Gram-Scale Robust Synthesis of 1-Chloro-2,3-dimethyl-4-phenylnaphthalene: A Promising Scaffold with Three Contiguous Reaction Positions

Article abstract of DOI:10.1055/s-0040-1706471

A three-step reaction sequence for the gram-scale synthesis of 1-chloro-2,3-dimethyl-4-phenylnaphthalene was developed. (i) Stereoselective dichlorocarbene addition to methyl angelate afforded methyl (1 S*,3 S*)-2,2-dichloro-1,3-dimethylcyclopropane-1-carboxylate (78% yield, >98% purity, distillation). (ii) Addition reaction of two molar amounts of PhLi afforded (1 S*,3 S*)-2,2-dichloro-1,3-dimethylcyclopropyldiphenylmethanol (81% yield, >98% purity, recrystallization). (iii) Key SnCl ₄-mediated benzannulation produced the desired product (83% yield, >98% purity, recrystallization) with three contiguous reaction sites. Five derivatization examples including benzylic reactions and cross-couplings at the pendant Cl-position are demonstrated. Some relevant distinctive benzannulations are also discussed.

Full text of DOI:10.1055/s-0040-1706471

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–G
psp
A
en
K. Moriguchi et al.
PSP
Synthesis
Gram-Scale Robust Synthesis of 1-Chloro-2,3-dimethyl-4-phenyl-
naphthalene: A Promising Scaffold with Three Contiguous Reaction
Positions
50% aq NaOH (10 equiv)
CO2Me
CO2Me
Kento Moriguchi
Taro Kono
BTEAC (5 mol%)
78%
>98% purity (q 1H NMR)
(simple distillation)
Cl Cl
CHCl3, 30–35 °C, 1 h
Shinzo Seko
Yoo Tanabe*
methyl angelate
O H
Ph
Ph
Ph
nBuLi (2.5 equiv)
PhBr (3.0 equiv)
SnCl4 (1.0 equiv)
Department of Chemistry, School of Science and Technology,
Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo,
669-1337, Japan
benzylic
reactions
2-MeTHF
–78 °C to 20–25 °C, 1 h
CH2Cl2
–78 °C, 0.5 h
Cl Cl
81%
>98% purity (q 1H NMR)
(recrystallization)
tanabe@kwansei.ac.jp
Cl
cross-coupling
partners
YDeMoeopaaiTClraotnmaranreebansebpteoo@nfkdCwihnaegnmAsieusit.rahyco,.rjSpchool of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda, Hyogo, 669-1337, Japan
83%
>98% purity (q 1H NMR)
(recrystallization)
Received: 22.07.2020
Accepted after revision: 14.08.2020
Published online: 30.09.2020
Multi-substituted naphthalenes comprise a wide range
of key synthetic building blocks for natural products, phar-
maceuticals, agrochemicals, and functionalized materials.
Benzannulation strategies provide unique access to regiose-
lective construction of multi-substituted naphthalene de-
rivatives. Among these strategies, the reaction starting from
benzenes bearing a mono-functionalized group is superb
due to its diverse synthetic scope (Scheme 1). The Döts
benzannulation utilizing Fisher carbene complexes1 and the
Danheiser benzannulation utilizing -diazoketones2 are
two pioneering methods.
Since the development of these innovative studies, sev-
eral approaches starting from benzenes bearing a mono-
functionalized group have appeared to date and are de-
scribed in chronologic order (Scheme 2). Five representative
benzannulation methods involve the appropriate alkyne
partners for the construction of multi-substituted naphtha-
lenes: (i) GaCl3-catalyzed aldehyde–alkyne condensation,3
DOI: 10.1055/s-0040-1706471; Art ID: ss-2020-f0394-psp
Abstract A three-step reaction sequence for the gram-scale synthe-
sis of 1-chloro-2,3-dimethyl-4-phenylnaphthalene was developed. (i)
Stereoselective dichlorocarbene addition to methyl angelate afforded
methyl (1S*,3S*)-2,2-dichloro-1,3-dimethylcyclopropane-1-carboxyl-
ate (78% yield, >98% purity, distillation). (ii) Addition reaction of two
molar amounts of PhLi afforded (1S*,3S*)-2,2-dichloro-1,3-dimethylcy-
clopropyldiphenylmethanol (81% yield, >98% purity, recrystallization).
(iii) Key SnCl4-mediated benzannulation produced the desired product
(83% yield, >98% purity, recrystallization) with three contiguous reac-
tion sites. Five derivatization examples including benzylic reactions and
cross-couplings at the pendant Cl-position are demonstrated. Some rel-
evant distinctive benzannulations are also discussed.
