Friedel-Crafts Alkylation of Aromatics by TiCl 4 -Promoted Ring Cleavage of 3-Arylcyclobutanones

Article abstract of DOI:10.1055/s-0036-1591497

Ring cleavage of 3-arylcyclobutanones and successive Friedel-Crafts alkylation of methoxy- or alkyl-substituted benzene derivatives proceeded to give 3,3-diarylbutan-2-ones by activation with titanium tetrachloride.

Full text of DOI:10.1055/s-0036-1591497

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
en
M. Kanie et al.
Paper
Synthesis
Friedel–Crafts Alkylation of Aromatics by TiCl4-Promoted Ring
Cleavage of 3-Arylcyclobutanones
R1
Mayu Kanie
X2
O
O
R2
Tomoyuki Yoshimura
Jun-ichi Matsuo*
R1
R2
TiCl4
+
CH2Cl2
0 °C
X2
X2 = OMe, Me, H
Division of Pharmaceutical Sciences, Graduate School of
Medical Sciences, Kanazawa University, Kakuma-machi,
Kanazawa 920-1192, Japan
X1
X1
R1, R2 = Me, Et, Bn, -(CH2)n-
X1 = H, OMe, Me, Br
18 examples
jimatsuo@p.kanazawa-u.ac.jp
up to 85% yield
Dedicated to Professor Teruaki Mukaiyama in celebration of
his 90th birthday
Received: 07.08.2017
Accepted after revision: 27.09.2017
Published online: 06.11.2017
Friedel–Crafts alkylation of 1a were screened by reacting
with anisole (Table 1). First, some Lewis acids were used for
the reaction with 20 equivalents of anisole in dichloro-
methane at 0 °C for 1 hour, and it was found that BF3·OEt2,
SnCl4, and EtAlCl2 did not activate cyclobutanone 1a; it was
recovered in these cases. The desired Friedel–Crafts alkyla-
tion proceeded by the use of 1.1 equivalents of AlCl3 and
TiCl4, and alkylated product 2a was obtained in 50% and
81% yield, respectively, as a mixture of ortho- and para-al-
kylated products (Table 1, entries 1 and 2). Dialkylated
products were not obtained in these reactions. It was found
that the more substituted C2–C3 bond of cyclobutanone 1a
was cleaved regioselectively with TiCl4.11 Catalytic use (0.2
equiv) of TiCl4 resulted in a substantial decrease in the yield
of 2a (entry 3). The reaction of 5 equivalents of anisole in
dichloromethane gave 2a in 46% yield, and 4-methyl-1-
phenylpent-1-en-3-one (3) was isolated from the reaction
mixture (entry 4). The same reaction without the solvent
DOI: 10.1055/s-0036-1591497; Art ID: ss-2017-f0515-op
Abstract Ring cleavage of 3-arylcyclobutanones and successive Friedel–
Crafts alkylation of methoxy- or alkyl-substituted benzene derivatives
proceeded to give 3,3-diarylbutan-2-ones by activation with titanium
tetrachloride.
Key words cyclobutanone, Friedel–Crafts alkylation, ring cleavage,
Lewis acid, aromatics
Friedel–Crafts alkylation is a fundamental carbon–
carbon bond-forming reaction and it has been frequently
utilized in organic synthesis.1 In addition to alkyl halides,
various electrophiles such as carbonyl compounds and ep-
oxides have been used in Friedel–Crafts alkylation. Friedel–
Crafts alkylations with carbonyl compounds have been de-
veloped for reactive aromatic compounds such as indoles,
pyrroles, and furans, and the reactions are categorized into
three groups.2 One group is the reactions with aldehydes or
ketones to hydroxymethyl aromatic compounds and bisaryl
compounds3 (Scheme 1, eq. 1), and the second group is
Michael-type additions of aromatic compounds to α,β-un-
saturated carbonyl compounds (Scheme 1, eq. 2).4,5 Recent-
ly, Lewis acid catalyzed Friedel–Crafts alkylation of donor-
acceptor cyclopropanes with electron-enriched arenes has
been actively studied as the third category (Scheme 1, eq.
3).6 However, Friedel–Crafts reaction of cyclobutane deriva-
tives7 with arenes has not been developed except the for-
mal [4+2] cycloaddition of indoles with 3-ethoxycyclobuta-
nones,8 which did not react with less reactive benzene de-
rivatives such as toluene. We report here the Friedel–Crafts
alkylation of various aromatics including toluene and ben-
zene with 3-arylcyclobutanones by cleaving the C2–C3
bond of the cyclobutanone ring to give 3,3-diarylbutan-2-
ones.9
R1 R2
R1
R2
OH
+
N
H
O
N
H
R1 R2
(1)
(2)
(3)
N
N
H
H
R1
O
O
R2
+
R1
R2
N
H
N
H
Ar
CO2R
CO2R
CO2R
CO2R
X
+
X
Ar
2,2-Dimethyl-3-phenylcyclobutanone (1a) was pre-
pared by [2+2] cycloaddition of a keteneiminium salt with
styrene followed by hydrolysis.10 Reaction conditions for
Scheme 1 Friedel–Crafts alkylation with carbonyl compounds
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
M. Kanie et al.
Paper
Synthesis
gave 2a in 73% yield. The use of 40 equivalents of anisole
without the solvent gave 2a in 85% yield (entry 5).
