Atropisomers of 1-(acyl or aroyl)-2-naphthylindolines. Isolation, X-ray crystal structure and conformational analysis

Article abstract of DOI:10.1248/cpb.51.688

A series of pairs of stable diastereomeric atropisomers caused by restricted rotation around the Csp3-Csp2 bond of [2-(2-hydroxynaphthalen-1-yl)- 3,3-dimethyl-2,3-dihydroindol-1-yl]-(3- or 4-substituted phenyl)-methanone or [2-(2-hydroxynaphthalen-1-yl)-3

Full text of DOI:10.1248/cpb.51.688

688
Chem. Pharm. Bull. 51(6) 688—696 (2003)
Vol. 51, No. 6
Atropisomers of 1-(Acyl or Aroyl)-2-naphthylindolines. Isolation, X-Ray
Crystal Structure and Conformational Analysis
Fumikazu ITO, Tetsuya MORIGUCHI, Yasuyuki YOSHITAKE, Masashi ETO,1) Shoji YAHARA, and
Kazunobu HARANO*
Faculty of Pharmaceutical Sciences, Kumamoto University; 5–1 Oe honmachi, Kumamoto 862–0973, Japan.
Received February 24, 2003; accepted March 11, 2003; published online March 13, 2003
A series of pairs of stable diastereomeric atropisomers caused by restricted rotation around the Csp3–Csp2
bond of [2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(3- or 4-substituted phenyl)-metha-
none or [2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-1-alkanone were isolated. The con-
1
formational analyses of the atropisomers were performed based on the X-ray crystallographic and H-NMR
spectral data. It became clear that rotation about the C2–naphthyl bond is restricted at room temperature,
whereas the ϾNCO–Ar bond rotates freely.
Key words 1-aroyl-2-aryl-3,3-dimethylindoline; diastereomeric atropisomer; X-ray analysis; NMR; conformational analysis;
crystal packing
Atropisomers have attracted much theoretical2—4) and bio-
pling reaction of (2-hydroxy-3,3-dimethyl-2,3-dihydroindol-
logical5) interest. Recently, it has been proposed that atropi-
1-yl)-(3- or 4-substituted phenyl)-methanone (1a—k) or (2-
somers can be used as a probe for detection of intramolecular
weak yet attractive interactions.4) In the system having paral-
lel-stacked aryl groups, it has been suggested that charge-
transfer or through-space polar/p interaction is operative be-
tween the two aryl units.6,7) In spite of the importance of atro-
pisomers, there has not been much crystallographic analyses
of a pair of atropisomers.
hydroxy-3,3-dimethyl-2,3-dihydroindol-1-yl)-1-alkanone
(1l—n) with b-naphthol (2) was performed in the presence
of BF3·Et2O in dioxane at room temperature or at 60 °C.10)
Each reaction gave a mixture of the atropisomers ([2-(2-
hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-
yl]-(3- or 4-substituted phenyl)-methanones (3a—k, 4a—k)
or [2-(2-hydroxy-naphthalen-1-yl)-3,3-dimethyl-2,3-dihydro-
indol-yl]-1-alkanones (3l—n, 4l—n)), which was separated
into a pair of atropisomers by fractional recrystallization or
chromatography on silica gel. The results are summarized in
Table 1.
The syn/anti relationship is defined with respect to the spa-
tial relationship between the C2–H and the OH group of the
naphthalene moiety in the symmetric aroyl groups, and the
substituent of the aryl ring in the unsymmetrical aroyl
groups. In each case, a pure isomer is converted to a mixture
of the syn and anti atropisomers upon heating. Therefore, the
reaction products are considered to be kinetically controlled
ones.
During the course of the study of 1-aroyl-2-arylindoline
derivatives, we isolated four pairs of diastereomeric atropiso-
mers of two types caused by restricted rotation about
(Csp3–Nsp2) or (Csp3–Csp2) bond of (2-aryl-3,3-dimethyl-
2,3-dihydroindol-1-yl)-(4-substituted phenyl)-methanones.8—13)
In the X-ray crystal structures of the 4-nitrobenzoyl deriva-
tives (3a, 4a), we found strong through-space interaction be-
tween the 4-nitrophenyl and naphthyl rings.12) To clarify the
conformation of the aroyl moiety in the solution, we prepared
several pairs of the atropisomers having an unsymmetrical
aroyl group and isolated pairs of the atropisomers (3g—i,
4g—i) of the 3-substituted benzoyl derivatives.13) On the
1
basis of the H-NMR analyses of the proton signals of the
Crystallographic Study of the Atropisomers During
the course of the study, X-ray analyses were performed on
the pairs of atropisomers of the 4-nitrobenzoyl (3a, 4a), 4-
chlorobenzoyl (3b, 4b), 3-nitrobenzoyl (3g, 4g) and 3-
methylbenzoyl (3h, 4h) derivatives. Of those, the X-ray
structural detail of a pair of the atropisomers of the 4-
chlorobenzoyl derivative (3b, 4b) was reported in a separate
paper9) and the molecular structural feature of a pair of the
atropisomers (3a, 4a) was communicated.12)
unsymmetrical aroyl rings, we communicated the rotational
mobility of the aroyl groups.13)
Here we report on the synthesis of the compounds (3a—n,
4a—n) (Table 1) and describe in detail the overall character
of the atropisomerism in comparison with previous works
and with further additional data that we have obtained.
Results and Discussion
The structures are solved by the direct method.14) The
crystal data for two pairs of the atropisomers [(3g, 4g) and
(3h, 4h)] are summarized in Tables 2 and 3.
Preparation and Isolation of the Atropisomers Cou-
The ORTEP15) drawings of two pairs of the atropisomers
[(3g, 4g) and (3h, 4h)] are depicted in Figs. 1a, b.
Molecular Structure As can be seen in Figs. 1a, b and
previously reported X-ray structures, each isomer of same
type has the same conformation, in which the amide carbonyl
oxygen turns to the C7–hydrogen (C7–H) of the indoline
moiety and the aryl ring is not coplanar with the ϾNCO-
plane. For example, the interplanar angles between the 3-
Chart 1
* To whom correspondence should be addressed. e-mail: harano@gpo.kumamoto-u.ac.jp
© 2003 Pharmaceutical Society of Japan

June 2003
689
Table 1. Reaction Conditions and Products (Diastereomeric Atropisomers 3 and 4)
Reaction condition
Yield (%)
mp (°C)
R
Compd. No.
Temp. (°C)
Time (h)
syn (3)
anti (4)
syn (3)
anti (4)
a
b
c
r.t.
60a)
r.t.
24
24
24
24
24
27
29
18
25
28
53
45
58
66
65
229—230
272—272.5
285—286
269—270
267—268
247—248
265—267
216—217
276—277
264—265
d
e
r.t.
r.t.
f
r.t.
r.t.
24
24
37
30
42
56
215—216
220—222
226.5—227.5
253—255
g
h
i
r.t.
r.t.
36
23
30
16
11
21
60
34
63
218—219
191—192
188—190
222—224
205—206
243—245
j
60a)
k
r.t.
48
8
40
196—197
190—191
–CH3
–CH2CH3
–CH2CH2CH3
l
m
n
60a)
r.t.
r.t.
21
36
18
57
13
13
23
40
26
202—204
221—223
195—196
279—280
225—227
209—211
a) Anti/syn ratio is different from the value at room temperature (r.t.).
