Preparation of 2,2-disubstituted 1,2-dihydro-3H-indol-3-ones via oxidation of 2-substituted indoles and Mannich-type reaction

Article abstract of DOI:10.1016/j.tet.2009.12.028

A novel preparative method for 2,2-disubstituted 1,2-dihydro-3H-indol-3-ones through the oxidation of 2-arylindoles followed by a Mannich-type reaction with carbon nucleophiles is described.

Full text of DOI:10.1016/j.tet.2009.12.028

Tetrahedron 66 (2010) 1236–1243
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Preparation of 2,2-disubstituted 1,2-dihydro-3H-indol-3-ones via oxidation
of 2-substituted indoles and Mannich-type reaction
Kazuhiro Higuchi, Yukihiro Sato, Shigeru Kojima, Mei Tsuchimochi, Kenta Sugiura,
*
Masatoshi Hatori, Tomomi Kawasaki
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel preparative method for 2,2-disubstituted 1,2-dihydro-3H-indol-3-ones through the oxidation of
2-arylindoles followed by a Mannich-type reaction with carbon nucleophiles is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 28 October 2009
Received in revised form
26 November 2009
Accepted 9 December 2009
Available online 16 December 2009
Keywords:
Oxidation of indole
Mannich-type reaction
2,2-Disubstituted 1,2-dihydro-
3H-indol-3-one
C-Acyliminium intermediate
1. Introduction
2,2-Disubstituted 1,2-dihydro-3H-indol-3-ones are useful syn-
thetic intermediates for natural products, such as austamide,1
brevianamides,2 aristotelone,3 and duocarmycin A.4 Therefore, the
preparation of 2,2-disubstituted 1,2-dihydro-3H-indol-3-ones in
a concise manner is highly desirable. Several reported methods for
the preparation of 2,2-disubstituted 1,2-dihydro-3H-indol-3-ones
have utilized acid-, base-, or thermal-induced rearrangements of
2,3-dihydroxyindolines5 and 3H-indol-3-ols,6 oxidative rearrange-
ment of 2,3-disubstituted indoles,7 alkylation of 2-substituted 3H-
indol-3-ones,8 cyclization of o-nitrogenated acetophenones,9 and
so on.10 Recently, the acid-mediated substitution of 2-alkoxy-1,2-
dihydro-3H-indol-3-one with aromatic, organosilicon, and orga-
noboron compounds as carbon nucleophiles has been disclosed.11
Here, we report the details of a new methodology for the prepa-
ration of 2,2-disubstituted 1,2-dihydro-3H-indol-3-ones 3 through
the successive oxidation of indoles 1 and Mannich-type reaction of
2-hydroxy-1,2-dihydro-3H-indol-3-ones 2 with various carbon
nucleophiles (Fig. 1).12
Figure 1. Preparation of 2,2-substituted 1,2-dihydro-3H-indol-3-ones.
2. Results and discussion
2.1. Oxidation of 2-substituted indoles
In order to prepare 2-hydoroxy-1,2-dihydro-3H-indol-3-ones,
the precursor of the subsequent Mannich-type reaction, we in-
vestigated the oxidation of 2-substituted indoles. Many oxidations
of 2-substituted indoles have been reported;13–21 however, there
are few examples of the production of 2-hydoroxy-1,2-dihydro-
3H-indol-3-ones from 2-arylindoles.17b Previously, we performed
MoO5 oxidation of N-acetyl-2-phenylindole to provide 2,3-dioxi-
genated indolines.14b Based on this result, the oxidation of
2-(2-nitrophenyl)indoles 1 was examined (Table 1). However, oxi-
dation of the N-acetyl derivative 1a did not proceed at all (entry 1).
Treatment of the N-unsubstituted indole 1b produced the oxidative
dimer 5 in 72% yield (entry 2).14b In order to accelerate the oxida-
tion, we used the electron-donating methoxymethyl (MOM)
substituent on the indole nitrogen and found that the desired
reaction occurred to produce 4c in 21% yield (entry 3).
* Corresponding author. Tel./fax: þ81 42 495 8763.
E-mail address: kawasaki@my-pharm.ac.jp (T. Kawasaki).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.028

K. Higuchi et al. / Tetrahedron 66 (2010) 1236–1243
1237
Table 1
Oxidation of 2-substituted indole
Entry
1
R1
Oxidants (equiv)
Solvents
Time
Results
1
2
3
4
a
b
c
c
Ac
H
MOM
MOM
MoO5$HMPA$H2O (1.0)
MoO5$HMPA$H2O (1.0)
MoO5$HMPA$H2O (1.0)
m-CPBA (2.5)
MeOH
MeOH
MeOH
THF
2 weeks
5 days
4 weeks
2 h
No reaction
5 (72%)
4c (R2¼Me, 21%)
2c (R2¼H, 76%)
A plausible mechanism for the generation of 4c is as follows
(Scheme 1). The 2,3-bond on the indole nucleus of 1c is oxidized
and generates an oxirane ring that opens to furnish iminium 7. After
deprotonation at the 3-position, secondary oxidation occurs at the
2,3-position of 8. Finally, the oxirane ring in 9 opens to form 2c and
substitution by methanol at the 2-position affords 4c.
o-nitrophenyl 1d to give 2g,h in 88% and 90% yields, respectively
(entries 1 vs 4,5). Oxidation of p-methoxyphenyl derivative 1i, due
to the decrease in the bulkiness around the 2,3-position of the
indole nucleus, proceeded more smoothly than o-methoxy de-
rivative 1h (entry 5 vs 6). 2-Ethoxycarbonyl indole 1j bearing
a much stronger electron-withdrawing substituent was success-
fully reacted to afford 2j (63%), although a prolonged reaction time
was required (entry 7). The results listed in Tables 1 and 2 indicate
that the electron density on the indole nucleus controlled by the
properties of the 1- and 2-substituents affects the reactivity of this
oxidation. With compounds 2 readily available, we proceeded to
investigate the Mannich-type reaction to assemble the quaternary
carbon center.
Table 2
Oxidation of 2-substituted indoles
Entry
1
R1
R2
Time
Yield (%)
1
2
3
4
5
6
7
d
e
f
g
h
i
PMB
Bn
o-O2NC6H4
o-O2NC6H4
o-O2NC6H4
C6H5
o-MeOC6H4
p-MeOC6H4
EtO2C
1 h
50 min
1 h
50 min
40 min
25 min
5 h
94
96
76
88
90
90
63
PNB
PMB
PMB
PMB
PMB
j
PMB: p-MeOC6H4CH2–, PNB: p-O2NC6H4CH2–.
Scheme 1. Plausible mechanism.
2.2. Mannich-type reaction of 2-hydroxy-1,2-dihydro-3H-
Secondary oxidation is faster than primary oxidation as shown
in Scheme 1, and Greci et al.15d has reported that treatment of
N-ethyl-2-phenylindole with 1.2 equiv of m-CPBA furnished
a dimer like 5 in 52% yield. Therefore, we envisioned that treatment
of 1c with 2.5 equiv of m-CPBA would effectively furnish aminal 2c
or 4c. We examined the oxidation of 1c with 2.5 equiv of m-CPBA in
THF instead of MoO5 reagent (Table 1, entry 4).22 To our delight, 2-
hydroxy-1,2-dihydro-3H-indol-3-one 2c was obtained in 76% yield
without formation of dimer 5.
We also found that p-methoxybenzyl (PMB) and benzyl (Bn)
substituents were best suited for this oxidation in terms of yield
and reaction time (Table 2, entries 1,2). p-Nitrobenzyl (PNB) de-
rivative 1f (entry 3) resulted in slightly lower yield than the PMB
and Bn derivatives. In entries 4–6, the effects of the substituent at
the C2-position of 1 were studied. Phenyl and o-methoxyphenyl
derivatives 1g,h required shorter reaction times compared with
indol-3-one
As shown in Table 3, when a solution of 2d and allyl-
trimethylsilane in CH2Cl2 was treated with TiCl4 at 0 ꢀC, the desired
reaction proceeded smoothly to afford 2,2-substituted 1,2-dihydro-
3H-indol-3-one 3d in 98% yield (entry 1). This result indicates that
2-hydroxy-1,2-dihydro-3H-indol-3-one 2 under acidic conditions
generates C-acyliminium intermediate 10, which reacts efficiently
with allyltrimethylsilane. Although there are many known exam-
ples of N-acyliminium species in Mannich-type reactions,23 10 is
a rare type of C-acyliminium species.24 The reaction of benzyl
derivative 2e provided 3e in high yield (entry 2). In the case of
p-nitrobenzyl derivative 2f, the desired product 3f was obtained in
80% yield together with N-dealkylated product 3k (19%) (entry 3).
Next, the effect of the substituent (R2) at the 2-position was studied.