membered spirocyclobutanones 1d–f also proceeded
smoothly (entries 3–5), whereas alkylation with 2-
monomethylcyclobutanone 1g and 2-nonsubstituted cy-
clobutanone 1h gave the corresponding products 4f and 4g
in low yields (entries 6 and 7). Checking the progress of
these reactions of 1g,h by TLC analysis revealed that ring
cleavage12 of these cyclobutanones 1g and 1h took place
sluggishly compared with that in the cases of 2,2-dialkylcy-
clobutanones. Investigation on the effects of substituent
groups at the aromatic group of 3-arylcyclobutanones 1i–k
Table 1 Optimization of Reaction Conditions
O
O
OMe
Lewis acid
+
CH2Cl2
Ph
2a
Ph
MeO
0 °C, 1 h
1a
Entry Lewis acid
(equiv)
Anisole
(equiv)
Yield (%)a
Ratio o/pb
Table 2 Reactions of Cyclobutanone 1a with Various Benzene Deriva-
1
AlCl3 (1.1)
TiCl4 (1.1)
TiCl4 (0.2)
TiCl4 (1.1)
TiCl4 (1.1)
20
20
20
5
50
6:94
20:80
NDc
tivesa
2
81
O
3
4
4d
5
46 (73)e
85e
17:83 (18:82)e
25:75
O
TiCl4
X
Ph
2b–h
+
40
X
CH2Cl2
Ph
a Isolated yield.
0 °C, 1 h
1a
b Ortho/para ratio determined by 1H NMR spectroscopy.
c Not determined.
Yield (%)b
Ratio o/pc
d 4-Methyl-1-phenylpent-1-en-3-one (3) 3% was also isolated from the re-
Entry
1
Aromatics
Product
action mixture.
e No solvent was used.
MeO
OMe
2b
63
69
–
Next, Friedel–Crafts alkylation of various aromatic com-
pounds with 1a was investigated under the conditions of
using 1.1 equivalents of TiCl4 and 20 equivalents of aromat-
ics in dichloromethane at 0 °C for 1 hour (Table 2). Reac-
tions of 1,4-dimethoxybenzene and 1,3-dimethoxybenzene
gave the corresponding alkylated products 2b and 2c in 63%
and 69% yield, respectively (Table 2, entries 1 and 2). 1,3,5-
Trimethoxybenzene reacted with 1a to afford the alkylated
product 2d in 20% yield, whereas reaction of 1,3,5-trimeth-
ylbenzene gave the alkylated product 2e in 80% yield (en-
tries 3 and 4). TLC analysis showed that the Friedel–Crafts
alkylation of 1,3,5-trimethoxybenzene gave many products.
The low yield of 2d was explained by further alkylation of
product 2d with 1,3,5-trimethoxybenzene since a by-prod-
uct 2d′ was obtained in 8% yield from the reaction mixture.
The yield of 2d was slightly improved to 36% when one
equivalent of 1,3,5-trimethoxybenzene was used. Friedel–
Crafts alkylation of p-xylene and toluene gave the alkylated
products 2f and 2g in 52% and 53% yield, respectively (en-
tries 5 and 6). It should be noted that benzene reacted with
1a to give the alkylated product 2h in 13% yield (entry 7).
However, Friedel–Crafts reactions of 1a with indole, N-to-
sylindole, and trimethylsilylbenzene gave complex mix-
tures.
OMe
2
3
2c
20:80d
MeO
MeO
OMe
OMe
2d
20e (36)f
–
–
4
2e
80
5
2f
52
53
13
–
6g
2g
2h
10:90
–
7g,h
Ar
2d' Ar = 1,3,5-(MeO)3C6H2
Ar
Ph
a Cyclobutanone 1a (1.0 equiv), aromatic compound (20 equiv), and TiCl4
(1.1 equiv) were used.
b Isolated yield.
The scope and limitations of the present alkylation were
studied by reactions of various 3-arylcyclobutanones with
anisole (Table 3). 2,2-Diethyl- (1b) and 2,2-dibenzylcy-
clobutanone (1c) reacted with anisole to give the corre-
sponding products 4a and 4b in good yields as in the reac-
tion of 2,2-dimethylcyclobutanone (1a) (Table 3, entries 1
and 2). Friedel–Crafts reaction with five-, six- and seven-
c Ortho/para ratio determined by 1H NMR spectroscopy.
d Ratio of 2-substituted and 4-substituted products.
e By-product 2d′ was isolated in 8% yield.
f One equivalent of 1,3,5-trimethoxybenzene was used.
g Aromatics (40 equiv) were used without solvent.
h 4-Methyl-1-phenylpent-1-en-3-one (3) 40% was also isolated from the re-
action mixture.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
M. Kanie et al.
Paper
Synthesis
revealed that introduction of a methoxy group lowered the
yield of the alkylated product 4h compared to the effects of
methyl and bromo groups (entries 8–10).
A proposed reaction mechanism for the present Friedel–
Crafts alkylation with cyclobutanone 1 is shown in Scheme
3. Activation of 1 with TiCl4 might give the intermediate 5
by ring cleavage of 1. Aromatics would react with 5 at the
benzylic position of 5 to give the alkylated product 6 (≡ 2 or
4)13 Stabilization of the benzylic cation by substitution with
a methoxy group retarded the reaction progress (Table 3,
entry 8).