Table 2. Crystal Data of 3g, 4g and Intensity Measurements
Table 3. Crystal Data of 3h, 4h and Intensity Measurement
Compound
Formula
mp (°C)
Formula weight
3g
4g
Compound
3h
4h
C27H22N2O4
220—222
438.48
C27H22N2O4
253—255
438.48
Formula
mp (°C)
Formula weight
C28H25NO2
218—219
407.51
C28H25NO2·(CH3)2CO
222—224
465.59
Crystal system
Monoclinic
Monoclinic
Crystal system
Monoclinic
Monoclinic
Lattice parameters
Lattice parameters
a
b
c
b
V
10.243(1) Å
14.167(2) Å
15.9060(9) Å
102.146(7)°
2256.6(4) Å3
P21/c(#14)
4
7.826(2) Å
24.570(2) Å
11.845(4) Å
98.30(3)°
2253.6(10) Å3
P21/c(#14)
4
a
b
c
b
V
10.477(2) Å
14.115(2) Å
15.650(1) Å
101.735(9)°
2265.9(5) Å3
P21/c(#14)
4
10.115(2) Å
23.587(2) Å
15.650(1) Å
91.234(8)°
2835.8(6) Å3
P21/c(#14)
4
Space Group
Space Group
Z
Z
Dc (g/cm3)
Dm (g/cm3)
Radiation
Scan range, deg
Reflections collected
Unique data collected
Unique data used
R
1.291
1.288
1.292
1.281
Dc (g/cm3)
Dm (g/cm3)
Radiation
Scan range, deg
Reflections collected
Unique data collected
Unique data used
R
1.194
1.200
1.191
1.196
MoKa (lϭ0.71069 Å)
2qϽ55.0°
5689
MoKa (lϭ0.71069 Å)
2qϽ55.0°
5723
2qϽ50°
3639
3332
2qϽ55.0°
6461
6129
5181
4540 (IϾ2.00s(I))
0.070
5439
3293 (IϾ3.00s(I))
0.046
2353 (IϾ3.00s(I))
0.042
2274 (IϾ3.00s(I))
0.082
Rw
0.067
0.051
Rw
0.059
0.118
R1
0.051
0.042
R1
0.046
0.082

690
Vol. 51, No. 6
and 4h, respectively.
This conformational feature was also found in the solu-
1
tion. The H-NMR spectra showed that the C7 aromatic pro-
ton resonated at 8.31 ppm as a characteristic low-field shifted
signal in both cases.
Crystal Packing Structure The crystal packing dia-
grams are shown in Figs. 3 and 4. There are many interesting
weak intermolecular interactions in the packing structures of
the atropisomers. In the anti 3-nitrobenzoyl isomer (4g), the
two molecules are firmly bound by the ϾCϭO···H–O–hydro-
gen bonds forming the 16-membered hydrogen-bond loop
(Fig. 3c).
The O···H–C short contacts are found between the nitro
group and the aromatic hydrogens on the naphthyl and 3-ni-
trobenzoyl rings of a neighboring molecule (Fig. 3a). The
s–p interaction22—26) is also found between a methyl hydro-
gen and the phenyl ring of the indoline moiety (Fig. 3b). In
the syn 3-nitrobenzoyl derivative (3g), edge-to-face interac-
tion22—26) is found between the naphthyl and dihydroindolyl
rings (Fig. 3d).
Fig. 1a. ORTEP Drawings of 3g and 4g
In the anti 4-nitrobenzoyl isomer (4a), the edge-to-face in-
teraction is found between the 4-nitrobenzoyl and naphthyl
rings of a neighboring molecule (Fig. 4a). The syn 4-ni-
trobenzoyl isomers (3a) are linked by intermolecular hydro-
gen bonds between ϾNCϭO and HO–naphthyl groups (Fig.
4b). The O···H–C short contacts are found between the nitro
group and the aromatic hydrogen of the 4-nitrobenzoyl group
of a neighboring molecule (Fig. 4c).
Conformation of Aroyl Groups The catalytic coupling
reaction of (2-hydroxy-3,3-dimethyl-2,3-dihydroindol-1-yl)-
m-tolylmethanone (1h) with b-naphthol (2) gave a mixture of
[2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydro-
indol-1-yl]-m-tolylmethanones [syn (3h), anti (4h)], which
was separated into a pair of atropisomers (3h: 16%, 4h:
60%) by chromatography on silica gel. The structures of the
diastereomeric atropisomers were established on the basis of
the commonly observed 1H-NMR spectral feature.
Fig. 1b. ORTEP Drawings of 3h and 4h
Both isomers were stable at room temperature and were
converted to an equilibrium mixture (4h/3hϭanti/synϭ1.20)
on heating at 80 °C for 48 h in benzene. The 1H-NMR spectra
of 3h and 4h showed the characteristic spectral feature10) of
atropisomers of this type. The 1H-NMR spectra indicated the
presence of a C–H···O type hydrogen bond19—21) between the
C7–hydrogen and the amide carbonyl oxygen, excluding the
possibility of atropisomerism due to restricted rotation about
the ϾN–CO bond.3) The C2 methine proton of 3h resonated
at a lower field than 4h, which is attributable to the proximity
effect of the oxygen atom of the naphthol moiety, which is
assumed to be a C–H···O type hydrogen bond.19—21) One of
the two methyl groups resonated at a ca. 0.6 ppm higher field
than the other owing to the ring current effect of the naphtha-
lene ring.
In consideration of these facts, there are four possible rota-
tional isomers caused by restricted rotation about the
C2–naphthyl and ϾNCO–(3-methylphenyl) bonds. The
AM1-optimized structures27—30) of the four isomers are de-
picted in Fig. 5. In order to obtain further information about
the molecular conformation, we performed the single-crystal
X-ray analyses of 3h and 4h. As can be seen in Fig. 1b, 3h is
the syn–syn isomer and 4h is the anti–syn isomer. The two
conformations are nearly identical except for the disposition
Fig. 2. Overlapping of Aromatic Rings Looking Perpendicular to the 3-
Methylphenyl Ring, Found in X-Ray Structures of the Atropisomers (3h,
4h)
methylphenyl ring and the amide plane are 64.1 and 51.0 °
for 3h and 4h, respectively. The N1–C2 and C2–C3 bonds
suffer elongation due to steric repulsion between the naphthyl
ring and the 3,3-dimethyl groups and the 3-methylphenyl
group, respectively. The C2–C3 bond lengths [1.572(3) Å for
3h and 1.567(9) Å for 4h] and N1–C2 bond lengths
[1.491(2) Å for 3h and 1.504(8) Å for 4h] are longer than the
normal values.16,17) The aroyl and the naphthyl rings take a
face-to-face disposition. The degree of overlap between the
aromatic rings for the anti isomer is larger than the syn iso-
mer.
Figure 2 shows the overlapping of the 3-methylphenyl and
naphthyl rings of both isomers looking perpendicular to the
3-methylphenyl ring.
The C2–H···OH distance of 3h is 2.14(2) Å, indicating the
presence of C–H···O type hydrogen bonding.19—21) The inter-
atomic distances between the amide carbonyl oxygen and C7
hydrogen (ϾCϭO···H–C7) are 2.30(2) and 2.24(6) Å for 3h

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691
Fig. 4. Weak Interactions in the 4-Nitrobenzoyl Derivative
a) Edge-to-face interaction in the anti isomer (4a). b) Hydrogen bond (CϭO···H–O)
in the syn isomer (3a). c) Ar–H···O Interaction in the anti isomer (4a).
of the naphthyl ring, in which the 3-methyl group is syn with
respect to the C2–hydrogen in both cases.
1
In the H-NMR spectra, the 3-methyl hydrogens of the
benzoyl rings of 3h and 4h resonate at 2.01 (singlet) and
1.80 ppm (broad singlet), respectively. At first glance, this
high-field shift seems to have arisen from the conformations
observed in the crystal structures of 3h and 4h. However, the
calculation of the ring-current effect based on the crystal
atomic coordinates suggests that the high-field shifted values
are Ϫ0.04 ppm for 3h and 0.4 ppm for 4h.31) In consideration
of the fact that the methyl protons of 3-methylbenzoic acid
resonate at 2.4 ppm, the 3-methyl hydrogens of the benzoyl
ring of 3h have suffered a significant high-field shift, indicat-
ing that the benzoyl moiety rotates about the Ar–CON bond.
