A novel substitution reaction of tetrahydropyrano[3,4-b]indole derivative - Chain extension and structural correlation study

Article abstract of DOI:10.3987/COM-02-9703

An unusual cyanation with rearrangement of a 1-chloromethyl-tetrahydropyrano[3,4-b]indole-1-acetic acid ester derivative is reported. The resulting C-1 chain extension product is identified by correlation studies and spectral method.

Full text of DOI:10.3987/COM-02-9703

HETEROCYCLES, Vol. 60, No. 5, 2003
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HETEROCYCLES, Vol. 60, No. 5, 2003, pp. 1095 - 1110
Received, 24th December, 2002, Accepted, 28th February, 2003, Published online, 3rd March, 2003
A
NOVEL
SUBSTITUTION
REACTION
OF
TETRAHYDROPYRANO[3,4-b]INDOLE DERIVATIVE
-
CHAIN
EXTENSION AND STRUCTURAL CORRELATION STUDY
Shan-Yen Chou
Chemical Process Development Division, Development Center For Biotechnology, 102, Lane
169, Kang Ning St., Hsichih, Taipei Hsien, Taiwan, R.O.C.
Abstract
-
An unusual cyanation with rearrangement of
a
1-chloromethyl-
tetrahydropyrano[3,4-b]indole-1-acetic acid ester derivative is reported. The resulting C-1
chain extension product is identified by correlation studies and spectral method.
Fused indoles are of general interest because they have a wide variety of medicinalinterest,including their
reported anti-inflammatory and analgesic properties.1,2 A versatile method for synthesizing pyranoindole
ring systems has been reported, including the preparation of 1,3,4,9-tetrahydropyrano[3,4-b]indole-
1-alkanoic acids and their derivatives.2 The exploration led to the discovery of an anti-inflammatorydrug,
etodolac (15) (brand name: Lodine). Recently, research in the field of cyclooxygenase-2 (COX-2)
inhibitors stimulated the reinvestigation of pyranoindoles.3-5 More recently, it was reported that COX-2
may play an important role during premalignant hyperproliferating.6 Therefore, exploring synthetic
methods for preparing fused indoles is valuable.
During the study of chiral etodolac synthesis,7 a novel ring-expansion reaction was discovered in an
Figure 1
Me
OSO2
O
O
O
1
Cl
Et
Me
OSO2
R
N
H
N
H
N
Et
Et
H
CO2
CN
Et
Et
1
A
CN
O
O
O
1
1
R
CN
CO2
R
N
H
CN
CN
N
N
H
Et
Et
H
Et
CO2
Et
2
B
C
(see reference 7)
attempt of a cyanide substitution on the C-1 methanesulfonyloxymethyl side chain of a

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HETEROCYCLES, Vol. 60, No. 5, 2003
tetrahydropyrano[3,4-b]indole derivative (1) (1-2, Figure 1). Further extension of this work has led to a
series of tetrahydropyrano[3,4-b]indoles with a chloromethyl side chain and an ester side chain at the C-1
position as characterized generically by structure (A), wherein the chloro group of A mimics the
methanesulfonyloxy group of 1. This article describes an unusual cyanide displacement with C-1 chain
extension executed by a linear chain rearrangement on derivative (A) (A-B, Figure 1), rather than by the
expected ring expansion (A-C, Figure 1).
As shown in Scheme 1, cyclocondensation of 7-ethyltryptophol (3) with the ketal ester (4) gave
pyranoindole (5). Heating of 5 with excessive amount of sodium cyanide in DMF led to a nitrile ester (6).
During the early stages of this study, 6 was proposed to be a skeletal rearrangement product (8) formed
through the ring expansion pathway (Figure 1).8 However, as revealed by the NMR spectrum, beside
methyleneoxy protons of ester (δ 4.08 (q), J = 7.2 Hz), only one pair of protons appeared at ~ δ 4.0, and
Scheme 1
O
OH
BF OEt
2
MeO OMe
Cl CO2Et
3
Cl
+
N
ClCH CH Cl
N
2
2
H
H
CO2Et
O
4
Et
Et
5
3
O
O
CN
CN
not
CO2Et
CN
N
N
CN
N
DMF
heat
H
H
H
CO2Et
Et
Et
CO2Et
Et
6
7
8
could not support structure (8) for the existence of three pairs of methyleneoxy protons in 8. The
preparation of an authentic simple displacement product (7) and its comparison with 6 are desirable to
Scheme 2 - Correlation synthesis : an unambiguous synthesis of an envisaged simple
displacement product of 5 (nitrile ester (7))
OH
MeO
BF OEt
CH N
3
2
OH
2
2
MeO2C
CO2Me
O
+
O
N
H
N
H
N
H
CO2H
CO2H
Et
CO2Me
Et
Et
CO2Me
3
9
10
11
oxalyl
chloride
1)
(CF CO) O
3
2
HCl
EtOH
O
O
O
O
N
H
N
H
pyridine
CH Cl
2) NH OH
N
H
N
4
CO2Me
CO2H
Et
CO2Me
CONH2
H
Et
CO2Me
CO2Et
Et
Et
2
2
CN
o
CN
0 C - rt
14
7
12
13
resolve this issue. Scheme 2 illustrates an unambiguous synthetic pathway of 7. Cyclization of

