Manganese(III)-Based Oxidative Cyclization of N -Aryl-2-oxocyclo-alkane-1-carboxamides: Synthesis of Spiroindolinones

Article abstract of DOI:10.1055/s-0037-1611563

The Mn(III)-based oxidative cyclization of twenty-five N -aryl-2-oxocycloalkane-1-carboxamides is investigated. The reactions progress efficiently to give the desired spiro[cycloalkane-1,3′-indoline]-2,2′-diones in high to quantitative yields. The easy conversion of the carbonyl functional group of one of the indoline products, 1′-methylspiro[cyclo-hexane-1,3′-indoline]-2,2′-dione, is also demonstrated.

Full text of DOI:10.1055/s-0037-1611563

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
S. Katayama, H. Nishino
Paper
Synthesis
Manganese(III)-Based Oxidative Cyclization of N-Aryl-2-oxocyclo-
alkane-1-carboxamides: Synthesis of Spiroindolinones
Shintaro Katayama
R4
n
R4
O
R3
R2
Hiroshi Nishino*
R3
R2
O
O
Mn(OAc)3
O
Department of Chemistry, Graduate School of Science,
Kumamoto University, Kurokami 2-39-1, Chûou-Ku,
Kumamoto 860-8555, Japan
N
AcOH, reflux
N
R1
R
or
AcOH/HCO2H (1:4)
r.t.
R
n
R1
nishino@kumamoto-u.ac.jp
R = alkyl
25 examples
69% to quant.
R1, R2, R3, R4 = H, Me, OMe, Cl, F
n = 0–2
This manuscript is dedicated to the late Professor Shô Ito,
Professor Emeritus of Tohoku University, Japan, who
showed Hiroshi Nishino the way as a chemist.
Received: 22.03.2019
Accepted after revision: 04.05.2019
Published online: 24.05.2019
ucts, for example, satavaptan, as a selective vasopressin V2
receptor antagonist11a,b and gelsemine, as a highly toxic
plant alkaloid,11c–e the yields and the synthetic applications
were not high enough. Recently, we developed the activa-
tion of Mn(OAc)3 by adding HCO2H to the reaction and dra-
matically changed the reaction time and temperature,
which improved the product yields.12 We then attempted to
scrutinize the reactions of N-aryl-2-oxocycloalkane-1-car-
boxamides in order to develop the synthesis of spiroindoli-
none derivatives.
DOI: 10.1055/s-0037-1611563; Art ID: ss-2019-f0190-op
Abstract The Mn(III)-based oxidative cyclization of twenty-five N-aryl-
2-oxocycloalkane-1-carboxamides is investigated. The reactions prog-
ress efficiently to give the desired spiro[cycloalkane-1,3′-indoline]-2,2′-
diones in high to quantitative yields. The easy conversion of the carbon-
yl functional group of one of the indoline products, 1′-methylspiro[cyclo-
hexane-1,3′-indoline]-2,2′-dione, is also demonstrated.
Key words spiro[cycloalkane-1,3′-indoline]-2,2′-diones, oxidative cy-
clization, 5-exo cyclization, radicals, heterocycles, spiro compounds, in-
dolinones
CO2Et
CO2Et
EtO2C CO2Et
Mn(OAc)3
R2
R2
(eq. 1)
AcOH
reflux
N
R1
O
N
R1
O
Cyclization is one of the most important techniques to
construct complex organic molecules,1 and can be accom-
plished via ionic,2 radical,3 and concerted techniques,4 and
by ring-closing metathesis.5 From the standpoint of the cy-
clization reaction, we have been studying the oxidative rad-
ical cyclization using Mn(OAc)3.6 For example, the oxidation
of 2-{2-[alkyl(aryl)amino]-2-oxoethyl}malonates gave 1-al-
kyl-2-oxo-2,3-dihydroquinoline-4,4(1H)-dicarboxylates
(Scheme 1, eq. 1),7 which could be converted into quino-
lines. A similar reaction of N,2-dialkyl-N-aryl-3-oxobutana-
mides produced 3-acetyl-1,3-dialkylindolin-2-ones in
quantitative yields (Scheme 1, eq. 2),8 which could be trans-
formed into indoles. On the other hand, indole-2-carboxylic
acids underwent oxidative trapping reactions with alkenes
followed by cyclization to give indolelactones (Scheme 1,
eq. 3).9 During the course of these studies, we communicat-
ed our preliminary results on the synthesis of spiro[cyclo-
hexane-1,3′-indoline]-2,2′-diones via the oxidation of N-
aryl-2-oxocyclohexane-1-carboxamides through a formal
5-exo-trig cyclization.10 Although the reaction was very
simple and convenient and the product spiroindolinones
are important for the total synthesis of some natural prod-
Me
R3
Me
O
R3
O
Mn(OAc)3
O
R2
R2
O
(eq. 2)
AcOH
reflux
N
R1
N
R1
Ar
Ar
Ar
Ar
R2
R2
O
(eq. 3)
CO2H
N
R1
Mn(OAc)3
AcOH/HCO2H
rt, argon
O
N
R1
Scheme 1 Synthesis of heterocycles using Mn(III)-based oxidations
N-Aryl-2-oxocycloalkane-1-carboxamides 1a–y were
prepared by the condensation of ethyl 2-oxocycloalkane-
carboxylates with the corresponding anilines (see the Sup-
porting Information). The oxidation of N-methyl-2-oxo-N-
phenylcyclohexane-1-carboxamide (1a) with Mn(OAc)3 in
AcOH gave 1′-methylspiro[cyclohexane-1,3′-indoline]-2,2′-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

B
S. Katayama, H. Nishino
Paper
Synthesis
dione (2a) (Table 1, entries 1–3);10 however, the reaction
took a long time in AcOH (2 days at r.t.), giving a low yield of
2a (entry 1), elevating the temperature (reflux) in AcOH
caused the retro-condensation of 1a (entry 2), and the use
of an excess amount of the oxidant led to 2a in 55% yield
(entry 3). Thus, we decided to explore the reaction under
milder conditions in the presence of HCO2H. The reaction in
AcOH/HCO2H (4:1 v/v) at room temperature afforded the
spiroindolinone 2a in 38% yield after 30 hours (entry 4).
When the amount of HCO2H was further increased, the
yield of 2a was higher, and a maximum yield of 88% was
achieved using AcOH/HCO2H (1:4 v/v) (entry 7). However,
the use of only HCO2H as the solvent decreased the yield of
2a, although the reaction time was shorter (entry 8). We
thus considered the reaction conditions in entry 7 to be op-
timum, and other N-alkyl-2-oxo-N-phenylcyclohexane-1-
carboxamides 1b–e underwent the reaction to give the de-
sired spiroindolinones 2b–e in good yields (entries 9–12).
These results indicated that the oxidative cyclization was
not influenced by the N-alkyl group of the carboxamides
1a–e, although the yield of 2d was slightly lower than those
of the 1′-alkylspiroindolinones 2a–c and 2e.
a,b
Table 1 Oxidation of N-Aryl-2-oxocycloalkane-1-carboxamides 1a–y with Mn(OAc)3
R4
n
R4
O
2
R3
R2
1
R3
R2
O
O
Mn(OAc)3
AcOH
2
3'
1
O
N
2'
N
R1
R
R
n
R1
1a–y
2a–y
c
Entry
Carboxamide
R2 R3
1/Mn(OAc)3
AcOH/HCO2H Temp
v/v
Time
2 d
Product
(yield)d
R
R1
R4
n
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
1:2.5
1:2.5
1:3
5:0
5:0
5:0
4:1
3:2
2:3
1:4
0:5
1:4
1:4
1:4
1:4
1:4
5:0
5:0
5:0
5:0
5:0
5:0
5:0
5:0
5:0
5:0
5:0
1:4
r.t.
2a (15%)
2a (69%)e
2a (55%)
2a (38%)
2a (60%)
2a (68%)
2a (88%)
2a (67%)
2b (83%)
2c (90%)
2d (69%)
2e (87%)
2f (37%)
2f (84%)
2g (86%)
2h (75%)
2i (90%)
2j (96%)
2k (88%)
2l (93%)
2m (92%)f
2n (95%)
2o (88%)
2p (87%)
2p (84%)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
reflux
reflux
r.t.
4 min
5 min
30 h
3
H
H
4
H
H
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2
5
H
H
r.t.
24 h
24 h
24 h
18 h
24 h
24 h
24 h
24 h
24 h
6
H
H
r.t.
7
H
H
r.t.
8
H
H
r.t.
9
H
H
r.t.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
n-Pr
i-Pr
n-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
r.t.
H
H
r.t.
H
H
r.t.
H
H
Me
Me
OMe
Cl
F
r.t.
1f
H
H
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
r.t.
1 min
1g
1h
1i
H
H
1:2
1 min
1 min
H
H
1:2.5
1:2.5
1:2
H
H
1 min
1j
Me
OMe
Cl
H
H
H
0.5 min
1 min
1k
1l
H
H
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
H
H
0.5 min
2 min
1m
1n
1o
1p
1p
Me
Me
Me
H
H
Me
H
H
1 min
H
Me
H
1 min
H
H
1 min
H
H
H
H
0.5 min
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

C
S. Katayama, H. Nishino
Paper
Synthesis
Table 1 (continued)
Entry
c
Carboxamide
1/Mn(OAc)3
AcOH/HCO2H Temp
v/v
Time
Product
R
R1
R2
R3
R4
n
(yield)d
26
27
28
29
30
31
32
33
34
35
1q
1r
Et
H
H
H
H
0
0
0
0
2
2
2
2
2
2
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:4
1:4
1:4
1:4
1:4
5:0
5:0
5:0
5:0
5:0
r.t.
0.5 min
2q (quant.)
2r (quant.)
2s (98%)
2t (97%)
n-Pr
i-Pr
n-Bu
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
r.t.
0.5 min
0.5 min
0.5 min
48 h
1s
H
H
r.t.
1t
H
H
r.t.
1u
1u
1v
1w
1x
1y
H
H
r.t.
