Iodobenzene-mediated intramolecular oxidative coupling of substituted 4-hydroxyphenyl-N-phenylbenzamides for the synthesis of spirooxindoles

Article abstract of DOI:10.1055/s-0030-1259444

Phenyliodine(III) bis(trifluoroacetate) (PIFA) can effect the intramolecular oxidative coupling of substituted 4-hydroxyphenyl-N- phenylbenzamides. The transformations could be realized in a catalytic manner by using iodobenzene as catalyst and m-chloro-p

Full text of DOI:10.1055/s-0030-1259444

860
PAPER
Iodobenzene-Mediated Intramolecular Oxidative Coupling of Substituted
4-Hydroxyphenyl-N-phenylbenzamides for the Synthesis of Spirooxindoles
I
odobenzene-M
h
ediated Oxid
e
ative Coup
n
ling of 4-H
y
g
droxyphenyl-
s
N
-phenyl
ebenzamidesn Yu, Xuhui Ju, Junyan Wang, Wei Yu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. of China
Fax +86(931)8915557; E-mail: yuwei@lzu.edu.cn
Received 15 November 2010; revised 5 January 2011
X
O
Abstract: Phenyliodine(III) bis(trifluoroacetate) (PIFA) can effect
the intramolecular oxidative coupling of substituted 4-hydroxyphe-
nyl-N-phenylbenzamides. The transformations could be realized in
a catalytic manner by using iodobenzene as catalyst and m-chloro-
peroxybenzoic acid or urea·H2O2 as terminal oxidant. This reaction
constitutes an efficient method for the synthesis of spirooxindoles.
(TMS)3SiH
Et3B, O2
n
n
R
R
N
O
N
O
Key words: hypervalent iodine , oxidative coupling, phenolic cou-
pling, spirooxindoles, iodobenzene
I
Me
Me
n = 0, 1
X = OTr, N3
(refs. 6 and 7)
Scheme 1
Organic hypervalent iodine reagents have found wide ap-
plications in organic synthesis over the last two decades.
The versatility and ready availability of hypervalent io-
dine compounds, combined with their environmentally
benign character, render them superior oxidants for a va-
riety of organic transformations.1 Recently, there has been
much interest in applying hypervalent iodine reagents,
such as PhI(OAc)2 (DIB or PIDA) and PhI(OCOCF3)2
(BTI or PIFA) in particular, to the oxidative coupling of
electron-rich aromatic compounds.2 The PIDA and PIFA-
mediated intramolecular phenolic coupling reactions con-
stitute powerful biomimetic strategies for the synthesis of
fused and spiral cyclic compounds.3,4
and was subjected to reaction with PIFA and PIDA at
room temperature. With PIFA as the oxidant, the reaction
took place smoothly in various solvents, and the corre-
sponding spirooxindole (2a) was obtained in good to ex-
cellent yield (Scheme 2). In contrast, PIDA was found to
be ineffective in the reaction.
OH
O
PIFA (1.2 equiv)
solvent, r.t.
O
N
O
N
Spirooxindoles are key intermediates in the syntheses of
some important biologically active compounds.5 Recent-
ly, two novel synthetic approaches employing aryl free
radical cyclizations have been developed to gain access to
spirooxindoles as well as spirodihydroquinolones
(Scheme 1).6,7 In another study, Doris et al. showed that
the spirodihydroquinolones could be prepared through
PIFA-promoted intramolecular coupling of 2-(4-hydroxy-
phenyl)-N-methyl-N-acetamide.8 However, the general
scope of the reaction was not explored, and the protocol
was not extended to the synthesis of spirooxindoles. In
light of the synthetic importance of spirooxindoles, we re-
investigated these reactions, and found that the method
was very effective for the synthesis of spirooxindoles
from substituted 4-hydroxyphenyl N-phenylbenzamides.
