, 126.3, 128.4,
128.5, 139.8, 201.5.
OH
7ob
OH
7qb
NaHSO4/SiO2 (4.2 mmol)
NaHSO4/SiO2 (7.4 mmol)
,
,
MS (CI): m/z = 241 [M + H]+, 243 [M + H + 2]+.
130 °C 53%
130 °C
Cl
53%
3,8-Dibromooctan-2-one (2e)
Br
Colorless oil; yield: 0.269 g (94%).
IR (neat): 1720 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.35–1.55 (m, 4 H), 1.84–2.09 (m, 4 H),
2.37 (s, 3 H), 3.41 (t, J = 6.8 Hz, 2 H), 4.24 (dd, J = 6.3, 8.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 26.3, 26.4, 27.4, 32.3, 33.2, 33.5, 54.0,
OH
201.9.
Cl
7sb
MS (CI): m/z = 285 [M + H]+, 287 [M + H + 2]+, 289 [M + H + 4]+.
NaHSO4/SiO2 (2.1 mmol)
,
110 °C 63%
1-Bromo-1-phenylacetone (2g)21
Figure 1
Yellow oil; yield: 0.213 g (99%).
IR (neat): 1733 cm–1
.
1H NMR (CDCl3): δ = 2.31 (s, 3 H), 5.43 (s, 1 H), 7.36–7.45 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 26.2, 56.3, 128.7, 129.0, 129.2, 135.1,
GCMS-QP2010 or on a JMS-GCmate (JEOL). Elemental analyses were
performed on a J-Science Lab Micro Corder JM-10. IR spectra were re-
corded on a Thermo Electron Nicolet 380 spectrometer.
199.3.
MS (EI): m/z = 212 [M+], 214 [M + 2]+.
Silica Sulfuric Acid (SSA)
2-Bromo-1,3-diphenylpropan-1-one (2j)22
Silica gel [Wakogel C-200 (Wako Pure Chemical), 10.0 g], previously
dried in vacuo at 120 °C for 2 h, was added to dried CHCl3 (50 mL),
and the mixture was stirred for 1 h. A solution of HSO₃Cl (33.3 mmol,
3.86 g) in CHCl3 (50 mL) was added, and the mixture was stirred for a
further 10 min. The CHCl3 was removed by decantation, and the solid
was washed with CHCl3 (3 × 50 mL). The resulting solid was dried in
vacuo at 120 °C for 2 h. Elemental analysis (found: S, 5.94%) gave an
estimated sulfonic acid content of 1.85 mmol/g.
White solid; yield: 0.282 g (98%).
IR (neat): 1674 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.36 (dd, J = 14.2, 7.3 Hz, 1 H), 3.67 (dd,
J = 14.2, 7.3 Hz, 1 H), 5.32 (t, J = 7.3 Hz, 1 H), 7.25–7.30 (m, 5 H), 7.43–
7.48 (m, 2 H), 7.55–7.59 (m, 1 H), 7.95–7.99 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 39.5, 46.6, 127.1, 128.5, 128.6, 128.8,
128.8, 129.4, 130.2, 133.7, 192.8.
MS (CI): m/z = 289 [M + H]+, 291 [M + H + 2]+.
Sodium Bisulfate/Silica Gel
Silica gel (Wakogel C-200, 10.0 g) was added to a solution of
NaHSO4∙H2O (30 mmol, 4.14 g) in distilled H2O (100 mL), and the mix-
ture was stirred at r.t. for 0.5 h. The H2O was removed on a rotary
evaporator under reduced pressure, and the resulting reagent was
dried in vacuo (10 mmHg) at 120 °C for 5 h.
2-Bromo-1-phenyldecan-1-one (2n)
Colorless oil; yield: 0.298 g (99%).
IR (neat): 1689 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.1 Hz, 3 H), 1.27–1.58 (m,
12 H), 2.07–2.22 (m, 2 H), 5.14 (dd, J = 7.8, 6.9 Hz, 1 H), 7.47–7.51 (m,
2 H), 7.58–7.62 (m, 1 H), 8.01–8.04 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 27.5, 29.1, 29.2, 29.3, 31.8,
33.5, 47.3, 128.8, 128.8, 133.6, 134.5, 193.3.