HETEROCYCLES, Vol. 60, No. 5, 2003
1097
7-ethyltryptophol (3) with 3-methoxypent-2-enedioic acid dimethyl ester (9) gave 10, which was
hydrolyzed to the diacid (11). Methylation of 11 using diazomethane led to the half ester (12), which was
converted to the amide (13), and followed by dehydration of 13 to the nitrile (14) by conventional means.
Finally, alcoholysis of 14 afforded the nitrile ester (7). Compounds (7) and (6) are not identical as shown
by NMR spectra and TLC comparisons, thus the envisaged simple displacement pathway is excluded.
Having excluded the regioisomer (7), there remains lack evidence to ensure ring expansion occurs during
cyanation of 5. If the envisaged skeletal rearrangement product (8) were the resulting nitrile ester rather
than 6, then transforming its C-1 ethoxycarbonylmethyl side chain to ethyl by successive reduction,
bromination and hydrogenolysis would lead to the known nitrile (2) (Figure 1). To author’s surprise,
starting from 6, after these transformations, the end product (see 22, Scheme 5) is not identical to the
nitrile (2) as revealed by NMR spectra and TLC comparisons. To clarify suspicions concerning the initial
assignment of 2 and for purposes of comparison, an unambiguous synthesis of the regioisomer (17) was
performed by conventional means (Scheme 3). Compounds (17) and (2) are not identical as shown by
Scheme 3 - Correlation synthesis : an unambiguous synthesis of an envisaged
1
17
)
simple displacement product of ( nitrile
oxalyl
chloride
1)
(CF CO) O
3
2
O
O
O
N
H
N
H
N
H
2) NH OH
pyridine
4
CO H
CONH
CN
Et
2
Et
Et
2
CH Cl
2
2
o
15
0 C - r t
17
16
etodolac
NMR spectra and TLC comparisons,7 therefore the structure of 2 is reconfirmed and the skeletal
rearrangement (8) is also excluded. Accordingly, the third possible structure, a linear chain rearrangement
product (6), is proposed. As shown in Scheme 4, the reaction is envisaged as involving first
intramolecular nucleophilic attack of the chloride by the pyrano oxygen to form a three-membered
oxonium ion, which is subsequently fragmented through an indole ring assisted C-1 chain migration to
the electrophilic carbon center. Cyanide ion is then collapsed onto the electrophilic C-1 position to afford
tetrahydropyrano[3,4-b]indole-1-cyano-1-propionic acid ethyl ester (6), a C-1 chain extension product. A
comparison with the ring-expansion pathway (Figure 1) enables the C-(1) chain migration to be explained
by the electron withdrawing property of its ester group, which stabilizes partial negative charge generated
during C-1 chain migration.
Consequently, the conversion of 6 to the chain extension nitrile (22) would be illustrated in Scheme 5.
The regiochemistry of the chain extension product (6) is supported by a HMBC spectrum (Figure 2),

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HETEROCYCLES, Vol. 60, No. 5, 2003
Scheme 4 - Proposed synthetic pathway for nitrile ester (6)
NaCN
DMF
CN
O
O
O
O
N
H
N
H
oC
N
N
105-110
H
H
Cl
Et
Et
Et
Et
Et
CO
CN
Et
CO
NC
2
Et
CO
2
2
Et
CO
2
6
5
wherein the correlations between the carbonyl carbon and its α-/β- methylene protons firmly establish
regiochemistry, since the nitrile ester (8) would not show comparable correlations.9
Scheme 5 - Correlation synthesis : synthesis of the chain-extended nitrile 22
1) LiOH
2) ClC(O)OBu-i
NEt / CHCl
[H]
(C H ) PBr
2
3
3
6
5 3
O
O
O
O
N
N
N
N
3) NaBH
4
H
H
H
NC
H
ClCH CH Cl
Et
Et
Et
2
2
Et
MeOH, H O
NC
2
NC
NC
CH
R
CO Et
Br
3
2
6
21
22
R = CO H, 18
2
R= CO Bu-i, 19
2
R = CH OH, 20
2
Figure 2 - HMBC correlation of 6
2.76, 3.00
7.07
CH
2
4.05, 4.33
(64.27)
7.10
CH
2
7.36
O
NH
(71.47)
2.60, 2.70
(135.34)
NC
CH
CH
2
2
CH
2
C
H
3
4.08 (q)
(60.97)
(118.72)
O
CH
2.85 (q)
(23.93)
(172.91)
2.40, 2.55
O
CH
3
2
Next, several pyranoindoles (29-34) that differ only in the substituents in benzene rings were prepared
from corresponding tryptophols,10 their reaction with sodium cyanide in DMF was examined. As shown
in Scheme 6, substituents R = 6-Cl (29), 6-OMe (31), 8-Me (33) and 8-CF3 (34), react with sodium
cyanide in DMF to afford the expected rearranged displacement products (37-40). Their NMR spectra
are comparable with that of 6. Instead of pyranoindoles (30) (R = 6-Me) and (32) (R = H), give fused

HETEROCYCLES, Vol. 60, No. 5, 2003
1099
lactams (35) and (36) respectively, which are in fact formed by the condensation of indolyl NH and C-1
ester. These nitrile esters might be difficult to prepare by other methods.
In conclusion, this study has demonstrated a novel chain extension of tetrahydropyrano[3,4-b]indole
derivative and verified the structure by rigorous correlation studies.
Scheme 6
4
3
R = 7-Et, 3
R = H, 23
R = 5-OMe, 25
R = 5-Cl, 26
OH
95 % ethanol
OEt
O
5
6
+
R
R
2
R = 5-Me, 24 R = 7-Me, 27
HCl
NHNH
N
1
heat
15.5 - 43.5 %
2
R = 7-CF , 28
7
3
H
for
32 and 30
R
O
CN
N
O
4
3
42.5 - 45.2 %
5
4
3
6
7
2
BF OEt
2
O
1
OH
3
NaCN
R = H, 35
OMe
MeO
Cl
5
Cl
+
R
2
R = 9-Me, 36
R
CO Et
for
29, 31,
33 and 34
2
4
3
DMF
heat
6
N
H
N
5
ClCH CH Cl
1
2
2
8
7
O
H
6
R
7
2
CO Et
2
4
1
52.3 - 78.5 %
CO Et
2
N
H
43.2 - 82.0 %
CN
R = H, 23
8
R = H, 32
R = 5-Me, 24
R = 6-Me, 30
R = 6-OMe, 31
R = 6-Cl, 29
R = 8-Me, 33
R = 5-OMe, 25
R = 6-Cl, 37
R = 6-OMe, 38
R = 8-Me, 39
R = 5-Cl, 26
R = 7-Me, 27
R = 7-CF , 28
R = 8-CF , 40
3
R = 8-CF , 34
3
3
EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer FT-IR (Spectrum GX)spectrophotometers,NMR spectra were
recorded on a Bruker-AC 500 (500 MHz) spectrometer, CDCl3 and DMSO-d6 were used as solvents, and
TMS was added as an internal standard. If determined, the type of carbon in 13C NMR spectra is indicated
in parentheses after the chemical shift : 0, quaternary, 1, methine, 2, methylene, and 3, methyl. Elemental
analysis were determined by a Perkin-Elmer 2400. MS spectra were measured on JEOL-JMS-D100
instrument. Melting points were measured in open capillary tubes using BÜchi immersion apparatus, and
are uncorrected. Separations by flash chromatography were performed on silica gel (230-400 mesh). All
reagents were of commercial quality and were used as received.
4-Chloro-3,3-dimethoxy-butylic acid ethyl ester (4). A mixture of ethyl 4-chloroacetoacetate (66.4 g,
0.40 mol), trimethyl orthoformate (60.0 g, 0.57 mol) and p-TSA·H2O (3.0 g, 15.9 mmol) was stirred at 25
oC for 72 h. The resulting mixture was evaporated at a water pump and then distilled under vacuum, the
fraction boiled at 95-100 oC(11.8 mmHg) was collected to provide 4 (58.0g, 68.1%) as a colorless oil. IR
(film) νmax:1738, 1714, 1636, 1141 cm-1. 1H-NMR (CDCl3): 4.16 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H),3.27 (s,