The reaction of 2-aryl derivatives 2g–i proceeded smoothly to

1238
K. Higuchi et al. / Tetrahedron 66 (2010) 1236–1243
Table 3
3. Conclusions
Mannich-type reaction of 2-hydroxy-1,2-dihydro-3H-indol-3-one
We have developed a general preparative method for 2,2-di-
substituted 1,2-dihydro-3H-indol-3-ones via m-CPBA oxidation of
2-arylindoles followed by a Mannich-type reaction with various
carbon nucleophiles. This method is effective for the construction
of the quaternary carbon center of indoline derivatives. Using this
methodology, we have also completed the total synthesis of
(ꢁ)-hinckdentine A.12 Further application of this methodology to
other alkaloid syntheses and the enantioselective preparation for
2,2-disubstituted 1,2-dihydro-3H-indol-3-ones are now under in-
vestigation in our laboratory.
Entry
2
R1
R2
Time
Yield (%)
1
2
3
4
5
6
7
d
e
f
g
h
i
PMB
Bn
o-O2NC6H4
o-O2NC6H4
o-O2NC6H4
C6H5
o-MeOC6H4
p-MeOC6H4
EtO2C
5 min
5 min
5 min
5 min
5 min
5 min
24 h
98
95
80a
90
93
91
35
PNB
PMB
PMB
PMB
PMB
4. Experimental section
4.1. General
j
a
3k (R1¼H, R2¼o-O2NC6H4) was obtained in 19% yield.
All melting points were measured on a Yanagimoto micro
melting point apparatus and were uncorrected. IR spectra were
recorded on a Shimadzu IRPrestige-21 spectrophotometer. 1H and
13C NMR spectra were measured on a JEOL JNM-AL300 (300 MHz),
JEOL JMN-AL400 (400 MHz) or JEOL JNM-LA500 (500 MHz) spec-
trometer with tetramethylsilane as an internal standard. J-Values
are given in Hertz. Mass spectra were recorded on a JEOL JMS-
DX302 or JEOL JMS 700 instrument with a direct inlet system. El-
emental analyses were obtained using a Yanaco MT-6 elemental
analyzer. Column chromatography was carried out on a silica gel
[Kanto Chemical Co. Inc. (Silica Gel 60 N, Spherical, neutral 40–
produce the corresponding 3g–i in excellent yields (entries 4–6);
however, ester 2j required a prolonged reaction time and gave 3j in
low yield (entry 7).
We subsequently explored the scope and the limitations of the
Mannich-type reaction of 2-hydroxy-1,2-dihydro-3H-indol-3-one
2d with various carbon nucleophiles (Table 4). A modified Petasis–
boronic acid–Mannich reaction with allylboronic ester25 produced
3d in 98% yield (entry 1). Alkylations with silylketenacetal and
silylenolate also furnished the corresponding carbonyl compounds
3l and 3m in highyields, respectively(entries 2,3). When using labile
vinyloxytrimethylsilane as a nucleophile under acidic conditions, 3n
was given in low yield (entry 4). The use of camphor sulfonic acid
(CSA) instead of TiCl4 improved the yield of 3n to 56% with recovery
of 41% of the starting material 2d (entry 5). Furan and N-methyl
indole also worked efficiently in the reaction of 2d with CSA to
provide 3o and 3p in excellent yields, respectively (entries 6,7).
50 mm) and Merck Ltd. (Silica Gel 60, 230–400 mesh)].
4.2. Preparation of 2-aryindoles 1a–j
4.2.1. 1-Acetyl-2-(2-nitrophenyl)-1H-indole (1a). To a solution of
2-(2-nitrophenyl)indole (1b)26 (5.5 g, 23 mmol), Bu4NHSO4 (81 mg,
2.3 mmol), and NaOH (powder 5.4 g, 133 mmol) in CH2Cl2 (54 mL)
was slowly dropped a solution AcCl (3.7 mL, 52 mmol) in CH2Cl2
(28 mL) via pressure equalizing dropping funnel at 0 ꢀC. After
stirring 30 min at the same temperature, the reaction mixture was
filtered and the filtrate was washed with brine. The organic layer
was dried over anhydrous MgSO4 and the filtrate was concentrated.
The residue was purified by column chromatography (n-hexane–
AcOEt¼5:1) to give 1a (3.5 g, 54%) as yellow amorphous: IR (CHCl3)
Table 4
Mannich-type reaction with various nucleophiles
n
d
1705, 1530, 1371, 1348, 1311 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
2.41 (3H, s), 6.54 (1H, s), 7.28 (1H, t, J¼7.2 Hz), 7.35 (1H, d,
Entry
1
Nu
Acid
TiCl4
R
Yield (%)
J¼8.4 Hz), 7.48 (1H, d, J¼7.6 Hz), 7.50–7.58 (2H, m), 7.64 (1H, d,
J¼7.2 Hz), 8.05 (1H, d, J¼8.4 Hz), 8.10 (1H, d, J¼8.0 Hz); 13C NMR
d 98
(100 MHz, CDCl3) d 26.7,111.4,115.3,120.9,123.3,124.3,125.0, 129.3,
129.4, 129.9, 132.2, 132.8, 135.1, 136.2, 148.0, 169.3; HRMS (EI) calcd
for C16H12N2O3 280.0848, found 280.0842.
2
TiCl4
l 93
4.2.2. General Procedure for Synthesis of 1c–j. A solution of
2-substituted indole in DMF was added NaH at 0 ꢀC. After 10 min
stirring, to the mixture was added tetrabutylammonium iodide
(TBAI) and alkyl halide (R1-X) and the mixture was stirred at room
temperature until starting material consumption monitored by TLC.
The mixture was added satd aqueous NH4Cl and extracted with
Et2O. The organic layer was washed with brine and dried over an-
hydrous MgSO4. The concentrated residue was purified by column
chromatography with n-hexane–AcOEt as an eluent to give 1.
3
4
TiCl4
TiCl4
m 98
n 39
5
6
CSA
CSA
n 56a
o 98
4.2.2.1. 1-Methoxymethyl-2-(2-nitrophenyl)-1H-indole (1c). 2-
(2-Nitrophenyl)indole (1.0 g, 4.2 mmol); MOMCl (474 mL,
6.3 mmol); NaH (252 mg, 60%, 6.3 mmol); TBAI (155 mg,
7
CSA
p 98
0.42 mmol); DMF (42 mL); 10 min; n-hexane–AcOEt¼5:1; 1c (1.1 g,
93%); orange oil: IR (CHCl3)
n ;
1531, 1456, 1348 cmꢂ1 1H NMR
a
2d was recovered in 41% yield.
(400 MHz, CDCl3)
d 3.16 (3H, s), 5.24 (2H, s), 6.53 (1H, s), 7.15–7.20

K. Higuchi et al. / Tetrahedron 66 (2010) 1236–1243
1239
(1H, m), 7.27 (1H, t, J¼7.2 Hz), 7.49–7.65 (5H, m), 7.98 (1H, d,
120.5, 121.3, 121.8, 127.5, 128.3, 130.0, 130.2, 132.6, 137.0, 138.4,
157.3, 158.3; HRMS (EI) calcd for C23H21NO2 343.1572, found
343.1569.
J¼8.4 Hz); 13C NMR (100 MHz, CDCl3)
d 55.8, 74.9,104.3,109.9,120.6,
120.7,122.6,124.0,126.8,127.9,129.6,132.1,133.4,135.2,137.6,149.6;
HRMS (EI) calcd for C16H14N2O3 282.1004, found 282.1000.
4.2.2.7. 1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-1H-indole
4.2.2.2. 1-(4-Methoxybenzyl)-2-(2-nitrophenyl)-1H-indole
(1d). 2-(2-Nitrophenyl)indole (10.0 g, 42 mmol); PMBCl (6.9 mL,
50 mmol); NaH (2.5 g, 60%, 63 mmol); DMF (0.42 L); TBAI (1.6 g,
4.2 mmol); 2.5 h; n-hexane–AcOEt¼10:1; 1d (13.5 g, 90%); yellow
(1i). 2-(4-Methoxyphenyl)indole28 (66 mg, 0.30 mmol); PMBCl
(44
30
46%); white solids: IR (CHCl3)
1H NMR (300 MHz, CDCl3)
3.75 (3H, s), 3.82 (3H, s), 5.27 (2H, s),
m
m
L, 0.33 mmol); NaH (18 mg, 60%, 0.44 mmol); TBAI (11 mg,
mol); DMF (3.0 mL); 2.5 h; n-hexane–CH2Cl2¼1:1; 1i (46 mg,
1612, 1512, 1499, 1460, 1248 cmꢂ1
n
;
crystals: mp 131–133 ꢀC; IR (CHCl3)
n
1530, 1512, 1348 cmꢂ1
;
1H
d
NMR (400 MHz, CDCl3)
d
3.72 (3H, s), 5.13 (2H, s), 6.52 (1H, s), 6.71
6.57 (1H, s), 6.79 (2H, d, J¼9.0 Hz), 6.87–6.96 (4H, m), 7.00–7.21 (3H,
(2H, d, J¼8.4 Hz), 6.83 (2H, d, J¼8.4 Hz), 7.12 (1H, tt, J¼6.8, 1.6 Hz),
7.17 (1H, tt, J¼6.8, 1.6 Hz), 7.23 (1H, d, J¼7.6 Hz), 7.31–7.37 (1H, m),
7.48–7.54 (2H, m), 7.63 (1H, d, J¼7.6 Hz), 7.95 (1H, dt, J¼9.6, 4.0 Hz);
m), 7.35 (2H, d, J¼9.0 Hz), 7.60–7.67 (1H, m); 13C NMR (100 MHz,
CDCl3)
d 47.1, 55.3, 55.4, 101.6, 110.4, 113.9, 114.0, 119.9, 120.2, 121.4,
125.0, 127.0, 128.2, 130.2, 130.3, 137.6, 141.4, 158.5, 159.3; HRMS (EI)
calcd for C23H21NO2 343.1572, found 343.1578.