Key words gem-dichrolocyclopropane, benzannulation, naphthalene,
gram-scale, benzylic, cross-coupling partners
X
X
Y
Döts benzannulation
i) Cr(CO)6
OR2
O
Cr(CO)5
OR2
i)
ii) MeN4Br
iii) AcCl; then R2OH
R1
RS
RL
RS
RL
ii) CO, – Cr(CO)5
X
X
X
OH
Danhheiser benzannulation
O
R1
LHMDS
CF3CO2CH2CF3
MsN3
O
R2
OR3
OR3
R2
R1
N2
UV irradiation
X
X
X
R1
OH
Scheme 1 Two pioneering naphthalene benzannulations
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. Moriguchi et al.
PSP
Synthesis
(ii) TiCl4-promoted aldehyde–alkyne condensation,4 (iii)
Iron-catalyzed Grignard coupling with two alkynes,5 (iv)
Tf2NH-catalyzed aldehyde–alkyne condensation,6 and (v)
FeCl3-promoted condensation of alkynyl alcohols concomi-
tant with selenylation.7
with hexane/2-propanol (1:1). The reaction using PhMgBr
instead of PhLi afforded not 2 (only ca. 10% yield) but main-
ly (ca. 60–70%) the phenyl ketone intermediate at 0–5 °C to
room temperature for 2 hours.
50% aq NaOH (10 equiv)
CO2Me
CO2Me
BTEAC (5 mol%)
R1
(i)
Cl Cl
CHCl3, 30–35 °C, 1 h
R2
R1
methyl angelate
1
cat. GaCl3
R2
CHO
78% (simple distillation)
+
O H
Ph
X
Ph
nBuLi (2.5 equiv)
PhBr (3.0 equiv)
SnCl4 (1.0 equiv)
Ph
X
(ii)
CH2Cl2
–78 °C, 0.5 h
2-MeTHF
–78 °C to 20–25 °C, 1 h
Cl Cl
R1
R1
Cl
R3
2
81%
(recrystallization)
3
TiCl4
CHO
+
83%
(recrystallization)
R2
R3
R2
Scheme 3 Present reaction sequences
(iii)
cat. Fe(acac)3
R
cat. 1,10-phenanthroline
cat. oxidant
The key SnCl4-promoted benzannulation of 2 proceeded
smoothly to produce 1-chloro-2,3-dimethyl-4-phenylnaph-
thalene (3) in 83% isolated yield with >98% purity (q 1H
NMR) by recrystallization with hexane/2-propanol (2:1).
Various Lewis or Brønsted acid screenings of the present
benzannulation are listed in Table 1 with the 1H NMR yield.
The use of SnCl4 or TiCl4 at –78 °C afforded the best results.
R
MgBr
R
R
+
X
2
R
R
(iv)
R1
R1
cat. Tf2NH
R2
CHO
+
X
X
Table 1 Lewis or Brønsted Acid Screening for the Benzannulation
R2
Y
Lewis or Brønsted acid
BF3·OEt2
Temp (°C)
1H NMR yield (%)a
Y
(v)
X
0–5
–78
88
84
OH
FeCl3
(R2Se)2
X
+
SnCl4
TMSOTf
TiCl4
0–5
–78
83
96
SeR2
R1
R1
0–5
–78
83
71
Scheme 2 Representative naphthalene benzannulations using mono-
functionalized arene substrates
0–5
–78
78
98
ZrCl4
0–5
–78
37
80
The present article describes an accessible synthesis of
elaborated tetra-substituted naphthalene 3 from methyl
angelate in three steps (Scheme 3). Fedorynski and Anilku-
mar’s group provided a comprehensive review of the syn-
thetic application of 1,1-dihalocyclopropanes.8 Stereoselec-
tive dichlorocarbene addition9 to methyl angelate afforded
methyl (1S*,3S*)-2,2-dichloro-1,3-dimethylcyclopropane-
1-carboxylate (1) in 78% yield with >98% purity [quantita-
AlCl3
0–5
0–5
0–5
59
ZnCl2
MgCl2
37
no reaction
a Internal standard: ethylene carbonate.
1
1
tive H NMR (q H NMR)] by a simple distillation purifica-
tion. A similar substrate, methyl (1S*)-2,2-dichloro-1-meth-
ylcyclopropane-1-carboxylate, derived from methyl meth-
acrylate is commercially available.9 An addition reaction of
two molar amounts of PhLi with 1 afforded (1S*,3S*)-2,2-di-
chloro-1,3-dimethylcyclopropyldiphenylmethanol (2) in
Derivatizations of the obtained naphthalene 3 were pre-
sented to demonstrate the utility (Scheme 4), because 3
possesses two promising contiguous benzylic positions and
a pendant 1-chloro group. (i) Dibromination of the 2,3-di-
methyl group proceeded smoothly using two molar
amounts of NBS-cat. AIBN to afford the product 4 in 77%
yield. Conversion of 4 using KOAc and KOH afforded diol 5
in 91% yield; this type of reaction was successfully em-
1
81% isolated yield with >98% purity (q H NMR), in which
the crude solids of 2 were purified by a recrystallization
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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K. Moriguchi et al.