Zinc(II) Chloride/Silica Gel
Silica gel (Wakogel C-200, 15.9 g) was added to a solution of ZnCl2 (30
mmol, 4.1 g) in distilled H2O (100 mL), and the mixture was stirred at
r.t. for 0.5 h. The H2O was removed on a rotary evaporator under re-
duced pressure, and the resulting reagent was dried in vacuo (10
mmHg) at 150 °C for 6 h.
MS (CI): m/z = 311 [M + H]+, 313 [M + H + 2]+.
Alkylated Aromatic Products; General Procedure
Bromo Ketones 2; General Procedure
A mixture of diketone 1 (1.0 mmol), aromatic 3 (3.0 mmol), and
NaHSO4/SiO2 (2.1 mmol/g, 1.00 g) in PhCl (5 mL) was stirred at 110 °C
for 6 h. The NaHSO4/SiO2 was removed by filtration, and the filtrate
was evaporated to give a crude product that was purified by column
chromatography (hexane–EtOAc).
A mixture of the appropriate diketone 1 (1 mmol) and SSA (1 g) in
DCE (10 mL) was stirred at 60 °C for 1 h, and then the SSA was re-
moved by filtration. The filtrate was evaporated to afford give corre-
sponding product with a purity of >98%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956

2955
T. Aoyama et al.
Special Topic
Synthesis
4-Chloro-2-(diphenylmethyl)phenol (4iq)
13C NMR (100 MHz, CDCl3): δ = 54.7, 115.3, 116.3, 121.9, 128.5, 130.6,
132.3, 136.1, 142.0, 142.1, 143.4.
Colorless oil; yield: 0.245 g (84%).
HRMS (EI): m/z [M+] calcd for C19H14O2Cl2: 344.0371; found:
344.0371.
1H NMR (400 MHz, CDCl3): δ = 4.78 (s, 1 H), 5.67 (s, 1 H), 6.68 (dd,
J = 7.1, 2.5 Hz, 1 H), 6.77 (d, J = 2.5 Hz, 1 H), 7.06–7.12 (m, 5 H), 7.21–
7.32 (m, 6 H).
Anal. Calcd for C19H14O2Cl2: C, 66.10; H, 4.09. Found: C, 66.14; H, 3.95.
13C NMR (100 MHz, CDCl3): δ = 50.73, 117.3, 125.7, 126.9, 127.7,
128.7, 129.2, 130.2, 132.2, 141.6, 152.0.
4-[(4-Methoxyphenyl)(phenyl)methyl]benzene-1,2-diol (4ti)
HRMS (EI): m/z [M+] calcd for C19H15OCl: 294.0811; found: 294.0809.
White solid; yield: 0.203 g (66%); mp 108–109 °C (hexane).
1H NMR (400 MHz, CDCl3): δ = 3.78 (s, 3 H), 5.03 (s, 1 H), 5.06 (s, 1 H),
5.38 (s, 1 H), 6.55 (dd, J = 8.2, 2.0 Hz, 1 H), 6.59 (d, J = 2.0 Hz, 1 H), 6.77
(d, J = 8.0 Hz, 1 H), 6.80–6.83 (m, 2 H), 7.00–7.29 (m, 7 H).
2-(Diphenylmethyl)-4-nitrophenol (4ir)
Yellow solid; yield: 0.092 g (30%); mp 254–257 °C (hexane).
13C NMR (100 MHz, CDCl3): δ = 55.2 (overlap), 113.6, 115.1, 116.5,
122.0, 126.2, 128.3, 129.3, 130.3, 136.2, 137.5, 141.8, 143.1, 144.3,
157.9.
1H NMR (400 MHz, CDCl3): δ = 5.75 (s, 1 H), 6.89 (d, J = 8.9 Hz, 1 H),
7.12–7.14 (m, 4 H), 7.27–7.37 (m, 7 H), 7.77 (d, J = 2.8 Hz, 1 H), 8.07
(dd, J = 8.9, 2.8 Hz, 1 H).
HRMS (EI): m/z [M+] calcd for C20H18O3: 306.1256; found: 306.1252.
