Role of 2-naphthyl ether intermediate in formation of isolable atropisomers derived from the coupling reaction of (2-hydroxy-3,3-dimethylindolin-l-yl)-(substituted phenyl)methanones with 2-naphthol

Article abstract of DOI:10.3987/COM-09-11644

The formation pathway of the atropisomers derived from the reaction of (2-hydroxy-3,3-dimethylindolin-l-yl)(4-substituted phenyl)methanones with 2-naphthol in the presence of BF₃·Et₂O was discussed on the basis of the isolation of the 2-naphthyl ether intermediate whose structure was determined by single crystal X-ray analysis. The results indicate that the coupling reaction proceeds through stepwise mechanism, i.e., the ether intermediate formation followed by Fries-type rearrangement.

Full text of DOI:10.3987/COM-09-11644

HETEROCYCLES, Vol. 78, No. 6, 2009
1485
HETEROCYCLES, Vol. 78, No. 6, 2009, pp. 1485 - 1496. © The Japan Institute of Heterocyclic Chemistry
Received, 8th January, 2009, Accepted, 6th March, 2009, Published online, 9th March, 2009
DOI: 10.3987/COM-09-11644
ROLE OF 2-NAPHTHYL ETHER INTERMEDIATE IN FORMATION OF
ISOLABLE ATROPISOMERS DERIVED FROM THE COUPLING
REACTION
OF
(2-HYDROXY-3,3-DIMETHYLINDOLIN-1-YL)-
(SUBSTITUTED PHENYL)METHANONES WITH 2-NAPHTHOL
Masashi Eto,a Fumikazu Ito,b Hidetoshi Sato,b Itaru Shinohara,b Koki
Yamaguchi,b Yasuyuki Yoshitake,b and Kazunobu Haranob,*
aLiberal Arts Education Center, Aso Campus, Tokai University, 5435 Kawayo,
b
Minami-Aso, Kumamoto 869-1404, Japan. Faculty of Pharmaceutical Sciences,
Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan. E-mail:
harano@ph.sojo-u.ac.jp
Abstract – The formation pathway of the atropisomers derived from the reaction
of (2-hydroxy-3,3-dimethylindolin-1-yl)(4-substituted phenyl)methanones with
2-naphthol in the presence of BF3•Et2O was discussed on the basis of the isolation
of the 2-naphthyl ether intermediate whose structure was determined by single
crystal X-ray analysis. The results indicate that the coupling reaction proceeds
through stepwise mechanism, i.e., the ether intermediate formation followed by
Fries-type rearrangement.
INTRODUCTION
In the previous papers,1 we reported a simple method for synthesis of 2-aryl substituted indoline
derivatives based on condensation of (2-hydroxy-3,3-dimethylindolin-1-yl)(substituted phenyl)-
methanones (so-called, 1-acyl-2-hydroxy-3,3-dimethylindolin, 1) with various electron-rich aromatic
compounds (e.g., 2-naphthol, 2a) in the presence of boron trifluoride diethyl ether (BF3•Et2O).1c The
reaction proceeds under mild reaction conditions and provides an important method for synthesis of
isolable diastereomeric atropisomers (3 and 4) arising from restricted rotation around a Csp3-Csp2 bond
(Scheme 1)2. We have isolated 16 pairs of atropisomers and clarified important structural features and
characterized weak interactions intervened in the restricted rotation.
During the course of the study of the coupling reaction of (2-hydroxy-3,3-dimethylindolin-
1-yl)(4-nitrophenyl)methanone (1a) with 4-methylphenol (2b), we isolated the corresponding ether

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HETEROCYCLES, Vol. 78, No. 6, 2009
derivative (6ab) besides the 2-aryl derivative (7ab) and the elimination product (5a) via the
Wagner-Meerwein type rearrangement.
OH
4
7
3
H
H
5
6
2
2-naphthol (2a)
OH
+
N
N
N
BF3·OEt2
1
O C
R1
O C
O C
OH
in dioxane
R1
R1
1
3 (syn)
4 (anti)
Scheme 1
This paper describes a possible formation pathway of the atropisomers in connection with the isolation of
the intermediary phenyl ethers.
RESULTS AND DISCUSSION
The reaction of 1a (4-nitrophenyl derivative) with 4-methylphenol (2b) in the presence of BF3•Et2O at
room temperature for 2 hr gave 6ab and 7ab in 38 and 24% yields, respectively.