The transformations could be realized catalytically by em-
ploying the catalytic system developed by Kita et al.9 and
Ochiai et al.10
Me
1a
Me
2a
Solvent
MeCN
MeOH
CF3CH2OH
CH2Cl2
THF
Yield (%)
90
84
93
82
84
Scheme 2
It is generally accepted that PIFA or PIDA-mediated oxi-
dative dearomatization of 4- or 2-substituted phenols pro-
ceeds either though cationic phenoxenium intermediates,
or through a concerted addition–elimination reaction after
initial conversion of the phenoxy group at the iodine cen-
ter.1a There is evidence to indicate that the former mecha-
nism might be more favorable.11 Consistent with this
notion, these types of reaction usually gave better results
in highly polar solvents, such as trifluoroethanol (TFE). In
the case of 1a, however, the formation of the cationic phe-
noxenium intermediate (I) might not be a favored process
due to the electron-withdrawing effect of the carbonyl
group (Scheme 3). Therefore, we assumed that the reac-
During the initial stages of the study, 4-hydroxyphenyl-N-
methyl-N-benzamide (1a) was chosen as the substrate,
SYNTHESIS 2011, No. 6, pp 0860–0866
x
x
.
x
x
.2
0
1
1
Advanced online publication: 31.01.2011
DOI: 10.1055/s-0030-1259444; Art ID: F20310SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Iodobenzene-Mediated Intramolecular Oxidative of 4-Hydroxyphenyl-N-phenylbenzamides
861
O+
O
+
path A
N
N
O
O
O
Me
Me
I
PhI(OCOCF3)2
Ph
1a
O
N
I
OCOCF3
Me
2a
O
path B
N
O
Me
Scheme 3
tion of 1a might follow the concerted addition–elimina- yields were still comparable to those obtained by using the
tion pathway (Scheme 3, path B). This hypothesis was free radical methods.6,7
supported by the observed solvent effect as shown in
Recently, there has been much interest in developing cat-
Scheme 2. Although acetonitrile and trifluoroethanol
alytic systems that require only catalytic amounts of hy-
were still the better solvents, good results were also ob-
tained in less polar dichloromethane and tetrahydrofuran.
This protocol could be used to prepare a variety of substi-
tuted spirooxindoles, as shown in Table 1. The yields
were generally satisfactory. When N-(3-chlorophenyl)-4-
hydoxyphenyl-N-methylbenzamide (1h) was used as the
substrate, two isomeric products 2h-1 and 2h-2 (Figure 1)
were generated. The yield of 2h-1 was higher than that of
2h-1, probably as a result of steric effects, which render
the formation of 2h-2 less favorable. Their structures
were confirmed by X-ray crystallographic analysis
(Figure 2).12
O
O
Cl
O
O
N
N
Cl
Me
Me
2h-2
2h-1
Figure 1
It is noteworthy that in this PIFA-promoted oxidative cou-
pling, there is no need for prehalogenation of substrate 1.
Therefore, this method provides a more convenient ap-
proach to the synthesis of 2. Spirooxindole 2j is a synthet-
ic intermediate that plays a pivotal role in the synthesis of
the vasopressin inhibitor SR121463A.13 By using this pro-
tocol, 2j was obtained in 80% yield from 1j. By compari-
son, the synthesis of spirodihydroquinolones (4) from the
corresponding 2-(4-hydroxyphenyl)-N-methyl-N-acet-
amides (3) was less efficient (Scheme 4). However, the
Figure 2
Synthesis 2011, No. 6, 860–866 © Thieme Stuttgart · New York

862
Z. Yu et al.
PAPER
alytic systems. Precedent work by Kita et al. demonstrated
that the oxidizing systems using iodoarene as catalyst
were applicable to the intramolecular C–C coupling of
phenolic substrates incorporating various tethers, with the
formation of five- to seven-membered spirodienones.16
Therefore, we investigated whether catalytic systems
could be applied to the synthesis of spirooxindoles.
Table 1 PIFA-Mediated Intramolecular Oxidative Coupling of
N-Phenylbenzamides (1)
O
OH
PIFA (1.2 equiv)
R1
O
R1
MeCN, r.t.