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HETEROCYCLES, Vol. 60, No. 5, 2003
6H), 2.86 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H). MS (EI) m/z (%) : 178 (M+-MeOH, 56), 133 (100), 91 (21). As
revealed by 1H NMR spectrum,4 contains ~11 mole %of the corresponding enol ether ester as co-distillate.
An analytical sample of the enol ether was isolated by silica gel column chromatography (eluent : ethyl
acetate/hexane =1/20).1H-NMR (CDCl3): 5.14 (s, 1H), 4.66 (s, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.72 (s,3H),
1.29 (t, J = 7.0 Hz, 3H). MS (EI) m/z (%) : 178 (M+, 65), 133 (100).
Typical procedure for synthesizing tryptophols - 7-Ethyltrtptophol (3). To a suspension of
2-ethylphenylhydrazine hydrochloride (26.6 g, 0.15 mol) in 95 % ethanol (272 mL) was added
2-ethoxytetrahydrofuran (25.0 g, 0.22 mol).After being refluxed for 12 h,the reaction mixture was filtered
through Celite and then evaporated. The reaction mixture was diluted with water and extracted with
1,2-dichloroethane. The combined extracts were washed with water, dried (MgSO4), and evaporated.
Purification by silica gel column chromatography (eluent : ethyl acetate/hexane = 1/6) provided 3 as a
dark brown oil (12.5 g, 43.0 %). The spectral data are identical to those of an authentic sample.10
Each of the following tryptophols was prepared following the typical procedure from the starting
phenylhydrazine in the same reaction scale.
Tryptophol 23. 21.5 % yield. The spectral data are identical to those of commercially available sample.
1
5-Methyltryptophol (24). Yellow oil, 32.0 % yield. IR (film) νmax: 3403, 1457, 1212 cm-1. H-NMR
(CDCl3) : 8.01 (br s, 1H), 7.39 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 7.00 (m, 1H),
3.88 (t, J = 6.5 Hz, 2H), 2.99 (t, J = 6.5 Hz, 2H), 2.45 (s, 3H). MS (EI) m/z (%) : 175 (M+, 30), 144 (100),
115 (40). Anal. Calcd for C11H13NO : C, 75.40; H, 7.48; N, 7.99. Found : C, 75.73; H, 7.78; N, 8.05.
1
5-Methoxytryptophol (25). Yellow oil, 33.5 % yield. IR (film) νmax: 3408, 1487, 1215 cm-1. H-NMR
(CDCl3) : 8.09 (br s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.98 (s, 1H), 6.84 (m, 1H),
3.82 (s, 3H), 3.76 (t, J = 6.4 Hz, 2H), 2.97 (t, J = 6.4 Hz, 2H). MS (EI) m/z (%) : 191 (M+, 35), 160 (100),
145 (40), 117 (62). Anal. Calcd for C11H13NO2 : C, 69.09; H, 6.85; N, 7.32. Found : C, 69.23; H, 6.98; N,
7.08.
1
5-Chlorotryptophol (26). Yellow oil, 42.3 % yield. IR (film) νmax: 3414, 1458, 1019 cm-1. H-NMR
(CDCl3) : 8.19 (br s, 1H), 7.56 (s, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 3.88 (t, J = 6.4 Hz, 2H),
2.97 (t, J = 6.4 Hz, 2H). MS (EI) m/z (%) : 195 (M+, 30), 144 (100), 115 (10). Anal. Calcd for

HETEROCYCLES, Vol. 60, No. 5, 2003
1101
C10H10NOCl : C, 61.39; H, 5.15; N, 7.16. Found : C, 61.25; H, 5.38; N, 7.03.
1
7-Methyltryptophol (27). Yellow oil, 43.5 % yield. IR (film) νmax: 3397, 1433, 1043 cm-1. H-NMR
(CDCl3) : 8.03 (br s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.06 (m, 2H), 7.01 (d, J = 7.0 Hz, 1H), 3.89 (t, J = 6.4
Hz, 2H), 3.02 (t, J = 6.4 Hz, 2H), 2.48 (s, 3H). MS (EI) m/z (%) : 175 (M+, 30), 144 (100), 115 (10). Anal.
Calcd for C11H13NO : C, 75.40; H, 7.48; N, 7.99. Found : C, 75.37; H, 7.87; N, 7.84.
7-Trifluoromethyltryptophol (28). Yellow oil, 15.5 % yield. IR (film) νmax: 3348,1448,1317,1046 cm-1.
1H-NMR (CDCl3) : 8.50 (br s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.20 (m, 1H), 7.17
(m, 1H), 3.91 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 6.8 Hz, 2H). MS (EI) m/z (%) : 229 (M+, 50), 198 (100), 178
(100), 51 (10). Anal. Calcd for C11H10NOF3 : C, 57.64; H, 4.40; N, 6.11. Found : C, 57.75; H, 4.56; N,
6.34.
Typical procedure for cyclocondensation – (1-Chloromethyl -6-chloro- 1,3,4,9- tetrahydropyrano-
[3,4-b]indol-1-yl)acetic acid ethyl ester (29). 5-Chlorotryptophol (26) (5.7 g, 29.1 mmol) in
1,2-dichloroethane (163 mL) was stirred to homogeneous, then the ketal ester (4) (7.7 g, ~36.5 mmol) and
BF3·OEt2 (2.0mL,15.8 mmol) were added successively with stirring.After being stirred at rt for 63 h, the
resulting dark mixture was diluted with ice water and 1,2-dichloroethane (60 mL) and adjusted to pH =7
with saturated NaHCO3. The separated organic layer was washed twice with water, dried (MgSO4), and
evaporated. The residue was diluted with 25 mL of isopropyl ether and stirred at rt overnight. The
precipitate was collected and washed with isopropyl ether to give 29 (6.7 g) as a white powder. The
o
filtrate was evaporated and diluted with isopropyl ether (5 mL) and left to stand at 0 C overnight. The
precipitate was collected and washed with isopropyl ether to give 29 (0.3 g) as a second crop. The yield
o
was 7.0 g (70.2 %), mp 110-112 C (1/4 ethyl acetate-hexane). IR (KBr) νmax : 3269, 1695, 1213 cm-1.
1H-NMR (CDCl3) : 9.27 (br s, 1H, NH), 7.50 (s, 1H), 7.29 (d, J = 9.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H),
4.22 (q, J = 7.0 Hz, 2H), 4.25, 3.97 (ABq, J = 11.9 Hz, 2H, CH2Cl), 4.06 (m, 2H, ArCH2CH2O), 3.30,
2.97 (ABq, J = 17.4 Hz, 2H, CH2C(O)), 2.81 (m, 2H, ArCH2CH2O), 1.32 (t, J = 7.0 Hz, 3H). MS (EI) m/z
(%): 341 (M+, 30), 292 (100), 254 (35), 204 (30). Anal. Calcd for C16H17NO3Cl2 : C, 56.15; H, 5.01; N,
4.09. Found : C, 56.23; H, 4.98; N, 4.05.
Each of the following solid pyranoindoles (5, 32-34)was prepared following the typical procedure starting
from the starting tryptophol and 4 in the same reaction scale. Liquid pyranoindole (30, 31), was isolated
by extraction and purified by column chromatography.