2u (76%)
2u (90%)
2v (86%)
2w (78%)
2x (93%)
2y (74%)
H
H
reflux
reflux
reflux
reflux
reflux
5 min
5 min
6 min
3 min
3 min
H
Me
Cl
H
H
Me
Cl
H
a The reactions of carboxamides 1 (0.5 mmol) were carried out in solvent (15 mL) under argon (entries 1–12).
b The reactions of carboxamides 1 (0.3 mmol) were carried out in solvent (10 mL) under argon (entries 13–35).
c Molar ratio.
d Yield of isolated product 2.
e The retro-condensation of 1a also occurred and no starting 1a was recovered.
f The regioisomers 2m (R2 = Me) and 2m′ (R4 = Me) were produced in a 2:1 regioisomeric ratio.
In order to investigate the influence of a substituent on
the phenyl group, the reaction of N-4-methylphenylcyclo-
hexane-1-carboxamide 1f was carried out under the opti-
mized conditions. Contrary to our expectation, the reaction
still took 24 hours and the decomposition of 1f occurred
somewhat before the oxidative cyclization, resulting in the
formation of product 2f in a low yield (Table 1, entry 13). It
was then necessary to activate the reaction and shorten the
reaction time, so that the reaction could be conducted at re-
flux temperature. Gratifyingly, the reaction was complete
within 1 minute and gave the desired spiroindolinone 2f in
84% yield (entry 14). Methyl-, methoxy-, chloro-, and fluo-
ro-substituted phenylcyclohexane-1-carboxamides 1g–o
also gave very good results under similar conditions (en-
tries 15–23). The reaction of N-3-methylphenylcyclohex-
ane-1-carboxamide 1m produced two regioisomers, 2m (R2
= Me) and 2m′ (R4 = Me) in a 2:1 regioisomeric ratio, proba-
bly due to the steric hindrance of the methyl group (entry
21). In any event, the oxidative cyclization was not influ-
enced by electron-donating and halo groups on the phenyl
group.
We also compared the reactivity of a 2-oxocyclohexyl
group to that of 2-oxocyclopentyl and 2-oxocycloheptyl
groups. The oxidation of N-methyl-2-oxocyclopentanecar-
boxamide 1p in boiling AcOH gave the desired spiroindoli-
none 2p in a high yield as expected (Table 1, entry 24). Sur-
prisingly, when a similar reaction was carried out in
AcOH/HCO2H (1:4 v/v) at room temperature, the oxidant
was consumed in an extremely short reaction time and 2p
was obtained in a similar yield (entry 25). The reaction of
other N-alkyl-2-oxocyclopentanecarboxamides 1q–t also
led to very good results, producing the corresponding
spiroindolinones 2q–t in excellent to quantitative yields
(entries 26–29). On the other hand, the reaction of N-meth-
yl-2-oxocycloheptanecarboxamide 1u at room temperature
needed a long reaction time (48 h) to consume the oxidant,
affording the corresponding spiroindolinone 2u in 76% yield
(entry 30). However, the reaction in AcOH at reflux tem-
perature was complete within 5 minutes to produce 2u in
90% yield (entry 31). The reactions of other substituted 2-
oxocycloheptanecarboxamides 1v–y were also carried out
in boiling AcOH to give the desired spiroindolinones 2v–y in
high yields (entries 32–35). Accordingly, it was found that
the trend in the reactivity decreased in the order: cyclopen-
tanecarboxamides > cyclohexanecarboxamides > cyclohep-
tanecarboxamides based on the reaction conditions de-
scribed above.
Finally, in order to investigate the synthetic applica-
tions, 1′-methylspiro[cyclohexane-1,3′-indoline]-2,2′-dione
(2a) was subjected to reduction, a Grignard reaction,13
Baeyer–Villiger oxidation,14 and to reactions with hydra-
zines (Scheme 2).15 The spiroindolinone 2a underwent re-
duction with NaBH4 in EtOH to afford the corresponding al-
cohol 3, of which the diastereomer 3′ (3:4 dr) could be iso-
lated by chromatographic separation (eq. 1). The Grignard
reaction with phenylmagnesium bromide followed by hy-
drolysis gave 2-hydroxy-1′-methyl-2-phenylspiro[cyclo-
hexane-1,3′-indolin]-2′-one (4) in 85% yield (eq. 2). The
Baeyer–Villiger oxidation/rearrangement occurred effec-
tively using m-chloroperbenzoic acid (mCPBA) in the pres-
ence of NaHCO3 to produce the corresponding spiro[indo-
line-3,2′-oxepane]-2,7′-dione 5 in 79% yield (eq. 3). The re-
actions with methylhydrazine, 4-nitrophenylhydrazine,
and 2,4-dinitrophenylhydrazine were carried out in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

D
S. Katayama, H. Nishino
Paper
Synthesis
MeOH/AcOH at 50 °C. The reactions proceeded smoothly
and the corresponding hydrazones 6a–c were obtained in
very good yields (eq. 4).
The anilines, 2-oxocycloalkane-1-carboxylates, and solvents were
commercially available and used as received. Manganese(III) acetate
dihydrate [Mn(OAc)3·2H2O] was synthesized according to our modi-
fied method.8 The N-alkyl-N-aryl-2-oxocycloalkane-1-carboxamides
1a–y were prepared by the condensation of N-alkylanilines with ethyl
2-oxocycloalkane-1-carboxylates (see the Supporting Information).
Melting points were recorded using a MP-J3 Yanagimoto micromelt-
ing point apparatus and are uncorrected. IR spectra were measured
neat or in CHCl3 using an IRAffinity-1S spectrophotometer with a
MIRacle 10 ATR accessory and are expressed in cm–1. NMR spectra
were recorded using a JNM ECX 500 spectrometer at 500 MHz for 1H
and at 125 MHz for 13C, with tetramethylsilane as the internal stan-
dard. The chemical shifts are reported as  values (ppm) and the cou-
pling constants in Hz. The following abbreviations are used for the
multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
High-resolution mass spectra were recorded using a JEOL JMS-700
MStation and were obtained at the Instrumental Analysis Center,
Kumamoto University, Kumamoto, Japan. Elemental analyses were
obtained using a J-Science Lab JM10 instrument.
HO
NaBH4
(eq. 1)
O
EtOH
N
Me
3 (71%)
Ph
1) PhMgBr/Et2O
HO
reflux, 2.5 h
(eq. 2)
O
2) H3O+
N
Me
2
4 (85%)
O
1
3'
O
2'
O
N
Me
O
mCPBA/CH2Cl2
2a
Oxidation of 2-Oxocycloalkane-1-carboxamides 1a–y; General
Procedure
(eq. 3)
O
NaHCO3
r.t., 1.5 h
N
The general procedure for the oxidation of 2-oxocycloalkane-1-car-
boxamides 1a–f and 1p–u at room temperature was as follows. To cy-
cloalkanecarboxamide 1 (0.3 mmol) dissolved in glacial AcOH (2
mL)/HCO2H (8 mL) was added Mn(OAc)3·2H2O (0.75 mmol), and the
resulting mixture was stirred at room temperature under an argon at-
mosphere until the brown-black color of the solution turned trans-
parent pale yellow. After the Mn(III) oxidant was completely con-
sumed (if needed, the presence of Mn(III) can be monitored using io-
dine–starch paper), the solvent was removed under reduced pressure.
Following removal of the solvent, 2 M HCl (15 mL) was added to dis-
solve the solid residue and the obtained aqueous mixture was ex-
tracted with CHCl3 (3 × 20 mL). The combined extracts were washed
with a saturated aqueous solution of NaHCO3 and H2O, dried over an-
hydrous MgSO4, then concentrated to dryness. The obtained residue
was separated by silica gel column chromatography eluting with
EtOAc/hexane (2:8 or 3:7 v/v) to give the desired spiro[cycloalkane-
1,3′-indoline]-2,2′-diones 2a–f and 2p–u (see Table 1).
Me
5 (79%)
RHNN
RNHNH2
(eq. 4)
O
MeOH/AcOH
(1:1 v/v)
50 °C, 10 min
N
Me
6a: R = Me
6b: R = 4-O2NC6H4
6c: R = 2,4-(O2N)C6H3
(quant.)
(97%)
(87%)
Scheme 2 Several transformations of the spiroindolinone 2a
In summary, we have demonstrated the facile synthesis
of spiroindolinones 2a–y and subsequent synthetic applica-
tions. That is, the oxidation of N-alkyl-2-oxo-N-phenylcy-
clohexane-1-carboxamides 1a–e and N-alkyl-2-oxo-N-
phenylcyclopentane-1-carboxamides 1p–t proceeded in
AcOH/HCO2H at room temperature, producing the corre-
sponding spiroindolinones 2a–e and 2p–t in yields ranging
from 69% to quantitative. 2-Oxocyclohexane-1-carboxam-
ides 1f–o, having substituents on the phenyl group, and the
N-aryl-2-oxocycloheptane-1-carboxamides 1u–y under-
went the oxidation in boiling AcOH, giving the desired
spiroindolinones 2f–o and 2u–y in high yields. The synthet-
ic and work-up procedures were very simple and the corre-
sponding spiroindolinones were obtained in high to quanti-
tative yields. In addition, spiroindolinone 2a was easily
transformed into the alcohols 3 and 4, the ring-expanded
lactone 5, and the hydrazones 6a–c. The obtained spiroin-
dolinones can be used as convenient starting materials for
the synthesis of natural products,11 and we believe this
methodology could be widely used by the chemistry com-
munity.
The oxidations of the 2-oxocycloalkane-1-carboxamides 1f–p and
1u–y at reflux temperature were as follows. To cycloalkanecarboxam-
ide 1 (0.3 mmol) dissolved in glacial AcOH (10 mL) was added
Mn(OAc)3·2H2O (0.75 mmol), and the mixture was quickly heated at
reflux temperature using a pre-heated oil bath at 140 °C under an ar-
gon atmosphere until the brown color of Mn(III) turned transparent.
After work-up as described above, the desired spiro[cycloalkane-1,3′-
indoline]-2,2′-diones 2f–p and 2u–y were obtained (see Table 1). The
solid products were further purified by recrystallization from appro-
priate solvents to prepare analytical samples. Specific details are giv-
en below.
1′-Methylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2a)11a
Yield: 97.8 mg (88%); colorless microcrystals (from EtOH/hexane); mp
97–99 °C (Lit.16 92–94 °C); Rf = 0.31 (EtOAc/hexane, 3:7).