PSP
Synthesis
ployed for the total syntheses of natural and unnatural lig-
nan lactones.10,11 (ii) Cyclopentane formation of 4 with di-
methyl malonate proceeded smoothly to afford tricyclic
product 6 (51%). (iii) Suzuki–Miyaura cross-coupling suc-
cessfully proceeded at the 1-chloro group of 3 to produce
the desired product 7 in excellent yield (92%), despite of the
highly stereocongested position. (iv) Buchwald–Hartwig
cross-coupling was implemented to afford aniline deriva-
tive 8 in 91% yield. (v) Buchwald hydroxylation cross-cou-
pling12 of 3 similarly produce the desired 1-naphthol prod-
uct 9 in excellent yield (98%).
A plausible mechanism of the key benzannulation is
shown in Scheme 5. The initially formed benzyl cation 10
derived from 2 by the action of SnCl4, in turn, rearranges
into the homoallyl cation 11 through regioselective ring-
cleavage of bond a.9 The Z-form of 11 undergoes intramo-
lecular Friedel–Crafts reaction to produce the desired 1-
chloro-2,3-dimethyl-3-phenylnaphthalene (3).
SnCl4
H
O
OH
Ph
Ph
Ph
Ph
SnCl4
– SnCl3(OH)
– HCl
Cl Cl
Cl Cl
Ph
Ph
2
benzylic
reactions
Ph
Cl
Ph
Ph
+
Cl
a
– H+
+
3
cross-coupling
partners
Cl Cl
– HCl
Cl Cl
3
11
10
(i)
Scheme 5 Plausible mechanism for the benzannulation
Ph
Cl
Ph
HO
HO
Br
Br
KOAc, KOH
2 NBS, cat. AIBN
3
The substrate scope for the benzannulation is depicted
in Scheme 6. Not only diaryl cyclopropylmethanols but also
monoarylcyclopropylmethanols served as the substrate 12
to furnish a variety of 1-chloro and 1-bromonaphthalenes
13. The introduction of a 1-chloro or 1-bromo group into
naphthalenes and the use of a cyclopropane unit for the
naphthalene formation are unique but practical strategies.
On the other hand, a related reaction using (1S*,3S*)-
2,2-dihalo-1-methyl-3-phenylcyclopropylmethanols 14 us-
ing CF3CO2H reagent proceeded smoothly to produce 2-
chloro (or 2-bromo)-3-methyl-1-phenylnaphthalenes 15
through highly regioselective cleavage of bond b (Scheme
7).10 Obviously, the formation of benzyl cation intermediate
16 predominates over that of the competitive dilaloge-
nomethylinium cation like 11. This distinctive switching
mode is a notable feature of the present benzannulation.
As an extension of primary non-regioselective benz-
annulation, we already reported a distinctive regiocon-
trolled benzannulation11 (Scheme 8). Stereodefined
(aryl1)(aryl2)(2,2-dichloro-1-methylcyclopropyl)methanols
18 were prepared by sequential addition of Ar1MgBr and
Ar2Li with (1S*)-2,2-dichlorocyclopropane-1-carbonyl chlo-
ride or the (1S*,3S*)-analogue 17. The obtained adducts 18
successfully underwent the desired SnCl4- or TiCl4-mediat-
ed regiocontrolled reactions to produce unsymmetrically
substituted 1-(aryl1)-4-chloronaphthalene families 19
bearing a variety of substituents. An application to the total
syntheses of unsymmetrically substituted natural lignan
lactones, justicidin B,13 retrojusticidin B,14 and dehy-
drodesoxypodophyllotoxin15 was achieved.11 In addition,
unique chirality-exchange benzannulations from central
4
5
91%
Cl
87%
(ii)
Ph
MeO2C
MeO2C
K2CO3
MeO2C
MeO2C
4
6
51%
Cl
(iii)
Ph
(p-MeO)C6H4B(OH)2
Pd(OAc)2, SPhos, K3PO4
3
7
92%
OMe
Ph
(iv)
PhNH2
Pd2(dba)3, XPhos, K2CO3
3
NHPh
Ph
8
91%
(v)
KOH
Pd(dba)2, tBu-XPhos
3
9
98%
OH
Scheme 4 Various useful derivatizations of naphthalene 3
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