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HETEROCYCLES, Vol. 60, No. 5, 2003
(1-Chloromethyl-8-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid ethyl ester (5). 58.6 %
o
yield. White powder, mp 106-107 C (1/4 ethyl acetate-hexane). IR (KBr) νmax : 3328, 1700, 1192 cm-1.
1H-NMR (CDCl3) : 9.19 (br s, 1H, NH), 7.38 (d, J = 7.5 Hz, 1H), 7.09 (d, J = 7.3 Hz,1H), 7.03 (m, 1H),
4.29, 3.97 (ABq, J = 11.9 Hz, 2H), 4.22 (q, J = 7.0 Hz, 2H), 4.04 (m, 2H), 3.30, 2.95 (ABq, J = 6.9 Hz,
2H), 2.86 (q, J = 7.5 Hz, 2H), 2.83 (m, 2H), 1.37 (t, J = 7.5 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H). MS (EI) m/z
(%):335 (M+, 26), 286 (100), 248 (22),198 (16). Anal.Calcd for C18H22NO3Cl :C, 64.38; H, 6.60; N, 4.17.
Found : C, 64.28; H, 6.58; N, 4.35.
3-(1-Chloromethyl-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid ethyl ester (30).
52.3 % yield. Yellow oil. IR (film) νmax : 3300, 1694, 1215, 1036 cm-1. 1H-NMR (CDCl3) : 9.00 (br s, 1H,
NH), 7.30 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 4.25, 3.94 (ABq, J = 11.9 Hz, 2H),
4.18 (q, J = 7.0 Hz, 2H), 4.03 (m, 2H), 3.27, 2.94 (ABq, J = 17.3 Hz, 2H), 2.80 (q, J = 7.0 Hz, 2H), 2.44
(s, 3H),1.28 (t,J=7.0 Hz, 3H). MS (EI) m/z (%): 321(M+, 18),272 (100), 234 (27),199 (37).Anal.Calcd for
C17H20NO3Cl : C, 63.45; H, 6.26; N, 4.35. Found : C, 63.56; H, 6.22; N, 4.36.
(1-Chloromethyl-6-methoxy-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid ethyl ester (31).
55.5 % yield. Yellow oil. IR (film) νmax : 3396, 1715, 1488, 1217 cm-1. 1H-NMR (CDCl3) : 9.00 (br s, 1H,
NH), 7.26 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.25, 3.95 (ABq, J = 11.9 Hz, 2H,
CH2Cl), 4.20 (q, J = 7.0 Hz, 2H), 4.04 (m, 2H, ArCH2CH2O), 3.86 (s, 3H), 3.27, 2.97 (ABq, J = 17.3 Hz,
2H, CH2C(O)), 2.79 (m, 2H, ArCH2CH2O), 1.29 (t, J = 7.0 Hz, 3H). MS (EI) m/z (%): 337 (M+, 65), 288
(100), 250 (68), 200 (70). Anal. Calcd for C17H20NO4Cl : C, 60.45; H, 5.97; N, 4.15. Found : C, 60.29; H,
5.83; N, 4.08.
(1-Chloromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid ethyl ester (32). 52.5 % yield.
o
White powder, mp 68-69 C (1/4 ethyl acetate-hexane). IR (KBr) νmax : 3378, 1731, 1699, 1078 cm-1.
1H-NMR (CDCl3) : 9.13 (br s, 1H, NH), 7.51 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.19 (m, 1H),
7.11 (m,1H), 4.22 (q, J = 7.0 Hz, 2H), 4.03 (m, 2H, ArCH2CH2O), 3.95, 3.78 (ABq, J = 11.9 Hz, 2H),
3.27 (m, 2H, ArCH2CH2O), 2.97, 2.86 (ABq, J = 17.1 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). MS (EI) m/z (%):
307 (M+, 30), 258 (100), 220 (30), 170 (30). Anal. Calcd for C16H18NO3Cl : C, 62.44; H, 5.89; N, 4.55.
Found : C, 62.32; H, 5.98; N, 4.36.
(1-Chloromethyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid ethyl ester (33).68.5