IR (CHCl3): 1690 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.31–7.28 (m, 2 H, arom H), 7.09 (dt, J =
7.6, 1.0 Hz, 1 H, arom H), 6.84 (dd, J = 8.0, 0.8 Hz, 1 H, arom H), 3.18 (s,
3 H, =N-Me), 3.05 (ddd, J = 14.3, 10.4, 5.6 Hz, 1 H, H-CH), 2.59 (dt, J =
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

E
S. Katayama, H. Nishino
Paper
Synthesis
14.3, 5.6 Hz, 1 H, H-CH), 2.45–2.37 (m, 1 H, H-CH), 2.26–2.21 (m, 1 H,
H-CH), 2.20–2.13 (m, 1 H, H-CH), 2.09 (ddd, J = 14.1, 10.3, 4.1 Hz, 1 H,
H-CH), 2.02–1.94 (m, 1 H, H-CH), 1.89–1.82 (m, 1 H, H-CH).
FAB HRMS (acetone/NBA): m/z [M
258.1494; found: 258.1489.
+
H]+ calcd for C16H20NO2:
13C NMR (125 MHz, CDCl3):  = 204.9 (C=O), 174.0 (-N-C=O), 143.0 (C-
7′a), 129.2 (C-3′a), 128.4, 124.3, 122.4, 108.2 (arom CH), 63.4 (C-1),
39.5, 37.0, 26.7 (CH2), 26.2 (=N-Me), 20.1 (CH2).
1′-Butylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2e)
Yield: 118.6 mg (87%); yellow oil; Rf = 0.28 (EtOAc/hexane, 3:7).
IR (CHCl3): 1694 (C=O) cm–1
.
Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.20;
H, 6.87; N, 6.09.
1H NMR (500 MHz, CDCl3):  = 7.31–7.27 (m, 2 H, arom H), 7.08 (t, J =
7.8 Hz, 1 H, arom H), 6.85 (d, J = 8.0 Hz, 1 H, arom H), 3.69 (t, J = 7.5
Hz, 2 H, -CH2-CH2-CH2-CH3), 3.09–3.03 (m, 1 H, H-CH), 2.61–2.56 (m,
1 H, H-CH), 2.46–2.39 (m, 1 H, H-CH), 2.24–2.17 (m, 2 H, CH2), 2.12–
2.07 (m, 1 H, H-CH), 2.02–1.95 (m, 1 H, H-CH), 1.88–1.84 (m, 1 H, H-
CH), 1.64 (quint, J = 7.5 Hz, 2 H, -CH2-CH2-CH2-CH3), 1.36 (sext, J = 7.4
Hz, 2 H, -CH2-CH2-CH2-CH3), 0.94 (t, J = 7.5 Hz, 3 H, -CH2-CH2-CH2-
CH3).
13C NMR (125 MHz, CDCl3):  = 205.1 (C=O), 174.1 (-N-C=O), 142.6 (C-
7′a), 129.5 (C-3′a), 128.4, 124.6, 122.3, 108.6 (arom C), 63.4 (C-1), 39.8
(CH2), 39.6 (-CH2-CH2-CH2-CH3), 37.3 (CH2), 29.3 (-CH2-CH2-CH2-
CH3), 26.8, 20.2 (CH2), 19.9 (-CH2-CH2-CH2-CH3), 13.6 (-CH2-CH2-CH2-
CH3).
1′-Ethylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2b)
Yield: 101.5 mg (83%); colorless microcrystals (from EtOH/hexane);
mp 64–66 °C; Rf = 0.31 (EtOAc/hexane, 3:7).
IR (CHCl3): 1694 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.31–7.27 (m, 2 H, arom H), 7.08 (t, J =
7.5 Hz, 1 H, arom H), 6.86 (d, J = 7.5 Hz, 1 H, arom H), 3.74 (q, J = 7.3
Hz, 2 H, -CH2-CH3), 3.06 (ddd, J = 16.5, 10.5, 6.0 Hz, 1 H, H-CH), 2.85
(dt, J = 14.0, 5.3 Hz, 1 H, H-CH), 2.49–2.39 (m, 1 H, H-CH), 2.25–2.21
(m, 1 H, H-CH), 2.19–2.17 (m, 1 H, H-CH), 2.11–2.15 (m, 1 H, H-CH),
2.02–1.93 (m, 1 H, H-CH), 1.89–1.82 (m, 1 H, H-CH), 1.24 (t, J = 7.25
Hz, 3 H, -CH2-CH3).
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C17H22NO2:
272.1651; found 272.1654.
13C NMR (125 MHz, CDCl3):  = 205.1 (C=O), 173.7 (-N-C=O), 142.2 (C-
7′a), 129.6 (C-3′a), 128.4, 124.6, 122.3, 108.4 (arom C), 63.4 (C-1),
39.6, 37.2 (CH2), 34.8 (-CH2-CH3), 26.8, 20.2 (CH2), 12.5 (-CH2-CH3).
1′,5′-Dimethylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2f)
+
H]+ calcd for C15H18NO2:
Yield: 102.5 mg (84%); colorless microcrystals (from EtOH/hexane);
mp 125–127 °C; Rf = 0.37 (EtOAc/hexane, 2:8).
FAB HRMS (acetone/NBA): m/z [M
244.1338; found: 244.1331.
IR (CHCl3): 1690 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.12–7.10 (m, 2 H, arom H), 6.73 (d, J =
8.0 Hz, 1 H, arom H), 3.18 (s, 3 H, =N-Me), 3.07 (ddd, J = 16.0, 11.0, 6.0
Hz, 1 H, H-CH), 2.59 (dt, J = 14.0, 5.0 Hz, 1 H, H-CH), 2.44–2.40 (m, 1 H,
H-CH), 2.36 (s, 3 H, Me), 2.25–2.27 (m, 2 H, H-CH), 2.08 (ddd, J = 13.5,
10.5, 4.0 Hz, 1 H, H-CH), 2.01–1.93 (m, 1 H, H-CH), 1.89–1.82 (m, 1 H,
H-CH).
13C NMR (125 MHz, CDCl3):  = 205.3 (C=O), 174.1 (-N-C=O), 140.8 (C-
7′a), 132.1 (C-5′), 129.4 (C-3′a), 128.9, 125.4, 108.1 (arom CH), 63.7
(C-1), 39.8, 37.3, 26.9 (CH2), 26.4 (=N-Me), 21.2 (Me), 20.3 (CH2).
1′-Propylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2c)
Yield: 109.1 mg (90%); colorless microcrystals (from EtOH/hexane);
mp 51–53 °C; Rf = 0.34 (EtOAc/hexane, 3:7).
IR (CHCl3): 1694 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.30–7.27 (m, 2 H, arom H), 7.08 (t, J =
7.8 Hz, 1 H, arom H), 6.85 (d, J = 8.5 Hz, 1 H, arom H), 3.66 (t, J = 7.3
Hz, 2 H, -CH2-CH2-CH3), 3.06 (ddd, J = 16.0, 10.5, 5.5 Hz, 1 H, H-CH),
2.59 (dt, J = 13.5, 4.8 Hz, 1 H, H-CH), 2.46–2.38 (m, 1 H, H-CH), 2.26–
2.16 (m, 2 H, CH2), 2.12–2.07 (m, 1 H, H-CH), 2.02–1.94 (m, 1 H, H-
CH), 1.88–1.84 (m, 1 H, H-CH), 1.73–1.69 (m, 2 H, -CH2-CH2-CH3),
0.94 (t, J = 7.5 Hz, 3 H, -CH2-CH2-CH3).
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C15H18NO2:
244.1338; found: 244.1321.
13C NMR (125 MHz, CDCl3):  = 205.1 (C=O), 174.2 (-N-C=O), 142.6 (C-
7′a), 129.5 (C-3′a), 128.4, 124.6, 122.3, 108.6 (arom C), 63.4 (C-1), 41.6
(-CH2-CH2-CH3), 39.6, 37.3, 26.7 (CH2), 20.6 (-CH2-CH2-CH3), 20.2
(CH2), 11.2 (-CH2-CH2-CH3).
5′-Methoxy-1′-methylspiro[cyclohexane-1,3′-indoline]-2,2′-dione
(2g)
Yield: 111.0 mg (86%); colorless microcrystals (from EtOH/hexane);
FAB HRMS (acetone/NBA): m/z [M + H]+ calcd for C16H20NO2 258.1494;
found: 258.1489.
mp 111–113 °C; Rf = 0.38 (EtOAc/hexane, 2:8).
IR (CHCl3): 1684 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 6.89 (d, J = 2.4 Hz, 1 H, arom H), 6.83
(dd, J = 8.5, 2.4 Hz, 1 H, arom H), 6.74 (d, J = 8.5 Hz, 1 H, arom H), 3.80
(s, 3 H, MeO), 3.17 (s, 3 H, =N-Me), 3.08 (ddd, J = 16.0, 11.0, 6.0 Hz, 1
H, H-CH), 2.57 (dt, J = 14.0, 5.0 Hz, 1 H, H-CH), 2.49–2.40 (m, 1 H, H-
CH), 2.25–2.17 (m, 2 H, CH2), 2.08 (ddd, J = 14.5, 11.0, 4.0 Hz, 1 H, H-
CH), 2.01–1.92 (m, 1 H, H-CH), 1.87–1.81 (m, 1 H, H-CH).
13C NMR (125 MHz, CDCl3):  = 205.1 (C=O), 173.8 (-N-C=O), 155.9 (C-
5′), 136.7 (C-7′a), 130.6 (C-3′a), 112.6, 112.3, 108.6 (arom CH), 64.0
(C-1), 55.8 (MeO), 39.7, 37.5, 26.9 (CH2), 26.5 (=N-Me), 20.3 (CH2).
1′-Isopropylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2d)
Yield: 88.5 mg (69%); yellow oil; Rf = 0.28 (EtOAc/hexane, 3:7).
IR (CHCl3): 1692 C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.28–7.26 (m, 2 H, arom H), 7.07 (t, J =
7.8 Hz, 1 H, arom H), 7.01 (d, J = 8.5 Hz, 1 H, arom H), 4.60 (hept, J =
6.9 Hz, 1 H, -CH-(CH3)2), 3.11–3.05 (m, 1 H, H-CH), 2.60–2.55 (m, 1 H,
H-CH), 2.47–2.40 (m, 1 H, H-CH), 2.22–2.17 (m, 2 H, CH2), 2.11–2.05
(m, 1 H, H-CH), 1.99–1.92 (m, 1 H, H-CH), 1.86–1.82 (m, 1 H, H-CH),
1.47 (d, J = 7.0 Hz, 6 H, -CH-(CH3)2).