D
K. Moriguchi et al.
PSP
Synthesis
H (or Ar)
OH
Ar
R2
R1
R1
acid
A: BF3•OEt2
B: SnCl4
H (or Ar)
R2
C: TiCl4
X
X
X
X = Cl, Br
1 = H, Et
12
13
R
R
2 = H, Me
OMe
Cl
Cl
Cl
Cl
Cl
A: 40%
A: 43%
B: 62%
A: 62%
A: 86%
A: 86%
OMe
Cl
NHAc
Cl
C: 27%
Cl
Cl
A: 65%
Br
A: 62%
Cl
A: 66%
A: 39%
O
O
O
O
O
O
O
O
+
O
O
O
O
O
O
O
3 steps
O
Cl
Justicidin E
Taiwanin C
B: 83%
Scheme 6 Substrate scope for the benzannulation
Ph
OH
chiral alcohols 20 into axially chiral -arylnaphthalenes 21
were performed with nearly complete transfer of the chiral-
ity (all five examples >98%) (Scheme 9).16
Ph
CF3CO2H
Ph
X
X
X
Ph
As a related work, one of the authors (S.S.) reported the
synthesis of 1-phenyldihydronaphthalene 23 from (2,2,3,3-
tetramethylcyclopropyl)diphenylmethanol (22) (Scheme
10).17 Following this study, the method was applied to the
syntheses of dihydronaphthalene derivatives including sev-
eral lignan natural products (Scheme 8).18
14a X = Cl
14b X = Br
15a X = Cl 78%
15b X = Br 64%
+
OH2
b
+
H+
Ph
Ph
Ph
Ph
14
– H2O
X
X
X
X
In conclusion, a three-step reaction sequence for the
synthesis of 1-chloro-2,3-dimethyl-4-phenylnaphthalene
was developed: (i) stereoselective dichlorocarbene addition
to methyl angelate, (ii) addition reaction of two molar
amounts of PhLi, and (iii) key benzannulation promoted by
SnCl4. All procedures are accessible and user-friendly to
produce multi-substituted naphthalenes. Extensive studies
on the development of a variety of unique and selective
benzannulations are discussed. This strategy will contrib-
ute to the construction of elaborated and useful naphtha-
lene synthetic blocks.
Ph
15
– H+
+
X
X
– HX
Ph
Scheme 7 Relevant regioselective benzannulation of 2,2-dihalo-1-
methyl-3-phenylcyclopropylmethanols
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

E
K. Moriguchi et al.
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Synthesis
Products 2–9 are new compounds.
Ar1
HO
Ar2
SnCl4 or
TiCl4
Methyl (1S*,3S*)-2,2-Dichloro-1,3-dimethylcyclopropane-1-car-
R
Ar1MgBr
COCl
R
Ar2Li
boxylate (1)11
Ar1
Ar2
CAUTION: The preparation of 50% NaOH viscous aqueous solution re-
quired careful procedure: gradual addition of NaOH pellet into H2O
with sufficient stirring and gentle cooling.
Cl Cl
18
R
Cl Cl
17
Cl
19
R = H, Me
stereodefined
alcohols
unsymmetrically
Using a 300 mL, four-necked, round-bottomed flask equipped with a
100 mL dropping funnel, a thermometer, a pressure-equalizing argon
balloon, aq NaOH (50% w/w, 80 g, 1.00 mol) was added through a 100
mL dropping funnel to a vigorously stirred solution of methyl angelate
(11.4 g, 0.10 mol), CHCl3 (29.7 g, 0.50 mol), and benzyltriethylammo-
nium chloride (BTEAC; 1.15 g, 5.0 mmol) over a period of 15 min
while maintaining the inner temperature at 30–35 °C [Vigorous stir-
ring was required throughout the phase-transfer reaction using a
magnetic stirring bar (for an example, egg-shaped, 50 mm length × 20
mm diameter). When the inner temperature raised over 40 °C, the
yield significantly decreased probably due to polymerization of meth-
yl angelate]. The reaction mixture was vigorously stirred for 1 h while
maintaining the same temperature, and then diluted with H2O (50
mL) below 30 °C. The black-colored mixture was filtered through a
Celite pad (15 g) on a glass filter (G3, 70 mm diameter), into a 200 mL
round-bottomed flask. The filtrate was moved into a 500 mL separa-
tory funnel. The organic phase was separated and the aqueous phase
was re-extracted with CHCl3 (2 × 50 mL). The combined organic
phases were washed with H2O (40 mL) and brine (40 mL), dried, and
concentrated. The obtained black-colored crude oil was purified by
distillation to give the desired colorless product 1 with >98% purity (q
1H NMR); yield: 16.50 g (84%); colorless oil; bp 65–66 °C/7.5 mmHg.
substituted products
O
OMe
OMe
O
O
O
MeO
O
O
OMe
OMe
OMe
O
O
O
O
O
OMe
O
justicidin B
dehydrodesoxy-
podophyllotoxin
retrojusticidin B
Scheme 8 Regiocontrolled benzannulation strategy
R2
HO
SnCl4 or
TiCl4
R2
R1
(S)
–78 °C
R1
Cl Cl
1H NMR (500 MHz, CDCl3):  = 1.41 (d, J = 6.9 Hz, 3 H), 1.55 (q, J = 6.9
20
Cl
Hz, 1 H), 1.57 (s, 3 H), 3.74 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 10.8, 21.1, 36.0, 36.8, 52.1, 67.6, 168.9.