HETEROCYCLES, Vol. 60, No. 5, 2003
1103
o
% yield. White powder, mp 130-131 C (1/4 ethyl acetate-hexane). IR (KBr) νmax : 3309, 1700, 1193
cm-1.1H-NMR (CDCl3) : 9.13 (br s, 1H, NH), 7.37 (d, J = 7.7 Hz, 1H), 7.04 (m, 1H), 7.00 (d, J = 7.1 Hz,
1H), 4.28, 3.96 (ABq, J = 11.9 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.04 (m, 2H), 3.30, 2.95 (ABq, J = 17.3
Hz, 2H), 2.83 (m, 2H), 2.49 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). MS (EI) m/z (%): 321(M+, 29), 272 (100),
234 (38), 184 (70).Anal.Calcd for C17H20NO3Cl :C, 63.45; H, 6.26; N, 4.35. Found :C, 63.28; H, 6.56; N,
4.56.
(1-Chloromethyl-8-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid ethyl ester
(34). 78.5 % yield. White powder, mp 108-110 oC (1/4 ethyl acetate-hexane). IR (KBr) νmax : 3299, 1707,
1040 cm-1. 1H-NMR (CDCl3): 9.71 (br s, 1H, NH), 7.68 (d, J = 7.9 Hz, 1H),7.45 (d, J = 7.5 Hz,1H),7.18
(m, 1H), 4.27, 3.98 (ABq, J = 12.0 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.06 (m, 2H), 3.30, 2.97 (ABq, J =
17.3 Hz, 2H), 2.87 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). MS (EI) m/z (%) : 375 (M+, 29), 326 (100), 288 (40),
238 (26). Anal. Calcd for C17H17NO3ClF3: C, 54.34; H, 4.56; N, 3.73. Found :C, 54.15; H, 4.58; N, 3.36.
Typical procedure for nitrile ester formation with C-1 side chain extension-3-(1-Cyano-
8-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)propionic acid ethyl ester (6). To a solution of the
chloride (5) (3.1 g, 9.3 mmol) in DMF (43 mL) was added powdered sodium cyanide (9.3 g, 188.8 mmol).
After being heated under nitrogen at 105-110 oC for 22 h, the reaction mixture was filtered and the filtrate
o
distilled at below 50 C to remove DMF. The residue was diluted with chloroform (80 mL) and washed
with water (40 mL x 2). The separated organic solution was dried (MgSO4) and evaporated. Purification
by silica gel column chromatography (eluent :ethyl acetate/hexane =1/6)provided pyranoindole (6)(1.8g,
60.0 %) as a yellow oil. IR (film) ν max: 3371, 1719, 1288, 1081 cm-1. 1H-NMR (CDCl3) : 8.62 (br s, 1H),
7.36 (m, 1H), 7.10 (m, 1H), 7.07 (m, 1H) 4.33 (m, 1H), 4.08 (q, J = 7.2 Hz, 2H), 4.05 (m, 1H), 3.00 (m,
1H), 2.85 (q, J = 7.5 Hz, 2H), 2.76 (m, 1H), 2.70 (m, 1H), 2.60 (m, 1H), 2.55 (m, 1H), 2.40 (m, 1H), 1.34
(t, J = 7.5 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13C-NMR (CDCl3) : 172.92 (0), 135.54 (0), 127.29 (0), 127.11
(0), 125.89 (0), 121.97 (1), 120.53 (1), 118.72 (0), 116.47 (1), 111.39 (0), 71.47 (0), 64.27 (2), 60.97 (2),
34.20 (2), 28.24 (2), 23.93 (2), 21.59 (2), 14.05 (3), 13.81 (3). MS (EI) m/z (%) : 326 (M+, 31), 299 (9),
281 (8), 225 (100). Anal. Calcd for C19H22N2O3 : C, 69.92; H, 6.79; N, 8.58. Found :C, 69.68; H, 6.76; N,
8.77.
6-Oxo-1,2,5,6-tetrahydro-4H-3-oxa-6a-azafluoranthene-3a-carbonitrile (35). Compound (35) was
prepared following the typical procedure starting from the chloride (32) (1.4 g, 4.6 mmol) in DMF (22 mL)
o
using sodium cyanide (4.6 g, 93.8 mmol) at 105-110 C to provide 0.5 g (45.2 %) of the product as a

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HETEROCYCLES, Vol. 60, No. 5, 2003
o
brown plate crystals, mp 66-68 C (1/4 ethyl acetate-hexane). IR (KBr) νmax : 2917, 1702, 1312, 1083
cm-1.1H-NMR (CDCl3): 8.39 (d, J = 8.2 Hz, 1H), 7.51(d, J = 7.8 Hz, 1H), 7.43 (m,1H),7.36 (m, 1H),4.49,
4.43 (each m, 2H, ArCH2CH2O), 3.18, 3.02 (each m, 2H, ArCH2CH2O), 3.00, 2.80 (each m, 2H,
CH2CH2C(O)), 2.65, 2.25 (each m, 2H, CH2CH2C(O)). MS (EI) m/z (%): 252 (M+, 75), 197 (100), 170
(25). Anal. Calcd for C15H12N2O2 : C, 71.42; H, 4.79; N, 11.10. Found : C, 71.28; H, 4.66; N, 10.78.
9-Methyl-6-oxo-1,2,5,6-tetrahydro-4H-3-oxa-6a-azafluoranthene-3a-carbonitrile (36). Compound (36)
was prepared following the typical procedure starting from the chloride (30) (1.5 g, 4.6 mmol) in DMF (22
mL) using sodium cyanide (4.6 g, 93.8 mmol) at 105-110 oC to provide 0.5 g (42.5 %) of the product as a
1
yellow oil. IR (film) νmax : 2924, 1702, 1018 cm-1. H-NMR (CDCl3) : 8.24 (d, J = 8.4 Hz, 1H), 7.29 (s,
1H), 7.24 (d, J = 8.4 Hz, 1H), 4.48 (m, 1H), 4.43 (dd, J = 11.5, 4.4 Hz, 1H), 3.18 (m, 1H), 2.98 (m, 1H),
2.78 (m, 1H), 2.65 (m, 1H), 2.46 (m, 1H), 2.44 (s, 3H), 2.26 (m, 1H). MS (EI) m/z (%): 266 (M+, 80), 240
(16), 211 (100), 184 (18). Anal. Calcd for C16H14N2O2 : C, 72.16; H, 5.30; N, 10.52. Found : C, 72.18; H,
5.36; N, 10.77.
3-(6-Chloro-1-cyano-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)propionic acid ethyl ester (37).
Compound (37) was prepared following the typical procedure starting from the chloride (29) (3.2 g, 9.3
mmol) in DMF (43 mL) using sodium cyanide (9.3 g, 188.8 mmol) at 75-80 oC to provide 1.3 g (43.2 %)
of the product as a brown oil. IR (film) νmax : 3256, 1708, 1041 cm-1. 1H-NMR (CDCl3) : 8.63 (br s, 1H,
NH), 7.50 (s, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 4.34 (dd, J = 11.7, 5.6 Hz, 1H), 4.10
(m, 1H), 4.06 (q, J = 7.0 Hz, 2H), 2.98 (m, 1H), 2.73, 2.69 (ABq, J = 32.0 Hz, 1H), 2.63 (m, 1H), 2.56 (m,
1H), 2.48, 2.40 (each m, 2H), 1.19 (t, J = 7.0 Hz, 3H). MS (EI) m/z (%):332 (M+, 60), 286 (40),231 (100),
204 (40). Anal. Calcd for C17H17N2O3Cl : C, 61.36; H, 5.15; N, 8.42. Found : C, 61.29; H, 5.34; N, 8.51.
3-(1-Cyano-6-methoxy-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)propionic acid ethyl ester (38).
Compound (38) was prepared following the typical procedure starting from the chloride (31) (3.1 g, 9.3
mmol) in DMF (43 mL) using sodium cyanide (9.3 g, 188.8 mmol) at 75-80 oC to provide 1.4 g (45.7 %)
of the product as a brown oil. IR (film) νmax : 3370, 1702, 1211 cm-1. 1H-NMR (CDCl3) : 8.20 (br s, 1H,
NH), 7.26 (d, J = 7.5 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J = 7.5 Hz, 1H), 4.40, 4.33 (each m, 2H,), 4.08 (q, J =
7.2 Hz, 2H), 3.86 (s, 3H), 2.98 (m, 2H), 2.73, 2.69 (ABq, J = 32.0 Hz, 2H), 2.63, 2.58 (each m, 1H), 2.48,
2.42 (each m, 1H), 1.19 (t, J = 7.2 Hz, 3H). MS (EI) m/z (%): 328 (M+, 30), 301 (35), 228 (100). Anal.
Calcd for C18H20N2O4 : C, 65.84; H, 6.14; N, 8.53. Found : C, 65.78; H, 6.35; N, 8.34.