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C15H18NO3:
260.1287; found: 260.1296.
13C NMR (125 MHz, CDCl3):  = 205.2 (C=O), 173.8 (-N-C=O), 141.8 (C-
7′a), 129.9 (C-3′a), 128.2, 124.7, 122.0, 109.9 (arom C), 63.2 (C-1), 43.9
(-CH-(CH3)2), 39.7, 37.5, 26.8, 20.2 (CH2), 19.3 (-CH-(CH3)2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

F
S. Katayama, H. Nishino
Paper
Synthesis
5′-Chloro-1′-methylspiro[cyclohexane-1,3′-indoline]-2,2′-dione
(2h)
1H NMR (500 MHz, CDCl3):  = 7.04 (t, J = 7.9 Hz, 1 H, arom H), 6.88 (s,
1 H, arom H), 6.88 (d, J = 8.0 Hz, 1 H, arom H), 3.84 (s, 3 H, MeO), 3.46
(s, 3 H, =N-Me), 3.10 (ddd, J = 16.5, 11.0, 6.0 Hz, 1 H, H-CH), 2.56 (dt,
J = 13.5, 4.8 Hz, 1 H, H-CH), 2.50–2.41 (m, 1 H, H-CH), 2.23–2.19 (m, 2
H, CH2), 2.07 (ddd, J = 14.0, 10.0, 4.0 Hz, 1 H, H-CH), 1.98–1.89 (m, 1 H,
H-CH), 1.85–1.80 (m, 1 H, H-CH).
13C NMR (125 MHz, CDCl3):  = 205.4 (C=O), 174.2 (-N-C=O), 145.3 (C-
7′a), 131.1 (C-3′a), 130.9 (C-7′), 123.1, 117.2, 112.4 (arom CH), 63.6
(C-1), 55.9 (MeO), 39.6, 37.6 (CH2), 29.7 (=N-Me), 26.8, 20.1 (CH2).
Yield: 58.4 mg (75%); colorless microcrystals (from EtOH/hexane); mp
89–91 °C; Rf = 0.34 (EtOAc/hexane, 2:8).
IR (CHCl3): 1694 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.29 (dd, J = 8.3, 2.0 Hz, 1 H, arom H),
7.25 (d, J = 2.0 Hz, 1 H, arom H), 6.76 (d, J = 8.3 Hz, 1 H, arom H), 3.18
(s, 3 H, =N-Me), 3.10 (ddd, J = 16.5, 11.5, 6.0 Hz, 1 H, H-CH), 2.57 (dt,
J = 14.0, 5.0 Hz, 1 H, H-CH), 2.50–2.42 (m, 1 H, H-CH), 2.25–2.19 (m, 2
H, CH2), 2.08 (ddd, J = 15.0, 11.5, 4.0 Hz, 1 H, H-CH), 2.00–1.91 (m, 1 H,
H-CH), 1.86–1.80 (m, 1 H, H-CH).
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C15H18NO3:
260.1287; found: 260.1277.
13C NMR (125 MHz, CDCl3):  = 204.4 (C=O), 173.6 (-N-C=O), 141.7 (C-
7′a), 130.9 (C-3′a), 128.5 (arom CH), 128.0 (C-5′), 125.2, 109.2 (arom
CH), 63.7 (C-1), 39.6, 37.5, 26.9 (CH2), 26.6 (=N-Me), 20.1 (CH2).
FAB HRMS (acetone/NBA): m/z [M + H]+ calcd for C14H15ClNO2:
264.0791; found: 264.0784.
7′-Chloro-1′-methylspiro[cyclohexane-1,3′-indoline]-2,2′-dione
(2l)
Yield: 72.8 mg (93%); yellow oil; Rf = 0.35 (EtOAc/hexane, 2:8).
IR (neat): 1699 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.23 (dd, J = 8.2, 1.1 Hz, 1 H, arom H),
7.12 (dd, J = 7.4, 1.1 Hz, 1 H, arom H), 7.01 (t, J = 7.5 Hz, 1 H, arom H),
3.56 (s, 3 H, =N-Me), 3.13 (ddd, J = 18.0, 12.5, 6.0 Hz, 1 H, H-CH), 2.55
(dt, J = 13.5, 4.3 Hz, 1 H, H-CH), 2.52–2.45 (m, 1 H, H-CH), 2.25–2.18
(m, 2 H, CH2), 2.08 (ddd, J = 15.5, 11.5, 4.0 Hz, 1 H, H-CH), 1.97–1.88
(m, 1 H, H-CH), 1.84–1.78 (m, 1 H, H-CH).
13C NMR (125 MHz, CDCl3):  = 204.5 (C=O), 174.1 (-N-C=O), 139.0 (C-
7′a), 131.9 (C-3′a), 130.8, 123.4, 123.2 (arom CH), 115.5 (C-7′), 63.2
(C-1), 39.5, 37.9 (CH2), 29.8 (=N-Me), 26.9, 20.0 (CH2).
5′-Fluoro-1′-methylspiro[cyclohexane-1,3′-indoline]-2,2′-dione
(2i)
Yield: 66.4 mg (90%); colorless microcrystals (from EtOH/hexane); mp
76–78 °C; Rf = 0.27 (EtOAc/hexane, 2:8).
IR (CHCl3): 1697 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.04–6.99 (m, 2 H, arom H), 6.77–6.75
(m, 1 H, arom H), 3.18 (s, 3 H, =N-Me), 3.12 (ddd, J = 17.0, 11.5, 5.5 Hz,
1 H, H-CH), 2.56 (dt, J = 13.5, 4.5 Hz, 1 H, H-CH), 2.52–2.43 (m, 1 H, H-
CH), 2.25–2.19 (m, 2 H, CH2), 2.08 (ddd, J = 15.5, 11.5, 4.0 Hz, 1 H, H-
CH), 2.00–1.91 (m, 1 H, H-CH), 1.85–1.79 (m, 1 H, H-CH).
FAB HRMS (acetone/NBA): m/z [M + H]+ calcd for C14H15ClNO2:
264.0791; found: 264.0777.
13C NMR (125 MHz, CDCl3):  = 204.5 (C=O), 173.7 (-N-C=O), 159.0 (d,
J = 239 Hz, C-5′), 139.0 (d, J = 3 Hz, C-7′a), 130.7 (d, J = 9 Hz, C-3′a),
114.7 (d, J = 23 Hz, C-6′), 112.8 (d, J = 23 Hz, C-4′), 108.6 (d, J = 9 Hz, C-
7′), 63.8 (d, J = 1 Hz, C-1), 39.5, 37.5, 26.9 (CH2), 26.5 (=N-Me), 20.0
(CH2).
FAB HRMS (acetone/NBA): m/z [M + H]+ calcd for C14H15FNO2:
248.1087; found: 248.1091.
1′,6′-Dimethylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2m)
Yield: 45.0 mg (61%); colorless microcrystals (from EtOH/hexane); mp
168–170 °C; Rf = (EtOAc/hexane, 2:8).
IR (neat): 1688 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.18 (d, J = 7.5 Hz, 1 H, arom H), 6.91
(d, J = 7.5 Hz, 1 H, arom H), 6.67 (s, 1 H, arom H), 3.17 (s, 3 H, =N-Me),
3.02 (ddd, J = 15.5, 9.5, 5.0 Hz, 1 H, H-CH), 2.59 (dt, J = 13.5, 5.3 Hz, 1
H, H-CH), 2.44–2.34 (m, 1 H, H-CH), 2.38 (s, 3 H, Me), 2.26–2.21 (m, 1
H, H-CH), 2.19–2.15 (m, 1 H, H-CH), 2.07 (ddd, J = 13.5, 9.5, 3.5 Hz, 1
H, H-CH), 2.02–1.94 (m, 1 H, H-CH), 1.89–1.83 (m, 1 H, H-CH).
1′,7′-Dimethylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2j)
Yield: 117.0 mg (96%); colorless microcrystals (from EtOH/hexane);
mp 128–130 °C; Rf = 0.33 (EtOAc/hexane, 2:8).
13C NMR (125 MHz, CDCl3):  = 205.3 (C=O), 174.5 (-N-C=O), 143.2 (C-
7′a), 138.8 (C-6′), 126.4 (C-3′a), 124.2, 123.1, 109.3 (arom C), 63.4 (C-
1), 39.6, 37.1, 26.8 (CH2), 26.3 (=N-Me), 21.7 (Me), 20.3 (CH2).
IR (CHCl3): 1684 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.09 (d, J = 7.2 Hz, 1 H, arom H), 7.03
(d, J = 7.6 Hz, 1 H, arom H), 6.99 (t, J = 7.6 Hz, 1 H, arom H), 3.47 (s, 3
H, =N-Me), 3.08 (ddd, J = 16.5, 11.5, 5.5 Hz, 1 H, H-CH), 2.59–2.57 (m,
1 H, H-CH), 2.56 (s, 3 H, Me), 2.48–2.41 (m, 1 H, H-CH), 2.21–2.18 (m,
2 H, CH2), 2.07 (ddd, J = 14.0, 10.5, 4.0 Hz, 1 H, H-CH), 1.99–1.90 (m, 1
H, H-CH), 1.86–1.81 (m, 1 H, H-CH).
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C15H18NO2:
244.1338; found: 244.1320.
1′,4′-Dimethylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2m′)
13C NMR (125 MHz, CDCl3):  = 205.4 (C=O), 174.8 (-N-C=O), 140.9 (C-
7′a), 132.3 (arom CH), 130.0 (C-3′a), 122.5 (2 C, arom CH), 119.9 (C-
7′), 63.0 (C-1), 39.7, 37.7 (CH2), 29.8 (=N-Me), 26.9, 20.3 (CH2), 19.1
(Me).
Yield: 22.6 mg (31%); colorless microcrystals (from EtOH/hexane); mp
81–83 °C; Rf = (EtOAc/hexane, 2:8).