Table 3 Reactions of Various 3-Phenylcyclobutanones with Anisolea
O
R1
O
R1
R2
OMe
R2
TiCl4
+
MeO
O
CH2Cl2
0 °C
TiCl4
X
O
O
X
OMe
TiCl4
1b–k
4a–j
Ar
Entry
1
X
R1
R2
Et
4
Yield (%)b
Ratio o/pc
Ar
Ar
OMe
6
1
5
1
2
1b
1c
1d
1e
1f
H
Et
Bn
4a
4b
4c
4d
4e
4f
85
65
83
71
82
24
4
21:79
21:79
17:83
18:82
19:81
27:73
NDe
Scheme 3 Proposed mechanism
H
H
H
H
H
H
Bn
3
-(CH2)4-
-(CH2)5-
-(CH2)6-
Me
In conclusion, we have developed the titanium tetra-
chloride mediated ring cleavage of 3-arylcyclobutanones at
the more substituted C2–C3 bond and Friedel–Crafts alkyla-
tion of benzene derivatives to afford 3,3-diarylbutan-2-
ones. This method enables the introduction of an aryl group
at the β-position of a carbonyl group. Similar introduction
of an aryl group can be performed by 1,4-addition of meta-
lated aromatics with α,β-unsaturated ketones.14
4
5d
6d
7
1g
1h
1i
H
H
H
4g
4h
4i
8
OMe
Me
Br
Me
Me
Me
Me
55f
74
74
<1:99
7:93
9
1j
Me
10
1k
Me
4j
16:84
a Cyclobutanone (1.0 equiv), aromatic compound (20 equiv), and TiCl4 (1.1
equiv) were used.
b Isolated yield as a mixture of ortho- and para-isomers.
c Ortho/para ratio determined by 1H NMR spectroscopy.
d Reaction time: 2 h.
All melting points were determined on Yanagimoto micro melting
point apparatus. IR spectra were recorded on Horiba IR-710 spectro-
photometer. 1H NMR spectra were recorded on a JEOL JNM ECA600
(600 MHz) or a JOEL JNM ECS400 (400 MHz) spectrometer at r.t.
Chemical shifts (δ) are reported in parts per million relative to te-
tramethylsilane. Standard abbreviations are used to designate the
splitting patterns. 13C NMR spectra were recorded on a JOEL JNM
ECA600 (150 MHz) or a JOEL JNM ECS400 (100 MHz) spectrometer
with complete proton decoupling. Chemical shifts are reported in
parts per million relative to TMS with the solvent resonance as the in-
ternal standard CDCl3. HRMS data were recorded on JEOL JMS-
T100TD. Analytical TLC was performed on Merck precoated TLC plates
(silica gel 60 GF254, 0.25 mm). Silica gel column chromatography was
carried out on silica gel 60 N (Kanto Kagaku Co., Ltd., spherical, neu-
tral, 63–210 μm or 40–50 μm). Preparative TLC (PTLC) was carried
out on silica gel Wakogel B-5F. All reactions were carried out under N2
in dried glassware with magnetic stirring. Cyclobutanones 1a,15 1d–
g,16 and 1h17 were prepared by reported procedures.
e Not determined.
f Determined by 1H NMR spectroscopy.
It was found that enone 3 was isolated in the TiCl4-cata-
lyzed reaction of cyclobutanone 1a with low equivalents of
anisole or less reactive aromatics such as benzene (see Ta-
ble 1, entry 4 and Table 2, entry 7). There was a possibility
that the present alkylation proceeded via the formation of
an enone such as 3, since Friedel–Crafts alkylation of
alkoxyarenes with α,β-unsaturated ketones has been re-
ported.4 However, an attempted Friedel–Crafts reaction of 3
with anisole by using TiCl4 did not proceed even when the
reaction temperature was elevated to room temperature
(Scheme 2). Therefore, it was thought that the present Frie-
del–Crafts reaction did not proceed via enone 3, which
could be formed by TiCl4-mediated ring cleavage of 1a.
3-Arylcyclobutanones 1b,c,i–k; 2,2-Diethyl-3-phenylcyclobuta-
none (1b); Typical Procedure
To a solution of 2-ethyl-1-(pyrrolidin-1-yl)butan-1-one (1.0 g, 5.9
mmol), styrene (1.35 mL, 11.8 mmol), and 2,4,6-collidine (95 μL, 0.71
mmol) in refluxing 1,2-dichloroethane (20 mL) was added dropwise a
solution of Tf2O (1.13 mL, 6.68 mmol) in anhyd 1,2-dichloroethane
(16 mL). The resulting reaction mixture was stirred at the same tem-
perature for 3 h. After cooling to r.t., aq NaOH was added, and the
mixture was stirred for 15 h. The mixture was extracted with CH2Cl2,
and the organic extracts were washed with brine, dried (anhyd
O
O
TiCl4
+
CH2Cl2
0 °C to r.t., 1 h
OMe
Ph
MeO
Ph
3
0%
Scheme 2 Attempted Friedel–Crafts alkylation of enone 3 with anisole
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
M. Kanie et al.
Paper
Synthesis
Na2SO4), filtered, and concentrated. The crude product was purified
by column chromatography on silica gel (hexane/EtOAc 40:1 to 20:1)
to afford 1b; yellow oil; yield: 537 mg (45%).