N
N
R2
1
O
To this end, two systems employing MCPBA and
urea·H2O2, respectively, as the terminal oxidants, were
examined for their effectiveness in promoting the trans-
formation of 1a into 2a;16 the results are outlined in
Table 2. Because compounds 1 did not readily dissolve in
trifluoroethanol, dichloromethane was chosen as the sol-
vent. The results showed that when 0.1 equivalent of io-
dobenzene was used as the catalyst, and MCPBA was
used as the terminal oxidant, the reaction took place
smoothly in the presence of one equivalent of trifluoro-
acetic acid (TFA), and 2a was obtained in satisfactory
yield (Table 2, entries 1–3). It is noteworthy that only one
equivalent of MCPBA was enough to guarantee clean
conversion, although it took longer for the reaction to
reach completion (Table 2, entry 3). By comparison, no
reaction took place in the absence of iodobenzene
(Table 2, entry 5). The urea·H2O2/iodobenzene/trifluoro-
acetic acid anhydride (TFAA) system also worked very
well for the transformation. With two equivalents of
urea·H2O2 as oxidant and four equivalents of TFAA as ad-
ditive, 2a was formed in excellent yield (Table 2, entry 7).
R2
2
Entry Substrate 1 R1
R2
Product(s)
Yield (%)a
1
2
1a
1b
1c
1d
1e
1f
H
Me
Me
Me
2a
2b
2c
2d
2e
2f
90
82
83
88
78
90
61
4-EtO
4-Me
3
4
2-MeO
2-Me
4-Cl
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
5
6
7
1g
1h
1i
2-Cl
2g
8
3-Cl
2h-1 and 2h-2 55 and 37
9
H
2i
95
80
84
75
79
10
11
12
13
1j
4-EtO
4-Me
2-MeO
2-Cl
2j
1k
1l
2k
2l
Table 2 Examination of the Iodobenzene-Based Catalytic Systems
OH
O
1m
2m
a Isolated yield.
conditions
CH2Cl2, r.t.
O
O
N
O
N
OH
Me
Me
1a
2a
PIFA
Entry Oxidant
(equiv)
PhI
Additive
Time
(h)
Yield
(%)a
R
MeCN, r.t.
(equiv) (equiv)
R
N
O
N
O
Me
1
2
MCPBA (4.0)
0.1
TFA (1.0)
TFA (1.0)
4
7
86
Me
Yield (%)
3
4
MCPBA (2.0)
MCPBA (1.1)
MCPBA (2.0)
MCPBA (2.0)
urea·H2O2 (2.0)
urea·H2O2 (2.0)
urea·H2O2 (1.0)
MCPBA (2.0)
urea·H2O2 (2.0)
0.1
83
3a R = H
3b R = 4-EtO
3c R = 2-Me
4a
4b
4c
64
42
40
3
0.1
TFA (1.0)
TFA (1.0)
23
12
24
8
83
4
0.05
52
Scheme 4
5
none TFA (1.0)
N.R.b
tracec
pervalent iodine reagents to perform the oxidizing
function.14 The hypervalent iodine reagents could be recy-
cled by using another terminal oxidant. This strategy is
very attractive from both environmental and economical
points of view. Studies by Kita and Ochiai show that m-
chloroperoxybenzoic acid (MCPBA) and urea·H2O2 are
suitable terminal oxidants to effect the oxidation of io-
doarenes to hypervalent iodine(III) reagents in situ in the
catalytic cycle. Various types of oxidation reactions, in-
cluding oxidative C–O,9 C–N,15 and C–C16 coupling, have
been achieved by using hypervalent iodine(III)-based cat-
6
0.1
TFAA (1.0)
TFAA (4.0)
TFAA (4.0)
TFA (1.0)
7
0.1
15 min 96
15 min 41
8
0.1
9
0.1d
0.1d
10
84
10
TFAA (4.0)
20 min 89
a Isolated yield.
b No reaction took place.
c Most of the starting material was recovered.
d 4-Iodotoluene was used as catalyst.
Synthesis 2011, No. 6, 860–866 © Thieme Stuttgart · New York

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Iodobenzene-Mediated Intramolecular Oxidative of 4-Hydroxyphenyl-N-phenylbenzamides
863
Table 3 Synthesis of Spirooxindoles 2 Using 10 mol% Iodobenzene
as Catalyst (continued)
However, the reaction barely took place when only one
equivalent of TFAA was used (Table 2, entry 6), probably
due to the complexation of TFAA with urea. In addition
to iodobenzene, 4-iodotoluene was also found to be capa-
ble of catalyzing the reaction with high efficiency
(Table 2, entries 9 and 10).