IR (neat): 1695 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.21 (t, J = 8.0 Hz, 1 H, arom H), 6.90 (d,
J = 8.0 Hz, 1 H, arom H), 6.67 (d, J = 8.0 Hz, 1 H, arom H), 3.20–3.13 (m,
1 H, H-CH), 3.16 (s, 3 H, =N-Me), 2.64–2.55 (m, 2 H, CH2), 2.40 (dt, J =
14.0, 4.0 Hz, 1 H, H-CH), 2.28–2.23 (m, 1 H, H-CH), 2.22 (s, 3 H, Me),
2.05 (d, J = 14.0 Hz, 1 H, H-CH), 1.89–1.82 (m, 1 H, H-CH), 1.79–1.76
(m, 1 H, H-CH).
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C15H18NO2:
244.1338; found: 244.1326.
7′-Methoxy-1′-methylspiro[cyclohexane-1,3′-indoline]-2,2′-dione
(2k)
13C NMR (125 MHz, CDCl3):  = 204.5 (C=O), 173.6 (-N-C=O), 143.3 (C-
7′a), 135.0 (C-4′), 128.5 (arom C), 127.7 (C-3′a), 125.4, 105.9 (arom C),
63.5 (C-1), 40.3, 34.8 (CH2), 26.5 (=N-Me), 26.3, 20.0 (CH2), 19.2 (Me).
Yield: 68.7 mg (88%); colorless microcrystals (from EtOH/hexane); mp
94–96 °C; Rf = 0.33 (EtOAc/hexane, 2:8).
IR (CHCl3): 1684 (C=O) cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

G
S. Katayama, H. Nishino
Paper
Synthesis
FAB HRMS (acetone/NBA): m/z [M
244.1338; found: 244.1333.
+
H]+ calcd for C15H18NO2:
1H NMR (500 MHz, CDCl3):  = 7.28 (t, J = 7.0 Hz, 1 H, arom H), 7.09 (d,
J = 7.0 Hz, 1 H, arom H), 7.03 (t, J = 7.5 Hz, 1 H, arom H), 6.87 (d, 1 H,
J = 8.0 Hz, arom H), 3.74 (q, J = 7.3 Hz, 2 H, -CH2-CH3), 2.70–2.59 (m, 2
H, CH2), 2.55–2.46 (m, 2 H, CH2), 2.36 (dt, J = 14.0, 7.0 Hz, 1 H, H-CH),
2.26–2.17 (m, 1 H, H-CH), 1.26 (t, J = 7.3 Hz, 3 H, -CH2-CH3).
13C NMR (125 MHz, CDCl3):  = 212.6 (C=O), 174.6 (-N-C=O), 143.4 (C-
7′a), 130.5 (C-3′a), 128.5, 122.6, 122.5, 108.5 (arom C), 62.8 (C-1), 38.2
(CH2), 34.9 (-CH2-CH3), 34.0, 20.1 (CH2), 12.5 (-CH2-CH3).
1′,6′,7′-Trimethylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2n)
Yield: 74.2 mg (95%); colorless microcrystals (from EtOH/hexane); mp
132–134 °C; Rf = 0.37 (EtOAc/hexane, 2:8).
IR (CHCl3): 1684 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 6.99 (d, J = 7.5 Hz, 1 H, arom H), 6.92
(d, J = 7.5 Hz, 1 H, arom H), 3.49 (s, 3 H, =N-Me), 3.07 (ddd, J = 16.5,
11.0, 5.5 Hz, 1 H, H-CH), 2.56 (dt, J = 14.5, 5.0 Hz, 1 H, H-CH), 2.47 (s, 3
H, Me-C-7′), 2.45–2.38 (m, 1 H, H-CH), 2.30 (s, 3 H, Me-C-6′), 2.21–
2.17 (m, 2 H, CH2), 2.11–2.02 (m, 1 H, H-CH), 1.98–1.89 (m, 1 H, H-
CH), 1.86–1.79 (m, 1 H, H-CH).
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C14H16NO2:
230.1181; found: 230.1185.
1′-Propylspiro[cyclopentane-1,3′-indoline]-2,2′-dione (2r)
Yield: 76.0 mg (quant.); colorless microcrystals (from EtOH/hexane);
mp 69–71 °C; Rf = 0.32 (EtOAc/hexane, 2:8).
13C NMR (125 MHz, CDCl3):  = 205.5 (C=O), 175.2 (-N-C=O), 141.2 (C-
7′a), 138.4 (C-6′), 127.9 (C-3′a), 124.2, 121.7 (arom C), 119.1 (C-7′),
62.7 (C-1), 39.6, 37.6 (CH2), 30.6 (=N-Me), 26.8 (CH2), 20.8 (Me-C-7′a),
20.3 (CH2), 14.1 (Me-C-6′a).
IR (neat): 1748 (-C=O), 1695 (-N-C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.27 (t, J = 4.0 Hz, 1 H, arom H), 7.08 (d,
J = 7.5 Hz, 1 H, arom H), 7.03 (t, J = 7.8 Hz, 1 H, arom H), 6.86 (d, J = 8.0
Hz, 1 H, arom H), 3.72–3.60 (m, 2 H, -CH2-CH2-CH3), 2.70–2.60 (m, 2
H, CH2), 2.55–2.47 (m, 2 H, CH2), 2.36 (dt, J = 13.0, 7.0 Hz, 1 H, H-CH),
2.25–2.19 (m, 1 H, H-CH), 1.74–1.69 (m, 2 H, -CH2-CH2-CH3), 0.95 (t,
J = 7.3 Hz, 3 H, -N-CH2-CH2-CH3).
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C16H20NO2:
258.1494; found: 258.1505.
1′,4′,6′-Trimethylspiro[cyclohexane-1,3′-indoline]-2,2′-dione (2o)
13C NMR (125 MHz, CDCl3):  = 212.7 (C=O), 175.1 (-N-C=O), 143.8 (C-
7′a), 130.5 (C-3′a), 128.5, 122.54, 122.49, 108.6 (arom C), 62.8 (C-1),
41.6 (-CH2-CH2-CH3), 38.2, 34.0 (CH2), 20.6 (-CH2-CH2-CH3), 20.1
(CH2), 11.1 (-CH2-CH2-CH3).
Yield: 68.4 mg (88%); colorless microcrystals (from EtOH/hexane); mp
164–166 °C; Rf = 0.31 (EtOAc/hexane, 1:9).
IR (CHCl3): 1686 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 6.72 (s, 1 H, arom H), 6.49 (s, 1 H, arom
H), 3.19–3.15 (m, 1 H, H-CH), 3.13 (s, 3 H, =N-Me), 2.64–2.54 (m, 2 H,
CH2), 2.38 (dt, J = 13.8, 4.5 Hz, 1 H, H-CH), 2.33 (s, 3 H, Me-C-6′), 2.27–
2.22 (m, 1 H, H-CH), 2.17 (s, 3 H, Me-C-4′), 2.05–2.01 (m, 1 H, H-CH),
1.87–1.79 (m, 1 H, H-CH), 1.78–1.74 (m, 1 H, H-CH).
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C15H18NO2:
244.1338; found: 244.1322.
1′-Isopropylspiro[cyclopentane-1,3′-indoline]-2,2′-dione (2s)
Yield: 71.1 mg (98%); colorless microcrystals (from EtOH/hexane); mp
61–63 °C; Rf = 0.36 (EtOAc/hexane, 2:8).
13C NMR (125 MHz, CDCl3):  = 204.6 (C=O), 173.8 (-N-C=O), 143.4 (C-
7′a), 138.6 (C-6′), 134.6 (C-4′), 125.9 (arom C), 124.7 (C-3′a), 125.9 (ar-
om C), 63.3 (C-1), 40.3, 34.8, 26.4 (CH2), 26.3 (=N-Me), 21.5 (Me-C-6′),
20.0 (CH2), 19.0 (Me-C-4′).
FAB HRMS (acetone/NBA): m/z [M + Na]+ calcd for C16H19NO2Na:
280.1313; found: 280.1315.
IR (neat): 1749 (-C=O), 1694 (-N-C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.26 (t, J = 7.8 Hz, 1 H, arom H), 7.08 (d,
J = 6.0 Hz, 1 H, arom H), 7.03–7.00 (m, 2 H, arom H), 4.56 (hept, J = 7.3
Hz, 1 H, -CH-(CH3)2), 2.69–2.59 (m, 2 H, CH2), 2.54–2.46 (m, 2 H, CH2),
2.35 (dt, J = 14.0, 7.0 Hz, 1 H, H-CH), 2.24–2.16 (m, 1 H, H-CH), 1.48 (d,
J = 7.3, 6 H, -CH-(CH3)2).
1′-Methylspiro[cyclopentane-1,3′-indoline]-2,2′-dione (2p)
13C NMR (125 MHz, CDCl3):  = 212.6 (C=O), 174.8 (-N-C=O), 143.1 (C-
7′a), 130.8 (C-3′a), 128.3, 122.6, 122.2, 109.9 (arom C), 62.7 (C-1), 41.2
(-CH-(CH3)2), 38.2, 34.0, 20.1 (CH2), 19.4, 19.2 (-CH-(CH3)2).
Yield: 54.4 mg (84%); colorless microcrystals (from EtOH/hexane); mp
123–125 °C; Rf = 0.28 (EtOAc/hexane, 2:8).
IR (neat): 1742 (-C=O), 1694 (-N-C=O) cm–1
.
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C15H18NO2:
1H NMR (500 MHz, CDCl3):  = 7.21 (dd, J = 15.5, 8.0 Hz, 1 H, arom H),
7.02–6.95 (m, 2 H, arom H), 6.77 (d, J = 7.5 Hz, 1 H, arom H), 3.12 (s, 3
H, =N-Me), 2.62–2.52 (m, 2 H, CH2), 2.49–2.39 (m, 2 H, CH2), 2.29 (dt,
J = 13.0, 7.5 Hz, 1 H, H-CH), 2.17–2.12 (m, 1 H, H-CH).
244.1338; found: 244.1326.
1′-Butylspiro[cyclopentane-1,3′-indoline]-2,2′-dione (2t)
Yield: 75.0 mg (97%); colorless microcrystals (from EtOH/hexane); mp
42–44 °C; Rf = 0.37 (EtOAc/hexane, 2:8).
13C NMR (125 MHz, CDCl3):  = 212.7 (C=O), 175.0 (-N-C=O), 144.2 (C-
7′a), 130.2 (C-3′a), 128.6, 122.8, 122.3, 108.4 (arom C), 62.8 (C-1),
38.2, 34.0 (CH2), 26.4 (=N-Me), 20.1 (CH2).
IR (neat): 1748 (-C=O), 1697 (-N-C=O) cm–1
.
