Asymmetric syntheses of pyrrolidine and piperidine derivatives Via regio-and stereo-selective ring-opening reactions of chiral aziridine

Article abstract of DOI:10.3987/COM-12-S(N)26

Asymmetric synthesis of cyclic β-amino alcohols (pyrrolidine and piperidine derivatives) has been achieved using a chiral aziridine as the starting material. The key step of this synthetic methodology is regio- and stereo-controlled ring-opening of the chiral aziridine with acetic acid or acetyl chloride.

Full text of DOI:10.3987/COM-12-S(N)26

HETEROCYCLES, Vol. 86, No. 1, 2012
435
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 435 - 453. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 19th June, 2012, Accepted, 24th July, 2012, Published online, 27th July, 2012
DOI: 10.3987/COM-12-S(N)41
NUCLEOPHILIC
SUBSTITUTION
REACTION
OF
1-METHOXYINDOLE-3-CARBALDEHYDE1,#
Fumio Yamada, Daisuke Shinmyo, Masahiro Nakajou, and Masanori
Somei*,‡
Faculty of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
Corresponding author: e-mail address: somei.home@topaz.plala.or.jp
Abstract – 1-Methoxyindole-3-carbaldehyde is proved to be a versatile
electrophile and reacts regioselectively at the 2-position with various types of
nucleophiles providing 2-substituted indole-3-carbaldehydes.
Indole is one of the electron rich hetero-aromatics. This is the reason why electrophilic substitution
reactions have been well studied2 in the indole chemistry (shown in general formula in Scheme 1, A). On
the other hand, nucleophilic substitution reaction3 was not familiar until we developed 1-hydroxyindole
chemistry.4 We demonstrated that a hydroxy or a methoxy group at the 1-position of indole skeleton
functions as a good leaving group when at least one electron withdrawing group3b,4 (ester, halogen)3c is
present in the indole nucleus (Scheme 1, B). Since various types of 1-hydroxy- and 1-methoxyindoles are
available,4 they can now be utilized as substrates for nucleophilc substitution reactions.
1-Methoxyindole-3-carbaldehyde5 (1, Scheme 2) is one of the simplest 1-methoxyindoles and a natural
product, isolated from radish as a phytoalexin by Takasugi6 and co-workers. They also isolated another
phytoalexin, brassicanal A (2), from Chinese cabbage.7 Taking these reports into consideration, we
A: Known Chemistry
B: Our Chemistry
Electrophilic Substitution Reactions
Nucleophilic Substitution Reactions
R
R
R
R
E
Nu
N
N
N
N
H
Nu
H
H
E
Nu
OR
E
(R = H, Me, etc.)
Scheme 1
# Dedicated to the 77th birthday of Prof. Ei-ichi Negishi. ‡ Professor Emeritus of Kanazawa
University. Present address: 56-7 Matsuhidai, Matsudo-shi, Chiba-ken, 270-2214, Japan.

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HETEROCYCLES, Vol. 86, No. 1, 2012
came up with the idea that plant family Brassicaceae utilizes simple indole-3-carbaldehydes for not only
protecting them from diseases and insects, but also promoting their growth.8 To examine the idea we
needed many kinds of 2-substituted indole-3-carbaldehydes. In this paper, we wish to report the
preparation of them, which are rarely available by electrophilic substitution reactions. Since we have
established a rapid and high yield synthetic method4 for 1 employing our 1-hydroxyindole chemistry, we
chose it as a starting material for nucleophilic substituion reactions.
I. Reaction of 1 with Sulfur- and Oxygen-Centered Nucleophiles
First of all, we tried potent nucleophiles such as sulfur- and oxygen-centered species and the results are
summarized in Scheme 2. As expected, NaSMe reacted with 1 in refluxing MeOH for 2 h to give
brassicanal A (2) in 94% yield. With this simple and successful synthesis of phytoalexin in hand, we next
tried the reaction of 1 with NaOMe and NaOEt in refluxing MeOH and EtOH, respectively. The
expected 2-methoxy- (3) and 2-ethoxyindole-3-carbaldehyde (4) were obtained in 90 and 95% yields,
respectively. In reactions of 1 with sodium salt of ethylene glycol, 1,3-propanediol, glycerol, and
N,N-dimethylethanol, the yield of the desired product decreased even though longer reaction time was
employed. Thus, 5, 6, 7, and 8 were obtained in 50, 76, 30, and 36% yields, respectively.
2,2-Dimethyl-1,3-dioxolan-4-methanol also reacted with 1 in the presence of Na metal in
N,N-dimethylformamide (DMF) to produce 9 in 57% yield. Hydrolysis of 9 with aqueous 6% HCl at
room temperature (rt) afforded 7 in 63% yield.
CHO
SMe
CHO
OEt
CHO
OMe
;
;
;
;
N
H
N
H
N
H
2
5
4
7
3
6
CHO
O
CHO
CHO
OH
N
H
N
H
O
OH
OH
N
H
O
OH
CHO
NuH
6% HCl
R1
CHO
O
CHO
O
N
OHC
R1
R2
R2
OMe
Base
;
;
;
N
H
N
H
1
NMe2
N
H
O
O
8
9
O
Me
a: R1=Me, R2=H
b: R1=H, R2=Me
Me
10
Me
Me Me
OHC
Me
Me
Me
N
H
O
N
H
O
N
O
H
13
11
12
MeOH, reflux
Scheme 2. Reaction of 1 with Sulfur- and Oxygen-Centered Nucleophiles

HETEROCYCLES, Vol. 86, No. 1, 2012
437
When 3-methylbut-2-en-1-ol was reacted with 1 at rt for 24 h in the presence of NaH in DMF, the
expected 10a was not obtained. Instead of 10a, a 2:5 mixture of 2-oxindoles, 11 and 12, was obtained.
Heating a MeOH solution of the mixture at reflux for 24 h transformed 12 into 11. By carrying out these
reactions continually, 11 was prepared in 75% yield directly from 1.
Since 12 is an unstable intermediate, its isolation as pure compound was not successful. However,
1H-NMR inspection of the crude reaction residue clearly showed the presence of 12. The mechanism of
the formation of 11 is considered as follows. Initial production of 10a, followed by Claisen
rearrangement to give 12, and subsequent liberation of formyl group of 12 result in the formation of 11.
Similarly, the reaction of 1 with potassium salt of 2-methylbut-3-en-2-ol in hexamethylphosphoric
triamide (HMPA) produced 26% yield of 13 through unstable intermediate 10b.
II. Reaction of 1 with Nitrogen-Centered Nucleophiles
Reactions of 1 with nitrogen containing heterocycles were examined in the presence of NaH in DMF at rt
and the results are summarized in Scheme 3. Nucleophiles, such as pyrrole, indole, imidazole, and
(8aS)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, afforded the expected products, 14, 15, 16, and 17 in
99, 95, 80, and 67% yields, respectively. In the reaction of 1 with benzimidazole, the reaction rate was
slow and even after 5 days, the desired 18 was obtained in only 30% yield with starting material as the
major product (62%).
The reactions of 1 with sodium salts of alicyclic amines are interesting to note. Although 19 and 20 were
obtained in 71 and 26% yields in the respective reactions with pyrrolidine and piperidine, a significant
amount of 3 was generated in both cases in 24 and 63% yields respectively. The reaction of 1 with
piperazine provided 21 in 16% yield together with 48% yield of 3. Similar reaction with
N-methylpiperazine afforded 22 in 13% yields in addition to 36% yield of 3.
The formation of 3 observed in the reactions utilizing these weak nucleophiles and NaH in DMF may be
explained as follows (Scheme 4). The initial reductive cleavage of N–OMe bond in 1 with NaH by a or b
path liberates indole-3-carbaldehyde (23) and MeOH. Hydride reduction of 3-formyl group and the
liberation of MeOH is another possible mechanism. Excess NaH instantly convert MeOH into NaOMe.
Once NaOMe is generated, it attacks the second molecule of 1 giving 3 and NaOMe, which in turn
attacks the third molecule of 1, and infinite repetition of the processes leads to complete transformation
of 1 to 3. In order to examine this explanation, treatment of 1 with NaH in DMF at rt was attempted
proving the formation of 3 as a sole isolable product in 78% yield, though the formation of 23 was not
detected at all.
The reaction of 1 with (R)-(–)-2-pyrrolidinemethanol in the presence of NaH afforded
2-[(R)-2-hydroxymethylpyrrolidin-1-yl]indole-3-carbaldehyde (24) in 14% yield together with a