R
R
1 = Cl, MeO, Me
2 = H, Cl, Me
(R)-form
21
5 examples: 47–97%
> 98% ee
sp3 central chirality
axial chirality
[(1S*,3S*)-2,2-Dichloro-1,3-dimethylcyclopropyl]diphenylmetha-
Scheme 9 Chirality exchange benzannulation
nol (2)
nBuLi (1.57 M in hexane, 49 mL, 77 mmol) was added dropwise
through a 100 mL dropping funnel to a stirred solution of bromoben-
zene (16.5 g, 105 mmol) in 2-methyltetrahydrofuran (55 mL) over a
period of 15 min while maintaining the inner temperature at –60 to –
75 °C (slightly exothermic) and the mixture was stirred at –60 to –75
°C for 1 h. Then, methyl ester 1 (6.90 g, 35 mmol) in 2-methyltetrahy-
drofuran (15 mL) was added to the stirred mixture through a 30 mL
dropping funnel over 10 min, while maintaining the inner tempera-
ture at –60 to –75 °C (slightly exothermic). The mixture was stirred at
the same temperature for 1 h, and was gradually warmed up to 20–25
°C. Sat. aq NH4Cl (70 mL) was added to the mixture below 25 °C over
15 min, and the mixture was moved into a 500 mL separatory funnel.
The organic phase was separated and the aqueous phase was re-ex-
tracted with EtOAc (2 × 50 mL). The combined organic phases were
washed with H2O (70 mL) and brine (70 mL), dried, and concentrated.
The obtained crude solid (12.2 g) was purified by recrystallization
from hexane/2-propanol (1:1; 13 mL) to give the desired product 2
Ph
OH
CO2Me
SnCl4, MS 3Å
2 PhMgBr
Ph
Ph
rt, 10 min
23
22
97%
Scheme 10 Synthesis of dihydronaphthalene 23
All reactions were carried out in oven-dried glassware under an argon
atmosphere. Flash column chromatography was performed with sili-
ca gel Merck 60 (230–400 mesh ASTM). TLC analysis was performed
on 0.25 mm silica gel Merck 60 F254 plates. Melting points were de-
termined on a hot stage microscope apparatus (AS ONE, ATM-01) and
were uncorrected. NMR spectra were recorded on a JEOL DELTA 300
or JEOLRESONANCE ECX-500 spectrometer, operating at 300 MHz or
500 MHz for 1H NMR and 75 MHz or 125 MHz for 13C NMR. Chemical
shifts ( ppm) in CDCl3 were reported downfield from TMS (= 0) for
1H NMR. For 13C NMR, chemical shifts were reported in the scale rela-
tive to CDCl3 (77.00 ppm) as an internal reference. IR spectra were re-
corded on a JASCO FT/IR-5300 spectrophotometer. Mass spectra were
measured on a JEOL JMS-T100LC spectrometer.
1
with >98% purity (q H NMR); yield: 9.02 g (81%); colorless crystals;
mp 95–96 °C.
When THF solvent was used instead, the yield decreased slightly (ca.
65%).
IR (neat): 3578, 3059, 3024, 2995, 2932, 2878, 1447, 1028 cm–1
.
1H NMR (500 MHz, CDCl3):  = 1.17 (s, 3 H), 1.52 (q, J = 6.9 Hz, 1 H),
1.78 (d, J = 6.9 Hz, 3 H), 2.80 (s, 1 H), 7.20–7.23 (m, 2 H), 7.27–7.32 (m,
3 H), 7.35–7.39 (m, 1 H), 7.41–7.45 (m, 2 H), 7.52–7.53 (m, 2 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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K. Moriguchi et al.
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Synthesis
13C NMR (125 MHz, CDCl3):  = 11.1, 27.1, 36.3, 38.1, 73.9, 83.8, 127.1,
127.5 (2 C), 127.8, 128.2 (4 C), 128.9 (2 C), 144.6, 146.5.
HRMS (DART): m/z calcd for C18H18Cl2O [M + H]+: 320.0735; found:
320.0731.
same temperature for 2 h. Aq 1 M HCl was added to the mixture,
which was extracted with Et2O (2 × 50 mL). The combined organic
phases were washed with H2O (3 ×) and brine, dried (Na2SO4), and
concentrated. The obtained crude solid was washed by hexane to give
desired product 5; yield: 817 mg (91%); colorless crystals; mp 151–
153 °C.
1H NMR (500 MHz, CDCl3):  = 2.63 (br s, 1 H), 2.95 (br s, 1 H), 4.69 (s,
2 H), 5.28 (s, 2 H), 7.29–7.32 (m, 2 H), 7.39–7.44 (m, 2 H), 7.47–7.53
(m, 3 H), 7.59–7.62 (m, 1 H), 8.42–8.43 (m, 1 H).
1-Chloro-2,3-dimethyl-4-phenylnaphthalene (3)
A 300 mL, four-necked, round-bottomed flask equipped with a 100
mL dropping funnel, a thermometer, a pressure-equalizing argon bal-
loon was charged with alcohol 2 (8.03 g, 25 mmol) in CH2Cl2 (50 mL).