13C NMR (CDCl3, 150 MHz): δ = 212.8, 138.0, 131.5, 129.3, 120.5, 63.8,
46.0, 41.1, 23.4, 18.9.
HRMS (DART+): m/z [M + H]+ calcd for C12H14BrO: 255.0208; found:
255.0204.
IR (CHCl3): 2970, 1768, 1454, 1213, 1080, 787, 741, 702, 675 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.36–7.22 (m, 5 H), 3.54 (t, J = 9.0 Hz, 1
H), 3.39 (dd, J = 17.8, 7.8 Hz, 1 H), 3.24 (dd, J = 17.8, 9.4 Hz, 1 H), 1.82
(dq, J = 16.4, 7.2 Hz, 1 H), 1.73 (dq, J = 16.4, 7.2, 1 H), 1.41 (dq, J = 14.8,
7.2 Hz, 1 H), 1.14 (dq, J = 14.8, 7.2 Hz, 1 H), 1.01 (t, J = 7.4 Hz, 3 H), 0.67
(t, J = 7.4 Hz, 3 H).
13C NMR (CDCl3, 150 MHz): δ = 213.8, 139.2, 128.3, 128.1, 126.5, 71.5,
46.4, 38.8, 25.7, 22.9, 8.6, 8.2.
Friedel–Crafts Alkylation of 1 to 2a–h and 4a–j; 1-(4-Methoxyphe-
nyl)-4-methyl-1-phenylpentan-3-one (2a); Typical Procedure
To a stirred solution of 1a (50 mg, 0.29 mmol) and anisole (627 mg,
5.8 mmol) in anhyd CH2Cl2 (3 mL) was added TiCl4 (1.0 M, 0.32 mL) at
0 °C. The resulting solution was stirred for 1 h at 0 °C and the reaction
was quenched by adding an aq solution of potassium sodium (+)-tar-
trate. The resulting mixture was extracted with EtOAc (3 ×) and the
combined organic extracts were washed with brine, dried (anhyd
Na2SO4), filtered, and concentrated. The crude product was purified
by column chromatography on silica gel (hexane/EtOAc 20:1) to af-
ford 2a; yellow oil; yield: 66.3 mg (81%).
HRMS (DART+): m/z [M + H]+ calcd for C14H19O: 203.1436; found:
203.1427.
2,2-Dibenzyl-3-phenylcyclobutanone (1c)
Yellow oil; yield: 193 mg (10%).
IR (CHCl3): 1709, 1512, 1248, 1178, 777, 702, 671 cm–1
.
IR (CHCl3): 3531, 1770, 1730, 1603, 1495, 1452, 818, 756, 702, 669
1H NMR (CDCl3, 400 MHz): δ = 7.28–7.12 (m, 7 H), 6.80 (d, J = 8.7 Hz, 2
H), 4.58 (t, J = 7.6 Hz, 1 H), 3.75 (s, 3 H), 3.16 (d, J = 7.6 Hz, 2 H), 2.52–
2.45 (m, 1 H), 0.97 (d, J = 6.8 Hz, 6 H).
13C NMR (CDCl3, 100 MHz): δ = 212.6, 158.0, 144.5, 136.2, 128.7,
128.5, 127.6, 126.2, 113.8, 55.2, 46.8, 45.0, 41.4, 17.8.
cm–1
.
1H NMR (CDCl3, 600 MHz): δ = 7.36–7.18 (m, 11 H), 7.11 (d, J = 7.8 Hz,
2 H), 6.92 (d, J = 7.2 Hz, 2 H), 3.62 (t, J = 9.0 Hz, 1 H), 3.33 (dd, J = 17.9,
9.0 Hz, 1 H), 3.08 (d, J = 14.4 Hz, 1 H), 2.83–2.79 (d + dd, J = 14.4 + 17.9,
9.0 Hz, 2 H), 2.67 (d, J = 14.4 Hz, 1 H), 2.44 (d, J = 14.4 Hz, 1 H).
13C NMR (CDCl3, 150 MHz): δ = 211.3, 138.5, 137.6, 136.6, 130.6,
130.1, 128.6, 128.5, 128.2, 128.0, 126.7, 126.6, 126.5, 72.0, 46.6, 40.2,
39.5, 35.7.
HRMS (DART+): m/z [M + H]+ calcd for C19H23O2: 283.1698; found:
283.1706.
1-(2,5-Dimethoxyphenyl)-4-methy-1-phenylpentan-3-one (2b)
HRMS (DART+): m/z [M + H]+ calcd for C24H23O: 327.1749; found:
327.1758.
White solid; yield: 57.1 mg (63%); mp 56.0–56.5 °C.