HETEROCYCLES, Vol. 60, No. 5, 2003
1105
3-(1-Cyano-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)propionic acid ethyl ester (39).
Compound (39) was prepared following the typical procedure starting from the chloride (33) (3.0 g, 9.3
mmol) in DMF (43 mL) using sodium cyanide (9.3 g,188.8 mmol) at 105-110 oC to provide 1.4 g (48.5 %)
of the product as a brown oil. IR (film) νmax : 3364, 1732, 1171 cm-1. 1H-NMR (CDCl3) : 8.17 (br s, 1H,
NH), 7.37 (d, J = 7.4 Hz, 1H), 7.08 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.34 (dd, J = 11.6, 5.6 Hz, 1H), 4.09
(q, J = 7.3 Hz, 2H), 4.06 (m, 1H), 3.03 (dd, J = 11.5, 5.8 Hz, 0.5H), 3.00 (dd, J=11.5, 5.8 Hz, 0.5 H), 2.75
(dd, J=15.8, 3.1 Hz, 1H), 2.67 (m, 1H), 2.62 (m, 1H), 2.55 (m, 1H), 2.54 (s, 3H), 2.46 (m, 1H), 1.18 (t, J =
7.3 Hz, 3H). 13C-NMR (CDCl3) : 172.75 (0), 136.22 (0), 127.16 (0), 125.75 (0), 124.08 (1), 120.98 (0),
120.52 (1), 118.61 (0), 116.51 (1), 111.58 (0), 71.40 (0), 64.25 (2), 60.94 (2), 34.25 (2), 28.22 (2), 21.58
(2), 16.70 (3), 14.06 (3). MS (EI) m/z (%): 312 (M+, 61), 285 (6), 267 (15), 211 (100), 184 (33). Anal.
Calcd for C18H20N2O3 : C, 69.21; H, 6.45; N, 8.97. Found : C, 69.15; H, 6.62; N, 8.76.
3-(1-Cyano-8-trifluoromethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)propionic acid ethyl ester
(40). Compound (40) was prepared following the typical procedure starting from the chloride (34) (3.5 g,
o
9.3 mmol) in DMF (43 mL) using sodium cyanide (9.3 g, 188.8 mmol) at 105-110 C to provide 2.8 g
o
(82.0 %) of the product as a white powder, mp 153-154 C (1/4 ethyl acetate-hexane). IR (KBr) νmax : 3346,
1708, 1296, 1159 cm-1. 1H-NMR (CDCl3) : 8.88 (br s, 1H, NH), 7.70 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.5
Hz, 1H), 7.22 (m, 1H), 4.37 (dd, J = 11.5, 5.0 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 4.07 (m, 1H), 3.00 (m,
1H), 2.79 (m, 1H), 2.72 (m, 1H), 2.60 (m, 1H), 2.53 (m, 1H), 2.47 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H).
13C-NMR (CDCl3) : 172.81 (0), 132.20 (0), 129.37 (0), 127.95 (0), 125.92 (0), 123.10 (1), 121.19 (1),
119.91 (1),118.25 (0),111.54 (0), 71.42 (0), 64.19 (2), 61.26 (2), 52.27 (0), 34.19 (2), 28.52 (2), 21.50 (2),
14.24 (3).MS (EI) m/z (%):366 (M+, 32), 321 (22), 265 (100), 238 (14). Anal.Calcd for C18H17N2O3 F3: C,
59.02; H, 4.68; N, 7.65. Found : C, 58.83; H, 4.58; N, 7.36.
(8-Ethyl-1-methoxycarbonylmethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid methyl
ester (10). To a solution of 3 (5.0 g, 26.4 mmol) and 3-methoxypent-2-enedioic acid dimethyl ester (9)
(11.3 g, 60 mmol) in dichloromethane (100 mL) was added BF3·OEt2 (1.2 mL, 9.5 mmol) and the mixture
was stirred at rt for 12 h. The reaction mixture was washed with 1 % Na2CO3 and water. The separated
organic layer was dried (MgSO4) and evaporated. Purification by silica gel column chromatography
(eluent : ethyl acetate/hexane = 1/10) provided 10 as a white powder (2.4 g, 25.7 %), mp 92-94 oC (ethyl
acetate). IR (KBr) νmax : 3380, 1736, 1698, 1207 cm-1. 1H-NMR (CDCl3) : 9.25 (br s, 1H), 7.35 (d, J = 7.0
Hz, 1H), 7.06 (m, 2H), 4.04 (m, 2H, ArCH2CH2O), 3.74 (s, 6H), 3.19 (s, 4H), 2.86 (q, J = 7.0 Hz, 2H),
2.78 (m, 2H), 1.37 (t, J = 7.0 Hz, 3H). MS (EI) m/z (%): 345 (M+, 45), 330 (100). Anal. Calcd for