Entry Product
Conditionsa Time (h) Yield (%)b
O
EtO
Table 3 Synthesis of Spirooxindoles 2 Using 10 mol% Iodobenzene
as Catalyst
7
A
3
86
O
N
Entry Product
Conditionsa Time (h) Yield (%)b
Bn
2j
O
O
A
B
7
83
1
20 min 96
O
8
A
5
79
N
O
N
Me
Bn
2a
O
2k
O
EtO
2
A
A
A
A
3
11
24
17
90
73
73
86
A
B
18
52
O
9
30 min 57
N
O
N
Me
Bn
2b
OMe
O
2l
O
3
A
B
10
30 min 74
85c
Cl
O
10
N
O
N
Me
2c
Bn
O
2n
O
4
A
B
10
30 min 74
80c
F
O
11
N
N
N
O
N
Me
OMe
Bn
2d
2o
O
O
5
O
12
A
7
71
O
N
Me
2e
O
2p
a Conditions A: MCPBA (2.0 equiv) was used as terminal oxidant;
TFA (1.0 equiv) was used unless otherwise specified. Conditions B:
urea·H2O2 (2.0 equiv) and TFAA (4.0 equiv) were used.
b Isolated yield.
6
A
4
83
O
c TFA (4.0 equiv) was used.
Bn
2i
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864
Z. Yu et al.
PAPER
MS (EI): m/z (%) = 269 (100) [M]+, 241 (78), 213 (57), 184 (58),
170 (16), 155 (19), 115 (26), 63 (27).
The iodobenzene-mediated systems were then applied to
the synthesis of variously substituted spirooxindoles
(Table 3); the yields were generally satisfactory. In the HRMS (ESI): m/z calcd for C16H16NO3: 270.1125; found:
270.1128.
case of substrates 2n and 2o, when MCPBA was used as
the oxidant, four equivalents of trifluoroacetic acid was
needed to complete the conversion (Table 3, entries 10
3¢-Methyloxy-1¢-methyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-in-
dol]-2¢,4(1¢H)-dione (2d)
and 11; conditions A). Because only 0.1 equivalent of io-
White solid; mp 150–153 °C.
dobenzene was used instead of a stoichiometric amount of
1H NMR (CDCl3, 400 MHz): d = 3.57 (s, 3 H), 3.91 (s, 3 H), 6.53
(dd, J = 8.0, 2.0 Hz, 2 H), 6.59 (dd, J = 8.0, 2.0 Hz, 2 H), 6.63 (d,
J = 7.6 Hz, 1 H), 6.95 (d, J = 7.6 Hz, 1 H), 7.04 (t, J = 7.6 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): d = 30.7, 56.0, 56.1, 113.5, 117.1,
124.2, 127.1, 131.2, 131.7, 143.8, 145.9, 171.4, 185.4.
MS (EI): m/z (%) = 255 (100) [M]+, 240 (40), 227 (29), 212 (63),
197 (18), 184 (53).
PIFA, the toxicity and cost associated with the synthesis
were greatly reduced, thus rendering the method more
synthetically attractive.
In summary, the PIFA-mediated intramolecular oxidative
coupling of substituted 4-hydroxyphenyl-N-phenylbenza-
mides constitutes an efficient method for the synthesis of
spirooxindoles. The synthesis could be accomplished by
using 0.1 equivalent of iodobenzene as catalyst and 2.0
equivalents of MCPBA or urea·H2O2 as the terminal oxi-
dant. As 3,3-spirocyclohexadienone-attached oxindoles 2
could be easily accessed from simple precursors 1 using
this protocol, it is hoped that they might serve as interme-
diates in the synthesis of a wide range of 3,3-disubstituted
oxindoles and other useful compounds.
HRMS (ESI): m/z calcd for C15H14NO3: 256.0968; found:
256.0973.