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HETEROCYCLES, Vol. 86, No. 1, 2012
significant amount (23%) of unknown compound (MS m/z: 226 (M+)). In the same reaction, treatment of
the crude reaction residue with Ac2O provided 2-[(R)-2-acetoxymethylpyrrolidin-1-yl]indole-
3-carbaldehyde (25) in 43% yield, which was converted to 24 by treatment with aqueous 8% NaOH in a
quantitative yield.
CHO
N
CHO
N
CHO
;
;
;
N
H
N
H
N
H
N
N
14
15
16
CHO
CHO
N
CHO
N
O
;
N
H
N
N
N
H
N
H
N
O
(S)
NuH
CHO
18
21
19
22
17
20
N
CHO
N
CHO
N
CHO
N
Base
OMe
;
1
;
N
H
N
H
N
H
NH
NMe
CHO
N
CHO
N
;
N
H
N
H
(R)
CH2OH
(R)
CH2OAc
24
25
8% NaOH
Scheme 3. Reaction of 1 with Nitrogen-Centered Nucleophiles
CHO
OMe
Hydride attack by a
or b path is possible.
Na+
N
H
excess
NaH
MeO–
MeOH
CHO
3
DMF
Na+
H–
+
N
b
CHO
OHC
Me O
N
H
N
a
O Me
1
1
23
Scheme 4

HETEROCYCLES, Vol. 86, No. 1, 2012
439
O
O
Acetone
CHO
Me
Me
CHO
CN
N
N
;
;
N
H
OMe
OMe
N
Me
O
O
H
28
29
27
30
O
26
CHO
N
CHO
KCN
N
H
;
;
;
;
N
H
N
O
CO2Me
OMe
N
NuH
N
CHO
31
34
37
32
35
38
NaOMe
OH
N
CHO
CHO
CO2Me
Base
OMe
1
N
;
;
N
H
N
H
OMe
CO2Me
Me
33
36
OH
Me
CHO
CHO
Me
Me
Me
N
N
H
N
H
Me
Me
OMe
Scheme 5. Reaction of 1 with Carbon-Centered Nucleophiles
III. Reaction of 1 with Carbon-Centered Nucleophiles
As for a carbon nucleophile, we chose KCN at first (Scheme 5). The reaction proceeded smoothly to give
26 in 98% yield. The reaction of 1 with acetone in the presence of KH in acetone–THF produced the
expected 27 together with 28 in 51 and 29% yields, respectively. On the other hand, when aqueous 8%
NaOH was used as base in acetone–MeOH, nucleophilic substitution reaction did not take place, instead
the aldol reaction product (29) was obtained exclusively in 92% yield. The structure of 28 was proved
through the conversion of 29 to 28 in 62% yield by the reaction with acetone in the presence of KH.
Similar results were observed when 3-acetylpyridine was used as a nucleophile. Thus, the reaction of 1 in
the presence of KH in THF produced 30 and 31 in 74 and 9% yields, respectively.
Dimethyl malonate reacted with 1 using NaOMe in refluxing MeOH to give 32 and 33 in 46 and 13%
yields, respectively. Treatment of 33 with NaOMe in refluxing MeOH afforded 32 in 64% yield.
When 1 was reacted with allyltrimethylsilane in the presence of Bu4NF in THF, 34 and 35 were obtained
in 23 and 28% yields, respectively. In the similar reaction using (3-methylbut-2-en-1-yl)trimethylsilane,
36, 37, and 38 were produced in 7, 12, and 14% yields, respectively.
In conclusion, we have demonstrated that 1 is a good electrophile and reacts regioselectively at the
2-position with sulfur-, oxygen-, nitrogen-, and carbon-centered nucleophiles. Consequently, various
types of 2-substituted indole-3-carbaldehydes become readily available, which are not accessible by
employing electrophilic reactions. With 30 and 32 in hand as useful building blocks for the respective

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HETEROCYCLES, Vol. 86, No. 1, 2012
synthesis of natural products, goniomitine9 (39, Scheme 6) and caulerpin10 (40), the attempts are now in
progress. Biological evaluation of novel 2-substituted indole-3-carbaldehydes reported in this paper is
also under investigation as sterilizer and plant growth regulator.8
CO2Me
OH
CHO
CHO
H
N
N
N
H
H
HN
N
H
N
H
O
CO2Me
CO2Me
N
caulerpin
40
goniomitine
30
39
32
Scheme 6
EXPERIMENTAL
Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected. IR
1
spectra were determined with a Shimadzu IR-420 or Horiba FT-720 spectrophotometer, and H-NMR
spectra with a JEOL EX-270 or GSX-500 spectrometer with tetramethylsilane as an internal standard.
MS spectra were recorded on Hitachi M-80 or JEOL JMS-SX 102A spectrometer. Preparative thin-layer
chromatography (p-TLC) was performed on Merck Kiesel-gel GF245 (Type 60) (SiO2). Column
chromatography was performed on silica gel (SiO2, 100—200 mesh, from Kanto Chemical Co., Inc.) or
activated alumina (Al2O3, 300 mesh, from Wako Pure Chemical Industries, Ltd.) throughout the present
study.
2-Methylthioindole-3-carbaldehyde (2) from 1-methoxyindole-3-carbaldehyde (1) — An aq. 15%
NaSMe (2.5 mL, 5.35 mmol) was added to a solution of 1 (43.7 mg, 0.25 mmol) in MeOH (4 mL) and
heated at reflux for 2 h. After evaporation of solvent under reduced pressure, sat. aq. NH4Cl was added.
The whole was extracted with CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over
Na2SO4, and evaporated under reduced pressure to leave an oil, which was column chromatographed on
SiO2 with CH2Cl2–MeOH (99:1, v/v) to give 2 (44.6 mg, 94%). 2: mp 233–234 °C (lit.,7 mp 210–213 °C
colorless prisms, recrystallized from MeOH). IR (KBr): 1626, 1581, 1447, 1371, 1347, 1225, 848, 755,
1
657 cm-1. H-NMR (CD3OD) !: 2.68 (3H, s), 7.19 (1H, ddd, J=7.1, 7.0, and 1.3 Hz), 7.22 (1H, ddd,
J=7.1, 7.0, and 1.5 Hz), 7.38–7.42 (1H, m), 8.04–8.08 (1H, m), 10.04 (1H, s). MS m/z: 191 (M+). Anal.
Calcd for C10H9NOS: C, 62.74; H, 4.74; N, 7.32. Found: C, 62.61; H, 4.80; N, 7.25.
2-Methoxyindole-3-carbaldehyde (3) from 1 — [General Procedure] (reaction with NaOMe): Na
(136.5 mg, 5.93 mmol) was added to an ice-cooled anhydrous MeOH (2 mL) and stirred at rt for 5 min.
To the resultant solution, a solution of 1 (40.1 mg, 0.23 mmol) in anhydrous MeOH (1 mL) was added.