4-methylphenol (2b) or
4-methoxyphenol (2c)
H
X
H
OH
+
+
1
N
N
N
BF3·Et2O
O
X
C O
R1
O C
O C
in dioxane
H
R1
R1
5
6
7
R1 = a :
b :
NO2
Cl
Yield (%)
7
Substrate Phenol
Solvent
Temp (°C)
Time (h)
6
5
1a
1a
1a
1a
1a
1b
1b
1b
1b
2b
2b
2b
2b
2c
2b
2b
2c
2c
dioxane
dioxane
dioxane
Et2O
rt
rt
rt
rt
rt
rt
0
rt
0
0.5
2
33 (6ab)
38 (6ab)
4 (6ab)
44 (6ab)
55 (6ac)
-
19 (7ab)
1 (5a)
24 (7ab)
3 (5a)
6
66 (7ab)
4 (5a)
3
-
-
-
Et2O
3
-
dioxane
Et2O
72
2
19 (7bb)
13 (5b)
71 (6bb)
-
-
59 (7bc)
-
-
-
-
Et2O
5
Et2O
1.5
22 (6bc)
Scheme 2

HETEROCYCLES, Vol. 78, No. 6, 2009
1487
The yields of the reaction products under various reaction conditions are summarized in Scheme 2. As
can be seen in Scheme 2, the formation of the phenyl ether derivative (6) is preferred for short reaction
times in ethereal solvents at room temperature and when the reaction was performed under milder
reaction conditions, the product ratio (7/6) decreased with an increase of the 2-phenyl ether derivative (6).
In order to confirm the isomerization of 6 to 7, the
time-course study in Et2O was performed. As depicted
◇ 1a
● 6ac
○ 7ac
in Figure 1, at the early stage of the reaction, the
80
2-phenyl ether (6ac) formed rapidly and immediately
60
reached a maximum point, and decreased with increase
●
//
of the 2-aryl derivative (7ac), indicating that the phenol
ether derivative is an intermediary product, at least, in
the reaction condition used. This assumption is
supported by the fact that 6ab was treated with
BF3·Et2O in dioxane at room temperature to give the
corresponding 2-aryl derivative 7ab (20%) besides 5a
(6%) and 1a (6%).
40
20
0
●
//
●
//
●
//
0
2
4
6
8
22
24
Figure 1. Time Cource of Reaction of 1a with 2c
in Et2O in the Presence of BF3•Et2O
H
H
H
OH
OH
N
N
N
C
N
O
HO
2-naphthol (2a)
O C
O
O
+
+
O
X
X
X
BF3·OEt2
X
1
8
3 (syn)
4 (anti)
4-NO2
4-Cl
4-H
3-CH3
2-NO2
X =
a :
c :
e:
b :
d:
Yield (%)
3 (syn )
Substrate
Solvent
Temp (°C)
Time (h)
8
4 (anti )
1a
1a
1b
1b
1c
1c
1d
1d
1e
dioxane
Et2O
rt
0
rt
0
rt
0
rt
0
0
24
3
-
27 (3aa)
-
53 (4aa)
-
59 (8aa)
dioxane
Et2O
24
3
-
15 (8ba)
-
29 (3ba)
16 (3ba)
18 (3ca)
11 (3ca)
38 (3da)
12 (3da)
-
45 (4ba)
28 (4ba)
58 (4ca)
28 (4ca)
43 (4da)
19 (4da)
-
dioxane
Et2O
24
3
8 (8ca)
-
dioxane
Et2O
24
3
13 (8da)
65 (8ea)
Et2O
3
Scheme 3

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HETEROCYCLES, Vol. 78, No. 6, 2009
In the case of 2-naphthol (2a), we have not yet isolated [3,3-dimethyl-2-(naphthalen-2-yloxy)-
indolin-1-yl](4-nitrophenyl)methanone (8aa). Therefore the reaction was reexamined under reaction
conditions similar to those used for monocyclic phenols described above.
When the reaction was carried out in an ice bath using diethyl ether as solvent, we found that the
2-naphthyl ether compound (8aa) was produced in 59% yield. Similarly, 2-nitrobenzoyl derivative (1e)
gave only the 2-naphthyl ether (8ea) in good yield. On the other hand, the 4-chlorobenzoyl (1b), benzoyl
(1c) and 3-methylbenzoyl (1d) derivatives of 1 gave mixtures of the ether derivative and a pair of
atropisomers (Scheme 3).
The structure of 8aa was confirmed by single crystal
X-ray analysis. The computer-generated molecular
structure3 is depicted in Figure 2.
The ether 8aa was treated with BF3•Et2O to give a
mixture of syn and anti atropisomers (3aa, 4aa)
besides 5a and 1a (Scheme 4). The observed syn:anti
product ratio (ca. 1:2) is identical with that observed
in the BF3•Et2O-catalyzed coupling reaction of the
2-hydroxyindoline derivative (1a) with 2-naphthol
(2a) at rt.
However, the syn/anti product ratio is quite different
from that observed in its equilibrium reaction products.
Figure 2. ORTEP Drawing of 8aa
Heating 4aa (anti) in 1,4-dioxane at 60 °C for 72 h
.
caused transformation into an equilibrium mixture of
the atropisomers [3aa (syn) / 4aa (anti) = 1.2]. This indicates that the BF3•Et2O-catalyzed
rearrangement reaction products from the 2-naphthyl ether are kinetically controlled ones.