IR (CHCl3): 3018, 1709, 1496, 1234, 810, 766, 712, 644 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.23 (d, J = 4.4 Hz, 4 H), 7.15–7.11 (m, 1
H), 6.75 (d, J = 8.8 Hz, 1 H), 6.72 (d, J = 2.8 Hz, 1 H), 6.67 (dd, J = 8.8, 2.8
Hz, 1 H), 4.96 (t, J = 7.6 Hz, 1 H), 3.72 (s, 3 H), 3.71 (s, 3 H), 3.19 (dd, J =
16.8, 8.0 Hz, 1 H), 3.14 (dd, J = 16.8, 6.8 Hz, 1 H), 2.54 (sept, J = 6.8 Hz,
1 H), 1.01 (d, J = 6.8 Hz, 3 H), 0.99 (d, J = 7.6 Hz, 3 H).
13C NMR (CDCl3, 150 MHz): δ = 212.5, 153.4, 151.2, 143.5, 133.8,
128.2, 127.9, 126.1, 114.9, 111.7, 110.7, 56.0, 55.5, 45.6, 40.9, 39.3,
18.0, 17.9.
3-(4-Methoxyphenyl)-2,2-dimethylcyclobutanone (1i)
Colorless oil; yield: 301 mg (25%).
IR (CHCl3): 1774, 1514, 1068, 800, 762, 733, 669 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.11 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 8.0
Hz, 2 H), 3.81 (s, 3 H), 3.44–3.25 (m, 3 H), 1.33 (s, 3 H), 0.78 (s, 3 H).
13C NMR (CDCl3, 150 MHz): δ = 214.0, 158.4, 130.9, 128.6, 113.8, 63.6,
55.3, 46.2, 40.8, 23.4, 18.8.
HRMS (DART+): m/z [M + H]+ calcd for C13H17O2: 205.1229; found:
HRMS (DART+): m/z [M + H]+ calcd for C20H25O3: 313.1804; found:
205.1225.
313.1803.
2,2-Dimethyl-3-(p-tolyl)cyclobutanone (1j)
Yellow oil; yield: 200 mg (18%).
1-(2,4-Dimethoxyphenyl)-4-methyl-1-phenylpentan-3-one (2c)
Colorless oil; yield: 62.5 mg (69%).
IR (CHCl3): 3020, 1709, 1610, 1504, 1217, 806, 789, 715, 681 cm–1
.
IR (CHCl3): 2966, 2925, 1774, 1514, 1462, 1213, 1068, 766, 721, 683,
652 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.29–7.00 (m, 6 H), 6.41–6.40 (s + d, 2
H), 4.89 (t, J = 7.3 Hz, 1 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.15 (d, J = 7.3 Hz,
2 H), 2.60–2.50 (m, 1 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3
H).
1H NMR (CDCl3, 400 MHz): δ = 7.16 (d, J = 8.0 Hz, 2 H), 7.08 (d, J = 8.0
Hz, 2 H), 3.44 (dd, J = 15.6, 8.0 Hz, 1 H), 3.36 (t, J = 8.0 Hz, 1 H), 3.27
(dd, J = 15.6, 8.0 Hz, 1 H), 2.35 (s, 3 H), 1.34 (s, 3 H), 0.79 (s, 3 H).
13C NMR (CDCl3, 150 MHz): δ = 213.9, 136.2, 135.8, 129.1, 127.5, 63.6,
46.0, 41.1, 23.4, 21.0, 18.8.
HRMS (DART+): m/z [M + H]+ calcd for C13H17O: 189.1279; found:
189.1272.
13C NMR (CDCl3, 150 MHz): δ = 212.9, 159.3, 157.8, 144.1, 128.24,
128.16, 127.9, 127.7, 125.9, 103.9, 98.8, 55.4, 55.3, 45.8, 40.9, 39.0,
18.01, 17.95.
HRMS (DART+): m/z [M + H]+ calcd for C20H25O3: 313.1804; found:
313.1796.
3-(4-Bromophenyl)-2,2-dimethylcyclobutanone (1k)
Yellow solid; yield: 612 mg (41%); mp 49.0–49.5 °C.
4-Methy-1-phenyl-1-(2,4,6-trimethoxyphenyl)pentan-3-one (2d)
Colorless oil; yield: 19.9 mg (20%).
IR (CHCl3): 3030, 1703, 1603, 1462, 1122, 816, 762, 634 cm–1
IR (CHCl3): 2966, 1776, 1491, 1462, 1383, 1215, 1074, 1011, 856, 818,
779, 741, 690, 650 cm–1
.
.
1H NMR (CDCl3, 400 MHz): δ = 7.48 (d, J = 8.4 Hz, 2 H), 7.07 (d, J = 8.4
Hz, 2 H), 3.44–3.27 (m, 3 H), 1.35 (s, 3 H), 0.79 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

E
M. Kanie et al.
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Synthesis
1H NMR (CDCl3, 400 MHz): δ = 7.27–7.25 (m, 2 H), 7.19 (t, J = 7.6 Hz, 2
H), 7.09 (t, J = 7.1 Hz, 1 H), 6.10 (s, 2 H), 5.20 (t, J = 7.6 Hz, 1 H), 3.77 (s,
3 H), 3.76 (s, 6 H), 3.40 (dd, J =16.8, 7.6 Hz, 1 H), 3.33 (dd, J = 16.8, 7.2
Hz, 1 H), 2.58 (sept, J = 6.8 Hz, 1 H), 1.01 (t, J = 7.6 Hz, 6 H).