13C NMR (100 MHz, CDCl3)
d 47.5, 55.2, 103.1, 110.4, 113.8, 120.0,
120.7,122.2,123.9,127.2,127.4,127.9,129.4,132.0,133.3,135.1,137.2,
149.7, 158.6. Anal. Calcd for C22H18N2O3: C, 73.73; H, 5.06; N, 7.82.
Found: C, 73.95; H, 5.19; N, 7.83; HRMS (EI) calcd for C22H18N2O3
358.1317, found 358.1312.
4.2.2.8. Ethyl
1-(4-methoxybenzyl)-1H-indole-2-carboxylate
(1j). Ethyl indole-2-carboxyrate (1.0 g, 5.3 mmol); PMBCl (0.79 mL,
5.8 mmol); NaH (316 mg, 60%, 63 mmol); TBAI (196 mg,
0.53 mmol); DMF (52 mL); 1.5 h; n-hexane–AcOEt¼10:1; 1j (1.5 g,
4.2.2.3. 1-Benzyl-2-(2-nitrophenyl)-1H-indole (1e). 2-(2-Nitro-
phenyl)indole (1.0 g, 4.2 mmol); BnBr (0.55 mL, 5.0 mmol); NaH
(252 mg, 60%, 6.3 mmol); DMF (42 mL); TBAI (155 mg, 0.42 mmol);
45 min; n-hexane–AcOEt¼5:1; 1e (1.2 g, 89%); orange solids: IR
91%); colorless oil: IR (CHCl3)
1H NMR (400 MHz, CDCl3)
n ;
1703, 1612, 1514, 1458, 1248 cmꢂ1
d
1.33 (3H, t, J¼7.2 Hz), 3.68 (3H, s), 4.31
(2H, q, J¼7.2 Hz), 5.74 (2H, s), 6.74 (2H, d, J¼8.8 Hz), 7.00 (2H, d,
J¼8.4 Hz), 7.12 (1H, t, J¼7.2 Hz), 7.27 (1H, ddd, J¼1.2, 6.8, 8.0 Hz),
7.34 (1H, d, J¼9.2 Hz), 7.36 (1H, s), 7.67 (1H, d, J¼8.0 Hz); 13C NMR
(CHCl3)
n ; d 5.18
1529, 1460, 1348 cmꢂ1 1H NMR (400 MHz, CDCl3)
(2H, s), 6.53 (1H, s), 6.86–6.93 (2H, m), 7.09–7.23 (6H, m), 7.30–7.33
(100 MHz, CDCl3) d 14.4, 47.3, 55.1, 60.5, 110.7, 110.8, 113.8, 120.6,
(1H, m), 7.44–7.48 (2H, m), 7.63 (1H, d, J¼6.8 Hz), 7.89–7.94 (1H, m);
122.4, 125.0, 126.0, 127.5, 130.2, 139.2, 158.4, 161.7; HRMS (EI) calcd
for C19H19NO3 309.1365, found 309.1366.
13C NMR (100 MHz, CDCl3)
d 47.9, 103.2, 110.3, 120.0, 120.7, 122.2,
123.9, 126.1, 127.0, 127.1, 127.8, 128.4, 129.4, 132.0, 133.2, 135.1, 137.2,
137.3, 149.7; HRMS (EI) calcd for C21H16N2O2 328.1212, found
328.1217.
4.3. Oxidation of 2-substituted indoles
4.3.1. Representative procedure for MoO5 HMPA H2O oxidation
of 2-arylindoles.
4.2.2.4. 1-(4-Nitrobenzyl)-2-(2-nitrophenyl)-1H-indole (1f). 2-(2-
Nitrophenyl)indole (300 mg, 1.3 mmol); PNBBr (300 mg, 1.4 mmol);
NaH (76 mg, 60%, 1.9 mmol); DMF (13 mL); 3 h; n-hexane–
4.3.1.1. 2-(2-Nitrophenyl)-2-[2-(2-nitrophenyl)-1H-indol-3-
yl]1,2-dihydro-3H-indol-3-one (5). A solution of 1b (23.8 mg,
0.1 mmol) in MeOH (1.0 mL) was added MoO5 HMPA H2O (36.6 mg,
0.1 mmol) and the mixture was stirred at room temperature for five
days. The mixture was quenched with satd aqueous Na2SO3 and
concentrated under reduced pressure. The residue was extracted
with AcOEt and the organic layer was washed by brine and dried
over anhydrous MgSO4. The concentrated residue was purified by
column chromatography (n-hexane–AcOEt¼5:1) to give 5 (17.7 mg,
AcOEt¼4:1; 1f (240 mg, 51%); orange amorphous: IR (CHCl3)
n 1529,
5.29 (2H, s), 6.59 (1H,
1458, 1348 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
s), 7.07 (2H, d, J¼8.8 Hz), 7.13 (1H, dd, J¼1.2, 7.6 Hz), 7.15–7.23 (2H, m),
7.33–7.38 (1H, m), 7.54–7.60 (2H, m), 7.64–7.68 (1H, m), 7.95–8.00
(1H, m), 8.06 (2H, d, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3)
d 47.4,
104.0, 109.9, 120.5, 121.1, 122.7, 123.8, 124.2, 126.6, 126.9, 128.0, 129.9,
132.2, 133.1, 134.9, 137.0, 144.6, 147.1, 149.8; HRMS (EI) calcd for
C21H15N3O4 373.1063, found 373.1058.
72%) as yellow crystals: mp 248–250 ꢀC; IR (CHCl3)
n
3456, 1714,
4.2.2.5. 1-(4-Methoxybenzyl)-2-phenyl-1H-indole (1g). 2-Phe-
nylindole (1.0 g, 5.2 mmol); PMBCl (0.7 mL, 5.2 mmol); NaH
(250 mg, 60%, 5.2 mmol); TBAI (192 mg, 0.52 mmol); DMF (52 mL);
3 h; n-hexane–CH2Cl2¼1:2; 1g (960 mg, 60%); colorless crystals:
1616, 1530, 1358 cmꢂ1 1H NMR (400 MHz, DMSO-d6)
; d 6.40–7.70
(16H, m), 8.10 (1H, m), 11.29 (1H, s). Anal. Calcd for C28H18N4O5: C,
68.57; H, 3.70; N, 11.42. Found: C, 68.37; H, 3.95; N, 11.31; HRMS
(FAB) calcd for C28H18N4O5 490.1277, found 490.1360.
mp 161–164 ꢀC; IR (CHCl3)
n
1612, 1512, 1462, 1346, 1248 cmꢂ1; 1H
NMR (300 MHz, CDCl3)
(2H, d, J¼8.4 Hz), 6.93 (2H, d, J¼8.4 Hz), 7.09–7.22 (3H, m), 7.33–
7.45 (5H, m), 7.63–7.68 (1H, m); 13C NMR (100 MHz, CDCl3)
47.2,
55.3, 102.2, 110.5, 114.0, 120.0, 120.4, 121.7, 127.0, 127.8, 128.2, 128.4,
129.1, 130.1, 132.6, 137.8, 141.6, 158.5; HRMS (EI) calcd for C22H19NO
313.1467, found 313.1468.
d
3.74 (3H, s), 5.30 (2H, s), 6.63 (1H, s), 6.78
4.3.1.2. 2-Methoxy-1-methoxymethyl-2-(2-nitrophenyl)-1,2-di-
hydro-3H-indol-3-one (4c). Compound 1c (36.3 mg, 0.13 mmol);
MoO5 HMPA H2O (36.6 mg, 0.1 mmol); MeOH (1.3 mL); four weeks;
n-hexane–AcOEt¼5:1; 4c (8.9 mg, 21%); orange oil: IR (CHCl3)
d
n
1722, 1614,1531, 1362 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 3.22 (3H,
s), 3.25 (3H, s), 4.39 (1H, d, J¼11.1 Hz), 4.64 (1H, d, J¼10.8 Hz), 6.90–
6.99 (2H, m), 7.40–7.69 (5H, m), 8.12 (1H, d, J¼7.8 Hz); 13C NMR
4.2.2.6. 1-(4-Methoxybenzyl)-2-(2-methoxyphenyl)-1H-indole
(1h). 2-(2-Methoxyphenyl)indole27 (2.5 g, 11 mmol); PMBCl
(1.8 mL, 13 mmol); NaH (672 mg, 60%, 17 mmol); TBAI (406 mg,
0.11 mmol); DMF (0.11 L); 30 min; n-hexane–AcOEt¼10:1; 1h
(100 MHz, CDCl3) d 51.7, 56.0, 74.7, 91.2, 108.7, 119.2, 120.4, 123.4,
124.2, 129.3, 129.8, 130.7, 131.8, 137.9, 148.5, 158.9, 196.7; HRMS (EI)
calcd for C17H16N2O5 328.1059, found 328.1057.