HETEROCYCLES, Vol. 86, No. 1, 2012
441
The mixture was refluxed for 2 h with stirring. After evaporation of solvent under reduced pressure, sat.
aq. NH4Cl was added. The whole was extracted with CH2Cl2–MeOH (95:5, v/v). The extract was washed
with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column
chromatographed on SiO2 with CH2Cl2–MeOH (97:3, v/v) to give 3 (35.9 mg, 90%). 3: mp 251–252 °C
(colorless plates, recrystallized from MeOH). IR (KBr): 1611, 1583, 1567, 1502, 1345, 1307, 1233, 1058,
745, 715 cm-1. 1H-NMR (CD3OD) !: 4.19 (3H, s), 7.13 (1H, ddd, J=6.1, 6.0, and 1.5 Hz), 7.15 (1H, ddd,
J=6.1, 6.0, and 1.5 Hz), 7.28 (1H, dd, J=6.1 and 1.5 Hz), 7.95 (1H, dd, J=6.1 and 1.5 Hz), 9.75 (1H, s).
MS m/z: 175 (M+). Anal. Calcd for C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.42; H, 5.22; N,
7.98. [Second Procedure] (reaction with NaH): A solution of 1 (32.9 mg, 0.19 mmol) in anhydrous
DMF (3 mL) was added to 60% NaH (168.4 mg, 4.21 mmol) and stirred at rt for 17 h. After the same
work-up as described in general procedure, 3 (25.8 mg, 78%) was obtained.
2-Ethoxyindole-3-carbaldehyde (4) from 1 — In the general procedure for 3, Na (180.3 mg, 7.84
mmol), anhydrous EtOH (2 mL), and 1 (46.1 mg, 0.26 mmol) in anhydrous EtOH (2 mL) were used.
After the same work-up and column chromatography, 4 (47.2 mg, 95%) was obtained. 4: mp 227–228 °C
(decomp., colorless prisms, recrystallized from MeOH). IR (KBr): 1604, 1573, 1485, 1364, 1344, 1234,
1050, 743, 657 cm-1. 1H-NMR (CD3OD) !: 1.52 (3H, t, J=7.1 Hz), 4.47 (2H, q, J=7.1 Hz), 7.12 (1H, ddd,
J=7.3, 7.2, and 1.7 Hz), 7.15 (1H, ddd, J=7.3, 7.2, and 1.5 Hz), 7.24–7.29 (1H, m), 7.93–7.98 (1H, m),
9.75 (1H, s). MS m/z: 189 (M+). Anal. Calcd for C11H11NO2: C, 69.82; H, 5.68; N, 7.40. Found: C, 69.82;
H, 5.88; N, 7.31.
2-(2-Hydroxyethoxy)indole-3-carbaldehyde (5) from 1 — [General procedure] Na (105.4 mg, 4.58
mmol) was added to an ice-cooled anhydrous ethylene glycol (3 mL) and stirred at rt for 2.5 h. To the
resultant solution, a solution of 1 (76.4 mg, 0.44 mmol) in anhydrous ethylene glycol (3 mL) was added
and the mixture was heated at 60 °C for 19 h with stirring. Sat. aq. NH4Cl was added and the whole was
extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure to leave an oil, which was column chromatographed on SiO2 with CH2Cl2–MeOH (99:1,
v/v) to give 1 (3.7 mg, 5%) and 5 (44.9 mg, 50%). 5: mp 188–190 °C (yellow prisms, recrystallized from
MeOH). UV (MeOH) "max nm (log #): 304 (4.12), 267 (4.11), 244 (4.21). IR (KBr): 1608, 1545, 1345,
1
1258, 1233, 1070, 1052, 883, 750 cm-1. H-NMR (CD3OD) !: 3.96 (2H, ddd, J=4.5, 3.7, and 1.4 Hz),
4.46 (2H, ddd, J=4.5, 3.7, and 1.4 Hz), 7.13 (1H, ddd, J=7.4, 7.3, and 1.7 Hz), 7.15 (1H, ddd, J=7.4, 7.3,
and 1.4 Hz), 7.25–7.29 (1H, m), 7.94–7.98 (1H, m), 9.82 (1H, s). MS m/z: 205 (M+). Anal. Calcd for
C11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.08; H, 5.50; N, 6.86.
2-(3-Hydroxypropyloxy)indole-3-carbaldehyde (6) from 1 — Na (71.9 mg, 3.126 mmol) was added to
an ice-cooled anhydrous 1,3-propanediol (1 mL) and stirred at rt for 5 min. To the resultant solution, a
solution of 1 (105.9 mg, 0.60 mmol) in anhydrous 1,3-propanediol (2 mL) was added and the mixture

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HETEROCYCLES, Vol. 86, No. 1, 2012
was heated at 70 °C for 5 h with stirring. After the same work-up in the general procedure for 5 except
for employing CHCl3–MeOH–28%NH3 (46:5:0.5, v/v) as an eluent, 6 (100.3 mg, 76%) was obtained. 6:
mp 172–174 °C (yellow powder, recrystallized from CHCl3). UV (MeOH) "max nm (log #): 305 (4.13),
267 (4.06), 244 (4.17), 211 (4.26). IR (KBr): 1605, 1480, 1450, 1348, 1237, 1054, 1007, 908, 874, 738,
1
715, 645 cm-1. H-NMR (CD3OD) !: 2.10 (2H, quint, J=6.1 Hz), 3.79 (2H, t, J=6.1 Hz), 4.53 (2H, t,
J=6.1 Hz), 7.11–7.17 (2H, m), 7.28 (1H, dd, J=7.3 and 1.7 Hz), 7.95 (1H, dd, J=5.6 and 2.4 Hz), 9.77
(1H, s). MS m/z: 219 (M+). Anal. Calcd for C12H13NO3ꢀ1/8H2O: C, 65.07; H, 5.92; N, 6.32. Found: C,
65.25; H, 5.94; N, 6.31.
2-(2,3-Dihydroxypropyloxy)indole-3-carbaldehyde (7) from 1 — Na (133.2 mg, 5.79 mmol) was
added to a solution of glycerol (1 mL) in anhydrous DMF (1 mL) and the mixture was heated at 70 °C
for 17 h. To the resultant solution, a solution of 1 (201.5 mg, 1.15 mmol) in anhydrous DMF (4 mL) was
added and heated at 70 °C for additional 5 h. After the same work-up in the general procedure for 5
except for employing CHCl3–MeOH–28%NH3 (46:2:0.2, v/v) as an eluent, 7 (80.6 mg, 30%) was
obtained. 7: mp 194.0–195.0 °C (yellow powder, recrystallized from MeOH-benzene). UV (MeOH)
"max nm (log #): 304 (4.15), 267 (4.10), 244 (4.21), 210 (4.41). IR (KBr): 1608, 1560, 1486, 1460, 1360,
1239, 1124, 1062, 885, 748 cm-1. 1H-NMR (CD3OD) !: 3.70 (2H, d, J=5.6 Hz), 4.06 (1H, dtd, J=6.1, 5.6
and 3.9 Hz), 4.41 (1H, dd, J=9.8 and 6.1 Hz), 4.50 (1H, dd, J=9.8 and 3.9 Hz), 7.11–7.17 (2H, m),
7.26–7.29 (1H, m), 7.94–7.97 (1H, m), 9.81 (1H, s). MS m/z: 235 (M+). Anal. Calcd for C12H13NO4: C,
61.27; H, 5.27; N, 5.95. Found: C, 60.97; H, 5.55; N, 6.00.
2-(2-N,N-Dimethylaminoethoxy)indole-3-carbaldehyde (8) from 1 — Na (156.4 mg, 6.80 mmol) was
added to an ice-cooled anhydrous N,N-dimethylaminoethanol (3 mL) and stirred at rt for 5 min. To the
resultant solution, a solution of 1 (240.8 mg, 1.37 mmol) in anhydrous THF (7 mL) was added and the
mixture was heated at 70 °C for 2 h with stirring. After the same work-up in the general procedure for 5
except for employing CHCl3–MeOH–28%NH3 (46:2:0.2, v/v) as an eluent, 8 (114.1 mg, 36%) was
obtained. 8: mp 148–149 °C (yellow plates, recrystallized from MeOH-H2O). UV (MeOH) "max nm
(log #): 304 (4.16), 267 (4.11), 244 (4.22), 210 (4.45). IR (KBr): 1601, 1580, 1485, 1348, 1238, 1238,
1
1045, 880, 734, 650 cm-1. H-NMR (CDCl3) !: 2.49 (6H, s), 2.85 (2H, t, J=4.2 Hz), 4.46 (2H, t, J=4.2
Hz), 7.15 (1H, dd, J=7.6 and 7.1 Hz), 7.19 (1H, d, J=7.6 Hz), 7.21 (1H, dd, J=7.8 and 7.1 Hz), 8.34 (1H,
d, J=7.8 Hz), 9.96 (1H, s). MS m/z: 232 (M+). Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06.
Found: C, 67.28; H, 6.93; N, 12.00.
2-(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxyindole-3-carbaldehyde (9) from 1 — Na (139.6 mg, 6.07
mmol) was added to (2,2-dimethyl-1,3-dioxolane-4-yl)methanol (2 mL) and the mixture was heated at
80 °C for 1.5 h. To the resultant solution, a solution of 1 (205.7 mg, 1.17 mmol) in anhydrous DMF (6
mL) was added and heated at 80 °C for additional 1 h. After addition of H2O, the whole was made acidic