13C NMR (CDCl3, 150 MHz): δ = 212.6, 144.3, 141.1, 135.8, 129.2,
128.5, 127.7, 127.6, 126.2, 46.6, 45.4, 41.4, 20.9, 17.83, 17.77.
HRMS (DART+): m/z [M + H]+ calcd for C19H23O: 267.1749; found:
267.1757.
13C NMR (CDCl3, 150 MHz): δ = 214.0, 159.6, 158.9, 144.7, 127.7,
127.5, 125.4, 113.0, 91.2, 55.7, 55.2, 44.1, 40.6, 34.6, 18.2, 18.1.
HRMS (DART+): m/z [M + H]+ calcd for C21H27O4: 343.1909; found:
4-Methyl-1,1-diphenylpentan-3-one (2h)
Colorless oil; yield: 9.5 mg (13%).
343.1908.
IR (CHCl3): 1711, 1217, 769, 723, 702, 642 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.28–7.15 (m, 10 H), 4.63 (t, J = 7.3 Hz,
1 H), 3.20 (d, J = 7.8 Hz, 2 H), 2.50 (sept, J = 6.8 Hz, 1 H), 0.98 (d, J = 6.9
Hz, 6 H).
13C NMR (CDCl3, 150 MHz): δ = 212.4, 144.1, 128.5, 127.7, 126.3, 46.6,
45.8, 41.4, 17.8.
2,2′-(4-Methyl-1-phenylpent-3-ene-1,3-diyl)bis(1,3,5-trimethoxy-
benzene) (2d′)
White solid; yield: 11.4 mg (8%); mp 107.8–108.2 °C.
IR (CHCl3): 1602, 1456, 1219, 1151, 1128, 791, 758, 698 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.23 (d, J = 8.8 Hz, 2 H), 7.12 (t, J = 7.4
Hz, 2 H), 7.02 (t, J = 7.2 Hz, 1 H), 5.98 (s, 1 H), 5.96 (s, 3 H), 4.51 (t, J =
7.6 Hz, 1 H), 3.79 (s, 3 H), 3.74 (s, 3 H), 3.58 (s, 6 H), 3.56 (s, 3 H), 3.53
(s, 3 H), 3.30 (dd, J = 14.6, 7.4 Hz, 1 H), 3.20 (dd, J = 14.2, 7.8 Hz, 1 H),
1.79 (s, 3 H), 1.39 (s, 3 H).
13C NMR (CDCl3, 150 MHz): δ = 159.4, 158.9, 158.24, 158.18, 146.5,
129.7, 128.1, 127.2, 126.3, 124.7, 115.0, 113.3, 91.0, 90.0, 89.7, 55.5,
55.34, 55.28, 55.22, 55.15, 38.6, 35.9, 22.3, 20.1.
HRMS (DART+): m/z [M + H]+ calcd for C18H21O: 253.1592; found:
253.1585.
4-Ethyl-1-(4-methoxyphenyl)-1-phenylhexan-3-one (4a)
Yellow oil; yield: 76.5 mg (85%).
IR (CHCl3): 2966, 1732, 1512, 1248, 781, 708 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.28–7.15 (m, 7 H), 6.80 (d, J = 8.8 Hz, 2
H), 4.60 (t, J = 7.2 Hz, 1 H), 3.76 (s, 3 H), 3.15 (d, J = 7.2 Hz, 2 H), 2.29–
2.22 (m, 1 H), 1.55–1.46 (m, 2 H), 1.41–1.30 (m, 2 H), 1.68 (t, J = 7.6
Hz, 3 H), 1.67 (t, J = 7.4 Hz, 3 H).
HRMS (DART+): m/z [M + H]+ calcd for C30H23O6: 493.2590; found:
493.2597.
13C NMR (CDCl3, 150 MHz): δ = 212.2, 158.0, 144.5, 136.3, 128.7,
128.4, 127.7, 126.2, 113.8, 55.7, 55.2, 48.5, 44.6, 23.7, 11.5.
HRMS (DART+): m/z [M + H]+ calcd for C21H27O2: 311.2011; found:
311.2005.
1-Mesityl-4-methyl-1-phenylpentan-3-one (2e)
Yellow oil; yield: 68.3 mg (80%).
IR (CHCl3): 3018, 1709, 1464, 1217, 802, 758, 725, 663 cm–1
1H NMR (CDCl3, 400 MHz): δ = 7.25–7.12 (m, 3 H), 6.98 (d, J = 7.3 Hz, 2
H), 6.83 (s, 2 H), 5.23 (t, J = 6.2 Hz, 1 H), 3.47 (dd, J = 17.2, 7.6 Hz, 1 H),
3.05 (dd, J = 17.2, 5.5 Hz, 1 H), 2.61 (sept, J = 6.9 Hz, 1 H), 2.25 (s, 3 H),
2.18 (br s, 6 H), 1.14 (d, J = 6.9 Hz, 3 H), 1.02 (d, J = 6.9 Hz, 3 H).
.
4-Benzyl-1-(4-methoxyphenyl)-1,5-diphenylpentan-3-one (4b)
Yellow oil; yield: 81.9 mg (65%).
IR (CHCl3): 1714, 1510, 1211, 771, 702, 654 cm–1
.