Fig. 3. Weak Interactions in the 3-Nitrobenzoyl Derivative
a) Ar–H···O Interaction in the anti isomer (4g). b) s–p Interaction in the anti isomer
(4g). c) Hydrogen bond (CϭO···H–O) loop in the anti isomer (4g). d) Edge-to-face in-
teraction between the naphthyl and dihydroindolyl rings in the syn isomer (3g).

692
Vol. 51, No. 6
Fig. 5. Possible Four Conformational Isomers in the 3-Methylbenzoyl De-
rivative
1
This assumption is supported by the H-NMR spectral fea-
ture observed in a pair of the atropisomers [syn (3k) and anti
(4k)] of the 3,5-dimethylbenzoyl derivatives. Inspection of
the C2 and C7 methine proton signals of both atropisomers
indicated that the rotations around the ϾN–CO and
C2–naphthyl bonds were restricted at room temperature (see
Fig. 6). Heating 3k or 4k in benzene at 80 °C for 48 h caused
transformation into an equilibrium mixture of the atropiso-
mers (anti/synϭ1.50). The two methyl signals of the 3,5-di-
methylbenzoyl group of pure 3k appeared as a sharp singlet
and those of 4k as a broad singlet, indicating that the two
methyl groups of the benzoyl ring are magnetically equiva-
lent at room temperature and the rotation of the 3,5-di-
methylphenyl ring about the Ar–CON bond is not frozen. In
the anti isomer (4k), the appearance of the methyl signal as a
broad singlet indicates that the rotation of the 3,5-di-
methylphenyl ring about the Ar–CON bond is moderately
hindered in comparison with the syn isomer (3k).
Fig. 6. The 1H-NMR Spectral Data (d) of Some 3-Substituted Benzoyl
Isomers
1
The anti isomer 4h showed a similar H-NMR spectral
feature. As shown in Fig. 6, the chemical shifts of the methyl
groups of 3k and 4k are identical with those of syn (3h) and
anti (4h), respectively. These facts indicate that the rotation
of the 3-methylphenyl ring about the Ar–CON bond is not
frozen in solution at room temperature. The 1H-NMR spectra
of the 3-methoxybenzoyl derivatives (3i, 4i) supports this as-
sumption, in which the methoxy signals of 3i and 4i appeared
as a sharp singlet (3.44 ppm) and a broad singlet (3.41 ppm),
respectively (see Fig. 6).
1
In order to confirm this assumption, the H-NMR spectra
of 4h were taken at several low temperatures (25®Ϫ50 °C).
At room temperature (25 °C), the signal of the 3-methyl
group appeared as a broad singlet at 1.76 ppm. When the
temperature was lowered, the signal underwent a high-field
shift to 1.70 ppm with sharpening. The sharp singlet signal at
Ϫ50 °C corresponds to the anti–syn conformation of the
crystal structure, wherein the methyl protons suffer an effec-
tive high-field shift due to the naphthalene ring current (Fig.
7).
Fig. 7. Methyl Signal of 3-Methylenzoyl Ring of 4h at Low Temperatures
basis of the crystal structure of 4h.
This indicates that at low-temperature, the anti–syn con-
Comparison of the crystal structures of pairs of several at-
formation is predominant as observed in the crystal structure. ropisomers indicates that the strong face-to-face (p–p) inter-
The relative positioning of the methyl group and naphthyl action between the aroyl and the naphthyl rings is present in
ring for the rotational isomers are depicted in Fig. 7 on the the crystal structure of the anti isomer of the 4-nitrobenzoyl

June 2003
693
Fig. 8. Comparison of the Interactions between the Benzoyl and Naphthyl
Rings in the Crystal Structures of 4a and 4g
Fig. 10. Equilibrium Reaction between Several syn and anti Isomers
fected by the donor–acceptor interaction between the aryl
moieties. This intramolecular donor-acceptor attractive force
might be operative in a solution. This interaction is consid-
ered to be one of the factors to exert an influence on the rela-
tive stability of the atropisomers leading to the preference of
the anti isomer of the 4-nitro derivative.
The effect of the substituent of the aroyl ring on the atrop-
isomerism (Fig. 10) is interesting. Both electron-donating
and electron-withdrawing substituents cause the anti prefer-
ence in the atropisomerism, in which the unsubstituted ben-
zoyl group has the lowest anti/syn ratio.
These indicate that the p–p interaction between the aryl
rings plays an important role in the stabilization of the anti
conformation wherein the orbital interaction is considered to
Fig. 9. FMO Interaction between Naphthyl and Benzoyl Rings Calculated
by PM3 Method
derivative. The face-to-face interactions of the anti isomers be controlled by the “neutral-type” interaction.33,34)
of the 4- and 3-nitrobenzoyl derivatives are depicted in Fig.
8. In the former, the aromatic rings are significantly closer Conclusion
together.
The atropisomers of the [2-(2-hydroxynaphthalen-1-
In the crystal packing structure of the anti isomer of 4-ni- yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(3- or 4-substituted
trobenzoyl derivative, the intermolecular edge-to-face inter- phenyl)-methanone derivatives were synthesized and four-
action is found between the naphthyl hydrogens at the 3,4- teen pairs of the atropisomers were isolated. Based on the X-
1
positions and at the 4-nitrobenzoyl ring of the adjacent mole- ray crystallographic and H-NMR spectral data, a conforma-
cule. As shown in Fig. 4a, the closest interatomic distance is tional analysis of the aryl moieties was performed and the
2.81 Å. The distance is assumed to be longer than the typical role of aryl–aryl interaction involved in the restricted rotation
edge-to-face interaction distances,22—26) indicating that the process was investigated. The information obtained seems to
effective approach of the two aromatic rings is not a result of be valuable for the design of new type diastereomeric atropi-
the crystal packing force.
somers and for the clarification of weak interactions in mole-
Inspection of the frontier molecular orbital (FMO)32—34) cular recognition.
calculation data based on the crystal structure coordinate of
The role of intramolecular weak interactions such as
the anti 4-nitrobenzoyl derivative indicates that the HOMO C–H···p and edge-to-face is under investigation.
localizes on the naphthalene ring and the LUMO on the 4-ni-
trophenyl ring (see Fig. 9). The effective face-to-face interac-
tion in the anti isomer of the 4-nitro derivative is rationalized
in terms of the FMO theory, assuming that there is an inter-
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
action of the HOMO of naphthalene with the LUMO of the
3-nitro or 4-nitrobenzoic acid.35) Inspection of the orbital-
phase relationship based on the X-ray geometries indicates
that the overlaps of the FMOs are almost in phase for the anti
4-nitro derivative, whereas the orbital overlap for the anti
3-nitro derivative is not so effective. In addition to this, the
LUMO orbital energy level of 4-nitrobenzoic acid (Ϫ1.73 eV)
is lower than that of 3-nitrobenzoic acid (Ϫ1.46 eV), being
favorable for the donor–acceptor interaction between the aro-
matic rings.
or DMSO-d6 solution, using tetramethylsilane (TMS) as an internal stan-
dard. Chemical shifts are expressed as d (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. Thin-layer chromatographic
analyses were performed with a Shimadzu CS 920 high speed TLC scanner.
Materials 3,3-Dimethyl-3H-indole was prepared according to the re-
ported method.36)
(2-Hydroxy-3,3-dimethyl-2,3-dihydroindol-1-yl)-(3- or 4-substituted phe-
nyl)-methanones (1a—k) or (2-hydroxy-3,3-dimethyl-2,3-dihydroindoi-1-
yl)-1-alkanones (1l—n) were prepared by treatment of the correspondig 2-
chloro derivatives with water.37,38) Arens were commercially available com-
pounds.