HETEROCYCLES, Vol. 86, No. 1, 2012
443
with 6% HCl and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and
evaporated under reduced pressure to leave an oil (2.493 g), which was dissolved in pyridine (6 mL). To
the resultant solution, Ac2O (3 mL) was added and the mixture was stirred at rt for 1 h. After evaporation
of the solvent, sat. aq. NaHCO3 was added to the residue and the whole was extracted with
CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure to leave an oil, which was column chromatographed on SiO2 with
CHCl3–MeOH–28%NH3 (100:1:0.1, v/v) to give 9 (183.5 mg, 57%). 9: mp 214–215 °C (red brown
flakes, recrystallized from MeOH). UV (MeOH) "max nm (log #): 304 (4.16), 267 (4.11), 244 (4.23),
208 (4.43). IR (KBr): 1600, 1570, 1480, 1342, 1235, 1050, 835, 735, 655 cm-1. 1H-NMR (DMSO-d6) !:
1.31 (3H, s), 1.35 (3H, s), 3.87 (1H, dd, J=8.6 and 5.5 Hz), 4.13 (1H, dd, J=8.6 and 6.5 Hz), 4.41–4.46
(1H, m), 4.47–4.54 (2H, m), 7.10–7.15 (2H, m), 7.28–7.32 (1H, m), 7.89–7.93 (1H, m), 9.86 (1H, s),
12.13 (1H, br s). MS m/z: 275 (M+). Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C,
65.43; H, 6.21; N, 5.11.
7 from 9 — 6% HCl (2 mL) was added to a solution of 9 (19.2 mg, 0.070 mmol) in MeOH (2 mL) and
the mixture was stirred at rt for 0.5 h. Sat. aq. NaHCO3 was added and the whole was extracted with
CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure to leave an oil, which was column chromatographed on SiO2 with
CHCl3–MeOH–28%NH3 (46:10:1, v/v) to give 7 (10.4 mg, 63%).
3-(1,1-Dimethylallyl)-2-oxindole (11) through 3-(1,1-dimethylallyl)-3-formyl-2-oxindole (12) from 1
— 3-Methylbut-2-en-1-ol (350.3 mg, 4.0 mmol) in anhydrous DMF (1 mL) was added to 60% NaH
(122.7 mg, 3.1 mmol) at rt and stirred for 10 min. To the resultant mixture, a solution of 1 (53.0 mg, 0.30
mmol) in anhydrous DMF (2 mL) was added and stirred at rt for 24 h. After addition of sat. aq. NH4Cl,
the whole was extracted with CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over
Na2SO4, and evaporated under reduced pressure to leave an oil, which was column chromatographed on
SiO2 with CH2Cl2 to give a 2:5 mixture (50.7 mg) of 11 and 12. The mixture was dissolved in MeOH (4
mL) and refluxed for 24 h. After evaporation of solvent, the resultant crude 11 was purified by column
chromatography on SiO2 with CH2Cl2 to give pure 11 (12.1 mg, 75%). 11: mp 149–150 °C (colorless
leaves, recrystallized from MeOH–H2O). IR (KBr): 1706, 1661, 1617, 1470, 1332, 1233, 920, 735, 680
cm-1. 1H-NMR (CDCl3) !: 1.12 (3H, s), 1.34 (3H, s), 3.25 (1H, s), 4.98 (1H, dd, J=17.5 and 1.0 Hz), 5.06
(1H, dd, J=10.7 and 1.0 Hz), 5.98 (1H, dd, J=17.5 and 10.7 Hz), 6.82 (1H, d, J=7.5 Hz), 6.95 (1H, ddd,
J=7.5, 7.4, and 1.1 Hz), 7.19 (1H, ddd, J=7.7, 7.4, and 1.1 Hz), 7.31 (1H, d, J=7.7 Hz), 7.83 (1H, br s,
disappeared on addition of D2O). MS m/z: 201 (M+). Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N,
1
6.96. Found: C, 77.68; H, 7.59; N, 6.92. 12: Unstable intermediate. H-NMR (CDCl3) !: 1.22 (3H, s),
1.29 (3H, s), 5.02 (1H, dd, J=17.4 and 0.7 Hz), 5.16 (1H, dd, J=10.8 and 0.7 Hz), 6.13 (1H, dd, J=17.4

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and 10.8 Hz), 6.90 (1H, ddd, J=7.7, 1.1, and 0.6 Hz), 7.06 (1H, ddd, J=7.7, 7.6, and 1.1 Hz), 7.26 (1H,
ddd, J=7.7, 7.6, and 1.1 Hz), 7.49 (1H, ddd, J=7.7, 1.1, and 0.6 Hz), 8.63 (1H, br s), 9.88 (1H, s).
3-(3-Methylbut-2-en-1-yl)-2-oxindole (13) from 1 — 2-Methylbut-3-en-2-ol (0.60 mL, 5.66 mmol)
was added to a suspension of 35% KH (288.0 mg, 2.51 mmol) in HMPA (0.5 mL), and the whole was
stirred at rt for 10 min. To the resultant solution, a solution of 1 (100.8 mg, 0.57 mmol) in HMPA (2.0
mL) was added and stirred at rt for 1 h. After addition of H2O, the whole was made acidic by adding 6%
HCl and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated
under reduced pressure to leave an oil, which was column chromatographed on SiO2 with EtOAc–hexane
(1:3, v/v) to give 13 (29.8 mg, 26%) and 3 (37.8 mg, 38%). 13: mp 109–109.5 °C (pale yellow prisms,
recrystallized from EtOAc–hexane). IR (KBr): 1699, 1652, 1608, 1453, 1385, 1324, 1229, 821, 742 cm-1.
1H-NMR (CDCl3) !: 1.58 (3H, s), 1.67 (3H, s), 2.58 (1H, ddd, J=14.5, 7.5, and 6.5 Hz), 2.69–2.76 (1H,
m), 3.46 (1H, dd, J=7.5 and 5.0 Hz), 5.11–5.16 (1H, m), 6.87 (1H, d, J=7.6 Hz), 7.00 (1H, td, J=7.6 and
1.1 Hz), 7.20 (1H, td, J=7.6 and 1.1 Hz), 7.23 (1H, d, J=7.6 Hz), 8.19 (1H, br s, disappeared on addition
of D2O). MS m/z: 201 (M+). Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.51; H,
7.57; N, 6.83.
2-(Pyrrol-1-yl)indole-3-carbaldehyde (14) from 1 — [General procedure] A solution of pyrrole (71.4
mg, 1.06 mmol) in anhydrous DMF (1 mL) was added to 60% NaH (35.3 mg, 0.88 mmol) at 0 °C with
stirring. After 10 min, a solution of 1 (49.9 mg, 0.28 mmol) in anhydrous DMF (2 mL) was added at 0 °C.
After stirring at rt for 3 h, sat. aq. NH4Cl was added. The whole was extracted with CH2Cl2–MeOH (95:5,
v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to
leave solid, which was column chromatographed on SiO2 with CH2Cl2–MeOH (99:1, v/v) to give 14
(59.1 mg, 99%). 14: mp 266–268 °C (decomp., colorless leaves, recrystallized from MeOH). IR (KBr):
1612, 1582, 1564, 1487, 1457, 1372, 1071, 726 cm-1. 1H-NMR (5% DMSO-d6 in CDCl3) !: 6.44 (2H, dd,
J=2.2 and 2.1 Hz), 7.22 (2H, dd, J=2.2 and 2.1 Hz), 7.25–7.30 (2H, m), 7.39–7.44 (1H, m), 8.25–8.30
(1H, m), 10.07 (1H, s), 12.04 (1H, br s, disappeared on addition of D2O). MS m/z: 210 (M+). Anal. Calcd
for C13H10N2O: C, 74.27; H, 4.79; N, 13.33. Found: C, 74.54; H, 4.87; N, 13.04.
2-(Indol-1-yl)indole-3-carbaldehyde (15) from 1 — In the general procedure for 14, indole (51.4 mg,
0.44 mmol) instead of pyrrole, 60% NaH (14.2 mg, 0.35 mmol), 1 (47.0 mg, 0.27 mmol), and 24 h as for
reaction time were employed. After the same work-up except for employing EtOAc as an extraction
solvent and CH2Cl2–hexane (1:1, v/v) as an eluent, 15 (66.4 mg, 95%) was obtained. 15: mp 259–260 °C
(colorless leaves, recrystallized from MeOH). IR (KBr): 1615, 1578, 1555, 1486, 1449, 1381, 1355, 747,
1
736, 721 cm-1. H-NMR (5% DMSO-d6 in CDCl3) !: 6.80 (1H, dd, J=3.4 and 0.9 Hz), 7.25 (1H, ddd,
J=7.0, 6.8, and 1.1 Hz), 7.27–7.35 (3H, m), 7.46–7.51 (1H, m), 7.49 (1H, d, J=3.4 Hz), 7.60 (1H, ddd,
J=8.2, 0.9, and 0.8 Hz), 7.71 (1H, ddd, J=8.9, 0.9, and 0.8 Hz), 8.29–8.34 (1H, m), 9.92 (1H, s), 12.29