(2.7 g, 71%); colorless oil: IR (CHCl3)
NMR (300 MHz, CDCl3)
n
1512, 1460, 1248 cmꢂ1
;
1H
4.3.2. General procedure for m-CPBA oxidation of 2-arylindole.
m-CPBA was added to a solution of indole 1 in THF. After stirring at
room temperature, the mixture was cooled with ice bath, quenched
with satd aqueous Na2SO3, and neutralized with satd aqueous
NaHCO3. The resulting precipitate was filtered off and rinsed with
AcOEt. The filtrate was washed with brine, dried over anhydrous
d
3.53 (3H, s), 3.60 (3H, s), 5.07 (2H, s), 6.53
(1H, s), 6.66 (2H, d, J¼8.7 Hz), 6.83 (2H, d, J¼8.7), 6.85 (1H, d,
J¼8.7 Hz), 6.93 (1H, td, J¼7.2, 0.9 Hz), 7.00–7.11 (2H, m), 7.12–7.19
(1H, m), 7.26–7.34 (2H, m), 7.57–7.65 (1H, m); 13C NMR (75 MHz,
CDCl3)
d 47.2, 54.96, 55.00, 102.4, 110.4, 110.6, 113.6, 119.4, 120.3,

1240
K. Higuchi et al. / Tetrahedron 66 (2010) 1236–1243
MgSO4, and concentrated under reduced pressure. The residue was
purified by column chromatography with n-hexane–AcOEt as an
eluent to afford 2c–j.
d, J¼16.4 Hz), 6.59 (1H, d, J¼8.4 Hz), 6.75 (1H, t, J¼7.6 Hz), 6.81 (2H,
d, J¼8.8 Hz), 7.22 (2H, d, J¼8.4 Hz), 7.28–7.46 (6H, m), 7.55 (1H, d,
J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 38.3, 48.1, 55.6, 76.7, 109.4,
114.1, 117.9, 119.7, 120.2, 125.4, 126.8, 128.2, 128.7, 129.1, 129.7, 131.8,
137.7, 158.9, 161.8, 201.3. Anal. Calcd for C22H19NO3: C, 76.50; H,
5.54; N, 4.06. Found: C, 76.55; H, 5.64; N, 4.11; HRMS (EI) calcd for
C22H19NO3 345.1365, found 345.1361.
4.3.2.1. 2-Hydroxy-1-methoxymethyl-2-(2-nitrophenyl)-1,2-dihy-
dro-3H-indol-3-one (2c). Compound 1c (951 mg, 3.4 mmol);
m-CPBA (1.9 g, 77%, 8.5 mmol); THF (34 mL); 2 h; n-hexane–
AcOEt¼5:1–1:1; 2c (807 mg, 76%); orange oil: IR (CHCl3)
n 1724,
3.25 (3H, s), 4.16 (1H,
1614, 1531 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
4.3.2.6. 2-Hydroxy-1-(4-methoxybenzyl)-2-(2-methoxyphenyl)-
1,2-dihydro-3H-indol-3-one (2h). Compound 1h (1.5 g, 4.4 mmol);
m-CPBA (2.4 g, 77%, 10.9 mmol); THF (44 mL); 40 min; n-hexane–
AcOEt¼5:1; 2h (1.5 g, 90%); yellow crystals: mp: 139–141 ꢀC; IR
s), 4.42 (1H, d, J¼10.8 Hz), 4.82 (1H, d, J¼10.8 Hz), 6.96 (1H, d,
J¼8.4 Hz), 7.03 (1H, td, J¼7.2, 0.8 Hz), 7.51–7.58 (2H, m), 7.67–7.77
(3H, m), 8.24 (1H, dd, J¼1.6, 8.0 Hz); 13C NMR (100 MHz, CDCl3)
d
56.1, 75.3, 87.9, 109.6, 118.6, 121.1, 123.8, 125.5, 129.8, 130.1, 130.8,
(CHCl3) n ;
3543, 1715, 1614, 1489 cmꢂ1 1H NMR (400 MHz, CDCl3)
132.2, 136.9, 148.0, 157.0, 195.0; HRMS (EI) calcd for C16H14N2O5
314.0903, found 314.0898.
d
3.48 (1H, s), 3.56 (3H, s), 3.75 (3H, s), 4.28 (1H, d, J¼16.0 Hz), 4.33
(1H, d, J¼16.0 Hz), 6.51 (1H, d, J¼8.4 Hz), 6.73–6.80 (1H, m), 6.75
(2H, d, J¼8.8 Hz), 6.83 (1H, d, J¼8.4 Hz), 7.00 (1H, t, J¼7.2 Hz), 7.10
(2H, d, J¼8.4 Hz), 7.31 (1H, t, J¼7.6 Hz), 7.36 (1H, t, J¼7.6 Hz), 7.63
(1H, d, J¼7.6 Hz), 7.71 (1H, d, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
4.3.2.2. 2-Hydroxy-1-(4-methoxybenzyl)-2-(2-nitrophenyl)-1,2-
dihydro-3H-indol-3-one (2d). Compound 1d (11.5 g, 31 mmol);
m-CPBA (21.1 g, 77%, 94 mmol); THF (0.31 L); 2 h; n-hexane–
AcOEt¼5:1–3:1; 2d (11.8 g, 94%); yellow crystals: mp 143–145 ꢀC;
d
46.0, 55.3, 55.7, 89.1, 108.9, 111.5, 113.7, 117.8, 118.6, 120.9, 124.8,
126.1,128.0,128.4,130.0,130.1,137.3,156.6,158.4,159.3, 200.0. Anal.
Calcd for C23H21NO4: C, 73.58; H, 5.64; N, 3.73. Found: C, 73.74; H,
5.85; N, 3.74; HRMS (EI) calcd for C23H21NO4 375.1471, found
375.1467.
IR (CHCl3)
CDCl3)
n
1703, 1612, 1529, 1512, 1483 cmꢂ1; 1H NMR (400 MHz,
3.16 (1H, s), 3.75 (3H, s), 4.25 (1H, d, J¼16.4 Hz), 4.35 (1H, d,
d
J¼16.4 Hz), 6.65 (1H, d, J¼8.0 Hz), 6.74 (2H, d, J¼8.8 Hz), 6.92 (1H, t,
J¼7.2 Hz), 7.05 (2H, d, J¼8.4 Hz), 7.44 (1H, t, J¼8.0 Hz), 7.49 (1H, t,
J¼7.2 Hz), 7.64 (1H, t, J¼7.6 Hz), 7.72 (2H, t, J¼7.6 Hz), 8.11 (1H, d,
4.3.2.7. 2-Hydroxy-1-(4-methoxybenzyl)-2-(4-methoxyphenyl)-
1,2-dihydro-3H-indol-3-one (2i). Compound 1i (1.0 g, 2.9 mmol);
m-CPBA (1.6 g, 77%, 7.3 mmol); THF (29 mL); 25 min; n-hexane–
J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 46.5, 55.3, 88.4, 110.1, 113.8,
118.5, 119.8, 124.4, 125.5, 128.4, 128.8, 129.7, 130.5, 131.0, 132.5,
137.5,148.0,158.5,159.8,196.8. Anal. Calcd for C22H18N2O5: C, 67.69;
H, 4.65; N, 7.18. Found: C, 67.90; H, 4.72; N, 7.17; HRMS (EI) calcd for
C22H18N2O5 390.1216, found 390.1212.
AcOEt¼3:1; 2i (1.1 g, 90%); yellow oil: IR (CHCl3)
n 3564, 1710, 1614,
1512, 1249 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
3.40 (1H, s), 3.76 (3H,
s), 3.79 (3H, s), 4.33 (2H, s), 6.57 (1H, d, J¼8.0 Hz), 6.74 (1H, t,
J¼7.2 Hz), 6.81 (2H, d, J¼8.4 Hz), 6.87 (2H, d, J¼8.8 Hz), 7.22 (2H, d,
J¼8.4 Hz), 7.35 (2H, d, J¼8.8 Hz), 7.40 (1H, d, J¼8.0 Hz), 7.54 (1H, d,
4.3.2.3. 1-Benzyl-2-hydroxy-2-(2-nitrophenyl)-1,2-dihydro-3H-
indol-3-one (2e). Compound 1e (1.0 g, 3.1 mmol); m-CPBA (2.3 g,
77%, 9.2 mmol); THF (30 mL); 50 min; n-hexane–AcOEt¼3:1; 2e
J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 46.6, 55.29, 55.34, 91.4,
108.8, 113.9, 114.1, 117.5, 118.2, 125.8, 127.3, 128.2, 129.6, 132.2, 138.3,
158.5, 159.8, 160.3, 199.5; HRMS (EI) calcd for C23H21NO4 375.1471,
found 375.1467.