FAB HRMS (acetone/NBA): m/z [M
216.1025; found: 216.1005.
+
H]+ calcd for C13H14NO2:
1H NMR (500 MHz, CDCl3):  = 7.28 (t, J = 7.8 Hz, 1 H, arom H), 7.08 (d,
J = 7.5 Hz, 1 H, arom H), 7.03 (t, J = 7.8 Hz, 1 H, arom H), 6.87 (d, J = 8.0
Hz, 1 H, arom H), 3.75–3.63 (m, 2 H, -CH2-CH2-CH2-CH3), 2.69–2.60
(m, 2 H, CH2), 2.55–2.47 (m, 2 H, CH2), 2.36 (dt, J = 13.5, 7.0 Hz, 1 H, H-
CH), 2.25–2.18 (m, 1 H, H-CH), 1.70–1.62 (m, 2 H, -CH2-CH2-CH2-CH3),
1.42–1.34 (m, 2 H, -CH2-CH2-CH2-CH3), 0.94 (t, J = 7.5 Hz, 3 H, -CH2-
CH2-CH2-CH3).
13C NMR (125 MHz, CDCl3):  = 212.7 (C=O), 175.0 (-N-C=O), 143.7 (C-
7′a), 130.5 (C-3′a), 128.5, 122.52, 122.47, 108.6 (arom C), 62.8 (C-1),
39.8 (-CH2-CH2-CH2-CH3), 38.2, 34.0 (CH2), 29.3 (-CH2-CH2-CH2-CH3),
20.1 (CH2), 19.9 (-CH2-CH2-CH2-CH3), 13.6 (-CH2-CH2-CH2-CH3).
1′-Ethylspiro[cyclopentane-1,3′-indoline]-2,2′-dione (2q)
Yield: 69.9 mg (quant.); colorless microcrystals (from EtOH/hexane);
mp 72–74 °C; Rf = 0.28 (EtOAc/hexane, 2:8).
IR (neat): 1747 (-C=O), 1695 (-N-C=O) cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

H
S. Katayama, H. Nishino
Paper
Synthesis
FAB HRMS (acetone/NBA): m/z [M
258.1494; found: 258.1474.
+
H]+ calcd for C16H20NO2:
CH), 2.55 (s, 3 H, Me), 2.28 (dd, J = 14.5, 9.0 Hz, 1 H, H-CH), 2.18–2.12
(m, 1 H, H-CH), 2.00 (dd, J = 14.5, 9.5 Hz, 1 H, H-CH), 1.88–1.76 (m, 5
H, H-CH-CH2-CH2).
13C NMR (125 MHz, CDCl3):  = 207.6 (C=O), 176.0 (-N-C=O), 141.1 (C-
7′a), 132.3 (arom C), 131.1 (C-3′a), 122.4, 121.2 (arom C), 120.0 (C-7′),
64.7 (C-1), 42.3, 35.0, 30.8 (CH2), 29.7 (=N-Me), 26.6, 25.2 (CH2), 19.0
(Me).
1′-Methylspiro[cycloheptane-1,3′-indoline]-2,2′-dione (2u)
Yield: 65.6 mg (90%); colorless microcrystals (from EtOH/hexane); mp
113–115 °C (Lit.16 104–107 °C); Rf = 0.32 (EtOAc/hexane, 2:8).
IR (neat): 1709 (-C=O), 1683 (-N-C=O) cm–1
.
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C16H20NO2:
1H NMR (500 MHz, CDCl3):  = 7.30 (t, J = 7.8 Hz, 1 H, arom H), 7.26 (d,
J = 7.5 Hz, 1 H, arom H), 7.07 (t, J = 7.3 Hz, 1 H, arom H), 6.85 (d, J = 8.0
Hz, 1 H, arom H), 3.19 (s, 3 H, =N-Me), 3.06 (t, J = 10.5 Hz, 1 H, H-CH),
2.73 (t, J = 9.3 Hz, 1 H, H-CH), 2.32 (dd, J = 14.0, 9.0 Hz, 1 H, H-CH),
2.16–2.12 (m, 1 H, H-CH), 2.02 (dd, J = 14.5, 9.5 Hz, 1 H, H-CH), 1.92–
1.87 (m, 1 H, H-CH), 1.83–1.78 (m, 4 H, -CH2-CH2).
258.1494; found: 258.1473.
7′-Chloro-1′-methylspiro[cycloheptane-1,3′-indoline]-2,2′-dione
(2y)
Yield: 62.4 mg (74%); colorless microcrystals (from EtOH/hexane); mp
116–118 °C; Rf = 0.43 (EtOAc/hexane, 2:8).
IR (neat): 1726 (-C=O), 1688 (-N-C=O) cm–1
13C NMR (125 MHz, CDCl3):  = 207.4 (C=O), 175.1 (-N-C=O), 143.3 (C-
7′a), 130.6 (C-3′a), 128.5, 123.4, 122.5, 108.4 (arom C), 65.3 (C-1),
42.1, 34.6, 30.7, 26.6 (CH2), 26.3 (=N-Me), 25.2 (CH2).
.
1H NMR (500 MHz, CDCl3):  = 7.22 (t, J = 8.0 Hz, 1 H, arom H), 7.13 (d,
J = 7.0 Hz, 1 H, arom H), 6.98 (t, J = 8.0 Hz, 1 H, arom H), 3.56 (s, 3 H,
=N-Me), 3.09 (t, J = 10.5 Hz, 1 H, H-CH), 2.69 (t, J = 10.0 Hz, 1 H, H-CH),
2.31 (dd, J = 14.5, 9.5 Hz, 1 H, H-CH), 2.17–2.11 (m, 1 H, H-CH), 2.00
(dd, J = 15.0, 9.0 Hz, 1 H, H-CH), 1.93–1.88 (m, 1 H, H-CH), 1.84–1.74
(m, 4 H, -CH2-CH2).
13C NMR (125 MHz, CDCl3):  = 206.8 (C=O), 175.2 (-N-C=O), 139.2 (C-
7′a), 133.3 (C-3′a), 130.8, 123.3, 122.1 (arom C), 115.7 (C-7′), 65.0 (C-
1), 42.1, 35.0, 30.7 (CH2), 29.8 (=N-Me), 26.6, 25.2 (CH2).
1′,5′-Dimethylspiro[cycloheptane-1,3′-indoline]-2,2′-dione (2v)
Yield: 65.9 mg (86%); colorless microcrystals (from EtOH/hexane); mp
112–114 °C; Rf = 0.24 (EtOAc/hexane, 2:8).
IR (neat): 1707 (-C=O), 1690 (-N-C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.10 (d, J = 7.5 Hz, 1 H, arom H), 7.08 (s,
1 H, arom H), 6.73 (d, J = 8.0 Hz, 1 H, arom H), 3.17 (s, 3 H, =N-Me),
3.07 (t, J = 10.8 Hz, 1 H, H-CH), 2.72 (t, J = 9.8 Hz, 1 H, H-CH), 2.35 (s, 3
H, Me), 2.32–2.23 (m, 1 H, H-CH), 2.17–2.12 (m, 1 H, H-CH), 2.04–1.98
(m, 1 H, H-CH), 1.93–1.88 (m, 1 H, H-CH), 1.84–1.77 (m, 4 H, -CH2-
CH2).
FAB HRMS (acetone/NBA): m/z [M + H]+ calcd for C15H17ClNO2:
278.0948; found: 278.0939.
13C NMR (125 MHz, CDCl3):  = 207.6 (C=O), 175.1 (-N-C=O), 140.9 (C-
7′a), 132.1 (C-3′a), 130.7 (C-5′), 128.8, 124.3, 108.1 (arom C), 65.5 (C-
1), 42.2, 34.7, 30.8, 26.6 (CH2), 26.4 (=N-Me), 25.3 (CH2), 21.1 (Me).
2-Hydroxy-1′-methylspiro[cyclohexane-1,3′-indoline]-2′-one (3)
and (3′)
The spiroindolinone 2a (69 mg, 0.3 mmol) and NaBH4 (14 mg, 0.3
mmol) were dissolved in EtOH (5 mL) and the mixture was stirred at
room temperature for 10 min. After removal of the solvent, H2O (10
mL) was added and the aqueous mixture was extracted with CHCl3
(3 × 10 mL). The combined extracts were washed with a saturated
aqueous solution of NaHCO3 and H2O, dried over anhydrous MgSO4,
then concentrated to dryness. The obtained residue was separated by
silica gel column chromatography eluting with EtOAc/hexane (1:1
v/v), affording the corresponding alcohol 3 and the diastereomer 3′.
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C16H20NO2:
258.1494; found: 258.1487.
5′-Chloro-1′-methylspiro[cycloheptane-1,3′-indoline]-2,2′-dione
(2w)
Yield: 64.9 mg (78%); colorless microcrystals (from EtOH/hexane); mp
125–127 °C; Rf = 0.31 (EtOAc/hexane, 2:8).
IR (neat): 1713 (-C=O), 1688 (-N-C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.27 (d, J = 8.0 Hz, 1 H, arom H), 7.24 (s,
1 H, arom H), 6.77 (d, J = 8.0 Hz, 1 H, arom H), 3.18 (s, 3 H, =N-Me),
3.12 (t, J = 10.8 Hz, 1 H, H-CH), 2.67 (t, J = 9.3 Hz, 1 H, H-CH), 2.33 (dd,
J = 14.5, 10.0 Hz, 1 H, H-CH), 2.18–2.12 (m, 1 H, H-CH), 2.00 (dd, J =
15.0, 9.0 Hz, 1 H, H-CH), 1.96–1.90 (m, 1 H, H-CH), 1.86–1.72 (m, 4 H,
-CH2-CH2).
13C NMR (125 MHz, CDCl3):  = 206.7 (C=O), 174.4 (-N-C=O), 141.9 (C-
7′a), 132.3 (C-3′a), 128.4 (arom C), 127.9 (C-5′), 124.2, 109.3 (arom C),
65.6 (C-1), 42.1, 34.7, 30.7, 26.6 (CH2), 26.5 (=N-Me), 25.3 (CH2).Cl
Compound 3
Yield: 21.0 mg (31%); colorless microcrystals (from EtOH/hexane); mp
145–146 °C; Rf = 0.31 (EtOAc/hexane, 5:5).