HETEROCYCLES, Vol. 86, No. 1, 2012
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(1H, br s, disappeared on addition of D2O). MS m/z: 260 (M+). Anal. Calcd for C17H12N2O: C, 78.44; H,
4.65; N, 10.76. Found: C, 78.66; H, 4.60; N, 10.76.
2-(Imidazol-1-yl)indole-3-carbaldehyde (16) from 1 — In the general procedure for 14, imidazole
(33.7 mg, 0.49 mmol) instead of pyrrole, 60% NaH (19.8 mg, 0.49 mmol), 1 (52.7 mg, 0.30 mmol), and
48 h as for reaction time were employed. After the same work-up except for employing EtOAc–MeOH
(99:5, v/v) as an extraction solvent, Al2O3 as an adsorbent, and CH2Cl2–MeOH (97:3, v/v) as an eluent,
16 (51.3 mg, 80%) was obtained. 16: mp 233–234 °C (colorless needles, recrystallized from MeOH). IR
(KBr): 1638, 1567, 1531, 1486, 1465, 1398, 1066, 1021, 748 cm-1. 1H-NMR (5% DMSO-d6 in CDCl3) !:
7.28–7.36 (2H, m), 7.30 (1H, br d, J=1.2 Hz), 7.43–7.48 (1H, m), 7.56 (1H, br s), 8.14 (1H, br s),
8.24–8.29 (1H, m), 10.04 (1H, s), 12.44 (1H, br s, disappeared on addition of D2O). MS m/z: 211 (M+).
Anal. Calcd for C12H9N3O•1/6MeOH: C, 67.48; H, 4.50; N, 19.40. Found: C, 67.45; H, 4.35; N, 19.21.
(8aS)-2-(3-Formylindol-2-yl)hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (17) from 1 — In the
general procedure for 14, (8aS)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (551.9 mg, 3.58 mmol)
instead of pyrrole, 60% NaH (143.1 mg, 3.58 mmol), 1 (201.4 mg, 1.15 mmol), and 6 h as for reaction
time were employed. After the same work-up except for employing CH2Cl2–MeOH (95:5, v/v) as an
eluent, 17 (229.4 mg, 67%) was obtained. 17: mp 231–233 °C (colorless prisms, recrystallized from
1
MeOH). IR (KBr): 1701, 1680, 1608, 1577, 1469, 1406, 1351, 1314, 1206, 769 cm-1. H-NMR (5%
DMSO-d6 in CDCl3) !: 1.96–2.07 (1H, m), 2.07–2.15 (1H, m), 2.21–2.30 (1H, m), 2.42–2.49 (1H, m),
3.61–3.73 (2H, m), 4.19 (1H, d, J=16.1 Hz), 4.42 (1H, t, J=8.1 Hz), 4.86 (1H, d, J=16.1 Hz), 7.24–7.31
(2H, m), 7.39–7.43 (1H, m), 8.41–8.46 (1H, m), 10.07 (1H, s), 11.80 (1H, br s, disappeared on addition
of D2O). MS m/z: 297 (M+). Anal. Calcd for C16H15N3O3: C, 64.64; H, 5.08; N, 14.13. Found: C, 64.57;
H, 5.06; N, 14.03.
2-(Benzimidazol-1-yl)indole-3-carbaldehyde (18) from 1 — In the general procedure for 14,
benzimidazole (75.3 mg, 0.64 mmol) instead of pyrrole, 60% NaH (22.3 mg, 0.56 mmol), 1 (49.0 mg,
0.28 mmol), and 5 days as for reaction time were employed. After the same work-up except for
employing EtOAc as an eluent, 18 (21.8 mg, 30%) was obtained together with 1 (30.3 mg, 62%). 18: mp
278–280 °C (colorless prisms, recrystallized from MeOH). IR (KBr): 1657, 1562, 1490, 1472, 1451,
1
1392, 1213, 741 cm-1. H-NMR (5% DMSO-d6 in CDCl3) !: 7.34–7.40 (2H, m), 7.41–7.46 (2H, m),
7.50–7.54 (1H, m), 7.58–7.63 (1H, m), 7.89–7.94 (1H, m), 8.31–8.36 (1H, m), 8.42 (1H, m), 9.95 (1H, s),
12.60 (1H, br s, disappeared on addition of D2O). MS m/z: 261 (M+). Anal. Calcd for C16H11N3O: C,
73.55; H, 4.24; N, 16.08. Found: C, 73.72; H, 4.16; N, 15.98.
2-(Pyrrolidin-1-yl)indole-3-carbaldehyde (19) from 1 — In the general procedure for 14, pyrrolidine
(414.5 mg, 5.83 mmol) instead of pyrrole, 60% NaH (219.8 mg, 5.50 mmol), 1 (49.3 mg, 0.28 mmol),
and 6 h as for reaction time were employed. After the same work-up except for employing

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CH2Cl2–MeOH (95:5, v/v) as an eluent, 3 (11.8 mg, 24%) and 19 (42.7 mg, 71%) were obtained. 19: mp
343 °C (decomp., colorless leaves, recrystallized from MeOH). IR (KBr): 1625, 1608, 1591, 1563, 1477,
1454, 1410, 1370, 1352, 1327, 742, 670 cm-1. 1H-NMR (DMSO-d6) !: 2.00–2.07 (4H, m), 3.45–3.61 (4H,
m), 6.95–7.00 (2H, m), 7.11–7.16 (1H, m), 8.01–8.07 (1H, m), 9.79 (1H, s), 10.82 (1H, br s, disappeared
on addition of D2O). MS m/z: 214 (M+). Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59; N, 13.08. Found:
C, 72.62; H, 6.58; N, 12.98.
2-(Piperidin-1-yl)indole-3-carbaldehyde (20) from 1 — In the general procedure for 14, piperidine
(467.2 mg, 5.49 mmol) instead of pyrrole, 60% NaH (211.2 mg, 5.28 mmol), 1 (47.5 mg, 0.27 mmol),
and 6 h as for reaction time were employed. After the same work-up except for employing
CH2Cl2–MeOH (97:3, v/v) as an eluent, 20 (16.0 mg, 26%) and 3 (30.0 mg, 63%) were obtained. 20: mp
262–263 °C (decomp., colorless leaves, recrystallized from MeOH). IR (KBr): 1597, 1563, 1444, 1382,
1
1241, 743 cm-1. H-NMR (CD3OD) !: 1.70–1.81 (6H, m), 3.58–3.63 (4H, m), 7.02–7.08 (2H, m),
7.13–7.17 (1H, m), 7.90 (1H, br s), 9.77 (1H, s). MS m/z: 228 (M+). Anal. Calcd for C14H16N2O: C,
73.66; H, 7.06; N, 12.27. Found: C, 73.57; H, 6.95; N, 12.04.
2-(Piperazin-1-yl)indole-3-carbaldehyde (21) from 1 — A solution of piperazine (797.2 mg, 9.25
mmol) in anhydrous DMF (8 mL) was added to 60% NaH (369.7 mg, 9.24 mmol, washed with hexane)
under ice cooling and stirring was continued at rt for 1 h. To the resultant solution, a solution of 1 (81.0
mg, 0.46 mmol) in anhydrous DMF (2 mL) was added and the mixture was heated at 60 °C for 3 h with
stirring. After addition of H2O, the whole was extracted with EtOAc. The extract was washed with brine,
dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was column
chromatographed on SiO2 with CHCl3–MeOH–28%NH3 (46:2:0.2, v/v) to give 3 (38.6 mg, 48%) and 21
(16.7 mg, 16%). 21: mp 198–200 °C (yellow flakes, recrystallized from MeOH-benzene). UV (MeOH)
"max nm (log #): 329 (4.02), 275 (4.16), 255 (4.33), 219 (4.38). IR (KBr): 1595, 1565, 1465, 1375, 1230,
995, 745, 657 cm-1. 1H-NMR (CD3OD) !: 3.02 (4H, t, J=5.0 Hz), 3.59 (4H, t, J=5.0 Hz), 7.05–7.09 (2H,
m), 7.18–7.20 (1H, m), 7.88 (1H, br s), 9.82 (1H, s). MS m/z: 229 (M+). Anal. Calcd for C13H15N3O: C,
68.10; H, 6.59; N,18.33. Found: C, 67.96; H, 6.51; N, 17.95.
2-(4-Methylpiperazin-1-yl)indole-3-carbaldehyde (22) from 1 — A solution of 1-methylpiperazine
(4.630 g, 46.2 mmol) in anhydrous DMF (4 mL) was added to 60% NaH (1.836 g, 45.9 mmol, washed
with hexane) under ice cooling and stirring was continued at rt for 1 h. To the resultant solution, a
solution of 1 (201.5 mg, 1.15 mmol) in anhydrous DMF (4 mL) was added and the mixture was heated at
65 °C for 1 h with stirring. After addition of H2O, the whole was made acidic with 6% HCl and extracted
with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated under reduced
pressure to leave an oil, which was column chromatographed on SiO2 with CHCl3–MeOH–28%NH3
(46:5:0.5, v/v) to give 3 (72.8 mg, 36%) and 22 (36.2 mg, 13%). 22: mp 229–230 °C (brown powder,