3¢-Methyl-1¢-methyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-
2¢,4(1¢H)-dione (2e)
White solid; mp 174–178 °C.
1H NMR (CDCl3, 400 MHz): d = 2.64 (s, 3 H), 3.58 (s, 3 H), 6.52
(dd, J = 8.0, 2.0 Hz, 2 H), 6.58 (dd, J = 8.0, 2.0 Hz, 2 H), 6.84 (d,
J = 7.2 Hz, 1 H), 6.97 (t, J = 7.6 Hz, 1 H), 7.12 (d, J = 7.6 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): d = 19.0, 30.6, 55.4, 120.9, 122.7,
1H and 13C NMR spectra were recorded with a Bruker AM-400
MHz spectrometer with TMS as the internal standard in CDCl3. The
MS (EI) spectra were measured with an HP 5988A spectrometer by
direct inlet at 70 eV. The high-resolution mass spectra (HRMS)
were measured with a Bruker Daltonics APEX II 47e spectrometer
by ESI. Melting points were measured with an XT-4 melting point
apparatus and are uncorrected.
123.5, 126.3, 131.2, 133.6, 141.6, 143.8, 172.1, 185.3.
MS (EI): m/z (%) = 239 (100) [M]+, 224 (15), 211 (28), 196 (47).
HRMS (ESI): m/z calcd for C15H14NO2: 240.1019; found:
240.1012.
5¢-Chloro-1¢-methyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-
2¢,4(1¢H)-dione (2f)
White solid; mp 231–232 °C.
Synthesis of 2; General Procedure (Conditions A)
To a slurry of MCPBA (345 mg, 2.0 mmol) in CH2Cl2 (10 mL) was
added TFA (75 mL, 1.0 mmol). After the MCPBA was completely
dissolved, PhI (11 mL, 0.10 mmol) and 1 (1.0 mmol) were added
quickly to the solution, and the mixture was stirred at r.t. until the
reaction was complete as indicated by TLC. The mixture was dilut-
ed with CH2Cl2 (15 mL) and washed sequentially with sat. Na2S2O3
(2 × 12 mL), sat. Na2CO3 (12 mL), and brine (12 mL), and then
dried with anhydrous Na2SO4. After filtration, the solvent was re-
moved under reduced pressure and the residue was purified by silica
gel chromatography to give product 2.
1H NMR (CDCl3, 400 MHz): d = 3.30 (s, 3 H), 6.56 (s, 4 H), 6.90
(d, J = 8.4 Hz, 1 H), 7.03 (d, J = 2.0 Hz, 1 H), 7.38 (dd, J = 8.4,
2.0 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): d = 27.4, 55.6, 110.0, 125.2, 127.7,
129.1, 129.9, 131.8, 142.3, 142.5, 170.9, 184.8.
MS (EI): m/z (%) = 259 (71) [M]+, 231 (100), 215 (31), 202 (34),
168 (36).
HRMS (ESI): m/z calcd for C14H11ClNO2: 260.0473; found:
260.0467.
Synthesis of 2; General Procedure (Conditions B)
3¢-Chloro-1¢-methyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-
2¢,4(1¢H)-dione (2g)
To CH2Cl2 (10 mL) was added urea·H2O2 (188 mg, 2.0 mmol), and
TFAA (563 mL, 4.0 mmol). The mixture was stirred at r.t. until
urea·H2O2 was completely dissolved, then PhI (11 mL, 0.10 mmol)
and 1 (1.0 mmol) were added quickly to the solution, and the mix-
ture was stirred at r.t. until the reaction was complete as indicated
by TLC. The solvent was then evaporated under reduced pressure
and the residue was purified by silica gel chromatography to give
product 2.
White solid; mp 143–145 °C.
1H NMR (CDCl3, 400 MHz): d = 3.67 (s, 3 H), 6.54 (d, J = 10.4 Hz,
2 H), 6.57 (d, J = 10.4 Hz, 2 H), 6.91 (dd, J = 7.6, 0.8 Hz, 1 H), 7.02
(t, J = 8.0 Hz, 1 H), 7.33 (dd, J = 8.0, 0.8 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): d = 30.7, 55.3, 116.3, 123.3, 124.2,
131.5, 132.2, 139.7, 142.8, 171.5, 184.9.