IR (neat): 3435 (OH), 1690 (-C=O) cm–1
1H NMR (500 MHz, CDCl3):  = 7.36 (d, J = 7.0 Hz, 1 H, arom H), 7.32–
7.29 (t, J = 7.8 Hz, 1 H, arom H), 7.09 (t, J = 6.5 Hz, 1 H, arom H), 6.86
(d, J = 8.0 Hz, 1 H, arom H), 3.85–3.84 (m, 1 H, H-C-OH), 3.21 (s, 3 H,
=N-Me), 2.78 (s, 1 H, -OH), 2.24–2.17 (m, 1 H, H-CH), 2.02–1.96 (m, 3
H, H-CH/CH2), 1.93–1.87 (m, 1 H, H-CH), 1.69–1.62 (m, 1 H, H-CH),
1.60–1.50 (m, 2 H, H-CH).
.
FAB HRMS (acetone/NBA): m/z [M + H]+ calcd for C15H17ClNO2:
278.0948; found: 278.0940.
13C NMR (125 MHz, CDCl3):  = 179.1 (-N-C=O), 143.7 (C-7′a), 132.4
(C-3′a), 128.1, 123.3, 122.3, 108.0 (arom C), 72.3 (C-2), 52.3 (C-1),
31.4, 28.5 (CH2), 26.0 (=N-Me), 22.1, 20.0 (CH2).
1′,7′-Dimethylspiro[cycloheptane-1,3′-indoline]-2,2′-dione (2x)
Yield: 71.8 mg (93%); colorless microcrystals (from EtOH/hexane); mp
119–121 °C; Rf = 0.32 (EtOAc/hexane, 2:8).
FAB HRMS (acetone/NBA): m/z [M
231.1259; found: 231.1258.
+
H]+ calcd for C14H17NO2:
IR (neat): 1713 (-C=O), 1686 (-N-C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.10 (d, J = 7.0 Hz, 1 H, arom H), 7.02
(d, J = 8.0 Hz, 1 H, arom H), 6.94 (t, J = 7.5 Hz, 1 H, arom H), 3.48 (s, 3
H, =N-Me), 3.02 (t, J = 10.3 Hz, 1 H, H-CH), 2.73 (t, J = 10.3 Hz, 1 H, H-
Compound 3′
Yield: 27.8 mg (40%); colorless microcrystals (from EtOH/hexane); mp
153–156 °C; Rf = 0.19 (EtOAc/hexane, 5:5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

I
S. Katayama, H. Nishino
Paper
Synthesis
IR (neat): 3431 (-OH), 1682 (-C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.37 (d, J = 7.5 Hz, 1 H, arom H), 7.32 (t,
J = 7.8 Hz, 1 H, arom H), 7.09 (t, J = 7.5 Hz, 1 H, arom H), 6.81 (d, J = 8.0
Hz, 1 H, arom H), 3.86 (m, 1 H, H-CH), 3.18 (s, 3 H, =N-Me), 2.86 (dd,
J = 15.0, 6.5 Hz, 1 H, H-CH), 2.36–2.30 (m, 1 H, H-CH), 2.29–2.21 (m, 1
H, H-CH), 2.15–2.11 (m, 1 H, H-CH), 2.00–1.97 (m, 1 H, H-CH), 1.88–
1.85 (m, 1 H, H-CH), 1.76–1.68 (m, 1 H, H-CH).
13C NMR (125 MHz, CDCl3):  = 174.8 (-N-C=O), 173.3 (-C=O), 141.6
(C-7′a), 130.7 (C-3′a), 130.0, 123.4, 123.2, 108.4 (arom C), 81.5 (C-1),
37.2, 36.7 (CH2), 26.3 (=N-Me), 23.0, 22.9 (CH2).
1H NMR (500 MHz, CDCl3):  = 7.57 (d, J = 7.0 Hz, 1 H, arom H), 7.34 (t,
J = 7.8 Hz, 1 H, arom H), 7.07 (t, J = 8.0 Hz, 1 H, arom H), 6.89 (d, J = 8.0
Hz, 1 H, arom H), 4.07–4.05 (m, 1 H, H-C-OH), 3.23 (s, 3 H, =N-Me),
2.06–1.97 (m, 2 H, CH2), 1.93–1.86 (m, 1 H, H-CH), 1.84–1.78 (m, 1 H,
H-CH), 1.75–1.70 (m, 2 H, CH2), 1.64–1.58 (m, 2 H, CH2), 1.25 (s, 1 H, -
OH).
13C NMR (125 MHz, CDCl3):  = 179.5 (-N-C=O), 144.4 (C-7′a), 130.2
(C-3′a), 128.2, 125.4, 121.8, 108.2 (arom C), 73.1 (C-2), 54.9 (C-1),
32.7, 30.9 (CH2), 26.4 (=N-Me), 24.0, 20.5 (CH2).
FAB HRMS (acetone/NBA): m/z [M]+ calcd for C14H15NO3: 245.1052;
found: 245.1062.
FAB HRMS (acetone/NBA): m/z [M
+
H]+ calcd for C14H17NO2:
231.1259; found: 231.1259.
1′-Methyl-2-(2-methylhydrazineylidene)spiro[cyclohexane-1,3′-
indolin]-2′-one (6a); Typical Procedure
2-Hydroxy-1′-methyl-2-phenylspiro[cyclohexane-1,3′-indolin]-2′-
A mixture of the spiroindolinone 2a (45.9 mg, 0.2 mmol) and methyl-
hydrazine (18.4 mg, 0.4 mmol) was heated at 50 °C in MeOH/AcOH
(1:1 v/v, 4 mL) for 10 min. After removal of the solvent, H2O (10 mL)
was added and the aqueous solution was extracted with CHCl3 (3 × 10
mL). The combined extracts were washed with a saturated aqueous
solution of NaHCO3 and H2O, dried over anhydrous MgSO4, then con-
centrated to dryness. The obtained residue was separated by silica gel
column chromatography, eluting with EtOAc/hexane (1:1 v/v), to give
the corresponding methylhydrazone 6a.
one (4)
Bromobenzene (393 mg, 2.5 mmol) dissolved in dry Et2O (2 mL) was
added dropwise over 20 min to Mg turnings (61 mg, 2.5 mmol) in dry
Et2O (3 mL) in a 50 mL three-necked flask under an argon atmo-
sphere, then the mixture was heated at 50 °C for 30 min. The spiroin-
dolinone 2a (112.4 mg, 0.5 mmol) in dry Et2O (3 mL) was added drop-
wise over 30 min to the mixture, then the mixture was heated under
reflux for 2 h. The reaction was quenched by adding crushed ice and
the obtained aqueous solution was acidified with a saturated aqueous
solution of NH4Cl, then extracted with EtOAc (3 × 20 mL). The com-
bined extracts were washed with a saturated aqueous solution of
NaHCO3 and H2O, dried over anhydrous MgSO4, then concentrated to
dryness. The obtained residue was separated by silica gel column
chromatography, eluting with EtOAc/hexane (2:8 v/v), to give the cor-
responding alcohol 4.
Yield: 54.0 mg (quant.); colorless microcrystals (from EtOH/hexane);
mp 131–132 °C; Rf = 0.31 (EtOAc/hexane, 6:4).
IR (neat): 1664 (-N-C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.23 (d, J = 7.5 Hz, 1 H, arom H), 7.18 (t,
J = 7.5 Hz, 1 H, arom H), 6.81 (t, J = 7.5 Hz, 1 H, arom H), 6.53 (d, J = 8.0
Hz, 1 H, arom H), 4.21 (s, 1 H, =NNH-CH3), 3.03 (s, 3 H, =N-CH3), 2.82
(s, 3 H, =NNH-CH3), 2.20–2.18 (m, 1 H, H-CH), 2.09–2.04 (m, 1 H, H-
CH), 1.69–1.63 (m, 2 H, CH2), 1.49–1.29 (m, 4 H, CH2-CH2).
13C NMR (125 MHz, CDCl3):  = 173.3 (-N-C=O), 141.6 (C-7′a), 130.7
(C-3′a), 130.0, 123.4, 123.2, 108.4 (arom C), 81.5 (C-1), 37.2, 36.7
(CH2), 26.3 (=N-Me), 23.0, 22.9 (CH2).
Yield: 127.5 mg (85%); colorless microcrystals (from EtOH/hexane);
mp 137–139 °C; Rf = 0.26 (EtOAc/hexane, 1:9).
IR (neat): 3350 (OH), 1672 (-C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.83 (d, J = 7.5 Hz, 1 H, arom H), 7.20 (t,
J =7.8 Hz, 1 H, arom H), 7.10 (t, J = 7.5 Hz, 1 H, arom H), 6.98–6.93 (m,
5 H, arom H), 6.54 (d, J = 7.5 Hz, 1 H, arom H), 6.00 (s, 1 H, -OH), 2.88
(s, 3 H, =N-Me), 2.60–2.52 (m, 2 H, CH2), 2.34–2.24 (m, 1 H, H-CH),
2.06–1.96 (m, 1 H, H-CH), 1.90–1.82 (m, 3 H, CH2/H-CH), 1.49–1.46
(m, 1 H, H-CH).
13C NMR (125 MHz, CDCl3):  = 180.3 (-N-C=O), 143.7, 143.1, 131.6,
127.9 (arom C), 126.7 (2 C, arom C), 126.4, 125.7 (arom C), 125.5 (2 C,
arom C), 122.1, 108.3 (arom C), 74.9 (C-2), 55.7 (C-1), 32.5, 29.8 (CH2),
25.7 (=N-Me), 20.1, 19.9 (CH2).
Anal. Calcd for C15H19N3O: C, 70.01; H, 7.44; N, 16.33. Found: C, 69.91;
H, 7.64; N, 16.20.
1′-Methyl-2-[2-(4-nitrophenyl)hydrazineylidene]spiro[cyclohex-
ane-1,3′-indolin]-2′-one (6b)
The reaction of 2a (68.6 mg, 0.3 mmol) with 4-nitrophenylhydrazine
(91.9 mg, 0.6 mmol) gave 4-nitrophenylhydrazone 6b.
Yield: 112.6 mg (97%); orange microcrystals (from EtOH/hexane); mp
214–217 °C; Rf = 0.23 (EtOAc/hexane, 3:7).
FAB HRMS (acetone/NBA): m/z [M
307.1572; found: 307.1591.