13C NMR (100 MHz, CDCl3): δ = 50.6, 116.1, 124.4, 126.5, 127.3, 128.9,
129.2, 131.5, 141.0, 141.7, 159.2.
4-[(4-Chlorophenyl)(phenyl)methyl]benzene-1,2-diol (4ui)
HRMS (EI): m/z [M+] calcd for C19H15NO3: 305.1052; found: 305.1054.
White solid; yield: 0.218 g (70%); mp 135–136 °C (hexane).
Anal. Calcd for C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found: C, 74.89;
H, 4.83; N, 4.51.
1H NMR (400 MHz, CDCl3): δ = 5.03 (s, 1 H), 5.05 (s, 1 H), 5.40 (s, 1 H),
6.52 (dd, J = 8.0, 2.0 Hz, 1 H), 6.57 (d, J = 2.0 Hz, 1 H), 6.78 (d, J = 8.0
Hz, 1 H), 7.01–7.08 (m, 4 H), 7.21–7.30 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 55.4, 115.3, 116.5, 122.0, 126.5, 128.4
(overlap), 129.3, 130.7, 132.1, 136.6, 142.0, 142.5, 143.2, 143.5.
3-(Diphenylmethyl)-4-hydroxybenzaldehyde (4is)
White solid; yield: 0.074 g (26%); mp 231–233 °C.
1H NMR (400 MHz, DMSO): δ = 5.83 (s, 1 H), 7.00 (d, J = 8.2 Hz, 1 H),
7.06–7.08 (m, 4 H), 7.20–7.33 (m, 7 H), 7.68 (dd, J = 8.2, 2.3 Hz, 1 H),
9.69 (s, 1 H), 10.8 (s, 1 H).
HRMS (EI): m/z [M+] calcd for C19H15O2Cl: 310.0761; found: 310.0760.
Anal. Calcd for C19H15O2Cl: C, 73.43; H, 4.86. Found: C, 73.53; H, 4.71.
13C NMR (100 MHz, DMSO): δ = 49.1, 115.4, 126.3, 128.0, 128.4, 129.0,
130.6, 131.2, 142.9, 160.9, 191.1.
4,4-Bis(4-chlorophenyl)butan-2-one (2s)
+
Colorless oil; yield: 0.049 g (17%).
HRMS (CI): m/z [M + H]
calcd for C20H17O2: 289.1223; found:
1H NMR (400 MHz, CDCl3): δ = 2.10 (s, 3 H), 3.13 (d, J = 7.6 Hz, 2 H),
4.56 (t, J = 7.6 Hz, 1 H), 7.10–7.13 (m, 4 H), 7.23–7.26 (m, 4 H).
289.1221.
4-[1-(4-Methoxyphenyl)ethyl]benzene-1,2-diol (4pi)
13C NMR (100 MHz, CDCl3): δ = 30.7, 44.5, 49.3, 128.8, 129.0, 132.4,
White solid; yield: 0.090 g (37%); mp 116–118 °C (hexane).
141.9, 206.0.
1H NMR (400 MHz, CDCl3): δ = 1.55 (d, J = 7.1 Hz, 3 H), 3.78 (s, 3 H),
3.99 (q, J = 7.1 Hz, 1 H), 5.01 (s, 1 H), 5.07 (s, 1 H), 6.66 (dd, J = 7.9, 2.0
Hz, 1 H), 6.69 (d, J = 2.0 Hz, 1 H), 6.77 (d, J = 7.9 Hz, 1 H), 6.80–6.84 (m,
2 H), 7.10–7.13 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 22.1, 43.2, 55.2, 113.7, 114.7, 115.1,
119.9, 128.4, 138.7, 140.2, 141.4, 143.2, 157.7.
HRMS (EI): m/z [M+] calcd for C16H14OCl2: 292.0422; found: 292.0422.
Anal. Calcd for C16H14OCCl2: C, 65.55; H, 4.81. Found: C, 65.36; H, 4.84.
4-(2-Bromoethyl)-2-[1-(4-chlorophenyl)ethyl]phenol (7qb)
Colorless oil; yield: 0.180 g (53%).