OH
H
H
H
H
N
O C
N
O C
N
O C
N
C O
N
O C
OH
O
BF3·Et2O
HO
+
+
+
in dioxane
NO2
8aa
NO2
NO2
NO2
NO2
3aa (syn)
4aa (anti)
5a
5%
1a
15%
31%
6%
Scheme 4

HETEROCYCLES, Vol. 78, No. 6, 2009
1489
Next, we explored the possibility of direct Friedel-Craft type reaction using 2-methoxynaphthol (2a-Me)
under the reaction conditions used in the previous study (Scheme 5). Inspection of the 1H-NMR spectrum
of the coupling products (9a and 10a) showed a regularly observed characteristic spectral feature
attributable to a pair of the atropisomers,1b in which a downfield shift of >C2-H proton signal was
recognized in the syn isomer due to C-H•••O< type weak interaction4 [δ 6.13 (syn), δ 5.73 (anti)].
The reaction with 2a-Me was found to proceed significantly slower than the reaction with 2a, showing an
increase of the elimination product (5) via the Wagner-Meerwein type rearrangement. This fact indicates
that the product via direct Friedel-Craft reaction is present in only small amounts at least under the
reaction condition used.
H
OH
H
H
OMe
N
N
N
N
OMe
BF3·OEt2
+
H
+
H
+
O C
O C
MeO
in dioxane
O
O
2a-Me
X
X
X
X
1
9 (syn)
10 (anti)
5
X = a : NO2 , b : Cl , c : H
Yield (%)
9 (syn ) 10 (anti )
Substrate Temp (°C) Time (h)
5
1a
1b
1c
rt
rt
rt
48
70
48
12 (9a)
15 (9b)
9 (9c)
25 (10a) 32 (5a)
65 (10b) 19 (5b)
38 (10c) 21 (5c)
Scheme 5
In the Lewis-acid catalyzed rearrangement of phenolic ethers, evidence has been found for inter- and
intramolecular processes.5 The intermolecular nature of the reaction was confirmed by the exchange
reaction of 6ab with external-additive 4-methoxyphenol (2c). The reaction gave the non-exchanged
product (7ab) and the exchange product (7ac) in 26% and 24% yields, respectively (Scheme 6).
OH
Me
OH
H
Me
2c:
H
H
O
N
N
N
N
HO
OMe
O C
O C
O C
C O
+
+
OMe
BF3·Et2O
in dioxane
rt, 24 hr
NO2
NO2
NO2
7ac 24%
NO2
6ab
7ab 26%
5a 5%
Scheme 6

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HETEROCYCLES, Vol. 78, No. 6, 2009
The result of the exchange reaction suggests that the rearrangement reaction is considered to proceed
partly through an intramolecular pathway because the non-exchanged reaction product (formally
speaking) persists in the reaction product although there exists a large excess of phenols during the whole
reaction period. The non-exchanged reaction product was presumably derived from the internal return of
the external ion-pair intermediate (a loosely-dissociated ion-pair intermediate) rather than free ions in
view of the low dielectric constant of the solvent (1,4-dioxane, ε=2.2) comparable to that of benzene. The
recombination behavior of the ion pair may be explained by the primary FMO (frontier molecular orbital)
interaction6 between the largest LUMO coefficient (C2) of indoline cation and the largest HOMO
coefficient (C1) of the naphthol (Scheme 7).
LUMO
H
H
O
N
C
N
C
H
BF3
HOMO
O
O
O
X
X
Scheme 7
In conclusion, the formation reaction of the diastereomeric atropisomers in the BF3•Et2O-catalyzed
coupling reaction of 1 with 2 proceeds through the 2-naphthyl ether intermediate followed by Fries-type
rearrangement.
EXPERIMENTAL
Melting points are uncorrected. IR spectra were measured on a HITACHI 270-30 IR spectrophotometer.
NMR spectra were taken with JNM-EX 270, JNM-AL 300, JNM-GX 400 and JNM-A 500 NMR
spectrometers in CDCl3 or DMSO-d6 solution, using tetramethylsilane (TMS) as an internal standard.
Chemical shifts are expressed as δ (ppm) and coupling constants (J) are described as Hz. EI MS and high
resolution MS (HR-MS) spectra were measured on a JEOL GC-Mate spectrometer.
Materials (2-Hydroxy-3,3-dimethylindolin-1-yl)(substituted phenyl)methanones (1a-e) were prepared
by addition of substituted benzoyl chloride to 3,3-dimethyl-3H-indole followed by treatment of the
corresponding 2-chloro derivatives with water. 1c Phenols were commercially available compounds.