13C NMR (CDCl3, 150 MHz): δ = 213.2, 143.5, 138.2, 136.9, 135.8,
130.0, 128.2, 126.6, 125.5, 44.2, 41.2, 38.0, 21.2, 20.7, 18.4, 18.1.
HRMS (DART+): m/z [M + H]+ calcd for C21H27O: 295.2062; found:
295.2059.
1H NMR (CDCl3, 400 MHz): δ = 7.33–6.93 (m, 15 H), 6.86 (d, J = 8.7 Hz,
2 H), 6.71 (d, J = 6.8 Hz, 2 H), 4.33 (t, J = 7.2 Hz, 1 H), 3.73 (s, 3 H),
3.12–3.04 (m, 1 H), 2.83–2.75 (m, 2 H), 2.71 (d, J = 7.2 Hz, 2 H), 2.61
(dd, J = 13.7, 6.0 Hz, 2 H).
13C NMR (CDCl3, 150 MHz): δ = 211.4, 157.8, 144.3, 139.3, 136.0,
128.9, 128.6, 128.5, 128.3, 127.6, 126.3, 126.1, 113.7, 55.9, 55.2, 51.1,
44.3, 37.8.
HRMS (DART+): m/z [M + H]+ calcd for C31H31O2: 435.2324; found:
435.2316.
1-(2,5-Dimethylphenyl)-4-methyl-1-phenylpentan-3-one (2f)
Yellow oil; yield: 42.3 mg (52%).
IR (CHCl3): 2972, 1709, 1232, 781, 704, 648 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.26–7.12 (m, 5 H), 7.03 (s, 1 H), 7.00
(d, J = 7.6 Hz, 1 H), 6.92 (d, J = 7.6 Hz, 1 H), 4.78 (t, J = 7.2 Hz, 1 H), 3.19
(dd, J = 16.4, 7.6 Hz, 1 H), 3.13 (dd, J = 16.4, 6.8 Hz, 1 H), 2.49 (sept, J =
6.9 Hz, 1 H), 2.31 (s, 3 H), 2.24 (s, 3 H), 1.01 (d, J = 6.9 Hz, 3 H), 0.95 (d,
J = 6.9 Hz, 3 H).
13C NMR (CDCl3, 150 MHz): δ = 212.6, 143.8, 141.6, 135.1, 133.3,
130.6, 128.3, 128.0, 126.99, 126.97, 126.1, 46.9, 41.6, 41.4, 21.2, 19.4,
17.9, 17.8.
1-Cyclopentyl-3-(4-methoxyphenyl)-3-phenylpropan-1-one (4c)
Colorless oil; yield: 74.2 mg (83%).
IR (CHCl3): 3741, 3020, 1703, 1512, 1221, 768, 739, 671 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.30–7.12 (m, 7 H), 6.81 (d, J = 6.8 Hz, 2
H), 4.57 (t, J = 7.2 Hz, 1 H), 3.76 (s, 3 H), 3.17 (d, J = 7.2 Hz, 2 H), 2.82–
2.73 (m, 1 H), 1.70–1.50 (m, 8 H).
HRMS (DART+): m/z [M + H]+ calcd for C20H25O: 281.1905; found:
281.1911.
13C NMR (CDCl3, 150 MHz): δ =211.0, 158.0, 144.5, 136.3, 128.7,
128.4, 127.6, 126.2, 113.8, 55.2, 51.9, 48.2, 45.0, 28.5, 28.4, 25.9, 25.8.
HRMS (DART+): m/z [M + H]+ calcd for C21H25O2: 309.1855; found:
4-Methyl-1-phenyl-1-(p-tolyl)pentan-3-one (2g)
309.1852.
Colorless oil; yield: 40.9 mg (53%).
IR (CHCl3): 1711, 1215. 783, 731, 644 cm–1
.
1-Cyclohexyl-3-(4-methoxyphenyl)-3-phenylpropan-1-one (4d)
1H NMR (CDCl3, 400 MHz): δ = 7.26–7.06 (m, 9 H), 4.59 (t, J = 7.6 Hz, 1
H), 3.18 (d, J = 7.6 Hz, 2 H), 2.53–2.46 (m, 1 H), 2.29 (s, 3 H), 0.98 (dd,
J = 6.9, 2.7 Hz, 6 H).
Colorless oil; yield: 66.4 mg (71%).
IR (CHCl3): 2935, 1705, 1512, 1248, 1180, 791, 727, 669 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
M. Kanie et al.
Paper
Synthesis
1H NMR (CDCl3, 400 MHz): δ = 7.30–7.12 (m, 7 H), 6.80 (d, J = 8.8 Hz, 2
H), 4.57 (t, J = 7.4 Hz, 1 H), 3.76 (s, 3 H), 3.15 (d, J = 7.6 Hz, 2 H), 2.34–
2.18 (m, 1 H), 1.83–1.53 (m, 5 H), 1.29–1.10 (m, 5 H).
13C NMR (CDCl3, 150 MHz): δ = 211.8, 157.9, 144.5, 136.3, 128.6,
128.4, 127.6, 126.2, 113.8, 55.17, 55.14 51.23, 51.20, 47.0, 44.8, 28.1,
25.7, 25.5.
1-(4-Methoxyphenyl)-4-methyl-1-(p-tolyl)pentan-3-one (4i)
White solid; yield: 63.6 mg (74%); mp 45.8–46.5 °C.