(1.1 g, 96%); orange crystals: mp 141–143 ꢀC; IR (CHCl3)
n
1703,
1612, 1530, 1483 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 3.17 (1H, s),
4.32 (1H, d, J¼16.0 Hz), 4.42 (1H, d, J¼16.4 Hz), 6.62 (1H, d,
J¼8.0 Hz), 6.93 (1H, t, J¼7.6 Hz), 7.10–7.22 (5H, m), 7.44 (1H, ddd,
J¼1.2, 7.2, 8.4 Hz), 7.48 (1H, dt, J¼1.2, 7.6 Hz), 7.64 (1H, dt, J¼1.2,
7.6 Hz), 7.72 (2H, dt, J¼1.2, 7.6 Hz), 8.13 (1H, dd, J¼1.2, 7.6 Hz); 13C
4.3.2.8. Ethyl
2-hydroxy-1-(4-methoxybenzyl)-3-oxo-1,2-dihy-
dro-3H-indol-2-carboxylate (2j). Compound 1j (500 mg, 1.6 mmol);
m-CPBA (907 mg, 77%, 4.1 mmol); THF (16 mL); 5 h; n-
hexane:AcOEt¼5:1; 2j (350 mg, 63%); yellow crystals: mp
NMR (100 MHz, CDCl3)
d 47.0, 88.4, 110.1, 118.5, 119.9, 124.5, 125.5,
127.0, 127.1, 128.4, 129.8, 130.5, 131.0, 132.5, 136.9, 137.6, 147.9, 159.7,
196.7. Anal. Calcd for C21H16N2O4: C, 69.99; H, 4.48; N, 7.77. Found:
C, 69.83; H, 4.72; N, 7.77; HRMS (EI) calcd for C21H16N2O4 360.1110,
found 360.1106.
79–82 ꢀC; IR (CHCl3) 3497, 1740, 1722, 1614, 1512, 1483 cmꢂ1 1H
n ;
NMR (400 MHz, CDCl3)
d
1.13 (3H, t, J¼7.2 Hz), 3.78 (3H, s), 4.01 (1H,
ddd, J¼6.8, 10.4, 14.4 Hz), 4.11 (1H, ddd, J¼7.2, 10.4, 14.4 Hz), 4.40
(1H, d, J¼16.0 Hz), 4.46 (1H, d, J¼16.0 Hz), 6.65 (1H, d, J¼8.0 Hz),
6.79 (1H, t, J¼7.2 Hz), 6.85 (2H, d, J¼8.8 Hz), 7.27 (2H, d, J¼7.6 Hz),
7.41 (1H, ddd, J¼1.6, 7.6, 8.8 Hz), 7.57 (1H, d, J¼7.6 Hz); 13C NMR
4.3.2.4. 2-Hydroxy-1-(4-nitrobenzyl)-2-(2-nitrophenyl)-1,2-dihy-
dro-3H-indol-3-one (2f). Compound 1f (500 mg, 1.3 mmol);
m-CPBA (925 mg, 77%, 4.0 mmol); THF (13 mL); 1 h; n-hexane–
AcOEt¼3:1; 2f (414 mg, 76%); yellow crystals: mp 137–138 ꢀC; IR
(100 MHz, CDCl3)
d 14.0, 46.0, 55.3, 63.4, 87.6, 109.3, 113.8, 117.8,
118.8, 125.4, 128.4, 128.6, 138.2, 158.8, 161.0, 168.9, 195.3. Anal. Calcd
for C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found: C, 66.73; H, 5.72; N,
4.19; HRMS (EI) calcd for C19H19NO5 341.1263, found 341.1266.
(CHCl3)
(400 MHz, CDCl3)
n ;
1722, 1612, 1528, 1477, 1348, 1261 cmꢂ1 1H NMR
d
3.84 (1H, s), 4.46 (1H, d, J¼16.8 Hz), 4.51 (1H, d,
J¼17.2 Hz), 6.54 (1H, d, J¼8.0 Hz), 6.98 (1H, t, J¼7.6 Hz), 7.31 (2H, d,
4.4. General procedure for Mannich-type reaction of
2-hydroxy-1,2-dihydro-3H-indol-3-ones 2
J¼8.0 Hz), 7.45–7.74 (5H, m), 8.05 (2H, d, J¼8.8 Hz), 8.10 (1H, d,
J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 46.6, 88.2, 109.8, 118.7,
120.5, 123.6, 124.6, 125.8, 127.8, 130.1, 130.3, 130.7, 132.7, 137.8,
144.5, 147.0, 147.9, 159.1, 196.3. Anal. Calcd for C21H15N3O6: C, 62.22;
H, 3.73; N, 10.37. Found: C, 62.37; H, 3.72; N, 10.28; HRMS (EI) calcd
for C21H15N3O6 405.0961, found 405.0964.
To a solution of 2 in CH2Cl2 was added nucleophile and acids at
0 ꢀC. After starting material consumption monitored by TLC, the
resulting mixture was neutralized with satd aqueous NaHCO3 at
0 ꢀC and extracted with CH2Cl2. Combined organic layer was
washed with brine, dried over anhydrous MgSO4, and then con-
centrated under reduced pressure. The residue was purified by
column chromatography with n-hexane–AcOEt as an eluent to af-
ford 3d–p.
4.3.2.5. 2-Hydroxy-1-(4-methoxybenzyl)-2-phenyl-1,2-dihydro-
3H-indol-3-one (2g). Compound 1g (300 mg, 0.93 mmol); m-CPBA
(526 mg, 77%, 2.4 mmol); THF (9.3 mL); 50 min; n-hexane–
AcOEt¼4:1; 2g (292 mg, 88%); yellow crystals: mp 136–138 ꢀC; IR
(CHCl3)
CDCl3)
n
3564, 1713, 1614, 1512, 1485 cmꢂ1
;
1H NMR (400 MHz,
4.4.1. 2-Allyl-1-(4-methoxybenzyl)-2-(2-nitrophenyl)-1,2-dihydro-
3H-indol-3-one (3d). Compound 2d (100 mg, 0.26 mmol);
d
3.34 (1H, s), 3.77 (3H, s), 4.31 (1H, d, J¼16.0 Hz), 4.36 (1H,

K. Higuchi et al. / Tetrahedron 66 (2010) 1236–1243
1241
allyltrimethylsilane (81
CH2Cl2, 0.28 mmol); CH2Cl2 (2.6 mL); n-hexane–AcOEt¼4:1; 3d
(104 mg, 98%); yellow crystals: mp 110–112 ꢀC; IR (CHCl3)
1703,
1612, 1530, 1512 cmꢂ1 1H NMR (400 MHz, CDCl3)
2.90 (1H, dd,
m
L, 0.51 mmol); TiCl4 (0.28 mL, 1.0 M in
J¼7.2, 14.0 Hz), 3.17 (1H, dd, J¼6.8, 14.0 Hz), 3.77 (3H, s), 4.23 (1H, d,
J¼16.4 Hz), 4.50 (1H, d, J¼16.4 Hz), 4.91 (1H, dd, J¼10.0 Hz), 5.02
(1H, dd, J¼1.2, 16.8 Hz), 5.50 (1H, tdd, J¼7.2, 10.4, 17.2 Hz), 6.70 (1H,
d, J¼8.4 Hz), 6.75 (1H, d, J¼7.2 Hz), 6.79 (2H, d, J¼8.4 Hz), 7.09 (2H,
d, J¼8.8 Hz), 7.19–7.34 (5H, m), 7.41 (1H, ddd, J¼1.2, 7.2, 8.4 Hz), 7.61
n
;
d
J¼6.8, 13.6 Hz), 3.09 (1H, dd, J¼7.2, 13.6 Hz), 3.75 (3H, s), 4.22 (1H,
d, J¼16.0 Hz), 4.44 (1H, d, J¼16.0 Hz), 4.86 (1H, dd, J¼1.6, 10.0 Hz),
5.00 (1H, dd, J¼1.6, 16.8 Hz), 5.33, (1H, tdd, J¼6.8, 10.0, 16.8 Hz),
6.73 (2H, d, J¼8.8 Hz), 6.76 (1H, d, J¼8.0 Hz), 6.87 (1H, t, J¼7.6 Hz),
7.03 (2H, d, J¼8.8 Hz), 7.40–7.48 (2H, m), 7.52–7.59 (2H, m), 7.64–
(1H, d, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 38.3, 48.1, 55.6, 76.7,
109.4, 114.1, 117.9, 119.7, 120.2, 125.4, 126.8, 128.2, 128.7, 129.1, 129.7,
131.8, 137.7 (2C), 158.9, 161.8, 201.3. Anal. Calcd for C25H23NO2: C,
81.27; H, 6.27; N, 3.79. Found: C, 81.53; H, 6.46; N, 3.77; HRMS (EI)
calcd for C25H23NO2 369.1729, found 369.1731.
7.68 (2H, m); 13C NMR (100 MHz, CDCl3)
d 40.6, 47.3, 55.3, 73.0,
108.9, 113.7, 118.8, 119.7, 120.8, 124.3, 124.6, 128.7, 129.0, 129.8,
130.2, 130.3, 130.5, 131.7, 136.8, 149.3, 158.8, 159.6, 199.5. Anal.