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HETEROCYCLES, Vol. 60, No. 5, 2003
C19H23NO5 : C, 66.07; H, 6.71; N, 4.06. Found : C, 66.02; H, 6.59; N, 4.15.
(1-Carboxymethyl-8-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid (11). To a solution
of diester (10) (2.0 g, 2.8 mmol) in methanol (40 mL) was added lithium hydroxide monohydrate (0.4 g,
9.6 mmol), and stirring was continued for 13 h. The reaction mixture was then diluted with 5 % HCl
solution, and extracted with chloroform. The combined extracts were washed with water, dried (MgSO4),
o
and evaporated to give 11 as a brown powder (1.6 g, 87.4 %), mp 180-182 C (ethyl acetate). IR (KBr)
1
νmax : 3420, 1699, 1078 cm-1. H-NMR (CDCl3) : 9.20 (br s, 1H), 7.26 (d, J=7.0 Hz, 1H), 7.05 (m, 2H),
4.12 (m, 2H, ArCH2CH2O), 3.24 (s, 4H), 2.98, 3.04 (each m, 2H), 2.84 (q, J = 7.0 Hz, 2H), 1.37 (t, J=7.0
Hz, 3H). MS (EI) m/z (%): 318 (M++1, 50), 252 (20), 158 (70), 113 (100). Anal. Calcd for C17H19NO5 : C,
4.34; H, 6.03; N, 4.41. Found : C, 64.02; H, 5.98; N, 4.25.
(8-Ethyl-1-methoxycarbonylmethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid (12). To a
solution of the diacid (11) (0.75 g, 2.36 mmol) in 1,2-dichloroethane (10 mL) was added dropwise a 0.6 M
diazomethane ether solution (~ 4.0 mL) for 2 h. The resulting solution was then evaporated. Purification
by silica gel column chromatography (eluent : ethyl acetate/hexane = 1/2) provided 12 as a dark brown oil
(0.3 g, 38.5 %). IR (film) νmax : 3397, 1732 cm-1. 1H-NMR (CDCl3) : 9.19 (br s, 1H, NH), 7.36 (d, J = 7.5
Hz, 1H), 7.05 (m, 2H), 4.07 (m, 2H, ArCH2CH2O), 3.74 (s, 3H), 3.27, 3.16 (each m, 4H), 2.85 (q, J = 7.5
Hz, 2H), 2.81 (m, 2H), 1.37 (t, J = 7.5 Hz, 3H). MS (EI) m/z (%):332 (M++1, 100), 172 (70). Anal. Calcd
for C18H21NO5 : C, 65.24; H, 6.39; N, 4.23. Found : C, 65.12; H, 6.25; N, 4.03.
(1-Carbamoylmethyl-8-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid methyl ester (13).
To a solution of the half ester (12) (0.3 g, 0.91 mmol) in toluene (3 mL) was added oxalyl chloride (1 mL)
and stirred at rt for 1 h. After evaporation of the reaction mixture, the residue was poured into ice-cooled
28 % ammonia (10 mL), and then the mixture was extracted with ethyl acetate (20 mL x 2). The combined
extracts were filtered through Celite and evaporated. Purification by silica gel column chromatography
(eluent : ethyl acetate/hexane = 1/3) provided 13 as a white powder (0.2 g, 67.0 %), mp 166-168 oC (ethyl
acetate). IR (KBr) νmax :3296, 1729, 1668, 1193 cm-1. 1H-NMR (CDCl3) : 9.67 (br s, 1H, NH),7.36 (d, J =
7.5 Hz, 1H), 7.05 (m, 2H), 6.24 (br s, 1H, NH), 5.49 (br s, 1H, NH), 4.07 (m, 2H, ArCH2CH2O), 3.73 (s,
3H), 3.16 (m, 2H), 3.03, 3.00 (ABq, J = 6.3 Hz, 2H),2.87 (q, J=7.5 Hz, 2H), 2.85, 2.79 (each m, 2H), 1.36
(t, J = 7.5 Hz, 3H).MS (EI) m/z (%):331 (M++1, 100),314 (25), 272 (30). Anal. Calcd for C18H22N2O4 : C,
65.44; H, 6.71; N, 8.48. Found : C, 65.32; H, 6.53; N, 8.51.

HETEROCYCLES, Vol. 60, No. 5, 2003
1107
(1-Cyanomethyl-8-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid methyl ester (14). To
a suspension of the amide (13) (0.12 g, 0.36 mmol) in dry dichloromethane (3 mL) were successively added
pyridine (0.06 g, 0.76 mmol) and trifluoroacetic anhydride (0.09 g, 0.42 mmol). The internal temperature
was maintained at < 30 oC. After being stirred at rt overnight, the reaction mixture was washed with 1 %
H2SO4 and water. The separated organic layer was dried (MgSO4) and evaporated. Purification by silica
gel column chromatography (eluent : ethyl acetate/hexane = 1/5) provided 14 as a white powder (0.10 g,
88.1 %), mp 112-113 oC (benzene). IR (KBr) νmax : 3300, 1713, 1205 cm-1. 1H-NMR (CDCl3) : 8.88 (br s,
1H, NH), 7.38 (d, J = 7.5 Hz, 1H),7.09 (m, 2H), 4.05 (m, 2H, ArCH2CH2O),3.77 (s,3H), 3.36, 3.23 (ABq,
J = 17.2 Hz, 2H), 3.13 (dd, J = 18.0, 17.0 Hz, 2H), 2.88 (q, J = 7.5 Hz, 2H), 2.82 (m, 2H), 1.36 (t, J = 7.5
Hz, 3H). MS (EI) m/z (%):313 (M++1, 90), 295 (100). Anal. Calcd for C18H20N2O3 : C, 69.21; H, 6.45; N,
8.97. Found : C, 68.87; H, 6.47; N, 8.66.
(1-Cyanomethyl-8-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid ethy ester (7). The
nitrile ester (14) (0.1 g, 0.32 mmol) was dissolved in anhydrous ethanol (5 mL) and cooled to 0 oC. To the
mixture was added dropwise acetyl chloride (0.66 g) and the mixture was stirred at rt for 44 h. After
evaporation of solvent, the residue was diluted with dichloromethane (10 mL) and washed in successively
with water,5% Na2CO3 and water.The separated organic layer was dried (MgSO4)and evaporated to give
7 (0.06 g, 60.4 %) as a white powder, mp 100-102 oC (benzene). IR (KBr) νmax : 3329, 1704, 1087 cm-1.
1H-NMR (CDCl3) : 8.92 (br s, 1H, NH), 7.37 (d, J = 7.5 Hz, 1H), 7.07 (m, 2H), 4.23 (q, J = 7.5 Hz, 2H),
4.05 (m, 2H, ArCH2CH2O),3.39, 3.22 (ABq, J = 17.1 Hz, 2H), 3.12 (dd, J = 18.0, 16.0 Hz, 2H), 2.86 (q, J
= 7.0 Hz, 2H), 2.82 (m, 2H), 1.35 (t, J = 7.5 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H). MS (EI) m/z (%) : 327
(M++1,100),309 (95). Anal. Calcd for C19H22N2O3 :C, 69.92; H, 6.79; N, 8.58. Found : C, 69.78; H, 6.84;
N, 8.63.
2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetamide (16). Compound (16) (0.19 g, 82.5
%) was prepared from etodolac (15) (0.23 g), by a similar procedure as that described for the amide ester
-1
(13) as a white powder, mp 174-175 oC (1/4 ethyl acetate-hexane). IR (KBr) νmax : 3259, 1673, 1040 cm .
1H-NMR (CDCl3) : 9.39 (br s, 1H, NH), 7.35 (d, J = 7.8 Hz, 1H), 7.05 (m, 1H), 6.98 (d, J = 7.8 Hz, 1H),
6.45 (br s, 1H), 5.58 (br s, 1H), 4.08, 4.04 (each m, 2H), 2.93 (m, 2H), 2.84 (q, J = 7.5 Hz, 2H), 2.79 (m,
2H), 2.13, 2.02 (each m, 2H), 1.30 (t, J=7.5 Hz, 3H),, 0.87 (t, J = 7.5 Hz, 3H). MS (EI) m/z (%): 287
(M++1,100),172 (33).Anal. Calcd for C17H22N2O2 : C, 71.30; H, 7.74; N, 9.78. Found : C, 71.29; H, 7.75;
N, 9.87.