IR (CHCl3): 1711, 1512, 1217, 748, 698 cm–1
1H NMR (CDCl3, 400 MHz): δ = 7.13–7.05 (m, 6 H), 6.79 (d, J = 8.7 Hz, 2
H), 4.53 (t, J = 7.3 Hz, 1 H), 3.76 (s, 3 H), 3.14 (d, J = 7.3 Hz, 2 H), 2.56–
2.45 (m, 1 H), 2.28 (s, 3 H), 0.98 (d, J = 7.2 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3
H).
.
HRMS (DART+): m/z [M + H]+ calcd for C22H27O2: 323.2011; found:
323.2018.
13C NMR (CDCl3, 150 MHz): δ = 212.7, 157.9, 141.5, 136.5, 135.7,
129.1, 128.6, 127.5, 113.8, 55.2, 46.8, 44.6, 41.3, 20.9, 17.8.
HRMS (DART+): m/z [M + H]+ calcd for C20H25O2: 297.1855; found:
297.1845.
1-Cycloheptyl-3-(4-methoxyphenyl)-3-phenylpropan-1-one (4e)
Yellow oil; yield: 80.0 mg (82%).
IR (CHCl3): 3018, 2931, 2858, 1707, 1608, 1512, 1460, 1248, 1178,
1036, 795, 712, 669 cm–1
.
1-(4-Bromophenyl)-1-(4-methoxyphenyl)-4-methylpentan-3-one
(4j)
1H NMR (CDCl3, 400 MHz): δ = 7.27–7.12 (m, 7 H), 6.78 (d, J = 8.8 Hz, 2
H), 4.56 (t, J = 7.4 Hz, 1 H), 3.75 (s, 3 H), 3.15 (d, J = 8.0 Hz, 2 H), 2.42–
2.38 (m, 1 H), 1.73–1.57 (m, 4 H), 1.57–1.30 (m, 8 H).
13C NMR (CDCl3, 150 MHz): δ = 212.2, 158.0, 144.5, 136.3, 128.9,
128.7, 127.7, 126.2, 113.8, 55.2, 52,8, 47.3, 45.0, 29.4, 28.2, 26.5.
Yellow oil; yield: 77.5 mg (74%).
IR (CHCl3): 2972, 1711, 1512, 1464, 1250, 1213, 1072, 1011, 908, 823,
771, 756, 665 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.37 (d, J = 8.0 Hz, 2 H), 7.12–7.07 (m, 4
H), 6.81 (d, J = 8.4 Hz, 2 H), 4.54 (t, J = 7.6 Hz, 1 H), 3.76 (s, 3 H), 3.13
(d, J = 7.6 Hz, 2 H), 2.56–2.46 (m, 1 H), 0.98 (d, J = 6.8 Hz, 6 H).
HRMS (DART+): m/z [M + H]+ calcd for C23H29O2: 337.2168; found:
337.2173.
13C NMR (CDCl3, 150 MHz): δ = 212.2, 158.1, 143.5, 135.6, 131.5,
129.4, 128.6, 120.0, 113.9, 55.2, 46.5, 44.3, 41.3, 17.8.
1-(4-Methoxyphenyl)-1-phenylpentan-3-one (4f)
Yellow oil; yield: 18.7 mg (24%).
IR (CHCl3): 3020, 1714, 1512, 1248, 766, 715, 696, 642 cm–1
HRMS (DART+): m/z [M + H]+ calcd for C19H22BrO2: 361.0803; found:
361.0803.
.
1H NMR (CDCl3, 400 MHz): δ = 7.28–7.10 (m, 7 H), 6.90–6.80 (m, 2 H),
4.56 (t, J = 7.6 Hz, 1 H), 3.76 (s, 3 H), 3.12 (d, J = 7.6 Hz, 2 H), 2.38–2.30
(m, 2 H), 0.98–0.93 (m, 3 H).
13C NMR (CDCl3, 150 MHz): δ = 209.7, 158.0, 144.3, 136.1, 128.6,
128.5, 127.6, 126.3, 113.9, 55.2, 48.7, 45.2, 36.7, 7.5.
Funding Information
This work was supported by JSPS KAKENHI Grant Number 15K07855.apaJn
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HRMS (DART+): m/z [M + H]+ calcd for C18H21O2: 269.1542; found:
269.1537.
Supporting Information
4-(4-Methoxyphenyl)-4-phenylbutan-2-one (4g)
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591497.
Yellow oil; yield: 3.0 mg (4%).
IR (CHCl3): 2956, 2927, 1716, 1512, 1257, 1207, 791, 737, 667 cm–1
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1H NMR (CDCl3, 400 MHz): δ = 7.29–7.05 (m, 7 H), 6.81 (d, J = 6.8 Hz, 2
H), 4.53 (t, J = 7.8 Hz, 1 H), 3.76 (s, 3 H), 3.15 (d, J = 7.8 Hz, 2 H), 2.07 (s,
3 H).
13C NMR (CDCl3, 150 MHz): δ = 207.1, 158.1, 144.2, 135.9, 128.64,
128.56, 127.6, 126.4, 113.9, 55.2, 49.9, 45.3, 30.7.
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313.1800.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G