Reaction of 1 with phenolic compounds 2 (General procedure) BF3·Et2O (10.0 mmol) was added to

HETEROCYCLES, Vol. 78, No. 6, 2009
1491
a solution of (2-hydroxy-3,3-dimethylindolin-1-yl)(substituted phenyl)methanones (1) (2.0 mmol) and
phenols (2) (4.0 mmol) in dry dioxane (10 mL) and the mixture was heated at given temperature under an
Ar atmosphere until the reaction had completed by TLC. After cooling, the reaction mixture was diluted
with Et2O (200 mL) and treated with water. The organic layer was separated, washed with aqueous
NaHCO3 solution and dried over anhydrous MgSO4. The Et2O was evaporated off. The residue was
chromatographed on silica gel eluting with benzene/EtOAc (100:1). The products separated were
crystallized from appropriate solvent.
Reaction of 1a with monocyclic phenols (2b-c) According to the general procedure, the reaction of
1a (2.0 mmol) with monocyclic phenols in dry dioxane (at rt) or ether (at 0 °C or rt) was carried out in the
presence of BF3·Et2O for given hour to give 6, 7 and 5a.
[3,3-Dimethyl-2-(4-tolyloxy)indolin-1-yl](4-nitrophenyl)methanone (6ab)
Yellow plates from
1
EtOH; mp 176-179 °C; H-NMR (300 MHz, CDCl3) δ: 1.38 (3H, s, C3-Me), 1.43 (3H, s, C3-Me), 2.26
(3H, s, CAr4-Me), 5.66 (1H, s, C2-H), 6.52 (2H, br s, CAr2, CAr6-H), 6.92 (2H, d, J= 8.3 Hz, CAr3, CAr5-H),
7.19-7.29 (3H, m, C4, C5, C6-H), 7.41 (2H, d, J= 8.6 Hz, CCOAr2, CCOAr6-H), 8.02 (3H, br d, J= 8.6 Hz,
CCOAr3, CCOAr5-H, C7-H); MS m/z: 402 (M+); Anal. Calcd for C24H22N2O4: C, 71.63; H, 5.51; N, 6.96.
Found: C, 71.14; H, 5.49; N, 6.73; IR (KBr) cm-1: 1666 (NC=O), 1601 (C=C), 1478, 1344 (NO2).
[2-(2-Hydroxy-5-methylphenyl)-3,3-dimethyl-indolin-1-yl](4-nitrophenyl)methanone (7ab)
Pale
yellow powder from EtOH; mp 273-279 °C; 1H-NMR (300 MHz, DMSO-d6) δ: 0.92 (3H, s, C3-Me), 1.41
(3H, s, C3-Me), 2.05 (3H, s, CAr5-Me), 5.26 (1H, s, C2-H), 6.43 (1H, s, CAr6-H), 6.48 (1H, br d, J= 7.9
Hz, CAr4-H), 6.81 (1H, d, J= 7.9 Hz, CAr3-H), 7.18-7.37 (5H, m, aromatic C-H), 8.11 (2H, br s, CCOAr3,
CCOAr5-H), 8.26 (1H, br s, C7-H), 9.00 (1H, br s, CAr2-OH); MS m/z: 402 (M+); Anal. Calcd for
C24H22N2O4: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.81; H, 5.47; N, 7.16; IR (KBr) cm-1: 3420 (OH),
1630 (NC=O), 1601 (C=C), 1524, 1348 (NO2).
[2-(4-Methoxyphenoxy)-3,3-dimethylindolin-1-yl](4-nitrophenyl)methanone (6ac)
Yellow plates
1
from EtOH; mp 129-131 °C; H-NMR (300 MHz, CDCl3) δ: 1.39 (3H, s, C3-Me), 1.47 (3H, s, C3-Me),
3.75 (3H, s, CAr4-OMe), 5.62 (1H, br s, C2-H), 6.58 (2H, br s, CAr2, CAr6-H), 6.66 (2H, d, J= 8.9 Hz, CAr3,
CAr5-H), 7.20-7.26 (3H, m, C4, C5, C6-H), 7.34 (2H, d, J= 8.3 Hz, CCOAr2, CCOAr6-H), 8.05 (3H, br d, J=
8.3 Hz, CAr3, CAr5-H, C7-H); MS m/z: 418 (M+); Anal. Calcd for C24H22N2O5: C, 68.89; H, 5.30; N, 6.69.
Found: C, 68.82; H, 5.27; N, 6.57; IR (KBr) cm-1: 1648 (NC=O), 1596 (C=C), 1518, 1344 (NO2).