The color of anti and syn isomers in crystal may be af-
Condensation Reaction of ([2-(2-Hydroxynaphthalen-1-yl)-3,3-di-

694
Vol. 51, No. 6
methyl-2,3-dihydroindol-1-yl]-(3- or 4-substituted phenyl)-methanones (3H, s, C3–CH3), 3.69 (3H, s, Cph4–OCH3), 6.27 (1H, s, C2–H), 6.62 (2H, d,
or [2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]- Jϭ8.6 Hz, Cph3, Cph5–H), 6.77—7.70 (7H, m, aromatic H), 6.88 (1H, d,
1-alkanones (3, 4) with b-Naphthol in the Presence of BF3·Et2O The Jϭ8.8 Hz, Cnaph3–H), 7.35 (2H, d, Jϭ8.6 Hz, Cph2, Cph6–H), 7.51 (1H, d,
compounds (3, 4) were prepared according to the reported method.10) The Jϭ8.8 Hz, Cnaph4–H), 7.90 (1H, br s, C7–H), 9.60 (1H, s, Cnaph2–OH). MS
reaction conditions and yield of the products are listed in Table 1.
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(4
m/z: 423 (Mϩ). Anal. Calcd for C28H25NO3: C, 79.41; H, 5.95; N, 3.31.
Found: C, 79.72; H, 5.97; N, 3.63. IR (KBr) cmϪ1: 3148 (OH), 1612
nitrophenyl)-methanone syn (3a): Pale yellow prisms. mp 229—230 °C. (NCϭO), 1588 (CϭC).
1
Yield 27%. H-NMR (400 MHz, DMSO-d6) d: 0.93 (3H, s, C3–CH3), 1.59
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(4-
(3H, s, C3–CH3), 6.16 (1H, s, C2–H), 6.67 (1H, d, Jϭ8.8 Hz, Cnaph3–H), methoxyphenyl)-methanone anti (4e): Colorless prisms. mp 264—265 °C.
1
6.88—7.85 (11H, m, aromatic H), 7.52 (1H, d, Jϭ8.8 Hz, Cnaph4–H), 8.39 Yield 65%. H-NMR (270 MHz, DMSO-d6) d: 0.94 (3H, s, C3–CH3), 1.57
(1H, d, Jϭ7.7 Hz, C7–H), 9.57 (1H, s, Cnaph2–OH). MS m/z: 438 (Mϩ). Anal. (3H, s, C3–CH3), 3.51 (3H, s, Cph4–OCH3), 6.07 (1H, s, C2–H), 6.46—7.70
Calcd for C27H22N2O4: C, 73.95; H, 5.07; N, 6.39. Found: C, 74.07; H, 5.16; (13H, m, aromatic H), 7.90 (1H, br s, C7–H), 9.51 (1H, s, Cnaph2–OH). MS
N, 6.44. IR (KBr) cmϪ1: 3200 (OH), 1626 (NCϭO), 1580 (CϭC), 1520, m/z: 423 (Mϩ). Anal. Calcd for C28H25NO3: C, 79.41; H, 5.95; N, 3.31.
1346 (NO2).
Found: C, 79.36; H, 6.03; N, 3.61. IR (KBr) cmϪ1: 3144 (OH), 1612
(NCϭO), 1584 (CϭC).
(4-Dimethylaminophenyl)-[2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-
2,3-dihydroindol-1-yl]-methanone syn (3f): Pale orange prisms. mp 215—
216 °C. Yield 37%. 1H-NMR (300 MHz, DMSO-d6) d: 0.92 (3H, s,
C3–CH3), 1.55 (3H, s, C3–CH3), 2.88 (6H, s, N(CH3)2), 6.35 (1H, s, C2–H),
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(4
nitrophenyl)-methanone anti (4a): Yellow prisms. mp 247—248 °C. Yield
53%. 1H-NMR (400 MHz, DMSO-d6) d: 0.98 (3H, s, C3–CH3), 1.62 (3H, s,
C3–CH3), 5.89 (1H, s, C2–H), 6.95 (1H, d, Jϭ8.8 Hz, Cnaph3–H), 7.03—7.47
(7H, m, aromatic H), 7.19 (2H, d, Jϭ8.4 Hz, Cph2, Cph6–H), 7.51 (2H, d,
Jϭ8.4 Hz, Cph3, Cph5–H), 7.58 (1H, d, Jϭ8.8 Hz, Cnaph4–H), 8.31 (1H, d, 6.45 (2H, d, Jϭ8.6 Hz, Cph3, Cph5–H), 6.90—7.55 (11H, m, aromatic H),
Jϭ7.7 Hz, C7–H), 9.80 (1H, s, Cnaph2–OH). MS m/z: 438 (Mϩ). Anal. Calcd 7.67 (1H, d, Jϭ7.5 Hz, C7–H), 9.66 (1H, s, Cnaph2–OH). MS m/z: 436 (Mϩ).
for C27H22N2O4: C, 73.95; H, 5.07; N, 6.39. Found: C, 73.68; H, 4.99; N,
6.40. IR (KBr) cmϪ1: 3272 (OH), 1622 (NCϭO), 1590 (CϭC), 1518, 1346
(NO2).
Anal. Calcd for C29H28N2O2: C, 79.79; H, 6.46; N, 6.42. Found: C, 79.62; H,
6.68; N, 6.33. IR (KBr) cmϪ1: 3450 (OH), 1598 (NCϭO).
(4-Dimethylaminophenyl)-[2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-
(4-Chlorophenyl)-[2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihy- 2,3-dihydroindol-1-yl]-methanone anti (4f): Pale orange prisms. mp 226.5—
droindol-1-yl]-methanone syn (3b): Colorless prisms. mp 272—272.5 °C. 227.5 °C. Yield 42%. 1H-NMR (300 MHz, DMSO-d6) d: 0.95 (3H, s,
1
Yield 29%. H-NMR (400 MHz, DMSO-d6) d: 0.91 (3H, s, C3–CH3), 1.59 C3–CH3), 1.56 (3H, s, C3–CH3), 2.74 (6H, s, N(CH3)2), 6.10 (1H, s, C2–H),
(3H, s, C3–CH3), 6.22 (1H, s, C2–H), 6.68—7.70 (13H, m, aromatic H), 6.31 (2H, br s, Cph3, Cph5–H), 6.92—7.68 (11H, m, aromatic H), 7.78 (1H,
8.17 (1H, br d, Jϭ8.0 Hz, C7–H), 9.66 (1H, s, Cnaph2–OH). MS m/z: 427
br s, C7–H), 9.49 (1H, s, Cnaph2–OH). MS m/z: 436 (Mϩ). Anal. Calcd for
(Mϩ). Anal. Calcd for C27H22ClNO2: C, 75.78; H, 5.18; N, 3.27. Found: C, C29H28N2O2: C, 79.79; H, 6.46; N, 6.42. Found: C, 79.96; H, 6.33; N, 6.61.
75.30; H, 5.14; N, 3.16. IR (KBr) cmϪ1: 3150 (OH), 1618 (NCϭO), 1588 IR (KBr) cmϪ1: 3450 (OH), 1610 (NCϭO), 1590 (CϭC).
(CϭC).
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(3-
(4-Chlorophenyl)-[2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihy- nitrophenyl)-methanone syn (3g): Pale yellow prisms. mp 220—222 °C.
1
droindol-1-yl]-methanone anti (4b): Colorless prisms. mp 265—267 °C.