SnCl4 (1 M in CH2Cl2, 25 mL, 25 mmol) was added through a 100 mL
dropping funnel to the stirred solution at –55 to –75 °C for 30 min [At
the initial addition stage of SnCl4 (ca. 5 mL), the reaction was consid-
erably exothermic. Then, it changed over slightly exothermic stage],
and the mixture was stirred at –72 to –75 °C for 30 min. After gradual
warming up to 20–25 °C, H2O (50 mL) was added to the mixture,
which was moved into a 500 mL separatory funnel. The mixture was
extracted with EtOAc (100 mL). The organic phase was separated and
the aqueous phase was re-extracted with EtOAc (2 × 50 mL). The com-
bined organic phases were washed with water (50 mL) and brine (50
mL), dried, and concentrated. The obtained crude solid (7.03 g) was
purified by recrystallization from hexane/2-propanol (2:1; 27 mL) to
give the desired first-crop product 3; yield: 4.67 g (70%) (q 1H NMR
purity: 98%). The mother liquid was concentrated to give crude solid,
which was recrystallized with hexane/2-propanol (2:1; 4 mL) to give
13C NMR (125 MHz, CDCl3):  = 60.8, 61.1, 125.1, 126.9, 127.3, 127.6,
127.7, 128.3 (2 C), 130.2 (2 C), 130.4, 132.3, 133.5, 134.5, 135.5, 138.0,
139.5.
HRMS: m/z calcd for C18H15ClO2 [M + H]+: 298.1551; found: 298.1547.
Dimethyl 4-Chloro-9-phenyl-1,3-dihydro-2H-cyclopenta[b]naph-
thalene-2,2-dicarboxylate (6)
A mixture of naphthalene 4 (425 mg, 1.00 mmol), dimethyl malonate
(132 mg, 1.00 mmol), K2CO3 (276 mg, 1.00 mmol) in MeCN (10 mL)
was stirred at reflux for 14 h. After cooling down, the mixture was fil-
tered through a Celite pad, and the obtained filtrate was concentrat-
ed. The obtained crude oil was purified by silica gel column chroma-
tography (hexane/EtOAc 10:1) to give the desired product 6; yield:
202 mg (51%); paled yellow crystals; mp 129–131 °C.
1H NMR (500 MHz, CDCl3):  = 3.53 (s, 2 H), 3.74 (s, 6 H), 3.89 (s, 2 H),
7.32–7.34 (m, 2 H), 7.36–7.39 (m, 1 H), 7.43–7.47 (m, 1 H), 7.49–7.54
(m, 2 H), 8.26–8.28 (m, 1 H),
1
the desired second-crop of product 3 (q H NMR purity: 94%); yield:
0.84 g (13%); colorless crystals; mp 110–111 °C.
Comparable temperature varying experiments were as follows: 78%
1H NMR yield at 0 °C and 89% 1H NMR yield at –20 °C. This result
means this reaction is sufficiently robust for temperature change.
13C NMR (125 MHz, CDCl3):  = 40.5, 40.8, 53.0 (2 C), 59.5, 123.7,
126.0, 126.2 (2 C), 127.6, 128.6 (2 C), 129.8 (2 C), 130.5, 133.3, 134.1,
136.5, 137.5, 137.9, 171.6.
IR (neat): 3063, 1584, 1501, 1441, 1379, 1329, 1155 cm–1
.
HRMS: m/z calcd for C23H19ClO4 [M + H]+: 394.1762; found: 394.1766.
1H NMR (500 MHz, CDCl3):  = 2.18 (s, 3 H), 2.62 (s, 3 H), 7.21–7.24
(m, 2 H), 7.29–7.33 (m, 2 H), 7.42–7.46 (m, 1 H), 7.47–7.52 (m, 3 H),
8.31 (d, J = 8.5 Hz, 1 H).
1-(4-Methoxyphenyl)-2,3-dimethyl-4-phenylnaphthalene (7)
A mixture of naphthalene 3 (134 mg, 0.50 mmol), p-MeOC6H4B(OH)2
(114 mg, 0.75 mmol), K3PO4 (212 mg, 1.0 mmol), Pd(OAc)2 (3.4 mg,
0.02 mmol), and SPhos (12 mg, 0.03 mmol) in toluene (1.0 mL) was
stirred at 80–85 °C for 2 h. After cooling down, H2O was added to the
mixture, which was extracted with EtOAc (2 × 20 mL). The combined
organic phases were washed with H2O and brine, dried (Na2SO4), and
concentrated. The obtained crude solid were purified by silica gel col-
umn chromatography (hexane/EtOAc 30:1) to give the desired prod-
uct 7; yield: 156 mg (92%); colorless crystals; mp 167–168 °C.