HETEROCYCLES, Vol. 86, No. 1, 2012
447
recrystallized from MeOH–benzene). UV (MeOH) "max nm (log #): 329 (4.06), 274 (4.18), 255 (4.36),
1
219 (4.40). IR (KBr): 1570, 1380, 1365, 1249, 1228, 1147, 993, 903, 830, 748, 663 cm-1. H-NMR
(CDCl3) !: 2.42 (3H, s), 2.71 (4H, t, J=4.6 Hz), 3.69 (4H, t, J=4.6 Hz), 7.11 (1H, ddd, J=8.1, 6.4, and 1.1
Hz), 7.18 (1H, ddd, J=7.1, 6.4, and 1.2 Hz), 7.22 (1H, dd, J=8.1 and 1.2 Hz), 7.96 (1H, dd, J=7.1 and 1.1
Hz), 8.88 (1H, br s), 10.06 (1H, s). MS m/z: 243 (M+). Anal. Calcd for C14H17N3O: C, 69.11; H, 7.04; N,
17.27. Found: C, 68.87; H, 6.95; N, 17.18.
(R)-(–)-2-(2-Hydroxymethylpyrrolidin-1-yl)indole-3-carbaldehyde (24) and an unknown compound
from 1 — A solution of (R)-(–)-2-pyrrolidinemethanol (597.6 mg, 5.92 mmol) in anhydrous DMF (3
mL) was added to 60% NaH (469.5 mg, 11.7 mmol, washed with hexane) under ice cooling and stirring
was continued at rt for 1 h. To the resultant solution, a solution of 1 (206.6 mg, 1.18 mmol) in anhydrous
DMF (4 mL) was added and the mixture was stirred at rt for 0.5 h. After addition of H2O, the whole was
extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure to leave an oil, which was column chromatographed on SiO2 with
CHCl3–MeOH–28%NH3 (46:2:0.2, v/v) to give 24 (39.4 mg, 14%) and unknown compound (61.1 mg,
23%). 24: mp 187.0–188.5 °C (purple prisms, recrystallized from MeOH). UV (MeOH) "max nm (log
#): 322 (4.17), 269 (4.23), 258 (4.40), 217 (4.36). [$]D24: –59 (c=0.5, MeOH). IR (KBr): 1560, 1368,
1
1238, 1040, 742, 662 cm-1. H-NMR (CD3OD) !: 2.11–2.25 (4H, m), 3.55–3.63 (1H, m), 3.69 (1H, dd,
J=11.5 and 5.6 Hz), 3.73 (1H, dd, J=11.5 and 5.6 Hz), 3.74–3.80 (1H, m), 4.21 (1H, br s), 7.02–7.04 (2H,
m), 7.11–7.13 (1H, m), 8.10 (1H, br s), 9.70 (1H, s). MS m/z: 244 (M+). Anal. Calcd for
C14H16N2O2•1/8H2O: C, 68.20; H, 6.54; N, 11.36. Found: C, 68.34; H, 6.59; N, 11.40. Unknown
compound: mp 221–223 °C (pale brown prisms, recrystallized from CH2Cl2–hexane). UV (MeOH) "max
nm (log #): 348 (4.30), 281 (4.18), 276 (4.26), 272 (4.17), 242 (3.81), 209 (4.57). [$]D30: –702 (c=0.36,
1
MeOH). IR (KBr): 1635, 1426, 1390, 1308, 1262, 1222, 1095, 1060, 1009, 922, 745 cm-1. H-NMR
(CDCl3) !: 1.63–1.73 (1H, m), 1.94–2.04 (2H, m), 2.25–2.32 (1H, m), 3.58–3.76 (4H, m), 4.48 (1H, d,
J=12.3 Hz), 7.03 (1H, dd, J=7.5 and 7.3 Hz), 7.12 (1H, dd, J=7.9 and 7.3 Hz), 7.29 (1H, d, J=7.5 Hz),
7.39 (1H, d, J=7.9 Hz), 7.41 (1H, s). MS m/z: 226 (M+). Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24; N,
12.38. Found: C, 74.29; H, 6.16; N, 12.31.
(R)-(–)-2-(2-Acetoxymethylpyrrolidin-1-yl)indole-3-carbaldehyde (25) from 1 — In the same
procedure as described for 24, (R)-(–)-2-pyrrolidinemethanol (586.5 mg, 5.80 mmol), 60% NaH (229.8
mg, 5.74 mmol, washed with hexane), 1 (202.4 mg, 1.15 mmol) were used. After the same work-up as
for 24, the resultant residue was dissolved into pyridine (4 mL). To the resultant solution, Ac2O (2 mL)
was added and the mixture was stirred at rt for 0.5 h. After evaporation of the solvent, sat. aq. NaHCO3
was added to the residue and the whole was extracted with CH2Cl2–MeOH (95:5, v/v). The extract was
washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was

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column chromatographed on SiO2 with CH2Cl2–MeOH (98:2, v/v) to give 25 (143.3 mg, 43%). 25: mp
156–157 °C (pale gray prisms, recrystallized from CH2Cl2–hexane). UV (MeOH) "max nm (log #):
321(4.17), 268 (4.24), 257 (4.40),217 (4.40). [$]D30: –69 (c=0.18, MeOH). IR (KBr): 1742, 1600, 1562,
1
1375, 1224, 1045, 922, 748, 667 cm-1. H-NMR (CDCl3) !: 2.00–2.22 (4H, m), 2.19 (3H, s), 3.49–3.55
(1H, m), 3.74 (1H, dd, J=11.5 and 9.2 Hz), 3.75–3.80 (1H, m), 4.06–4.13 (1H, m), 4.48 (1H, dd, J=11.5
and 2.5 Hz), 7.11 (1H, td, J=7.6 and 1.2 Hz), 7.15 (1H, td, J=7.6 and 1.0 Hz), 7.22 (1H, dd, J=7.6 and
1.2 Hz), 8.26 (1H, dd, J=7.6 and 1.0 Hz), 9.82 (1H, br s), 9.88 (1H, s). MS m/z: 286 (M+). Anal. Calcd
for C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C, 67.33; H, 6.27; N, 9.79.
24 from 25 — Aq. 8% NaOH (1 mL) was added to a solution of 25 (21.5 mg, 0.075 mmol) in DMF (1
mL) and the mixture was stirred at rt for 1 h. After addition of H2O, the whole was extracted with EtOAc.
The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave
24 (18.5 mg, 100%) as crystals.
2-Cyanoindole-3-carbaldehyde (26) from 1 — A solution of KCN (76.5 mg, 1.17 mmol) in H2O (1
mL) was added to a solution of 1 (37.3 mg, 0.21 mmol) in DMF (4 mL) and heated at 75–80 °C for 2 h
with stirring. After evaporation of solvent under reduced pressure, sat. aq. NH4Cl was added and the
whole was extracted with CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over
Na2SO4, and evaporated under reduced pressure to leave an oil, which was column chromatographed on
SiO2 with CH2Cl2–MeOH (99.5:0.5, v/v) to give 26 (35.6 mg, 98%). 26: mp 228–230 °C (decomp.,
colorless prisms, recrystallized from MeOH). IR (KBr): 2230, 1647, 1575, 1447, 1436, 1380, 654, 640
1
cm-1. H-NMR (CD3OD) !: 7.37 (1H, ddd, J=8.1, 7.1, and 1.0 Hz), 7.47 (1H, ddd, J=8.4, 7.1, and 1.2
Hz), 7.53 (1H, ddd, J=8.4, 1.0, and 0.9 Hz), 8.23 (1H, ddd, J=8.1, 1.2, and 0.9 Hz), 10.20 (1H, s). MS
m/z: 170 (M+). Anal. Calcd for C10H6N2O: C, 70.58; H, 3.55; N, 16.45. Found: C, 70.45; H, 3.84; N,
16.46.
1-(3-Formylindol-2-yl)propan-2-one (27) and 5-(1-methoxyindol-3-yl)-3-methylcyclohex-2-enone
(28) from 1 — Under Ar atmosphere, a solution of acetone (0.88 ml, 11.9 mmol) in anhydrous THF (1
mL) was added to a suspension of 35% KH (1.33 g, 11.6 mmol, washed with benzene) in anhydrous
THF (5 mL) with stirring under ice cooling. After gas evolution ceased, a solution of 1 (102.9 mg, 0.59
mmol) in anhydrous THF (6 mL) was added to the resultant solution and the mixture was stirred at rt for
6 h. After addition of H2O, the whole was made acidic with NH4Cl and extracted with CH2Cl2–MeOH
(9:1, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure
to leave an oil, which was column chromatographed on SiO2 with CH2Cl2–MeOH (98:2, v/v) to give 28
(42.9 mg, 29%) and 27 (61.3 mg, 51%) in the order of elution. 27: mp 133–135 °C (colorless prisms,
1
recrystallized from MeOH). IR (KBr): 1712, 1628, 1469, 1394, 1188, 740 cm-1. H-NMR (CDCl3) !:
2.39 (3H, s), 4.43 (2H, s), 7.25–7.31 (2H, m), 7.40–7.45 (1H, m), 8.07-8.12 (1H, m), 9.99 1H, br s,