Yield 30%. H-NMR (500 MHz, DMSO-d6) d: 0.92 (3H, s, C3–CH3), 1.59
Yield 45%. H-NMR (400 MHz, DMSO-d6) d: 0.97 (3H, s, C3–CH3), 1.60 (3H, s, C3–CH3), 6.15 (1H, s, C2–H), 6.68 (1H, d, Jϭ7.3 Hz, Cnaph3–H),
(3H, s, C3–CH3), 5.99 (1H, s, C2–H), 6.70—7.70 (7H, m, aromatic H), 6.92 7.14—7.43 (10H, m, aromatic H), 7.69 (1H, d, Jϭ7.3 Hz, Cnaph5–H), 7.99
1
(1H, d, Jϭ8.3 Hz, Cnaph3–H), 7.18 (2H, d, Jϭ8.8 Hz, Cph3, Cph5–H), 7.24 (1H, d, Jϭ7.3 Hz, Cnaph4–H), 8.38 (1H, br s, C7–H), 9.61 (1H, br s,
(2H, d, Jϭ8.8 Hz, Cph2, Cph6–H), 7.56 (1H, d, Jϭ8.3 Hz, Cnaph4–H), 8.20 Cnaph2–OH). MS m/z: 438 (Mϩ). Anal. Calcd for C27H22N2O4: C, 73.95; H,
(1H, br d, Jϭ8.0 Hz, C7–H), 9.62 (1H, s, Cnaph2–OH). MS m/z: 427 (Mϩ). 5.07; N, 6.39. Found: C, 74.18; H, 5.16; N, 6.48. IR (KBr) cmϪ1: 3200 (OH),
Anal. Calcd for C27H22ClNO2: C, 75.78; H, 5.18; N, 3.27. Found: C, 75.61; 1612 (NCϭO), 1592 (CϭC), 1530, 1348 (NO2).
H, 5.16; N, 3.24. IR (KBr) cmϪ1: 3236 (OH), 1620 (NCϭO), 1588 (CϭC).
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(3-
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-
nitrophenyl)-methanone anti (4g): Yellow prisms. mp 253—255 °C. Yield
phenylmethanone syn (3c): Colorless prisms. mp 285—286 °C. Yield 18%. 56%. 1H-NMR (500 MHz, DMSO-d6) d: 0.96 (3H, s, C3–CH3), 1.62 (3H, s,
1H-NMR (270 MHz, DMSO-d6) d: 0.91 (3H, s, C3–CH3), 1.59 (3H, s, C3–CH3), 5.94 (1H, s, C2–H), 6.92 (1H, br s, Cnaph3–H), 7.02 (1H, br s,
C3–CH3), 6.23 (1H, s, C2–H), 6.73—7.71 (14H, m, aromatic H), 8.27 (1H, Cph5–H), 7.12—7.52 (10H, m, aromatic H), 7.68 (1H, br s, Cph2–H), 8.29
br s, C7–H), 9.60 (1H, s, Cnaph2–OH). MS m/z: 393 (Mϩ). Anal. Calcd for (1H, br s, C7–H), 9.78 (1H, br s, Cnaph2–OH). MS m/z: 438 (Mϩ). Anal.
C27H23NO2: C, 82.42; H, 5.89; N, 3.56. Found: C, 82.46; H, 5.88; N, 3.71.
Calcd for C27H22N2O4: C, 73.95; H, 5.07; N, 6.39. Found: C, 74.16; H, 5.14;
N, 6.34. IR (KBr) cmϪ1: 3200 (OH), 1618 (NCϭO), 1592 (CϭC), 1528,
1346 (NO2).
IR (KBr) cmϪ1: 3100 (OH), 1618 (NCϭO), 1588 (CϭC).
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-
phenylmethanone anti (4c): Colorless prisms. mp 216—217 °C. Yield 58%.
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-m-
1H-NMR (270 MHz, DMSO-d6) d: 0.91 (3H, s, C3–CH3), 1.58 (3H, s, tolylmethanone syn (3h): Colorless prisms. mp 218—219 °C. Yield 16%.
C3–CH3), 6.02 (1H, s, C2–H), 6.77—7.71 (14H, m, aromatic H), 8.26 (1H, 1H-NMR (500 MHz, DMSO-d6) d: 0.91 (3H, s, C3–CH3), 1.56 (3H, s,
br s, C7–H), 9.59 (1H, s, Cnaph2–OH). MS m/z: 393 (Mϩ). Anal. Calcd for C3–CH3), 2.01 (3H, s, Cph3–CH3), 6.19 (1H, s, C2–H), 6.22—7.31 (11H, m,
C27H23NO2: C, 82.42; H, 5.89; N, 3.56. Found: C, 82.46; H, 5.69; N, 3.83. aromatic H), 7.51 (1H, d, Jϭ8.6 Hz, Cnaph8–H), 7.71 (1H, d, Jϭ8.6 Hz,
IR (KBr) cmϪ1: 3240 (OH), 1624 (NCϭO), 1592 (CϭC).
Cnaph5–H), 8.31 (1H, s, C7–H), 9.55 (1H, br s, Cnaph2–OH). MS m/z: 407
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-p- (Mϩ). Anal. Calcd for C28H27NO2: C, 82.53; H, 6.18; N, 3.44. Found: C,
tolylmethanone syn (3d): Colorless prisms. mp 269—270 °C. Yield 25%. 82.81; H, 6.23; N, 3.61. IR (KBr) cmϪ1: 3464 (OH), 1618 (NCϭO), 1590
1H-NMR (270 MHz, DMSO-d6) d: 0.90 (3H, s, C3–CH3), 1.56 (3H, s, (CϭC).
C3–CH3), 2.20 (3H, br s, Cph4–CH3), 6.25 (1H, s, C2–H), 6.68—7.71 (13H,
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-m-
m, aromatic H), 8.05 (1H, br s, C7–H), 9.59 (1H, s, Cnaph2–OH). MS m/z: tolylmethanone anti (4h): Colorless prisms. mp 222—224 °C. Yield 60%.
407 (Mϩ). Anal. Calcd for C28H25NO2: C, 82.53; H, 6.18; N, 3.44. Found: C, 1H-NMR (500 MHz, DMSO-d6) d: 0.93 (3H, s, C3–CH3), 1.57 (3H, s,
82.26; H, 6.18; N, 3.99. IR (KBr) cmϪ1: 3156 (OH), 1618 (NCϭO), 1590 C3–CH3), 1.80 (3H, br s, Cph3–CH3), 5.94 (1H, br s, C2–H), 7.12—7.52
(CϭC).
(13H, m, aromatic H), 8.31 (1H, s, C7–H), 9.57 (1H, br s, Cnaph2–OH). MS
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-p- m/z: 407 (Mϩ). Anal. Calcd for C28H27NO2: C, 82.53; H, 6.18; N, 3.44.
tolylmethanone anti (4d): Colorless prisms. mp 276—277 °C. Yield 66%. Found: C, 82.36; H, 6.21; N, 3.64. IR (KBr) cmϪ1: 3232 (OH), 1614
1H-NMR (270 MHz, DMSO-d6) d: 0.92 (3H, s, C3–CH3), 1.57 (3H, s, (NCϭO), 1578 (CϭC).
C3–CH3), 1.93 (3H, s, Cph4–CH3), 6.01 (1H, s, C2–H), 6.64—7.59 (13H, m,
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(3-
aromatic H), 8.18 (1H, br s, C7–H), 9.56 (1H, s, Cnaph2–OH). MS m/z: 407
methoxyphenyl)-methanone syn (3i): Colorless prisms. mp 191—192 °C.
1
(Mϩ). Anal. Calcd for C28H25NO2: C, 82.53; H, 6.18; N, 3.44. Found: C, Yield 11%. H-NMR (500 MHz, DMSO-d6) d: 0.91 (3H, s, C3–CH3), 1.57
82.62; H, 6.26; N, 3.65. IR (KBr) cmϪ1: 3228 (OH), 1618 (NCϭO), 1590 (3H, s, C3–CH3), 3.44 (3H, s, Cph3–OCH3), 6.08 (1H, br s, C2–H), 6.23—
(CϭC).