[2-(2-Hydroxy-5-methoxyphenyl)-3,3-dimethylindolin-1-yl](4-nitrophenyl)methanone (7ac)
Yellow needles from EtOH; mp 253-254 °C; 1H-NMR (300MHz, DMSO-d6) δ: 0.93 (3H, s, C3-Me), 1.41
(3H, s, C3-Me), 3.51 (3H, s, CAr5-OMe), 5.23 (1H, s, C2-H), 6.14 (1H, d, J= 2.9 Hz, CAr6-H), 6.55 (1H,
br d, J= 8.6 Hz, CAr3-H), 6.64 (1H, dd, J= 2.9, 8.6 Hz, CAr4-H), 7.18-7.29 (3H, m, C4, C5, C6-H), 7.38
(2H, br s, CCOAr2, CCOAr6-H), 8.13 (2H, br s, CCOAr3, CCOAr5-H), 8.24 (1H, br s, C7-H), 8.81 (1H, br s,

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HETEROCYCLES, Vol. 78, No. 6, 2009
CAr2-OH); MS m/z: 418 (M+); Anal. Calcd for C24H22N2O5: C, 68.89; H, 5.30; N, 6.69. Found: C, 68.72; H,
5.24; N, 6.84; IR (KBr) cm-1: 3448 (OH), 1634 (NC=O), 1592 (C=C), 1508, 1346 (NO2).
(4-Chlorophenyl)[3,3-dimethyl-2-(4-tolyloxy)indolin-1-yl]methanone (6bb) Colorless prisms from
1
EtOH; mp 154-156 °C; H-NMR (300MHz, CDCl3) δ: 1.35 (3H, s, C3-Me), 1.42 (3H, s, C3-Me), 2.28
(3H, s, CAr4-Me), 5.77 (1H, s, C2-H), 6.57 (2H, d, J= 7.7 Hz, CAr2, CAr6-H), 6.96 (2H, d, J= 8.4 Hz,
CCOAr3, CCOAr5-H), 7.12-7.25 (3H, m, C4, C5, C6-H), 7.17 (2H, d, J= 8.4 Hz, CCOAr3, CCOAr5-H), 7.24 (2H,
d, J= 7.7 Hz, CAr2, CAr6-H), 7.80 (1H, br s, C7-H); MS m/z: 391 (M+); Anal. Calcd for C24H22ClNO2: C,
73.56; H, 5.66; N, 3.57. Found: C, 73.85; H, 5.70; N, 3.47; IR (KBr) cm-1: 1666 (NC=O), 1594 (C=C).
(4-Chlorophenyl)[2-(2-hydroxy-5-methylphenyl)-3,3-dimethylindolin-1-yl]methanone (7bb)
1
Colorless powder from EtOH; mp 228-230 °C; H-NMR (300 MHz, DMSO-d6) δ: 0.93 (3H, s, C3-Me),
1.40 (3H, s, C3-Me), 2.03 (3H, s, CAr5-Me), 5.35 (1H, s, C2-H), 6.42 (1H, s, CAr6-H), 6.59 (1H, br s,
CAr4-H), 6.81 (1H, d, J= 7.9 Hz, CAr3-H), 7.16-7.36 (7H, m, aromatic C-H), 8.22 (1H, br s, C7-H), 9.18
(1H, br s, CAr2-OH); MS m/z: 391 (M+); Anal. Calcd for C24H22ClNO2: C, 73.56; H, 5.66; N, 3.57. Found:
C, 73.41; H, 5.45; N, 3.57; IR (KBr) cm-1: 3500-3200 (OH), 1622 (NC=O), 1588 (C=C).
(4-Chlorophenyl)[2-(4-methoxyphenoxy)-3,3-dimethylindolin-1-yl]methanone (6bc) Colorless prisms
1
from EtOH; mp 154-156 °C; H-NMR (300MHz, CDCl3) δ: 1.37 (3H, s, C3-Me), 1.46 (3H, s, C3-Me),
3.77 (3H, s, CAr4-OMe), 5.73 (1H, s, C2-H), 6.62 (2H, br s CAr2, CAr6-H), 6.70 (2H, br s CAr3, CAr5-H),
7.07-7.52 (7H, m, aromatic C-H), 7.83 (1H, br s C7-H). MS m/z: 407 (M+); Anal. Calcd for C24H22ClNO3:
C, 70.67; H, 5.44; N, 3.43. Found: C, 70.80; H, 5.41; N, 3.41; IR (KBr) cm-1: 1658 (NC=O), 1592 (C=C).
(4-Chlorophenyl)[2-(2-hydroxy-5-methoxyphenyl)-3,3-dimethylindolin-1-yl]-methanone (7bc)
1
Colorless powder from EtOH; mp 248-249°C; H-NMR (300 MHz, DMSO-d6) δ: 0.93 (3H, s, C3-Me),
1.38 (3H, s, C3-Me), 3.48 (3H, s, CAr5-OMe), 5.32 (1H, s, C2-H), 6.13 (1H, s, CAr6-H), 6.61 (2H, s, CAr3,
CAr4-H), 7.10-7.39 (7H, m, aromatic C-H), 8.18 (1H, br s, C7-H), 9.00 (1H, br s, CAr2-OH); MS m/z: 407
(M+); Anal. Calcd for C24H22ClNO3: C, 70.67; H, 5.44; N, 3.43. Found: C, 70.35; H, 5.44; N, 3.43; IR
(KBr) cm-1: 3500-3300 (OH), 1628 (NC=O), 1590 (C=C).