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disappeared on addition of D2O), 10.28 (1H, s). MS m/z: 201 (M+). Anal. Calcd for C12H11NO2: C, 71.63;
H, 5.51; N, 6.96. Found: C, 71.48; H, 5.45; N, 7.13. 28: mp 70–71 °C (pale brown prisms, recrystallized
from hexane). UV (MeOH) "max nm (log #): 290 (3.72), 277 (3.70), 224 (4.60). IR (KBr): 1645, 1440,
1368, 1239, 1205, 1021, 953, 880, 738 cm-1. 1H-NMR (CDCl3) !: 2.02 (3H, s), 2.57 (1H, dd, J=18.1 and
6.2 Hz), 2.60 (1H, dd, J=16.3 and 12.1 Hz), 2.71 (1H, dd, J=18.1 and 4.6 Hz), 2.81 (1H, dd, J=16.3 and
4.2 Hz), 3.60–3.68 (1H, m), 4.07 (3H, s), 6.00 (1H, s), 7.07 (1H, s), 7.12 (1H, ddd, J=7.9, 7.0, and 0.9
Hz), 7.26 (1H, ddd, J=8.2, 7.0, and 0.7 Hz), 7.43 (1H, dd, J=8.2 and 0.9 Hz), 7.51 (1H, dd, J=7.9 and 0.7
Hz). MS m/z: 255 (M+). Anal. Calcd for C16H17NO2•1/8H2O: C, 74.61; H, 6.65; N, 5.44. Found: C,
74.76; H, 6.87; N, 5.32.
(E)-4-(1-Methoxyindol-3-yl)but-3-en-2-one (29) from 1 — Aq. 8% NaOH (0.5 mL) was added to a
solution of 1 (103.0 mg, 0.59 mmol) in MeOH-acetone (1:1, v/v, 2 mL) and the mixture was stirred at rt
for 6 h. After evaporation of solvent under reduced pressure, brine was added. The whole was extracted
with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated under reduced
pressure to leave an oil, which was column chromatographed on SiO2 with CH2Cl2–MeOH (99:1, v/v) to
give 29 (116.5 mg, 92%). 29: pale yellow oil. IR (film): 1670, 1580 cm-1. 1H-NMR (CDCl3) !: 2.37 (3H,
s), 4.16 (3H, s), 6.77 (1H, d, J=16.1 Hz), 7.26 (1H, ddd, J=8.1, 7.1, and 1.1 Hz), 7.34 (1H, ddd, J=8.2,
7.1, and 1.1 Hz), 7.52 (1H, ddd, J=8.2, 1.1, and 0.9 Hz), 7.86 (1H, d, J=16.1 Hz), 7.92 (1H, ddd, J=8.1,
1.1, and 0.9 Hz), 8.00 (1H, s). High resolution MS m/z: Calcd for C13H13NO2: 215.0946. Found:
215.0941.
28 from 29 — Under Ar atmosphere, a solution of acetone (0.7 ml, 9.53 mmol) in anhydrous THF (1
mL) was added to a suspension of 35% KH (1.026 g, 8.98 mmol, washed with benzene) in anhydrous
THF (5 mL) with stirring under ice cooling. After gas evolution ceased, a solution of 29 (102.3 mg, 0.48
mmol) in anhydrous THF (6 mL) was added to the resultant solution and the mixture was stirred at rt for
1 h. After addition of H2O, the whole was made acidic with 6% HCl and extracted with CH2Cl2–MeOH
(95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced
pressure to leave an oil, which was column chromatographed on SiO2 with CH2Cl2–MeOH (98:2, v/v) to
give 28 (75.2 mg, 62%).
3-[2-(3-Formylindol-2-yl)acetyl]pyridine (30) and 1,5-di(pyrid-3-yl)-3-(1-methoxyindol-3-yl)-
pentane-1,5-dione (31) from 1 — Under Ar atmosphere, a solution of 3-acetylpyridine (88.1 mg, 0.72
mmol) in anhydrous THF (2 mL) was added to 35% KH (66.1 mg, 0.58 mmol, washed with hexane) with
stirring under ice cooling. After gas evolution ceased, a solution of 1 (83.2 mg, 0.47 mmol) in anhydrous
THF (2 mL) was added to the resultant solution and the mixture was stirred at rt for 40 min. After
addition of H2O, the whole was made acidic with 6% HCl and extracted with CH2Cl2–MeOH (9:1, v/v).
The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave

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an oil, which was column chromatographed on SiO2 with CHCl3–MeOH–28%NH3 (46:2:0.2, v/v) to give
1 (4.2 mg, 5%), 31 (16.5 mg, 9%), and 30 (93.1 mg, 74%) in the order of elution. 30: mp 208–210 °C
(orange needles, recrystallized from MeOH). UV (MeOH) "max nm (log #): 301 (4.08), 266 (4.15), 244
1
(4.31), 212 (4.57). IR (KBr): 1698, 1628, 1580, 1460, 1390, 1218, 1000, 977, 758 cm-1. H-NMR
(DMSO-d6) !: 5.09 (2H, s), 7.18–7.24 (2H, m), 7.48 (1H, dd, J=6.9 and 1.1 Hz), 7.65 (1H, ddd, J=8.0,
4.7, and 1.0 Hz), 8.10 (1H, d, J=7.2 Hz), 8.45 (1H, ddd, J=8.0, 2.2, and 1.9 Hz), 8.87 (1H, dd, J=4.7 and
2.2 Hz), 9.31 (1H, dd, J=1.9 and 1.0 Hz), 10.08 (1H, s), 12.04 (1H, br s). MS m/z: 264 (M+). Anal. Calcd
for C16H12N2O2: C, 72.72; H, 4.58; N, 10.60. Found: C, 72.51; H, 4.46; N, 10.40. 31: yellow oil. IR
1
(KBr): 1682, 1582, 1447, 1418, 1360, 1275, 1223, 739, 700 cm-1. H-NMR (CDCl3) !: 3.51 (2H, dd,
J=16.6 and 6.6 Hz), 3.62 (2H, dd, J=16.6 and 7.1 Hz), 4.00 (3H, s), 4.37 (1H, tt, J=7.1 and 6.6 Hz), 7.12
(1H, dd, J=8.1 and 5.8 Hz), 7.18 (1H, s), 7.24 (1H, dd, J=8.1 and 5.8 Hz), 7.38 (1H, d, J=8.1 Hz), 7.42
(2H, dd, J=7.8 and 4.9 Hz), 7.61 (1H, d, J=8.1 Hz), 8.24 (2H, ddd, J=7.8, 1.6, and 1.5 Hz), 8.76 (2H, dd,
J=4.9 and 1.5 Hz), 9.16 (2H, d, J=1.6 Hz). MS m/z: 399 (M+). High resolution MS m/z: Calcd for
C24H21N3O3: 399.1581. Found: 399.1580.
Methyl 2-(3-formylindol-2-yl)acetate (32) and dimethyl 2-(3-formylindol-2-yl)malonate (33) and
from 1 — A solution of dimethyl malonate (85.6 mg, 0.65 mmol) in anhydrous MeOH (1 mL) was
added to a NaOMe solution in anhydrous MeOH (prepared by dissolving Na (12.0 mg, 0.52 mmol) in
anhydrous MeOH (0.5 mL)) and stirred at rt for 1 h. To the resultant solution, a solution of 1 (49.8 mg,
0.28 mmol) in anhydrous MeOH (2 mL) was added and the mixture was refluxed for 30 min with stirring.
After addition of H2O, the whole was made acidic with 6% HCl and extracted with CH2Cl2–MeOH (95:5,
v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to
leave an oil, which was column chromatographed on SiO2 with CH2Cl2–MeOH (99:1, v/v) to give 1
(13.3 mg, 27%), 33 (10.5 mg, 13%), and 32 (31.6 mg, 46%) in the order of elution. 32: mp 116–118 °C
(colorless leaves, recrystallized from MeOH–H2O). IR (KBr): 1730, 1644, 1465, 1451, 1438, 1389, 1305,
1
1215, 1163, 1024, 756, 749 cm-1. H-NMR (CDCl3) !: 3.82 (3H, s), 4.29 (2H, s), 7.26–7.31 (1H, m),
7.39–7.44 (1H, m), 8.14–8.19 (1H, m), 9.88 (1H, s), 10.24 (1H, s). MS m/z: 217 (M+), 185, 158. Anal.
Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.44; H, 5.06; N, 6.48. 33: mp 162–163 °C
(colorless needles, recrystallized from MeOH). IR (KBr): 1757, 1734, 1626, 1449, 1384, 1325, 1238,
1147, 743 cm-1. 1H-NMR (CDCl3) !: 3.83 (6H, s), 5.84 (1H, s), 7.30 (1H, ddd, J=7.2, 7.1, and 1.5 Hz),
7.33 (1H, ddd, J=7.2, 7.1, and 1.6 Hz), 7.44–7.48 (1H, m), 8.14–8.19 (1H, m), 9,85 (1H, br s), 10.31 (1H,
s). MS m/z: 275 (M+), 243. Anal. Calcd for C14H13NO5: C, 61.09; H, 4.76; N, 5.09. Found: C, 61.25; H,
4.71; N, 5.04.
32 from 33 — A solution of 33 (56.1 mg, 0.19 mmol) in anhydrous MeOH (2 mL) was added to a
NaOMe solution in anhydrous MeOH (prepared by dissolving Na (8.9 mg, 0.38 mmol) in anhydrous