7.37 (13H, m, aromatic-H), 8.31 (1H, br s, C7–H), 9.60 (1H, br s,
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(4- Cnaph2–OH). MS m/z: 423 (Mϩ). Anal. Calcd for C28H25NO3: C, 79.41; H,
methoxyphenyl)-methanone syn (3e): Colorless prisms. mp 267—268 °C. 5.95; N, 3.31. Found: C, 79.36; H, 6.00; N, 3.44. IR (KBr) cmϪ1: 3064 (OH),
1
Yield 28%. H-NMR (270 MHz, DMSO-d6) d: 0.90 (3H, s, C3–CH3), 1.56 1620 (NCϭO), 1580 (CϭC).

June 2003
695
[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(3-
C
naph5–H), 7.75 (1H, d, Jϭ7.3 Hz, Cnaph8–H), 8.30 (1H, d, Jϭ7.3 Hz, C7–H),
10.23 (1H, s, Cnaph2–OH). MS m/z: 345 (Mϩ). Anal. Calcd for C23H23NO2:
C, 79.97; H, 6.71; N, 4.05. Found: C, 79.67; H, 6.70; N, 4.31. IR (KBr)
cmϪ1: 3308 (OH), 1630 (NCϭO), 1592 (CϭC).
methoxyphenyl)-methanone anti (4i): Colorless prisms. mp 205—206 °C.
1
Yield 34%. H-NMR (500 MHz, DMSO-d6) d: 0.92 (3H, s, C3–CH3), 1.58
(3H, s, C3–CH3), 3.41 (3H, br s, Cph3–OCH3), 5.99 (1H, br s, C2–H), 6.24—
7.56 (13H, m, aromatic-H), 8.29 (1H, br s, C7–H), 9.58 (1H, s, Cnaph2–OH).
MS m/z: 423 (Mϩ). Anal. Calcd for C28H25NO3: C, 79.41; H, 5.95; N, 3.31.
Found: C, 79.70; H, 6.00; N, 3.47. IR (KBr) cmϪ1: 3272 (OH), 1618
(NCϭO), 1580 (CϭC).
1-[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-
propan-1-one anti (4m): Colorless prisms. mp 225—227 °C. Yield 40%. 1H-
NMR (500 MHz, DMSO-d6) d: 0.69 (3H, s, –CH2–CH3), 0.89 (3H, s,
C3–CH3), 1.54 (3H, s, C3–CH3), 1.62 (1H, br s, –CH2–CH3), 2.34 (1H, q,
Jϭ7.9 Hz, –CH2–CH3), 6.09 (1H, s, C2–H), 6.99—7.00 (2H, m, C5,
Cnaph3–H), 7.15—7.18 (2H, m, C4, C6–H), 7.34 (1H, dd, Jϭ7.9, 7.9 Hz,
Cnaph6–H), 7.57 (1H, dd, Jϭ7.9, 7.9 Hz, Cnaph7–H), 7.71 (1H, d, Jϭ7.9 Hz,
Cnaph4–H), 7.83 (1H, d, Jϭ7.9 Hz, Cnaph5–H), 8.19 (1H, d, Jϭ7.9 Hz, C7–H),
8.19 (1H, d, Jϭ7.9 Hz, Cnaph8–H), 9.68 (1H, s, Cnaph2–OH). MS m/z: 345
(Mϩ). Anal. Calcd for C23H23NO2: C, 79.97; H, 6.71; N, 4.05. Found: C,
80.19; H, 6.85; N, 4.27. IR (KBr) cmϪ1: 3156 (OH), 1624 (NCϭO), 1590
(CϭC).
1-[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-
butan-1-one syn (3n): Colorless prisms. mp 195—196 °C. Yield 13%. 1H-
NMR (500 MHz, DMSO-d6) d: 0.46 (3H, t, Jϭ7.3 Hz, –CH2–CH2–CH3),
0.90 (3H, s, C3–CH3), 1.04 (1H, tq, Jϭ7.3, 7.3 Hz, –CH2–CH2–CH3), 1.27
(1H, tq, Jϭ7.3, 7.3 Hz, –CH2–CH2–CH3), 1.52 (3H, s, C3–CH3), 1.68 (1H, t,
Jϭ7.3 Hz, –CH2–CH2–CH3), 2.25 (1H, t, Jϭ7.3 Hz, –CH2–CH2–CH3), 6.23
(1H, s, C2–H), 7.00—7.17 (3H, m, C4, C5, C6–H), 7.14—7.16 (1H, d,
Jϭ7.3 Hz, Cnaph3–H), 7.26—7.33 (2H, m, aromatic H), 7.32—7.33 (1H, d,
Jϭ7.3 Hz, C6–H), 7.75 (1H, d, Jϭ7.3 Hz, Cnaph4–H), 7.75 (1H, d, Jϭ7.3 Hz,
Cnaph5–H), 8.29 (1H, d, Jϭ7.3 Hz, C7–H), 10.23 (3H, s, Cnaph2–OH). MS
m/z: 359 (Mϩ). Anal. Calcd for C24H25NO2: C, 80.19; H, 7.01; N, 3.90.
Found: C, 80.04; H, 7.06; N, 4.06. IR (KBr) cmϪ1: 3036 (OH), 1622
(NCϭO), 1590 (CϭC).
(3,5-Dinitrophenyl)-[2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-di-
hydroindol-1-yl]-methanone syn (3i): Yellow prisms. mp 188—190 °C.
1
Yield 21%. H-NMR (400 MHz, DMSO-d6) d: 0.95 (3H, s, C3–CH3), 1.61
(3H, s, C3–CH3), 6.15 (1H, s, C2–H), 6.61 (1H, d, Jϭ8.8 Hz, Cnaph3–H),
7.10—7.46 (7H, m, aromatic H), 7.38 (1H, d, Jϭ8.8 Hz, Cnaph4–H), 7.66—
7.82 (3H, m, Cph2, Cph4, Cph6–H), 8.39 (1H, d, Jϭ8.1 Hz, C7–H), 9.73 (1H,
s, Cnaph2–OH). MS m/z: 483 (Mϩ). Anal. Calcd for C27H21N3O6: C, 67.08; H,
4.38; N, 8.69. Found: C, 67.18; H, 4.37; N, 8.76. IR (KBr) cmϪ1: 3100 (OH),
1622 (NCϭO), 1594 (CϭC), 1512, 1342 (NO2).
(3,5-Dinitrophenyl)-[2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-di-
hydroindol-1-yl]-methanone anti (4i): Yellow plates. mp 243—245 °C. Yield
63%. 1H-NMR (400 MHz, DMSO-d6) d: 1.02 (3H, s, C3–CH3), 1.64 (3H, s,
C3–CH3), 5.96 (1H, s, C2–H), 6.92 (1H, d, Jϭ8.8 Hz, Cnaph3–H), 7.13—7.37
(7H, m, aromatic H), 7.43 (1H, d, Jϭ8.8 Hz, Cnaph4–H), 7.48—7.54 (2H, m,
Cph2, Cph6–H), 7.90 (1H, d, Jϭ2.2 Hz, Cph4–H), 8.21 (1H, br s, Cnaph2–OH),
8.31 (1H, d, Jϭ8.1 Hz, C7–H). MS m/z: 483 (Mϩ). Anal. Calcd for
C27H21N3O6: C, 67.08; H, 4.38; N, 8.69. Found: C, 66.82; H, 4.49; N, 8.72.
IR (KBr) cmϪ1: 3380 (OH), 1624 (NCϭO), 1594 (CϭC), 1540, 1342 (NO2).
(3,5-Dimethylphenyl)-[2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-
dihydroindol-1-yl]-methanone syn (3k): Colorless prisms. mp 196—197 °C.