Catalytic Rearrangement of 6ab to 7ab A solution of 6ab (1.0 mmol) in dry dioxane (5 mL)
containing BF3·Et2O (5.0 mmol) was stirred at room temperature for 24 hr. The same work-up as
described in the general procedure gave 7ab, 5a and 1a.
Phenol-exchange reaction of 6ab A solution of 6ab (0.5 mmol) and 2c (0.5 mmol) in dry dioxane (5
mL) containing BF3·Et2O (2.5 mmol) was stirred at rt for 24 h. The same work-up as described in the
general procedure gave 7ab, 7ac and 5a.
Time Course of reaction of 1a with 2c BF3·Et2O (10.0 mmol) was added to a solution of 1a (2.0
mmol) and p-methoxyphenols (2c) (4.0 mmol) in dry Et2O (10 mL) and the mixture was stirred at 0 °C
under an Ar atmosphere. At appropriate intervals of time, a small amount of the reaction mixture was

HETEROCYCLES, Vol. 78, No. 6, 2009
1493
withdrawn by a syringe, quenched with water, and extracted with Et2O. After evaporation of the solvent
1
under reduced pressure, the residue was analyzed by H-NMR. The relative ratio of the reaction product
(6ac, 7ac) and 1a were evaluated by the spectral integration of the methyl group.
Reaction of 1a-e with 2a (Formation of the naphthyl ether 8aa-ea) A solution of 1a (1.0 mmol) and
2a (1.0 mmol) in dry dioxane (5 mL) containing BF3·Et2O (5.0 mmol) was stirred at 0 °C. The same
work-up as described in the general procedure gave 8aa. Similarly, the reactions of 1b-e with 2a gave the
corresponding products, respectively.
[3,3-Dimethyl-2-(naphthalen-2-yloxy)indolin-1-yl](4-nitrophenyl)methanone (8aa) Yellow plates
1
from EtOH; mp 154-156 °C; H-NMR (300 MHz, CDCl3) δ: 1.45 (3H, s, C3-Me), 1.48 (3H, s, C3-Me),
5.92 (1H, br s, C2-H), 6.91-7.85 (15H, m, aromatic C-H); MS m/z: 438 (M+), 295 (M+-143); Anal. Calcd.
for C27H22N2O4: C, 73.96; H, 5.06; N, 6.39. Found: C, 74.04; H, 5.00; N, 6.41; IR (KBr) cm-1: 1660
(NC=O), 1480, 1346 (NO2), 998 (-O-).
(4-Chlorophenyl)[3,3-dimethyl-2-(naphthalen-2-yloxy)-indolin-1-yl]methanone
(8ba)
Colorless
prisms from EtOH, mp 159-161 °C; 1H-NMR (300 MHz, CDCl3) δ (ppm): 1.41 (3H. s, C3-Me), 1.46 (3H,
s, C3-Me), 6.01 (1H, s, C2-H), 6.90-7.77 (15H, m, aromatic C-H); MS m/z : 427 (M+), 284 (M+-143);
Ana1. Calcd. for C27H22C1NO2: C, 75.78; H, 5.18; N, 3.27. Found: C, 75.72; H, 4.96; N, 3.17; IR (KBr)
cm-1: 3160-2850 (aromatic C-H), 1662 (NC=O), 1594 (C=C), 1002 (-O-).
[3,3-Dimethyl-2-(naphthalen-2-yloxy)indolin-1-yl]-(phenyl)methanone (8ca) Colorless prisms from
EtOH, mp 107-108 °C; 1H-NMR (300 MHz, CDCl3) δ (ppm): 1.41 (3H, s, C3-Me), 1.44 (3H, s, C3-Me),
6.04 (1H, s, C2-H), 6.84-7.74 (15H, m, aromatic C-H), 7.75 (1H, brs, C7-H); MS m/z: 393 (M+), 250
(M+-143); Ana1. Calcd. for C27H23NO2: C, 82.42; H, 5.89; N, 3.56. Found: C, 82.63; H, 5.91; N, 3.61; IR
(KBr) cm-1: 3050-2800 (aromatic C-H), 1656 (NC=O), 1596 (C=C), 992 (-O-).
[3,3-Dimethyl-2-(naphthalen-2-yloxy)indolin-1-yl](3-tolyl)methanone (8da) Colorless powder from
EtOH, mp 109-111 °C; 1H-NMR (300 MHz, CDCl3) δ (ppm): 1.41 (3H, s, C3-Me), 1.44 (3H, s, C3-Me),
1.86 (3H, s, CAr3-Me), 6.00 (1H, s, C2-H), 6.84-7.75 (14H, m, aromatic C-H), 7.93 (1H, brs, C7-H); MS
m/z: 407 (M+), 264 (M+-143); Ana1. Calcd. for C28H25NO2: C, 82.53; H, 6.18; N, 3.44. Found: C, 82.28; H,
6.10; N, 3.26; IR (KBr) cm-1: 3052-2868 (aromatic C-H), 1660 (NC=O), 1596 (C=C), 990 (-O-).