HETEROCYCLES, Vol. 86, No. 1, 2012
451
MeOH (0.5 mL)) and the mixture was refluxed for 2 h with stirring. After addition of H2O, the whole
was made acidic with 6% HCl and extracted with CH2Cl2–MeOH (95:5, v/v). The extract was washed
with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was
subjected to p-TLC on SiO2 with CH2Cl2–MeOH (98:2, v/v) as a developing solvent. Extraction of the
band having an Rf value of 0.63–0.52 with CH2Cl2–MeOH (95:5, v/v) afforded 33 (4.3 mg, 8%).
Extraction of the band having an Rf value of 0.47–0.27 with CH2Cl2–MeOH (95:5, v/v) afforded 32 (28.6
mg, 64%).
2-[(E)-Propen-1-yl]indole-3-carbaldehyde (34) and 1-(1-methoxyindol-3-yl)but-3-en-1-ol (35) from
1 — Under an Ar atmosphere, a solution of 1 (54.1 mg, 0.31 mmol) in anhydrous THF (4 mL) was added
to a mixture of Bu4NF•3H2O (106.8 mg, 0.34 mmol, dried for 2 h under reduced pressure) and molecular
sieve (4 angstrom, 353.4 mg, flame dried, 1 h). To the mixture, allyltrimethylsilane (0.15 mL, 0.94
mmol) was added and stirred at rt for 6 h. After addition of sat. aq. NH4Cl, the whole was extracted with
CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure to leave an oil, which was column chromatographed on SiO2 with CH2Cl2–hexane (7:3,
v/v) to give 35 (18.9 mg, 28%), 34 (13.3 mg, 23%), and unknown product (8.8 mg) in the order of
elution. 34: mp 217–218 °C (yellow prisms, recrystallized from MeOH). IR (KBr): 1628, 1585, 1463,
1
1382, 1245, 948, 749, 740 cm-1. H-NMR (CD3OD) !: 2.03 (3H, dd, J=6.8 and 1.7 Hz), 6.66 (1H, dq,
J=15.9 and 6.8 Hz), 7.03 (1H, dq, J=15.9 and 1.7 Hz), 7.17 (1H, ddd, J=7.8, 7.1, and 0.9 Hz), 7.23 (1H,
ddd, J=8.1, 7.1, and 1.3 Hz), 7.37 (1H, ddd, J=8.1, 1.0, and 0.9 Hz), 8.11 (1H, ddd, J=7.8, 1.3, and 0.9
Hz), 10.12 (1H, s). MS m/z: 185 (M+), 170. Anal. Calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56.
Found: C, 77.77; H, 6.09; N, 7.51. 35: colorless oil. IR (film): 1638, 1450, 1438, 1350, 1319, 1226, 1092,
1
1046, 1031, 1010, 1000, 979, 954, 917, 758, 739 cm-1. H-NMR (CD3OD) !: 2.62–2.73 (2H, m), 4.05
(3H, s), 4.96 (1H, t, J=6.7 Hz), 5.01 (1H, ddt, J=10.2, 2.1, and 1.1 Hz), 5.07 (1H, ddt, J=17.1, 2.1, and
1.5 Hz), 5.85 (1H, ddt, J=17.1, 10.2, and 7.0 Hz), 7.05 (1H, ddd, J=7.9, 7.1, and 0.9 Hz), 7.19 (1H, ddd,
J=8.2, 7.1, and 1.1 Hz), 7.34 (1H, s), 7.38 (1H, ddd, J=8.2, 0.9, and 0.7 Hz), 7.67 (1H, ddd, J=7.9, 1.1,
and 0.7 Hz). High resolution MS m/z: Calcd for C13H15NO2: 217.1102. Found: 217.1101.
2-(3,3-Dimethylallyl)- (36), 2-(1,1-dimethylallyl)indole-3-carbaldehyde (37), and 2,2-dimethyl-1-
(1-methoxyindol-3-yl)but-3-en-1-ol (38) from 1 — Under an Ar atmosphere, a solution of 1 (53.5 mg,
0.31 mmol) in anhydrous THF (4 mL) was added to a mixture of Bu4NF•3H2O (108.5 mg, 0.34 mmol,
dried for 2 h under reduced pressure) and molecular sieve (4 angstrom, 416.4 mg, flame dried, 1 h). To
the mixture, (3-methylbut-2-en-1-yl)trimethylsilane (0.20 mL, 1.1 mmol) was added and stirred at rt for
3 h. After addition of sat. aq. NH4Cl, the whole was extracted with CH2Cl2–MeOH (95:5, v/v). The
extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil,
which was subjected to p-TLC on SiO2 with CHCl3–hexane (7:3, v/v) as a developing solvent. Extraction

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of the band having an Rf value of 0.65–0.58, 0.58–0.50, 0.49–0.43, 0.42–0.37 with CHCl3–MeOH (95:5,
v/v) afforded 38 (10.6 mg, 14%), unreacted 1 (20.5 mg, 38%), 37 (7.7 mg, 12%), and 36 (4.4 mg, 7%),
respectively. 36: mp 149–150 °C (colorless needles, recrystallized from MeOH–H2O). IR (KBr): 1627,
1
1580, 1461, 1381, 1232 cm-1. H-NMR (CDCl3) !: 1.77 (3H, s), 1.84 (3H, d, J=1.5 Hz), 3.88 (2H, d,
J=7,3 Hz), 5.40 (1H, tquint, J=7.3 and 1.5 Hz), 7.24 (1H, ddd, J=8.5, 7.1, and 1.3 Hz), 7.27 (1H, ddd,
J=8.5, 7.1, and 1.3 Hz), 7.33–7.36 (1H, m), 8.21–8.26 (1H, m), 8.47 (1H, br s, disappeared on addition of
D2O), 10.23 (1H, s). MS m/z: 213 (M+). Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.54. Found: C,
78.97; H, 7.16; N, 6.52. 37: mp 194–195 °C (colorless needles, recrystallized from CH2Cl2–hexane). IR
(KBr): 3160, 1621, 1581, 1440, 1369 cm-1. 1H-NMR (CDCl3) !: 1.69 (6H, s), 5.292 (1H, d, J=17.5 Hz),
5.294 (1H, d, J=10.6 Hz), 6.23 (1H, dd, J=17.5 and 10.6 Hz), 7.25 (1H, ddd, J=8.8, 7.3, and 1.5 Hz),
7.28 (1H, ddd, J=8.8, 7.3, and 1.5 Hz), 7.35–7.38 (1H, m), 8.35–8.39 (1H, m), 8.52 (1H, br s,
disappeared on addition of D2O), 10.47 (1H, s). MS m/z: 213 (M+). Anal. Calcd for C14H15NO: C, 78.84;
H, 7.09; N, 6.54. Found: C, 78.63; H, 7.13; N, 6.49. 38: colorless oil. IR (film): 1634, 1449, 1355, 1093,
1043, 1034, 1009, 955, 912, 662, 639 cm-1. 1H-NMR (CDCl3) !: 1.07 (3H, s), 1.08 (3H, s), 1.57 (1H, br s,
disappeared on addition of D2O), 4.08 (3H, s), 4.82 (1H, s), 5.14 (1H, dd, J=17.4 and 1.3 Hz), 5.15 (1H,
dd, J=10.8 and 1.3 Hz), 6.04 (1H, dd, J=17.4 and 10.8 Hz), 7.10 (1H, ddd, J=8.1, 7.1, and 0.9 Hz), 7.23
(1H, ddd, J=8.2, 7.1, and 0.9 Hz), 7.25 (1H, s), 7.41 (1H, ddd, J=8.2, 0.9, and 0.8 Hz), 7.66 (1H, ddd,
J=8.1, 0.9 and 0.8 Hz). High resolution MS m/z: Calcd for C15H19NO2: 245.1416. Found; 245.1415.
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