Yield 8%. 1H-NMR (500 MHz, DMSO-d6) d: 0.92 (3H, s, C3–CH3), 1.55
(3H, s, C3–CH3), 2.01 (6H, s, Cph3, Cph5–CH3), 6.16 (1H, s, C2–H), 6.22
(2H, br s, Cph2, Cph6–H), 6.77 (1H, s, Cph4–H), 6.85 (1H, br s, Cnaph3–H),
7.08—7.36 (6H, m, aromatic H), 7.52 (1H, d, Jϭ8.6 Hz, Cnaph8–H), 7.75
(1H, d, Jϭ7.3 Hz, Cnaph5–H), 8.20 (1H, br s, C7–H), 9.57 (1H, br s,
Cnaph2–OH). MS m/z: 421 (Mϩ). Anal. Calcd for C29H27NO2: C, 82.63; H,
6.46; N, 3.32. Found: C, 82.77; H, 6.54; N, 3.51. IR (KBr) cmϪ1: 3280 (OH),
1618 (NCϭO), 1580 (CϭC).
1-[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-
1
butan-1-one anti (4n): Colorless prisms. mp 209—211 °C. Yield 26%. H-
NMR (500 MHz, DMSO-d6) d: 0.40 (3H, s, –CH2–CH2–CH3), 0.91 (3H, s,
C3–CH3), 1.18 (1H, br s, –CH2–CH2–CH3), 1.29 (1H, br s, –CH2–CH2–
CH3), 1.54 (3H, s, C3–CH3), 1.69 (1H, br s, –CH2–CH2–CH3), 1.99 (1H,
br s, –CH2–CH2–CH3), 6.06 (1H, s, C2–H), 6.98—7.01 (2H, m, C5,
Cnaph3–H), 7.16 (2H, dd, Jϭ7.3, 7.9 Hz, C4, C6–H), 7.34 (1H, dd, Jϭ7.3,
7.9 Hz, Cnaph6–H), 7.58 (1H, dd, Jϭ7.3, 7.9 Hz, Cnaph7–H), 7.71 (1H, d,
Jϭ7.9 Hz, Cnaph4–H), 7.84 (1H, d, Jϭ7.9 Hz, Cnaph5–H), 8.18 (1H, d,
Jϭ7.9 Hz, Cnaph8–H), 8.31 (1H, s, C7–H), 9.57 (3H, s, Cnaph2–OH). MS m/z:
359 (Mϩ). Anal. Calcd for C24H25NO2: C, 80.19; H, 7.01; N, 3.90. Found: C,
80.02; H, 7.11; N, 4.17. IR (KBr) cmϪ1: 3036 (OH), 1616 (NCϭO), 1578
(CϭC).
Crystal Structure Analysis The single crystals of 3g, 4g, 3h and 4h
suitable for X-ray analysis were obtained from slow evaporation of the ace-
tone–EtOH solutions. The refraction data were measured on a RIGAKU
AFC7R four-circle autodiffractometer with graphite monochromated MoKa
radiation and a rotating anode generator. The structures were solved by the
direct method14) and refined by the full matrix least-squares method. The hy-
drogens are located on the calculated positions and refined except for the hy-
drogens on the 3,3-dimethyl and 3-methyl groups of 4h.
Neutral atom scattering factors were taken from International Tables for
X-ray Crystallography.39) All calculations were performed on a Silicon
Graphics IRIS Indigo workstation with teXsan Crystal Structure Analysis
Package.40) The results (crystal data, atomic coordinates, distances and an-
gles) are summarized in Tables 2, 3 and 4—9 (Supporting Information).
Supporting Information Available X-Ray crystallographic data have
been deposited at the Cambridge Crystallographic Data Center. The packing
diagrams of 3 (4) a, b, g, h and the atomic coordinates of the AM1-opti-
mized structures are available from our web page (URL http://yakko.
pharm.kumamoto-u.ac.jp/).
(3,5-Dimethylphenyl)-[2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-
dihydroindol-1-yl]-methanone anti (4k): Colorless prisms. mp 190—191 °C.
1
Yield 40%. H-NMR (500 MHz, DMSO-d6) d: 0.94 (3H, s, C3–CH3), 1.56
(3H, s, C3–CH3), 1.82 (6H, br s, Cph3, Cph5–CH3), 5.90 (1H, br s, C2–H),
6.23 (1H, br s, Cph4–H), 6.44 (2H, br s, Cph2, Cph6–H), 6.93 (1H, d,
Jϭ8.6 Hz, Cnaph8–H), 7.06 (1H, br s, aromatic H), 7.16—7.37 (5H, m, aro-
matic H), 7.56 (1H, d, Jϭ8.6 Hz, aromatic H), 7.62 (1H, br s, aromatic H),
8.24 (1H, br s, C7–H), 9.56 (1H, br s, Cnaph2–OH). MS m/z: 421 (Mϩ). Anal.
Calcd for C29H27NO2: C, 82.63; H, 6.46; N, 3.32. Found: C, 82.67; H, 6.50;
N, 3.57. IR (KBr) cmϪ1: 3292 (OH), 1614 (NCϭO), 1578 (CϭC).
1-[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-
ethanone syn (3l): Colorless needles. mp 202—204 °C. Yield 57%. 1H-NMR
(400 MHz, DMSO-d6) d: 0.90 (3H, s, C3–CH3), 1.54 (3H, s, C3–CH3), 1.68
(3H, s, COCH3), 6.19 (1H, s, C2–H), 7.01—7.04 (1H, m, aromatic H),
7.13—7.18 (2H, m, aromatic H), 7.17 (1H, d, Jϭ8.6 Hz, Cnaph3–H), 7.26—
7.33 (3H, m, aromatic H), 7.75 (1H, d, Jϭ8.6 Hz, Cnaph4–H), 7.77 (1H, d,
Jϭ7.3 Hz, aromatic H), 8.25 (1H, d, Jϭ7.9 Hz, C7–H), 10.25 (1H, s,
Cnaph2–OH). MS m/z: 331 (Mϩ). IR (KBr) cmϪ1: 3064 (OH), 1626 (NCϭO),
1580 (CϭC). The structure was confirmed by transformation into an equilib-
rium mixture of 3l and 4l.
1-[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-
1
ethanone anti (4l): Colorless plates. mp 279—280 °C. Yield 23%. H-NMR
(400 MHz, DMSO-d6) d: 0.90 (3H, s, C3–CH3), 1.54 (3H, s, C3–CH3), 1.68
(3H, s, COCH3), 6.07 (1H, s, C2–H), 7.00 (1H, d, Jϭ8.6 Hz, Cnaph3–H),
7.00—7.01 (1H, m, aromatic H), 7.14—7.18 (2H, m, aromatic H), 7.34 (1H,
dd, Jϭ7.3, 7.9 Hz, C5–H), 7.56 (1H, dd, Jϭ7.3, 7.9 Hz, C6–H), 7.72 (1H, d,
Jϭ8.6 Hz, Cnaph4–H), 7.84 (1H, d, Jϭ7.9 Hz, C4–H), 8.13 (1H, d, Jϭ8.0 Hz,
aromatic H), 8.19 (1H, d, Jϭ7.9 Hz, C7–H), 9.57 (1H, s, Cnaph2–OH). MS
m/z: 331 (Mϩ). Anal. Calcd for C22H21NO2: C, 79.73; H, 6.39; N, 4.23.
Found: C, 79.60; H, 6.33; N, 4.49. IR (KBr) cmϪ1: 3264 (OH), 1638
(NCϭO), 1590 (CϭC).
Acknowledgements A part of this work was supported by the grants-in-
Aid for Scientific Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan. The author is grateful to Dr. M. Nishio
(The CH/p Institute) for suggesting the presence of important weak interac-
tions in the crystal structures of the atropisomers. We thank Miss K. Meta
and Miss A. Watanabe for experimental assistance.