[3,3-Dimethyl-2-(naphthalen-2-yloxy)indolin-1-yl](2-nitrophenyl)methanone (8ea) Yellow plates
1
from EtOH, mp 158-160 °C; H-NMR (300 MHz, CDCl3) δ (ppm): 1.36 (3H, s, C3-Me), 1.44 (3H, s,
C3-Me), 5.64 (1H, brs, C2-H), 6.45-8.30 (14H, m, aromatic C-H), 8.00 (1H, brs, C7-H); MS m/z: 438
(M+), 295 (M+-143). Ana1. Calcd. for C27H22N2O4: C, 73.96; H, 5.06; N, 6.39. Found: C, 73.69; H, 4.96; N,
6.49. IR (KBr) cm-1: 3100-2950 (aromatic C-H), 1664 (NC=O), 1598 (C=C), 1484, 1350 (NO2), 1006
(-O-).
Catalytic Rearrangement of 8aa to 3aa and 4aa A solution of 8aa (0.7 mmol) in dry dioxane (5 mL)

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containing BF3·Et2O (5.0 mmol) was stirred at rt or 60 °C for 24 h. The same work-up as described in the
general procedure gave 3aa, 4aa, 5a and 1a.
Reaction of 1a-c with 2-methoxynaphthalene 2a-Me A solution of 1a-c (1.0 mmol) and 2a-Me (1.0
mmol) in dry dioxane (5 mL) containing BF3·Et2O (5.0 mmol) was stirred at rt. The same work-up as
described in the general procedure gave 5a-c, 9a-c and 10a-c.
[2-(2-Methoxynaphthalen-1-yl)-3,3-dimethylindolin-1-yl](4-nitrophenyl)methanone (9a) (syn) Pale
yellow prisms from EtOH; mp 210-211 °C; 1H-NMR (270MHz, CDCl3) δ: 0.98 (3H, s, C3-Me), 1.60 (3H,
s, C3-Me), 3.60 (3H, s, Cnaph2-OMe), 6.13 (1H, s, C2-H), 6.72-7.79 (13H, m, aromatic C-H), 8.51 (1H, d,
J= 7.9 Hz, C7-H); MS m/z: 452 (M+). Anal. Calcd for C28H24N2O4: C, 74.32; H, 5.35; N, 6.19. Found: C,
74.39; H, 5.11; N, 6.25; IR (KBr) cm-1: 1644 (NC=O), 1594 (C=C), 1514, 1346 (NO2).
[2-(2-Methoxynaphthalen-1-yl)-3,3-dimethylindolin-1-yl](4-nitrophenyl)methanone (10a) (anti)
1
Yellow prisms from EtOH; mp 175-176 °C; H-NMR (270 MHz, CDCl3) δ: 1.01 (3H, s, C3-Me), 1.63
(3H, s, C3-Me), 3.48 (3H, s, Cnaph2-OMe), 5.73 (1H, s, C2-H), 6.89 (1H, d, J= 8.3 Hz, Cnaph3-H),
7.13-7.36 (7H, m, aromatic C-H), 7.23 (1H, d, J= 8.3 Hz, Cnaph4-H), 7.55 (2H, d, J= 8.6 Hz, CAr2, CAr6-H),
7.73 (2H, d, J= 8.6 Hz, CAr3, CAr5-H), 8.51 (1H, d, J= 7.9 Hz, C7-H); MS m/z: 452 (M+); Anal. Calcd for
C28H24N2O4: C, 74.32; H, 5.35; N, 6.19. Found: C, 74.04; H, 5.20; N, 6.20; IR (KBr) cm-1: 1642 (NC=O),
1596 (C=C), 1520, 1346 (NO2).
1
(2,3-Dimethyl-1H-indol-1-yl)(4-nitrophenyl)methanone (5a) Yellow oil; H-NMR (400 MHz, CDCl3)
δ: 2.22 (3H, s, C3-Me), 2.30 (3H, s, C2-Me), 6.96 (1H, d, J= 8.4 Hz, C4-H), 7.04 (1H, dd, J= 8.1, 8.4 Hz,
C5-H), 7.19 (1H, dd, J= 7.7, 8.1 Hz, C6-H), 7.43 (1H, d, J= 7.7 Hz, C7-H), 7.83 (2H, d, J= 8.8 Hz, CAr2,
CAr6-H), 8.31 (2H, d, J= 8.8 Hz, CAr3, CAr5-H); MS m/z: 294 (M+); IR (film) cm-1: 1684 (NC=O), 1602
(C=C), 1522, 1342 (NO2).