1H NMR (500 MHz, CDCl3):  = 2.19 (s, 3 H), 2.21 (s, 3 H), 3.92 (s, 3 H),
7.05–7.07 (m, 2 H), 7.22–7.44 (m, 4 H), 7.31–7.32 (m, 3 H), 7.38–7.40
(m, 1 H), 7.43–7.47 (m, 1 H), 7.50–7.53 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 18.48, 18.51, 55.3, 113.8 (2 C), 124.6 (2
C), 126.3, 126.4, 126.9, 128.3 (2 C), 130.3 (2 C), 131.4 (3 C), 131.7,
132.9, 133.0, 133.4, 137.6, 137.8, 140.8, 158.5.
13C NMR (125 MHz, CDCl3):  = 18.0, 18.9, 124.4, 125.5, 125.9, 126.7,
127.1, 128.4 (2 C), 129.4, 130.2 (2 C), 130.5, 132.4, 133.2, 133.7, 137.4,
140.0.
HRMS (DART): m/z calcd for C18H15Cl [M + H]+: 267.0941; found:
267.0952.
2,3-Bis(bromomethyl)-1-chloro-4-phenylnaphthalene (4)
A mixture of naphthalene 3 (1.33 g, 5.0 mmol), NBS (1.96 g, 11.0
mmol), and AIBN (82 mg, 0.5 mmol) in CCl4 (10 mL) was refluxed for 1
h. After cooling down, H2O was added to the mixture, which was ex-
tracted with EtOAc (2 × 50 mL). The combined organic phases were
washed with aq 1 M HCl, H2O and brine, dried (Na2SO4), and concen-
trated. The obtained crude solid was washed with hexane/Et2O (1:1;
5 mL) to give the desired product 4; yield: 1.85 g (87%); colorless crys-
tals; mp 150–154 °C.
HRMS: m/z calcd for C25H22O [M + H]+: 338. 2461; found: 338.2457.
1H NMR (500 MHz, CDCl3):  = 4.59 (s, 2 H), 5.16 (s, 2 H), 7.32–7.47
(m, 4 H), 7.50–7.57 (m, 3 H), 7.59–7.63 (m, 1 H), 8.38–8.40 (m, 1 H).
2,3-Dimethyl-4-phenyl-1-(p-tolyamino)naphthalene (8)
13C NMR (125 MHz, CDCl3):  = 28.2, 29.5, 125.1, 127.67, 127.71,
128.0, 128.2, 128.5 (2 C), 129.8 (2 C), 130.8, 131.5, 132.1, 133.7, 137.0,
140.7.
PhNH2 (47 mg, 0.5 mmol), K2CO3 (138 mg, 1.0 mmol), Pd2(dba)3 (9
mg, 0.01 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphe-
nyl (XPhos) (16 mg, 0.03 mmol) were successively added to a stirred
suspension of naphthalene 3 (133 mg, 0.5 mmol ) in tBuOH (1.0 mL)
at 20–25 °C under argon atmosphere, and the mixture was stirred at
85–90 °C for 14 h. H2O was added to the mixture, which was extract-
ed with EtOAc (2 × 30 mL). The combined organic phases were
washed with H2O and brine, dried (Na2SO4), and concentrated. The
(1-Chloro-4-phenylnaphthalene-2,3-diyl)dimethanol (5)
A mixture of naphthalene 4 (1.27 g, 3.0 mmol) and KOAc (1.18 g, 12.0
mmol) in DMF (12 mL) was stirred at rt for 2 h. A solution of KOH
(1.01 g, 18.0 mmol) in H2O (6.0 mL) and MeOH (12 mL) were added to
the stirred mixture at 20–25 °C, and the mixture was stirred at the
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

G
K. Moriguchi et al.
PSP
Synthesis
obtained crude solid was purified by silica gel column chromatogra-
phy (hexane/EtOAc 30:1) to give the desired product 8; yield: 148 mg
(91%); pale yellow crystals; mp 143–145 °C.
1H NMR (500 MHz, CDCl3):  = 2.19 (s, 3 H), 2.40 (s, 3 H), 5.62 (s, 1 H),
6.58–6.59 (m, 2 H), 6.74–6.77 (m, 1 H), 7.15–7.19 (m, 2 H), 7.27–7.30
(m, 3 H), 7.33–7.36 (m, 2 H), 7.43–7.47 (m, 1 H), 7.50–7.53 (m, 2 H),
8.00–8.01 (m, 1 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706471. Su
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References
13C NMR (125 MHz, CDCl3):  = 15.6, 18.6, 113.4 (2 C), 117.95, 123.2,
125.1, 125.2, 126.8, 126.9, 128.4 (2 C), 129.3 (2 C), 130.0, 130.3 (2 C),
132.4, 133.4, 133.5, 133.7, 137.1, 140.5, 147.4.
(1) (a) Döts, K. H. Angew. Chem. Int. Ed. 1975, 14, 644. (b) Döts, K. H.
Pure Appl. Chem. 1983, 55, 1689. (c) Timko, J. M.; Yamashita, A.
Org. Synth. 1993, 71, 72.