MS (EI): m/z (%) = 259 (100) [M]+, 231 (58), 216 (40), 188 (22).
5¢-Ethyloxy-1¢-methyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-in-
dol]-2¢,4(1¢H)-dione (2b)
HRMS (ESI): m/z calcd for C14H11ClNO2: 260.0473; found:
260.0472.
White solid; mp 148–150 °C.
1H NMR (CDCl3, 400 MHz): d = 1.39 (t, J = 7.2 Hz, 3 H), 3.29 (s,
3 H), 3.97 (q, J = 7.2 Hz, 2 H), 6.54 (d, J = 9.6 Hz, 2 H), 6.61 (dd,
J = 10.0, 2.0 Hz, 2 H), 6.62–6.64 (m, 1 H), 6.86–6.94 (m, 2 H).
13C NMR (CDCl3, 100 MHz): d = 14.7, 27.3, 56.2, 64.2, 109.6,
112.1, 115.2, 127.0, 131.3, 136.9, 143.7, 156.0, 170.9, 185.3.
4¢-Chloro-1¢-methyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-
2¢,4(1¢H)-dione (2h-1)
White solid; mp 178–180 °C.
1H NMR (CDCl3, 400 MHz): d = 3.30 (s, 3 H), 6.55 (s, 4 H), 6.95–
6.97 (m, 2 H), 7.08–7.10 (m, 1 H).
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Iodobenzene-Mediated Intramolecular Oxidative of 4-Hydroxyphenyl-N-phenylbenzamides
865
13C NMR (CDCl3, 100 MHz): d = 27.4, 55.3, 109.9, 123.5, 124.3,
3¢-Methyloxy-1¢-benzyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-in-
125.6, 131.7, 136.0, 142.7, 144.9, 171.3, 184.9.
dol]-2¢,4(1¢H)-dione (2l)
White solid; mp 172–174 °C.
MS (EI): m/z (%) = 259 (90) [M]+, 231 (100), 216 (45), 202 (22),
196 (24), 188 (24), 168 (32), 139 (42), 126 (26).
1H NMR (CDCl3, 400 MHz): d = 3.78 (s, 3 H), 5.23 (s, 2 H), 6.54
(d, J = 10.0 Hz, 2 H), 6.61 (d, J = 10.0 Hz, 2 H), 6.64 (d, J = 8.0 Hz,
1 H), 7.03 (t, J = 8.4 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.23–7.32
(m, 5 H).
HRMS (ESI): m/z calcd for C14H11ClNO2: 260.0473; found:
260.0469.
6¢-Chloro-1¢-methyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-
2¢,4(1¢H)-dione (2h-2)
White solid; mp 205–207 °C.
13C NMR (CDCl3, 100 MHz): d = 46.6, 55.9, 56.0, 113.7, 117.2,
124.3, 127.3, 127.4, 128.5, 131.1, 131.3, 137.7, 143.6, 145.6, 171.6,
185.2.
1H NMR (CDCl3, 400 MHz): d = 3.31 (s, 3 H), 6.55 (d, J = 8.4 Hz,
2 H), 6.64 (d, J = 8.4 Hz, 2 H), 6.88 (d, J = 7.6 Hz, 1 H), 7.07 (d,
J = 8.0 Hz, 1 H), 7.37 (t, J = 8.0 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): d = 27.7, 56.0, 107.4, 123.5, 124.5,
131.1, 132.1, 133.0, 141.5, 145.2, 170.2, 185.2.
MS (EI): m/z (%) = 259 (62) [M]+, 231 (78), 224 (38), 196 (19), 168
(29), 141 (50), 121 (100).
MS (EI): m/z (%) = 331 (7) [M]+, 91 (100).
HRMS (ESI): m/z calcd for C21H18NO3: 332.1281; found:
332.1276.
3¢-Chloro-1¢-benzyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-
2¢,4(1¢H)-dione (2m)
White solid; mp 188–190 °C.