Calcd for C25H22N2O4: C, 72.45; H, 5.35; N, 6.76. Found: C, 72.40; H,
5.47; N, 6.73; HRMS (EI) calcd for C25H22N2O4 414.1580, found
414.1579.
4.4.5. 2-Allyl-1-(4-methoxybenzyl)-2-(2-methoxyphenyl)-1,2-dihy-
dro-3H-indol-3-one (3h). Compound 2h (30 mg, 80
trimethylsilane (88 L, 0.16 mmol); TiCl4 (88 L, 1.0 M in CH2Cl2,
mol); CH2Cl2 (0.80 mL); n-hexane–AcOEt¼4:1; 3h (30 mg, 93%);
green-yellow crystals: mp 104–105 ꢀC; IR (CHCl3)
1695, 1614,
1512, 1489, 1319, 1247 cmꢂ1; 1H NMR (400 MHz, CDCl3)
2.93 (1H,
mmol); allyl-
m
m
8
m
n
4.4.2. 2-Allyl-1-benzyl-2-(2-nitrophenyl)-1,2-dihydro-3H-indol-3-
d
one (3e). Compound 2e (100 mg, 0.28 mmol); allyltrimethylsilane
dd, J¼7.2, 14.0 Hz), 3.02 (1H, dd, J¼7.2, 13.6 Hz), 3.38 (3H, s), 3.73
(3H, s), 4.19 (1H, d, J¼16.0 Hz), 4.31 (1H, d, J¼16.0 Hz), 4.93 (1H, dd,
J¼0.8, 10.0 Hz), 5.08 (1H, dd, J¼1.6, 17.2 Hz), 5.53 (1H, tdd, J¼7.2,
10.0, 17.2 Hz), 6.57 (1H, d, J¼8.4 Hz), 6.68–6.73 (1H, m), 6.71 (2H, d,
J¼8.4 Hz), 6.76 (1H, d, J¼8.0 Hz), 6.91–6.99 (1H, m), 6.94 (2H, d,
J¼8.8 Hz), 7.23–7.29 (1H, m), 7.30–7.36 (1H, m), 7.45 (1H, dd, J¼1.6,
(88
CH2Cl2 (2.8 mL); n-hexane–AcOEt¼4:1; 3e (107 mg, 95%); orange
crystals: mp 102–104 ꢀC; IR (CHCl3)
1703, 1612, 1530, 1483, 1358,
1323 cmꢂ1 1H NMR (400 MHz, CDCl3)
2.91 (1H, dd, J¼6.4,
mL, 0.56 mmol); TiCl4 (0.31 mL, 1.0 M in CH2Cl2, 0.31 mmol);
n
;
d
14.0 Hz), 3.09 (1H, dd, J¼7.2, 14.0 Hz), 4.28 (1H, d, J¼16.0 Hz), 4.50
(1H, d, J¼16.4 Hz), 4.87 (1H, dd, J¼1.2, 10.4 Hz), 4.98 (1H, dd, J¼1.2,
16.8 Hz), 5.35 (1H, tdd, J¼6.8, 10.0, 16.8 Hz), 6.74 (1H, d, J¼8.4 Hz),
6.87 (1H, t, J¼7.2 Hz), 7.12 (2H, dd, J¼3.6, 7.2 Hz), 7.17–7.22 (3H, m),
7.39–7.48 (2H, m), 7.54 (1H, dd, J¼1.2, 6.8 Hz), 7.56 (1H, dd, J¼1.2,
8.0 Hz), 7.63 (1H, d, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 39.1,
46.7, 55.1, 55.2, 73.0, 108.6, 111.6, 113.6, 116.5, 119.0, 120.6, 122.0,
123.5, 127.0, 128.2, 128.7, 129.5, 130.0, 131.4, 136.0, 157.2, 158.3,
159.6, 202.7. Anal. Calcd for C26H25NO3: C, 78.17; H, 6.31; N, 3.51.
Found: C, 78.39; H, 6.44; N, 3.71; HRMS (EI) calcd for C26H25NO3
399.1834, found 399.1839.
7.6 Hz), 7.67 (2H, d, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 40.5,
47.9, 73.1, 109.0, 118.9, 119.7, 120.9, 124.3, 124.7, 127.4, 127.6, 128.3,
129.1, 130.28, 130.34, 131.8, 136.77, 136.80, 149.3, 159.5, 199.3. Anal.
Calcd for C24H20N2O3: C, 74.98; H, 5.24; N, 7.29. Found: C, 75.27; H,
5.43; N, 7.32; HRMS (EI) calcd for C24H20N2O3 384.1474, found
384.1477.
4.4.6. 2-Allyl-1-(4-methoxybenzyl)-2-(4-methoxyphenyl)-1,2-dihy-
dro-3H-indol-3-one (3i). Compound 2i (300 mg, 0.80 mmol);
allyltrimethylsilane (253
CH2Cl2, 0.88 mmol); CH2Cl2 (8.0 mL); n-hexane–AcOEt¼4:1; 3i
(292 mg, 91%); green-yellow oil: IR (CHCl3) 1694, 1612, 1512, 1485,
1465, 1319 cmꢂ1 1H NMR (400 MHz, CDCl3)
2.90 (1H, dd, J¼7.2,
mL, 1.6 mmol); TiCl4 (880 mL, 1.0 M in
4.4.3. 2-Allyl-1-(4-nitrobenzyl)-2-(2-nitrophenyl)-1,2-dihydro-3H-
indol-3-one (3f) and 2-allyl-2-(2-nitrophenyl)-1,2-dihydro-3H-indol-
n
;
d
3-one (3k). Compound 2f (30 mg, 74
mmol); allyltrimethylsilane
14.4 Hz), 3.12 (1H, dd, J¼6.8, 14.0 Hz), 3.73 (3H, s), 3.74 (3H, s), 4.22
(1H, d, J¼16.4 Hz), 4.47 (1H, d, J¼16.4 Hz), 4.89 (1H, dd, J¼1.6,
10.8 Hz), 5.00 (1H, dd, J¼1.2, 16.8 Hz), 5.49 (1H, tdd, J¼6.8, 10.0,
16.8 Hz), 6.69 (1H, d, J¼8.8 Hz), 6.73 (1H, d, J¼7.2 Hz), 6.79 (2H, d,
J¼8.4 Hz), 6.82 (2H, d, J¼9.2 Hz), 7.09 (2H, d, J¼8.8 Hz), 7.13 (2H, d,
J¼9.2 Hz), 7.38 (1H, ddd, J¼1.2, 7.2, 8.4 Hz), 7.59 (1H, d, J¼7.6 Hz);
(23 L, 0.15 mmol); TiCl4 (81 L, 1.0 M in CH2Cl2, 81 m
m
m
mol); CH2Cl2
(0.74 mL); n-hexane–AcOEt¼5:1–2:1; 3f (26 mg, 80%); 3k (5 mg,
19%).
Compound 3f: yellow crystals: mp 151–153 ꢀC; IR (CHCl3)
n
1709, 1612, 1530, 1348 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 2.99
(1H, dd, J¼7.2, 14.4 Hz), 3.14 (1H, dd, J¼7.2, 14.4 Hz) 4.49 (1H, d,
J¼16.8 Hz), 4.57 (1H, d, J¼16.8 Hz), 4.93 (1H, dd, J¼1.2, 10.4 Hz),
5.06 (1H, dd, J¼1.2, 16.8 Hz), 5.40 (1H, tdd, J¼6.8, 10.0, 16.8 Hz),
6.61 (1H, d, J¼8.4 Hz), 6.95 (1H, t, J¼7.6 Hz), 7.29 (2H, d, J¼8.4 Hz),
7.42–7.51 (2H, m), 7.57 (2H, d, J¼7.6 Hz), 7.71 (2H, t, J¼6.8 Hz),
13C NMR (100 MHz, CDCl3)
d 38.0, 47.5, 55.1, 75.8, 109.0, 113.6, 114.0,
117.3, 119.1, 119.7, 124.9, 127.6, 128.3, 129.2, 129.4, 131.5, 137.2, 158.5,
159.0, 160.0, 161.3, 201.2; HRMS (EI) calcd for C26H25NO3 399.1834,
found 399.1840.
8.06 (2H, d, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3)
d
40.4, 47.4,
4.4.7. Ethyl 2-allyl-1-(4-methoxybenzyl)-3-oxo-1,2-dihydro-3H-in-
dol-2-carboxylate (3j). Compound 2j (400 mg, 1.2 mmol); allyl-
73.0, 108.9, 119.6, 120.2, 121.3, 123.6, 124.6, 125.0, 128.0, 129.5,
130.1, 130.4, 132.1, 137.0, 144.3, 147.1, 149.2, 158.9, 198.4. Anal.