(2) Danheiser, L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller, R. F. J. Am.
Chem. Soc. 1990, 112, 3093.
HRMS: m/z calcd for C24H21N [M + H]+: 323.2464; found: 323.2467.
(3) Viswanathan, G. S.; Wang, M.; Li, C-J. Angew. Chem. Int. Ed. 2002,
41, 2138.
(4) Kabalka, G. W.; Ju, Y.; Wu, Z. J. Org. Chem. 2003, 68, 7915.
(5) Ilies, L.; Matsumoto, A.; Kobayashi, M.; Yoshikai, N.; Nakamura,
E. Synlett 2012, 23, 2381.
(6) Ponra, S.; Vitale, M. R.; Michelet, V.; Ratovelomanana-Vital, V.
J. Org. Chem. 2015, 80, 3250.
(7) Recchi, A. M. S.; Back, D. F.; Zeni, G. J. Org. Chem. 2017, 82, 2713.
(8) (a) Fedorynski, M. Chem. Rev. 2003, 103, 1099. (b) Thankachan,
A. P.; Shndhu, K. S.; Krishnan, K. K.; Anilkumar, G. Org. Biomol.
Chem. 2015, 13, 8780.
2,3-Dimethyl-4-phenylnaphthalen-1-ol (9)
A mixture of naphthalene 3 (133 mg, 0.50 mmol), Pd2(dba)3 (9.2 mg,
0.01 mmol), tBu-XPhos (17 mg, 0.04 mmol), and KOH (140 mg, 2.50
mmol) in 1,4-dioxane (0.50 mL) and H2O (0.50 mL) was stirred at 95–
100 °C for 14 h. After cooling down, aq 1 M HCl was added to the mix-
ture, which was extracted with EtOAc (2 × 20 mL). The combined or-
ganic phases were washed with H2O and brine, dried (Na2SO4), and
concentrated. The obtained crude crystals were purified by silica gel
column chromatography (hexane/EtOAc 5:1) to give the desired prod-
uct 9; yield: 121 mg (98%); colorless crystals: mp 93–94 °C.
1H NMR (500 MHz, CDCl3):  = 2.16 (s, 3 H), 2.40 (s, 3 H), 5.19 (s, 1 H),
7.23–7.25 (m, 2 H), 7.27–7.30 (m, 2 H), 7.38–7.43 (m, 2 H), 7.46–7.49
(m, 2 H), 8.10–8.12 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 12.5, 18.3, 116.7, 120.6, 122.7, 124.3,
125.2, 126.3, 126.7, 128.2 (2 C), 130.8 (2 C), 1315, 132.1, 133.4.
(9) Sigma-Aldrich Catalogue No. 35934.
(10) (a) Seko, S.; Tanabe, Y.; Suzukamo, G. Tetrahedron Lett. 1990, 31,
6883. (b) Tanabe, Y.; Seko, S.; Nishii, Y.; Yoshida, T.; Utsumi, N.;
Suzukamo, G. J. Chem. Soc., Perkin Trans. 1 1996, 2157.
(11) Nishii, Y.; Yoshida, T.; Asano, H.; Wakasugi, K.; Morita, J.; Aso,
Y.; Yoshida, E.; Motoyoshiya, J.; Aoyama, H.; Tanabe, Y. J. Org.
Chem. 2005, 70, 2667.
HRMS: m/z calcd for C18H16O [M + H]+: 248.1280; found: 248.1277.
(12) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2006, 128, 10694.
(13) Wada, K.; Munakata, K. Tetrahedron Lett. 1970, 2017.
(14) Lin, T.-Y.; Lo, T.-B.; Wang, K. T.; Weinstein, B. Tetrahedron Lett.
1967, 849.
(15) (a) Newmann, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461.
(b) Kumar, K.; Waldmann, H. Angew. Chem. Int. Ed. 2009, 48,
3224. (c) Zhao, C.; Rakesh, K. P.; Mumtaz, S.; Moku, B.; Asiri, A.
M.; Marwani, H. M.; Manukumar, H. M.; Qin, H. RSC Adv. 2018,
8, 9487.
Funding Information
This research was partially supported by Grant-in-Aids for Scientific
Research on Basic Areas (B) ‘18350056’, Priority Areas (A) ‘17035087’
and ‘18037068’, (C) 15K05508, and Exploratory Research ‘17655045’
from the Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT).
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(16) Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc.
2004, 126, 5358.
Acknowledgment
(17) Seko, S. Japan Kokai Tokkyo Koho. 1994271484, 1994.
(18) (a) Nishii, Y. J. Synth. Org. Jpn. 2015, 73, 701. (b) Nishii, Y.
J. Synth. Org. Jpn. 2018, 76, 922.
One of the author (Y.T.) offers his warmest congratulations to Profes-
sor Ben L. Feringa (University of Groningen, The Netherlands) on be-
ing awarded the 2016 Nobel Prize in Chemistry.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G