1H NMR (CDCl3, 400 MHz): d = 5.41 (s, 2 H), 6.58–6.65 (m, 4 H),
6.94 (dd, J = 7.2, 1.2 Hz, 1 H), 7.02 (m, 1 H), 7.25–7.36 (m, 6 H).
13C NMR (CDCl3, 100 MHz): d = 45.9, 55.4, 116.4, 123.5, 124.5,
126.6, 127.6, 128.5, 128.8, 131.6, 132.6, 136.7, 139.1, 143.0, 172.0,
185.1.
HRMS (ESI): m/z calcd for C14H11ClNO2: 260.0473; found:
260.0477.
1¢-Benzyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-2¢,4(1¢H)-
dione (2i)
Light-yellow solid; mp 119–121 °C.
MS (EI): m/z (%) = 335 (2) [M]+, 91 (100).
1H NMR (CDCl3, 400 MHz): d = 4.98 (s, 2 H), 6.59 (d, J = 10.0 Hz,
2 H), 6.67 (d, J = 10.4 Hz, 2 H), 6.88 (d, J = 8.0 Hz, 1 H), 7.03–7.10
(m, 2 H), 7.26–7.34 (m, 6 H).
HRMS (ESI): m/z calcd for C20H15ClNO2: 336.0786; found:
336.0782.
13C NMR (CDCl3, 100 MHz): d = 44.8, 56.0, 110.2, 123.7, 124.8,
5¢-Chloro-1¢-benzyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-
2¢,4(1¢H)-dione (2n)
125.8, 127.3, 128.0, 129.9, 131.4, 135.0, 142.9, 143.8, 171.4, 185.5.
Light-yellow solid; mp 137–139 °C.
MS (EI): m/z (%) = 301 (100) [M]+, 210 (40), 154 (16), 139 (10),
128 (22).
1H NMR (CDCl3, 400 MHz): d = 4.96 (s, 2 H), 6.57–6.76 (m, 4 H),
6.77 (d, J = 8.4 Hz, 1 H), 7.03 (d, J = 2.0 Hz, 1 H), 7.24–7.38 (m,
6 H).
13C NMR (CDCl3, 100 MHz): d = 44.9, 55.7, 111.1, 125.3, 127.3,
127.8, 128.2, 129.1, 129.2, 129.8, 131.9, 134.6, 141.4, 142.5, 171.1,
184.8.
HRMS (ESI): m/z calcd for C20H16NO2: 302.1176; found:
302.1184.
5¢-Ethyloxy-1¢-Benzyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-in-
dol]-2¢,4(1¢H)-dione (2j)
White solid; mp 126–128 °C.
1H NMR (CDCl3, 400 MHz): d = 1.35 (t, J = 7.2 Hz, 3 H), 3.92 (q,
J = 7.2 Hz, 2 H), 4.94 (s, 2 H), 6.55–6.58 (dd, J = 12.4, 2.0 Hz,
2 H,), 6.62–6.66 (m, 3 H), 6.73–6.80 (m, 2 H), 7.28–7.37 (m, 5 H).
MS (EI): m/z (%) = 335 (5) [M]+, 91 (100).
HRMS (ESI): m/z calcd for C20H15ClNO2: 336.0786; found:
336.0783.
13C NMR (CDCl3, 100 MHz): d = 14.7, 44.8, 56.3, 64.2, 110.7,
112.1, 115.3, 127.2, 127.3, 128.0, 129.0, 131.5, 135.2, 136.0, 143.5,
156.0, 171.1, 185.2.
5¢-Fluoro-1¢-benzyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-
2¢,4(1¢H)-dione (2o)
Light-yellow solid; mp 150–152 °C.
MS (EI): m/z (%) = 345 (4) [M]+, 91 (100).
1H NMR (CDCl3, 400 MHz): d = 4.96 (s, 2 H), 6.59 (d, J = 10.4 Hz,
2 H), 6.63 (d, J = 10.4 Hz, 2 H), 6.77–6.82 (m, 2 H), 6.98 (m, 1 H),
7.29–7.38 (m, 5 H).