1H NMR (400 MHz, CDCl3): δ = 1.58 (d, J = 7.1 Hz, 3 H), 3.07 (t, J = 7.6
Hz, 2 H), 3.50 (t, J = 7.6 Hz, 2 H), 4.36 (q, J = 7.1 Hz, 1 H), 4.74 (s, 1 H),
6.64 (d, J = 8.0 Hz, 1 H), 6.93 (dd, J = 8.0, 1.8 Hz, 1 H), 7.01 (d, J = 1.8
Hz, 1 H), 7.15 (d, J = 8.2 Hz, 2 H), 7.23 (d, J = 8.2 Hz, 2 H).
HRMS (EI): m/z [M+] calcd for C15H16O3: 244.1099; found: 244.1096.
Anal. Calcd for C15H16O3: C, 73.75; H, 6.60. Found: C, 73.61; H, 6.70.
4-[Bis(4-methoxyphenyl)methyl]benzene-1,2-diol (4ri)
13C NMR (100 MHz, CDCl3): δ = 20.8, 33.5, 37.7, 38.7, 115.8, 127.6,
Red oil; yield: 0.226 g (67%).
128.2, 128.5, 128.9, 131.3, 131.8, 131.8, 143.9, 151.9.
1H NMR (400 MHz, CDCl3): δ = 3.77 (s, 6 H), 5.15 (s, 1 H), 5.17 (s, 1 H),
5.33 (s, 1 H), 6.54 (dd, J = 8.0, 2.3 Hz, 1 H), 6.57 (d, J = 2.3 Hz, 1 H), 6.76
(d, J = 8.0 Hz, 1 H), 6.79–6.82 (m, 4 H), 6.98–7.01 (m, 4 H).
HRMS (EI): m/z [M+] calcd for C16H16OBrCl: 338.0073; found:
338.0069.
13C NMR (100 MHz, CDCl3): δ = 54.4, 55.2, 113.6, 115.1, 116.4, 121.9,
2-[Bis(4-chlorophenyl)methyl]-4-(2-bromoethyl)phenol (7sb)
130.2, 136.6, 137.8, 141.8, 143.1, 157.9.
HRMS (EI): m/z [M+] calcd for C21H20O4: 336.1361; found: 336.1364.
White solid; yield: 0.279 g (63%); mp 103–104.3 °C.
1H NMR (400 MHz, CDCl3): δ = 2.99 (t, J = 7.6 Hz, 2 H), 3.44 (t, J = 7.6
Hz, 2 H), 4.62 (s, 1 H), 5.72 (s, 1 H), 6.59 (d, J = 2.3 Hz, 1 H), 6.73 (d,
J = 8.0 Hz, 1 H), 6.99 (dd, J = 8.0, 2.3 Hz, 1 H), 7.01–7.04 (m, 4 H), 7.26–
7.29 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 33.6, 38.5, 49.1, 116.0, 128.3, 128.7,
129.7, 130.6 (overlap), 131.4, 132.6, 140.8, 152.0.
4-[Bis(4-chlorophenyl)methyl]benzene-1,2-diol (4si)
White solid; yield: 0.200 g (57%); mp 138–139 °C (hexane).
1H NMR (400 MHz, CDCl3): δ = 5.10 (s, 2 H), 5.36 (s, 1 H), 6.50 (dd,
J = 8.2, 2.0 Hz, 1 H), 6.55 (d, J = 2.0 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H),
7.00 (d, J = 8.2 Hz, 4 H), 7.25 (d, J = 8.2 Hz, 4 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956

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T. Aoyama et al.
Special Topic
Synthesis
HRMS (EI): m/z [M+] calcd for C21H17OBrCl2: 433.9840; found:
433.9839.
(6) (a) Liu, Y.; Sun, J.-W. J. Org. Chem. 2012, 77, 1191. (b) Xie, H.;
Jiang, Y.; Cheng, Y.; Zhu, C. Chem. Commun. 2012, 48, 979.
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Anal. Calcd for C21H17OBrCl2: C, 57.83; H, 3.93. Found: C, 57.94; H,
4.09.
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52, 3212. (b) Beckham, L. J.; Adkins, H. J. Am. Chem. Soc. 1934,
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Supporting Information
Supporting information for this article is available online at
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http://dx.doi.org/10.1055/s-0034-1378862.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2945–2956