+
H]+ calcd for C20H21NO2:
IR (neat): 1697 (-N-C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.03 (d, J = 9.5 Hz, 2 H, arom H), 7.86 (s,
1 H, -N-H), 7.37–7.32 (m, 2 H, arom H), 7.13 (t, J = 8.0 Hz, 1 H, arom
H), 6.89 (d, J = 7.5 Hz, 1 H, arom H), 6.76 (d, J = 9.0 Hz, 1 H, arom H),
3.24 (s, 3 H, =N-Me), 2.83–2.77 (m, 1 H, H-CH), 2.68–2.63 (m, 1 H, H-
CH), 2.34–2.26 (m, 1 H, H-CH), 2.12–2.09 (m, 1 H, H-CH), 2.08–1.94
(m, 2 H, CH2), 1.86–1.76 (m, 2 H, CH2), 1.76–1.68 (m, 1 H, H-CH).
13C NMR (125 MHz, CDCl3):  = 177.1 (-N-C=O), 150.5 (C-6), 150.1 (ar-
om C), 142.6 (C-7′a), 139.6 (arom C), 132.3 (C-3′a), 128.0 (arom C),
125.8 (2 C, arom C), 124.5, 122.2 (arom C), 111.5 (2 C, arom C), 108.4
(arom C), 55.8 (C-1), 35.8 (CH2), 26.3 (=N-Me), 24.7, 23.2, 20.1 (CH2).
1-Methylspiro[indoline-3,2′-oxepane]-2,7′-dione (5)
To the spiroindolinone 2a (69 mg, 0.3 mmol) in CH2Cl2 (4 mL) were
added m-chloroperbenzoic acid (106 mg, 0.6 mmol) and NaHCO3 (50
mg, 0.6 mmol). The mixture was stirred at room temperature for 1.5 h
and the reaction was quenched by adding brine. The organic layer was
separated, dried over anhydrous MgSO4, and concentrated to dryness.
The obtained residue was separated by silica gel column chromatog-
raphy, eluting with EtOAc/benzene (1:9 v/v), to give the correspond-
ing lactone 5.
Yield: 59.8 mg (79%); colorless microcrystals (from EtOH/hexane); mp
167–169 °C; Rf = 0.37 (EtOAc/benzene, 1:9).
FAB HRMS (MeOH-NBA-NaI): m/z [M + Na]+ calcd for C20H20N4NaO3:
387.1433; found 387.1489.
IR (neat): 1714 (-C=O) cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

J
S. Katayama, H. Nishino
Paper
Synthesis
2-[2-(2,4-Dinitrophenyl)hydrazineylidene]-1′-methylspiro[cyclo-
hexane-1,3′-indolin]-2′-one (6c)
Slebodnick, C.; Zackharov, L. N.; Rheingold, A. L.; Habenicht, B.;
Lobue, P.; Ratliff, A. E. Org. Biomol. Chem. 2005, 3, 2114.
(j) Pederson, A. M.-P.; Ward, E. M.; Schoonover, D. V.;
Slebodnick, C.; Gibson, H. W. J. Org. Chem. 2008, 73, 9094.
(3) (a) de Klein, W. J. In Organic Syntheses by Oxidation with Metal
Compounds; Mijis, W. J.; de Jonge, C. R. H. I., Ed.; Plenum Press:
New York, 1986, 261. (b) Snider, B. B. Chem. Rev. 1996, 96, 339.
(c) Melikyan, G. G. Org. React. 1997, 49, 427. (d) Radicals in
Organic Synthesis, Vol. 1; Renaud, P.; Sibi, M. P., Ed.; Wiley-VCH:
New York, 2001. (e) Zard, S. Z. Radical Reactions in Organic Syn-
thesis; Oxford University Press: New York, 2003. (f) Snider, B. B.
Tetrahedron 2009, 65, 10738. (g) Burton, J. W. In Encyclopedia of
Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C.;
Studer, A., Ed.; John Wiley & Sons: New York, 2012, 901.
(h) Krylov, I. B.; Terent’ev, A. O.; Timofeev, V. P.; Shelimov, B. N.;
Novikov, R. A.; Merkulova, V. M.; Nikishin, G. I. Adv. Synth. Catal.
2014, 356, 2266.
(4) (a) Kloetzel, M. C. Org. React. 1948, 4, 1. (b) Holmes, H. L. Org.
React. 1948, 4, 60. (c) Butz, L. W.; Rytina, A. W. Org. React. 1949,
5, 136. (d) Brieger, G.; Bennett, J. N. Chem. Rev. 1980, 80, 63.
(e) Takano, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105,
4779. (f) Mackay, E. G.; Sherburn, M. S. Synthesis 2015, 47, 1.
(g) Yang, R.-Y.; Sun, J.; Yan, C.-G. ACS Omega 2018, 3, 5406.
(5) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(c) Monfette, S.; Fogg, D. E. Chem. Rev. 2009, 109, 3783.
(6) (a) Nishino, H. In Topics in Heterocyclic Chemistry, Bioactive Het-
erocycles I; Eguchi, S., Ed.; Springer: Berlin, 2006, 39. (b) Asahi,
K.; Nishino, H. Tetrahedron 2008, 64, 1620. (c) Asahi, K.;
Nishino, H. Synthesis 2009, 409. (d) Cong, Z.-Q.; Miki, T.;
Urakawa, O.; Nishino, H. J. Org. Chem. 2009, 74, 3978. (e) Ito, Y.;
Tomiyasu, Y.; Kawanabe, T.; Uemura, K.; Ushimizu, Y.; Nishino,
H. Org. Biomol. Chem. 2011, 9, 1491. (f) Maemura, Y.; Tanoue, Y.;
Nishino, H. Heterocycles 2012, 85, 2491. (g) Matsumoto, C.;
Yasutake, K.; Nishino, H. Tetrahedron 2016, 72, 6963. (h) Huynh,
T.-T.; Nguyen, V.-H.; Nishino, H. Tetrahedron Lett. 2017, 58,
3619. (i) Huynh, T.-T.; Yamakawa, H.; Nguyen, V.-H.; Nishino, H.
ChemistrySelect 2018, 3, 6414.
The reaction of 2a (45.5 mg, 0.2 mmol) with 2,4-dinitrophenylhydra-
zine (39.8 mg, 0.2 mmol) gave the desired 2,4-dinitrophenylhydra-
zone 6c.
Yield: 70.3 mg (87%); orange microcrystals (from EtOH/hexane); mp
86–89 °C; Rf = 0.39 (EtOAc/hexane, 3:7).
IR (neat): 1699 (-N-C=O) cm–1
.
1H NMR (500 MHz, CDCl3):  = 11.16 (s, 1 H, -N-H), 9.04 (d, J = 2.5 Hz,
1 H, arom H), 8.17 (dd, J = 10.0, 3.0 Hz, 1 H, arom H), 7.44 (d, J = 9.5 Hz,
1 H, arom H), 7.39–7.35 (m, 2 H, arom H), 7.15 (t, J = 7.3 Hz, 1 H, arom
H), 6.92 (d, J = 8.0 Hz, 1 H, arom H), 3.26 (s, 3 H, =N-Me), 3.03–2.97
(m, 1 H, H-CH), 2.77 (dt, J = 16.5, 5.5 Hz, 1 H, H-CH), 2.37–2.30 (m, 1
H, H-CH), 2.19–2.08 (m, 2 H, CH2), 2.05–1.99 (m, 1 H, H-CH), 1.94–
1.87 (m, 2 H, CH2).
13C NMR (125 MHz, CDCl3):  = 176.1 (-N-C=O), 157.4 (C-6), 145.2 (ar-
om C), 142.8 (C-7′a), 137.9 (arom C), 131.6 (C-3′a), 129.9, 129.2,
128.3, 124.4, 123.2, 122.3, 116.4, 108.5 (arom C), 56.1 (C-1), 36.0
(CH2), 26.4 (=N-Me), 25.0, 24.6, 20.1 (CH2).
FAB HRMS (MeOH-NBA-NaI): m/z [M + Na]+ calcd for C20H19N5NaO5:
432.1284; found 432.1278.
Funding Information
This research was supported by the Japan Society for the Promotion
of Science, Grant-in-Aid for Scientific Research (C) (No. 25410049 and
18K05109). We also acknowledge the Nissan Chemical Corporation
for financial support.
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Acknowledgment
H.N. thanks Mr. Daichi Hirata, Department of Science, Faculty of Sci-
ence, Kumamoto University, Japan, for his technical assistance.
(7) Tsubusaki, T.; Nishino, H. Tetrahedron 2009, 65, 9448.
(8) Kikue, N.; Takahashi, T.; Nishino, H. Heterocycles 2014, 90, 540.
(9) Inoue, T.; Nishino, H. Heterocycles 2018, 97, 431.
Supporting Information
Supporting information for this article is available online at
(10) (a) Takayanagi, J.; Nishino, H. Abstracts of Papers, The 98th CSJ
Annual Meeting; Funabashi: Japan, 20–23.March.2018, 3PC-023.
(b) Katayama, S.; Nishino, H. Abstracts of Papers, The 99th CSJ
Annual Meeting; Kobe: Japan, 16–19.Mar.2019, 2PB-133.
(11) (a) Hurst, T. E.; Gorman, R.; Drouhin, P.; Taylor, R. J. K. Tetrahe-
dron 2018, 74, 6485. (b) Venkatesan, H.; Davis, M. C.; Altas, Y.;
Snyder, J. P.; Liotta, D. C. J. Org. Chem. 2001, 66, 3653. (c) Flann,
C. J.; Overman, L. E.; Sarkar, A. K. Tetrahedron Lett. 1991, 32,
6993. (d) Atarashi, S.; Choi, J.-K.; Ha, D.-C.; Hart, D. J.; Kuzmich,
D.; Lee, C.-S.; Ramesh, S. C.; Wu, S. C. J. Am. Chem. Soc. 1997, 119,
6226. (e) Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman,
L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054.
(12) Matsumoto, R.; Nishino, H. Synth. Commun. 2015, 45, 1807.
(13) Yamada, T.; Iwahara, Y.; Nishino, H.; Kurosawa, K. J. Chem Soc.,
Perkin Trans. 1 1993, 609.
(14) (a) Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 737. (b) Brink,
G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Chem. Rev. 2004, 104,
4105.
https://doi.org/10.1055/s-0037-1611563.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J