13C NMR (CDCl3, 100 MHz): d = 44.9, 55.9, 110.8, 110.9, 112.7,
113.0, 116.2, 116.4, 127.3, 127.7, 128.2, 129.1, 129, 131.8, 134.8,
138.8, 138.8, 142.7, 158.3, 160.8, 171.2, 184.8.
HRMS (ESI): m/z calcd for C22H20NO3: 346.1438; found:
346.1440.
5¢-Methyl-1¢-benzyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-
2¢,4(1¢H)-dione (2k)
White solid; mp 128–130 °C.
MS (EI): m/z (%) = 319 (5) [M]+, 91 (100).
1H NMR (CDCl3, 400 MHz): d = 2.28 (s, 3 H), 4.96 (s, 2 H), 6.58
(d, J = 10.4 Hz, 2 H), 6.66 (d, J = 10.0 Hz, 2 H), 6.76 (d,
J = 8.0 Hz, 1 H), 6.86 (s, 1 H), 7.08 (dd, J = 8.0, 0.8 Hz, 1 H), 7.27–
7.36 (m, 5 H).
13C NMR (CDCl3, 100 MHz): d = 21.0, 44.8, 56.2, 110.1, 125.6,
125.9, 127.4, 128.1, 129.0, 130.3, 131.4, 133.7, 135.2, 140.5, 144.1,
171.5, 185.7.
HRMS (ESI): m/z calcd for C20H15FNO2: 320.1081; found:
320.1085.
5¢-Methyl-1¢-allyl-4H-spiro[cyclohexa-2,5-diene-1,3¢-indol]-
2¢,4(1¢H)-dione (2p)
White solid; mp 104–105 °C.
1H NMR (CDCl3, 400 MHz): d = 2.31 (s, 3 H), 4.39 (d, J = 7.2 Hz,
2 H), 5.25–5.29 (m, 2 H), 5.82–5.90 (m, 1 H), 6.55 (d, J = 10.0 Hz,
2 H), 6.62 (d, J = 10.0 Hz, 2 H), 6.84–6.86 (m, 2 H), 7.16 (d,
J = 8.0 Hz, 1 H).
MS (EI): m/z (%) = 315 (5) [M]+, 91 (100).
HRMS (ESI): m/z calcd for C21H18NO2: 316.1332; found:
316.1337.
Synthesis 2011, No. 6, 860–866 © Thieme Stuttgart · New York

866
Z. Yu et al.
PAPER
13C NMR (CDCl3, 100 MHz): d = 20.9, 43.3, 56.0, 109.8, 118.2,
Angew. Chem. Int. Ed. 2008, 47, 3787. (e) Liang, J.; Chen,
J.; Du, F.; Zeng, X.; Li, L.; Zhang, H. Org. Lett. 2009, 11,
2820. (f) Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem.
Int. Ed. 2010, 49, 2175. (g) Liang, H.; Ciufolini, M. A.
Chem. Eur. J. 2010, 16, 13262.
125.5, 125.9, 130.1, 130.7, 131.3, 133.5, 140.5, 143.8, 171.0, 185.4.
MS (EI): m/z (%) = 265 (27) [M]+, 250 (28), 224 (71), 168 (37), 41
(100).
HRMS (ESI): m/z calcd for C17H16NO2: 266.1175; found:
266.1181.
(5) For reviews, see: (a) Marti, C.; Carreira, E. M. Eur. J. Org.
Chem. 2003, 2209. (b) Galliford, C. V.; Scheidt, K. A.
Angew. Chem. Int. Ed. 2007, 46, 8748. For recent examples
of spirooxindole synthesis, see: (c) Trost, B. M.; Cramer,
N.; Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396.
(d) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.;
Pesciaioli, F.; Song, M.-P.; Bartoli, G.; Melchiorre, P.
Angew. Chem. Int. Ed. 2009, 48, 7200. (e) Liang, B.;
Kalidindi, S.; Porco, J. A. Jr.; Stephenson, C. R. J. Org. Lett.
2010, 12, 573.
Acknowledgment
The authors thank the National Natural Science Foundation of
China (No. 20772053) for financial support.
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Synthesis 2011, No. 6, 860–866 © Thieme Stuttgart · New York