Calcd for C24H19N3O5: C, 67.38; H, 4.59; N, 9.76. Found: C, 67.13; H,
4.46; N, 9.79; HRMS (EI) calcd for C24H19N3O5 429.1325, found
429.1328.
trimethylsilane (371
1.3 mmol); CH2Cl2 (12 mL); n-hexane–AcOEt¼6:1; 3j (148 mg,
35%); pale-yellow oil; IR (CHCl3) 1736, 1701, 1612, 1512, 1485, 1321,
1246 cmꢂ1; 1H NMR (400 MHz, CDCl3)
1.15 (3H, t, J¼7.2 Hz), 2.94
mL, 2.3 mmol); TiCl4 (1.3 mL, 1.0 M in CH2Cl2,
n
d
Compound 3k: yellow oil: 1H NMR (300 MHz, CDCl3)
d
2.75 (1H,
(1H, dd, J¼7.2, 14.8 Hz), 3.02 (1H, dd, J¼6.8, 14.8 Hz), 3.80 (3H, s),
4.01 (1H, ddd, J¼7.2, 10.8, 14.4 Hz), 4.08 (1H, ddd, J¼7.2, 10.8,
14.4 Hz), 4.47 (1H, d, J¼16.0, Hz), 4.56 (1H, d, J¼16.4 Hz), 4.96 (1H,
d, J¼10.0 Hz), 5.03 (1H, d, J¼17.2 Hz), 5.45 (1H, tdd, J¼7.2, 10.0,
17.2 Hz), 6.65 (1H, d, J¼8.4 Hz), 6.78 (1H, t, J¼7.2 Hz), 6.86 (2H, d,
J¼7.2 Hz), 7.24 (2H, d, J¼8.4 Hz), 7.39 (1H, t, J¼7.2 Hz), 7.60 (1H, d,
dd, J¼7.5,14.1 Hz), 3.17 (1H, dd, J¼6.6,14.1 Hz) 4.99 (1H, s), 4.57 (1H,
d, J¼16.8 Hz), 5.11 (1H, dt, J¼0.9, 10.2 Hz), 5.19 (1H, dd, J¼1.5,
16.8 Hz), 5.59 (1H, tdd, J¼7.5, 10.2, 16.8 Hz), 6.88–6.95 (2H, m), 7.39
(1H, td, J¼1.2, 7.2 Hz), 7.44–7.53 (2H, m), 7.56 (1H, td, J¼1.5, 7.2 Hz),
7.63 (1H, d, J¼7.5 Hz), 8.07 (1H, dd, J¼0.9, 7.8 Hz).
J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 14.1, 37.0, 48.2, 55.3, 62.1,
4.4.4. 2-Allyl-1-(4-methoxybenzyl)-2-phenyl-1,2-dihydro-3H-indol-
3-one (3g). Compound 2g (100 mg, 0.29 mmol); allyl-
109.8, 113.9, 118.1, 119.8, 119.9, 124.9, 128.3, 128.8, 130.6, 137.5, 158.8,
161.6, 167.3, 195.5; HRMS (EI) calcd for C22H23NO4 365.1627, found
365.1632.
trimethylsilane (92
0.32 mmol); CH2Cl2 (2.9 mL); n-hexane–AcOEt¼4:1; 3g (97 mg,
90%); yellow crystals: mp 133–134 ꢀC; IR (CHCl3)
1695, 1612, 1512,
1487, 1321, 1246 cmꢂ1 1H NMR (400 MHz, CDCl3)
2.94 (1H, dd,
mL, 0.58 mmol); TiCl4 (0.32 mL, 1.0 M in CH2Cl2,
n
4.4.8. 2-Allyl-1-(4-methoxybenzyl)-2-(2-nitrophenyl)-1,2-dihydro-
3H-indol-3-one (3d). Compound 2d (200 mg, 0.51 mmol);
;
d

1242
K. Higuchi et al. / Tetrahedron 66 (2010) 1236–1243
allylboronic acid pinacol ester (0.19 mL, 1.0 mmol); TiCl4 (0.56 mL,
1.0 M in CH2Cl2, 0.56 mmol); n-hexane–AcOEt (3:1); 3d (208 mg,
98%).
(1H, dd, J¼1.6, 7.6 Hz), 7.73 (1H, d, J¼7.6 Hz); 13C NMR (100 MHz,
CDCl3)
d 47.3, 55.1, 73.8, 110.0, 110.3, 111.3, 113.6, 118.7, 118.9, 123.9,
124.9, 126.9, 128.4, 129.4, 129.7, 131.5, 133.0, 137.2, 143.8, 148.7,
149.0,158.0,158.3, 194.7; HRMS (EI) Calcd for C26H20N2O5 440.1372,
found 440.1371.
4.4.9. Methyl 2-[1-(4-methoxybenzyl)-2-(2-nitrophenyl)-3-oxo-1,2-
dihydro-3H-indol-2-yl]-2-methylpropanoate (3l). Compound 2d
(200 mg, 0.51 mmol); O-methyl O0-trimethylsilyl dimethylketene
acetal (0.21 mL, 1.0 mmol); TiCl4 (0.56 mL, 1.0 M in CH2Cl2,
0.56 mmol); n-hexane–AcOEt (3:1); 3l (228 mg, 93%) as brownish
4.4.13. 2-(1-Methyl-3-indolyl)-1-(4-methoxybenzyl)-2-(2-nitro-
phenyl)-1,2-dihydro-3H-indol-3-one (3p). Compound 2d (100 mg,
0.26 mmol); N-methyl indole (35
0.28 mmol); column chromatography eluent: CH2Cl2; 3p (128 mg,
98%) as orange powder: mp 255–257 ꢀC; IR (CHCl3)
1707, 1612,
1530, 1512, 1481 cmꢂ1 1H NMR (300 MHz, CDCl3)
3.67 (3H, s),
mL, 0.28 mmol); CSA (65 mg,
crystals: mp 102–104 ꢀC; IR (CHCl3)
n ;
1736, 1612, 1530, 1512 cmꢂ1
1H NMR (300 MHz, CDCl3)
d
1.24 (3H, s), 1.34 (3H, s), 3.62 (3H, s),
n
3.72 (3H, s), 4.92 (1H, d, J¼16.5 Hz), 5.28 (1H, d, J¼16.8 Hz), 6.68
(2H, d, J¼9.0 Hz), 6.77 (2H, d, J¼8.7 Hz), 7.08–7.23 (3H, m), 7.42 (1H,
dd, J¼2.1, 7.5 Hz), 7.53 (1H, dt, J¼1.8, 7.5 Hz), 7.58 (1H, dt, J¼1.5,
4.5 Hz), 7.62 (1H, dd, J¼1.5, 6.6 Hz), 8.08 (1H, dd, J¼1.5, 7.8 Hz); 13C
;
d
3.70 (3H, s), 4.70 (1H, d, J¼16.5 Hz), 4.80 (1H, d, J¼16.5 Hz), 6.50–
6.62 (2H, m), 6.72–6.95 (7H, m), 7.08–7.14 (1H, m), 7.18–7.24 (1H,
m), 7.33–7.49 (3H, m), 7.57–7.64 (2H, m), 7.83 (1H, br d, J¼8.4 Hz);
NMR (100 MHz, CDCl3)
d
25.0, 47.5, 52.3, 55.2, 82.0, 110.3, 113.8,
13C NMR (100 MHz, CDCl3)
d 33.1, 47.3, 55.2, 74.6, 108.6, 109.4, 110.4,
119.0, 119.7, 122.6, 123.3, 124.5, 125.6, 127.1, 127.2, 129.2, 129.3, 131.7,
132.4, 134.1, 134.8, 149.4, 158.5, 173.9. Anal. Calcd for C27H26N2O6: C,
68.34; H, 5.52; N, 5.90.Found: C, 68.56; H, 5.65; N, 5.86; HRMS (EI)
calcd for C27H26N2O6 474.1791, found 474.1787.
113.4, 118.0, 119.6, 120.3, 122.1, 125.0, 125.3, 125.9, 127.3, 128.9,
129.3, 131.1, 131.9, 134.5, 136.7, 137.7, 149.0, 157.9, 158.1. Anal. Calcd
for C31H25N3O4: C, 73.94; H, 5.00; N, 8.34. Found: C, 74.15; H, 5.24;
N, 8.35; HRMS (EI) calcd for C31H25N3O4 503.1845, found 503.1843.
4.4.10. 1-(4-Methoxybenzyl)-2-(2-nitrophenyl)-2-(2-oxo-2-phenyl-
ethyl)-1,2-dihydro-3H-indol-3-one (3m). Compound 2d (200 mg,
0.51 mmol); trimethyl(1-phenylvinyloxy)silane (0.21 mL, 1.0 mmol);
TiCl4 (0.56 mL, 1.0 M in CH2Cl2, 0.56 mmol); n-hexane–AcOEt (3:1);
Acknowledgements
We thank N. Eguchi, T. Koseki, and S. Kubota at the Analytical
Center of our university for microanalysis, NMR, and mass spectral
measurements. This research was partially supported by the Min-
istry of Education, Science, Sports and Culture, Grant-in-Aid for
Young Scientists (B), 21790027, 2009 and the High-Tech Research
Center Project, the Ministry of Education, Culture, Sports, Science
and Technology (MEXT), Japan (S0801043).