(4-Chlorophenyl)[2-(2-methoxynaphthalen-1-yl)-3,3-dimethylindolin-1-yl]methanone (9b) (syn)
Colorless prisms from EtOH; mp 181-182 °C; 1H-NMR (270 MHz, CDCl3) δ: 0.97 (3H, s, C3-Me), 1.58
(3H, s, C3-Me), 3.66 (3H, s, Cnaph2-OMe), 6.16 (1H, s, C2-H), 6.58-7.71 (13H, m, aromatic C-H), 8.47
(1H, br s, C7-H); MS m/z: 441 (M+); Anal. Calcd for C28H24ClNO2: C, 76.08; H, 5.48; N, 3.17. Found: C,
75.67; H, 5.41; N, 3.44; IR (KBr) cm-1: 1642 (NC=O), 1596 (C=C).
(4-Chlorophenyl)[2-(2-methoxynaphthalen-1-yl)-3,3-dimethylindolin-1-yl]methanone (10b) (anti)
Colorless needles from EtOH; mp 169-170 °C; 1H-NMR (270 MHz, CDCl3) δ: 0.98 (3H, s, C3-Me), 1.61
(3H, s, C3-Me), 3.44 (3H, s, Cnaph2-OMe), 5.82 (1H, s, C2-H), 6.70-7.73 (13H, m, aromatic C-H), 8.37
(1H, br s, C7-H); MS m/z: 441 (M+); Anal. Calcd for C28H24ClNO2: C, 76.08; H, 5.48; N, 3.17. Found: C,
76.04; H, 5.45; N, 3.19; IR (KBr) cm-1: 1620 (NC=O), 1592 (C=C).
[2-(2-Methoxynaphthalen-1-yl)-3,3-dimethylindolin-1-yl](phenyl)methanone (9c) (syn) Colorless
prisms from EtOH; mp 145-147 °C; 1H-NMR (300 MHz, DMSO-d6) δ: 0.97 (3H, s, C3-Me), 1.59 (3H, s,

HETEROCYCLES, Vol. 78, No. 6, 2009
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C3-Me), 3.58 (3H, s, Cnaph2-OMe), 6.23 (1H, br s, C2-H), 6.65-7.70 (14H, m, aromatic C-H), 8.52 (1H, br
s, C7-H); MS m/z: 407 (M+); Anal. Calcd. for C28H25NO2: C, 82.53 ; H, 6.18 ; N, 3.44. Found: C, 82.33; H,
6.13; N, 3.43; IR (KBr) cm-1: 1638 (NC=O), 1594 (C=C).
[2-(2-Methoxynaphthalen-1-yl)-3,3-dimethylindolin-1-yl](phenyl)methanone (10c) (anti) Colorless
prisms from EtOH; mp 185-187 °C; 1H-NMR (300 MHz, DMSO-d6) δ: 0.95 (3H, s, C3-Me), 1.62 (3H, s,
C3-Me), 3.46 (3H, s, Cnaph2-OMe), 5.90 (1H, br s, C2-H), 6.65-7.70 (14H, m, aromatic C-H), 8.41 (1H, br
s, C7-H); MS m/z: 407 (M+); Anal. Calcd. for C28H25NO2: C, 82.53 ; H, 6.18 ; N, 3.44. Found: C, 82.33 ;
H, 6.13 ; N, 3.43. IR (KBr) cm-1: 638 (NC=O), 1594 (C=C).
Single Crystal X-Ray Analysis of 8aa A colorless prismatic crystal having approximate dimensions of
0.10 x 0.20 x 0.10 mm of 8aa was mounted on a glass fiber. All measurements were made on a Rigaku
AFC7R four-circle autodiffractometer with graphite monochromated Mo-Kα radiation. The data were
collected at a temperature of 20 ± 1 °C to a maximum 2θ value of 55.0°. The structure was solved by
direct method (SIR-927), and hydrogen atoms were placed at the calculation. A full-matrix least-squares
technique was using with anisotropic thermal parameters for non-hydrogen atoms and riding model for
hydrogen atoms. All calculations were performed using the Crystal Structure7 crystallographic software
package.
Crystal Data of 8aa: Crystal Data; C27H22N2O4, M=438.47, monoclinic, Space group P21/a, a=12.281 (2),
b=20.134 (5), c=9.854 (1) Å, β=111.39 (1), V=2268 (7) Å3, Dc=1.284 g cm-3, Z=4, R=0.057, Rw=0.094.
The X-Ray crystallographic data have been deposited at the Cambridge Crystallographic Data Centre
(CCDC ref. No. 702823).
ACKNOWLEDGEMENTS
We thank Miss N. Mukai, Miss K. Miyazoe, Miss Y. Sugiyama, Miss Y. Nakamoto, Mr. K. Tsutsumi and
Mr. H. Tanaka for experimental assistance.
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