1-[2-(2-Hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-
propan-1-one syn (3m): Colorless prisms. mp 221—223 °C. Yield 13%. 1H-
NMR (500 MHz, DMSO-d6) d: 0.67 (3H, dd, Jϭ7.3, 7.9 Hz, –CH2–CH3),
0.90 (3H, s, C3–CH3), 1.53 (3H, s, C3–CH3), 1.60 (1H, br s, –CH2–CH3),
2.36 (1H, q, Jϭ7.9 Hz, –CH2–CH3), 6.23 (1H, s, C2–H), 6.99—7.03 (1H, m,
aromatic H), 7.12—7.19 (2H, m, aromatic H), 7.17—7.19 (1H, d, Jϭ7.9 Hz,
Cnaph3–H), 7.26—7.33 (3H, m, aromatic H), 7.74 (1H, d, Jϭ7.9 Hz,
References and Notes
1) Present address: School of Agriculture, Kyushu Tokai University, 5435
Kawayo, Choyoson, Asogun, Kumamoto 869–1404, Japan.
2) Oki M., Angew. Chem., 88, 67—74 (1976).
3) Oki M., “Topics in Stereochemistry,” Vol. 14, ed. by Allinger N. L.,
Eliel E. L., Wilen S. H., John Wiley & Sons Inc., New York, 1983, pp.

696
Vol. 51, No. 6
47—79.
4) Oki M., Acc. Chem. Res., 23, 351—356 (1990).
24) Steiner T., Starikov E. B., Amada A. M., Texia-Dias J. J. C., J. Chem.
Soc., Perkin Trans. 2, 1995, 1321—1326 (1995).
5) Randall W. C., Anderson P. S., Cresson E. L., Hunt C. A., Lyon T. F., 25) Boyd D. R., Evans T. A., Jennings W. B., Malone J. F., O’Sullivan W.,
Rittle K. E., Remy D. C., Springer J. P., Hirshfield J. M., Hoogsteen K., Smith A., J. Chem. Soc., Chem. Commun., 1996, 2269—2270 (1996).
Williams M., Risley E. A., Tataro J. A., J. Med. Chem., 22, 1222— 26) Nishio M., Hirota M., Umezawa Y., “The CH/p interaction; Evidence
1230 (1979). Nature and Consequences,” Wiley, New York, 1998.
6) Cozzi F., Cinquini M., Annunziata R., Dwyer T., Siegel J. S., J. Am. 27) Stewart J. J. P., J. Am. Chem. Soc., 107, 3902—3909 (1985).
Chem. Soc., 114, 5729—5733 (1992).
28) AM1 calculations were run through the CS Chem Pro interface using
MOPAC97 on a Power Macintosh G3 computer.
29) AM1 method is suitable for the structure optimization of atropisomers
involving amide groups.
30) The AM1-calculated heats of formation (kcal/mol) based on the four
frozen conformations are as follows; anti–syn 31.940, syn–anti
30.387, anti–anti 31.906, syn–syn 30.405. The calculations could not
reproduce the relative stability among them.
31) “Applications of Nuclear Magnetic Resonance Spectroscopy in Or-
ganic Chemistry,” 2nd ed., by Jackmann L. M., Sternhell S., Inc.,
1969, pp. 72—77.
7) Cozzi F., Cinquini M., Annunziata R., Siegel J. S., J. Am. Chem. Soc.,
115, 5330—5331 (1993), and references cited therein.
8) Harano K., Yasuda M., Ida Y., Komori T., Taguchi T., Cryst. Struc.
Commun., 10, 165—171 (1981).
9) Eto M., Harano K., Hisano T., Kitamura T., J. Heterocycl. Chem., 29,
311—315 (1992).
10) Kitamura T., Harano K., Hisano T., Chem. Pharm. Bull., 40, 2255—
2261 (1992).
11) Eto M., Ito F., Kitamura T., Harano K., Heterocycles, 38, 2159—2163
(1994).
12) Eto M., Ito F., Kitamura T., Harano K., Heterocycles, 43, 1159—1163 32) Fukui K., “Kagaku Hanno to Densi no Kido (Chemical Reactions and
(1996).
Electron Orbitals),” Maruzen, Tokyo, 1976.
33) Fleming I., “Frontier Orbitals and Organic Chemical Reactions,”
Wiley, London, 1976.
13) Watanabe A., Moriguchi M., Ito F., Yoshitake Y., Eto M., Harano K.,
Heterocycles, 53, 1—6 (2000).
14) SAPI91: Fan Hai-Fu (1991). Structure Analysis Programs with Intelli- 34) Sustmann first applied a FMO concept to reactivity in 1.3-dipolar reac-
gent Control, Rigaku Corporation, Tokyo, Japan.
15) Johnson C. K., ORTEP, Report ORNL-3794, Ork Ridge National Lab-
oratory, Oak Ridge, TN, 1965.
16) Allen F. H., Kennard O., Watson D. G., Brammer L., Orpen A. G.,
Taylor R., J. Chem. Soc., Perkin Trans. 2, 1987, S1—S19 (1987).
17) The single crystal X-ray analysis of 1a indicates that the N–C bond
length is 1.485(3) Å.18)
18) Ito F., Yoshitake Y., Harano K., manuscript in preparation. Crystal
Data; 1a: C19H22N2O4, Mϭ342.39, triclinic, Space group P(Ϫ1) (#2),
tions and Diels–Alder (DA) reactions and classified these reactions
into three types of cycloadditions according to the relative positions of
the frontier orbitals of the reagents. In the normal DA reaction, the in-
teractions LUMO-dienophile and HOMO-diene are the dominant sta-
bilizing factor. For the inverse type reaction the predominant interac-
tions become HOMO-dienophile and LUMO-diene. A third type of
orbital arrangement for a DA reaction might be called neutral. The
HOMO-LUMO separations are similar, therefore, electron attraction
and release should increase the reactivity.
aϭ8.561(1) Å, bϭ15.451(1) Å, cϭ7.1682(6) Å, aϭ102.456(7)°, 35) The AM1 FMO energy levels are as follows: 2-naphthol LUMO
bϭ97.495(8)°, gϭ101.679(8)°, Vϭ891.6(2) Å3, Dcϭ1.275 g cmϪ3
,
Ϫ0.35 eV, HOMO Ϫ8.64 eV; 3-nitrobenzoic acid LUMO Ϫ1.46 eV;
HOMO Ϫ10.97 eV; 4-nitrobenzoic acid LUMO Ϫ1.73 eV, HOMO
Ϫ10.90 eV.
Zϭ2, MoKa radiation (50 kV–150 mA), lϭ0.7107 Å, Reflections col-
lectedϭ4381, Unique data collectedϭ4103, Unique data used
(IϾ3.00s(I))ϭ3809, Rϭ0.086, Rwϭ0.149, R1ϭ0.080.
36) Brunner K., Monatsh. Chem., 16, 849 (1895).
37) Luechs H., Schlotzer A., Ber., 67, 1572—1576 (1934).
38) see also ref. 10 and references cited therein.
19) Taylor R., Kennard O., J. Am. Chem. Soc., 104, 5063—5070 (1982).
20) Desiraju G. R., Acc. Chem. Res., 24, 290—296 (1991).
21) Steiner T., Kanters J. A., Kroon J., Chem. Commun., 1996, 1277— 39) Cromer D. T., Abd Waber J. T., “International Tables for X-ray Crys-
1278 (1996).
tallography,” Vol. IV, The Kynoch Press, Birmingham, England,
1974, Table 2.2A.
22) Nishio M., Hirota M., Tetrahedron, 45, 7201—7245 (1989).
23) Hunter C. A., Sanders J. K. M., J. Am. Chem. Soc., 112, 5525—5534 40) Crystal Structure Analysis Package, Molecular Structure Corporation
(1990). (1985 & 1992).