3m (249 mg, 98%) as yellowish powder: mp 192–194 ꢀC; IR (CHCl3)
n
1711, 1697, 1612, 1528, 1512 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
3.50
(3H, s), 3.73 (1H, d, J¼17.1 Hz), 3.96 (1H, d, J¼17.4 Hz), 4.43 (1H, d,
J¼16.8 Hz), 4.60 (1H, d, J¼16.8 Hz), 6.42 (2H, d, J¼8.4 Hz), 6.79
(1H, d, J¼8.4 Hz), 6.89 (2H, d, J¼8.7 Hz), 6.91 (1H, t, J¼7.8 Hz),
7.22–7.30 (2H, m), 7.40–7.56 (8H, m), 7.67 (1H, dd, J¼0.6, 7.8 Hz);
13C NMR (100 MHz, CDCl3)
d 44.5, 47.0, 55.0, 71.9, 108.8, 113.6,
References and notes
118.9, 119.1, 123.9, 124.7, 127.5, 127.8, 127.9, 128.9, 129.0, 129.1,
130.4, 131.0, 132.8, 135.8, 137.3, 149.0, 158.2, 160.1, 193.9, 198.5.
Anal. Calcd for C30H24N2O5: C, 73.16; H, 4.91; N, 5.69. Found: C,
73.31; H, 5.12; N, 5.75; HRMS (EI) calcd for C30H24N2O5 492.1685,
found 492.1685.
1. Isolation: (a) Steyn, P. S. Tetrahedron Lett. 1971, 12, 3331–3334; (b) Steyn, P. S.
Tetrahedron 1973, 29, 107–120; Synthesis: (c) Hutchison, A. J.; Kishi, Y. J. Am.
Chem. Soc. 1979, 101, 6786–6788.
2. Isolation: (a) Birch, A. J.; Wright, J. J. J. Chem. Soc., Chem. Commun. 1969, 644–
645; (b) Birch, A. J.; Wright, J. J. Tetrahedron 1970, 26, 2329–2344; (c) Birch, A. J.;
Russell, R. A. Tetrahedron 1972, 28, 2999–3008; Synthesis: (d) Williams, R. M.;
Glinka, T.; Kwast, E.; Coffman, H.; Stille, J. K. J. Am. Chem. Soc. 1990, 112, 808–821.
3. Isolation: (a) Bhakuni, D. S.; Silva, M.; Matlin, S. A.; Sammes, P. G. Phytochem-
istry 1976, 15, 574–575; Synthesis: (b) Stoermer, D.; Heathcock, C. H. J. Org.
Chem. 1993, 58, 564–568.
4. Isolation: (a) Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.; Asano,
K.; Kawamoto, I.; Tomita, F.; Nakano, H. J. Antibiot. 1988, 41, 1915–1917 Syn-
thesis: (b) Fukuda, Y.; Nakatani, K.; Ito, Y.; Terashima, S. Tetrahedron Lett. 1990,
31, 6699–6702.
5. (a) Witkop, B. J. Am. Chem. Soc. 1950, 72, 614–620; (b) Witkop, B.; Ek, A. J. Am.
Chem. Soc. 1951, 73, 5664–5669; (c) Beitzke, B.; Schmidt, R. R. Chem. Ber. 1985,
118, 1726–1731.
4.4.11. 2-[1-(4-Methoxybenzyl)-2-(2-nitrophenyl)-3-oxo-1,2-dihy-
dro-3H-indol-2-yl]acetaldehyde (3n). For entry 4: 2d (200 mg,
0.51 mmol); trimethyl(vinyloxy)silane (0.15 mL, 1.0 mmol); TiCl4
(0.56 mL, 1.0 M in CH2Cl2, 0.56 mmol); n-hexane–AcOEt (3:1); 3n
(79 mg, 39%) as yellowish crystals. For entry 5: 2d (100 mg,
0.26 mmol); trimethyl(vinyloxy)silane (76
(60 mg, 0.26 mmol); n-hexane–AcOEt (4:1); 3n (60 mg, 56%, 41% of
recovered 2d) as yellowish crystals: mp 154–155 ꢀC; IR (CHCl3)
1715, 1612, 1530, 1512 cmꢂ1; 1H NMR (400 MHz, CDCl3)
3.00 (1H,
mL, 0.51 mmol); CSA
n
6. (a) Patrick, J. B.; Witkop, B. J. Am. Chem. Soc. 1950, 72, 633–634; (b) Witkop, B.;
Patrick, J. B. J. Am. Chem. Soc. 1951, 73, 2188–2194; (c) Lednicer, D.; Emmert, D. E.
J. Heterocycl. Chem. 1970, 7, 575–581.
d
dd, J¼2.4, 15.6 Hz), 3.23 (1H, dd, J¼2.0, 15.6 Hz), 3.74 (3H, s), 4.22
(1H, d, J¼16.4 Hz), 4.52 (1H, d, J¼16.4 Hz), 6.73 (2H, d, J¼8.4 Hz),
6.80 (1H, d, J¼8.8 Hz), 6.93 (1H, d, J¼7.2 Hz), 6.98 (2H, d, J¼8.8 Hz),
7.43–7.61 (5H, m), 7.73 (1H, dt, J¼8.0, 0.8 Hz), 9.32 (1H, t, J¼2.0 Hz);
7. Zhang, X.; Foote, C. S. J. Am. Chem. Soc. 1993, 115, 8867–8868.
8. (a) Berti, C.; Greci, L.; Marchetti, L. J. Chem. Soc., Perkin Trans. 2 1979, 233–236;
(b) Adam, J.-M.; Winkler, T. Helv. Chim. Acta 1984, 67, 2186–2191; (c) Tommasi,
G.; Bruni, P.; Greci, L.; Sgarabotto, P.; Righi, L. J. Chem. Soc., Perkin Trans. 1 1999,
681–686; (d) Liu, Y.; McWhorter, W. W., Jr. J. Org. Chem. 2003, 68, 2618–2622.
9. (a) Yamaguchi, K. Bull. Chem. Soc. Jpn. 1976, 49, 1366–1368; (b) Ardakani, M. A.;
Smalley, R. K. Tetrahedron Lett. 1979, 20, 4769–4772; (c) Kawasaki, T.; Ohtsuka,
H.; Chien, C.-S.; Omata, M.; Sakamoto, M. Chem. Pharm. Bull. 1987, 35, 1339–
1346.
10. (a) Ghavshou, M.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1983, 3065–
3070; (b) Me´rour, J.-Y.; Chichereau, L.; Finet, J.-P. Tetrahedron Lett. 1992, 33,
3867–3870; (c) Boger, D. L.; Nishi, T. Bioorg. Med. Chem. 1995, 3, 67–77; (d) Yun,
S.; Kim, K. J. Chem. Soc., Perkin Trans. 1 2002, 2360–2369; (e) Yamada, K.; Kur-
okawa, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 6630–6631;
(f) Astolfi, P.; Bruni, P.; Greci, L.; Stipa, P.; Righi, L.; Rizzoli, C. Eur. J. Org. Chem.
2003, 2626–2634; (g) Higuchi, K.; Masuda, K.; Koseki, T.; Hatori, M.; Sakamoto,
M.; Kawasaki, T. Heterocycles 2007, 73, 641–650.
13C NMR (100 MHz, CDCl3)
d 47.0, 48.6, 55.3, 71.4, 109.3, 114.0, 119.3,
119.5, 124.8, 125.0, 128.2, 128.4, 129.0, 129.6, 130.1, 132.0, 137.6,
148.9,158.9,159.2,197.1,198.0. Anal. Calcd for C24H20N2O5: C, 69.22;
H, 4.84; N, 6.73. Found: C, 69.25; H, 4.91; N, 6.78; HRMS (EI) calcd
for C24H20N2O5 416.1372, found 416.1377.
4.4.12. 2-(2-Furyl)-1-(4-methoxybenzyl)-2-(2-nitrophenyl)-1,2-di-
hydro-3H-indol-3-one (3o). Compound 2d (100 mg, 0.26 mmol);
furan (37
AcOEt¼3:1; 3o (110 mg, 98%); orange powder; IR (CHCl3): 1719,
1612, 1530, 1512, 1483 cmꢂ1; 1H NMR (400 MHz, CDCl3)
3.68 (3H,
mL, 0.51 mmol); CSA (65 mg, 0.28 mmol); 1 h; n-hexane–
d
11. Buller, M. J.; Cook, T. G.; Kobayashi, Y. Heterocycles 2007, 72, 163–166.
12. Higuchi, K.; Sato, Y.; Tsuchimochi, M.; Sugiura, K.; Hatori, M.; Kawasaki, T. Org.
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s), 4.57 (1H, d, J¼17.2 Hz), 4.75 (1H, d, J¼17.2 Hz), 6.34 (1H, dd,
J¼2.0, 3.2 Hz), 6.43 (1H, d, J¼3.6 Hz), 6.45 (1H, d, J¼8.4 Hz), 6.63
(4H, s), 6.85 (1H, t, J¼7.2 Hz), 7.05 (1H, dd, J¼2.0, 8.0 Hz), 7.22 (1H, d,
J¼1.6 Hz), 7.36 (1H, ddd, J¼1.2, 7.2, 8.4 Hz), 7.40–7.50 (2H, m), 7.57

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complex mixture.
14. MoO5; (a) Chien, C.-S.; Suzuki, T.; Kawasaki, T.; Sakamoto, M. Chem. Pharm. Bull.
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