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HETEROCYCLES, Vol. 60, No. 5, 2003
(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetonitrile (17). Compound (17) (0.14 g, 93.4
%) was prepared from the amide (16) (0.16 g), by a similar procedure as that described for the nitrile ester
o
14 as a yellow granular crystals, mp 126-128 C (1/4 ethyl acetate-hexane). IR (KBr) νmax : 3317, 2259,
1077 cm-1. 1H-NMR (CDCl3) : 7.89 (br s, 1H, NH), 7.31 (d, J = 7.6 Hz, 1H), 7.05 (m, 1H),6.98 (d, J = 7.6
Hz, 1H),4.03, 3.86 (each m, 2H), 2.82 (q, J = 7.5 Hz, 2H), 2.76 (m, 2H), 2.73, 2.70 (each m, 2H), 2.05 (m,
2H), 1.30 (t, J = 7.5 Hz, 3H), 0.81 (t, J = 7.5 Hz, 3H). MS (EI) m/z (%): 269 (M++1, 95), 228 (90), 172
(100). Anal. Calcd for C17H20N2O2 : C, 76.09; H, 7.51; N, 10.44. Found : C, 76.27; H, 7.55; N, 10.67.
3-(1-Cyano-8-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)propionic acid (18). To a solution of 6
(1.0 g, 3.1 mmol) in methanol (20 mL) was added lithium hydroxide monohydrate (0.2 g, 4.8 mmol), and
stirring was continued for 12 h. The reaction mixture was diluted with 5 % HCl solution, and extracted
with ethyl acetate. The combined organic extracts were washed with water, dried (MgSO4), and
evaporated. Purification by silica gel column chromatography (eluent : ethyl acetate/hexane = 1/1)
provided 18 as a yellow oil (0.85 g, 93.0 %). IR (film) νmax : 3364, 1703, 1310 cm-1. 1H-NMR (CDCl3) :
7.28 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.98 (m, 2H), 4.26, 3.98 (each m, 2H), 2.92, 2.70 (each m, 2H),
2.85 (q, J = 7.5 Hz, 2H), 2.65, 2.51 (each m, 2H), 2.43, 2.30 (each m, 2H), 1.28 (t, J = 7.5 Hz, 3H).
13C-NMR (CDCl3) : 174.38 (0), 135.56 (0), 128.01 (0), 127.68 (0), 125.73 (0), 121.34 (1), 119.80 (1),
119.13 (0), 116.10 (1), 109.80 (0), 71.92 (0), 64.07 (2), 33.76 (2), 28.18 (2), 24.02 (2), 21.57 (2), 19.19 (2),
14.25 (3). MS (EI) m/z (%): 299 (M++1, 100). Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39.
Found : C, 68.21; H, 6.26; N, 9.12.
8-Ethyl-1-(3-hydroxypropyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carbonitrile (20). To a solution
of 18 (0.94 g, 3.2 mmol) in dichloromethane (20 mL) containing triethylamine (0.4 g, 4.0 mmol) was
o
added at 0 C a solution of isobutyl chloroformate (0.43 g, 3.2 mmol) in dichloromethane (5 mL). After
being stirred at 0 oC for 1 h and at rt for 3 h, the reaction mixture was washed with water. The separated
rganic layer was dried (MgSO4) and evaporated to give the crude mixed anhydride (19) as an oil (0.74 g).
To an ice-cooled solution of the crude 19 (0.74 g, ~1.8 mmol) in dry THF (15 mL) was added sodium
borohydride (0.4 g, 10.6 mmol) with stirring. To the mixture was added water (5 mL) for a 1 h period.
After the mixture was stirred at 0 oC for 2 h, an additional amount of sodium borohydride (0.2 g, 5.3 mmol)
was introduced and the resulting mixture was stirred for 2 h at rt. The reaction mixture was diluted with 5
% HCl solution, evaporated off methanol, and then extracted twice with ethyl acetate. The combined
extracts were washed with water, dried (MgSO4) and evaporated. Purification by silica gel column
chromatography (eluent : ethyl acetate/hexane = 1/6) provided 20 as a white plate crystals (0.27 g, 30.0 %).

HETEROCYCLES, Vol. 60, No. 5, 2003
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o
mp 132-134 C, (1/4 ethyl acetate-hexane). IR (KBr) νmax : 3480, 2239, 1049 cm-1. 1H-NMR (CDCl3) : 8.36
(br s, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.10 (m, 2H), 4.35, 4.10 (each m, 2H, ArCH2CH2O), 3.74, 3.67 (each
m, 2H), 3.00, 2.77 (each m, 2H, ArCH2CH2O), 2.86 (q, J = 7.5 Hz, 2H), 2.50, 2.24 (each m, 2H), 1.85,
1.75 (each m, 2H), 1.36 (t, J = 7.5 Hz, 3H). MS (EI) m/z (%): 284 (M+, 65), 257 (20), 225 (100). Anal.
Calcd for C17H20N2O2: C, 71.81; H, 7.09; N, 9.85. Found : C, 71.79; H, 7.26; N, 9.68.
1-(3-Bromopropyl)-8-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carbonitrile (21). To a solution
of 20 (0.17 g, 0.60 mmol) in dry 1,2-dichlorethane (5 mL) was added triphenylphosphine dibromide (0.26
g, 0.61 mmol)at 0 oC,and the resulting solution was stirred for 2 h. The reaction mixture was washed with
water, dried (MgSO4), and evaporated. Purification by silica gel column chromatography (eluent : ethyl
acetate/hexane = 1/10) provided 21 as a yellow oil (0.08 g, 38.3 %). IR (film) νmax : 3335, 2246, 1174,
1081, 1033 cm-1. 1H-NMR (CDCl3): 8.00 (br s, 1H, NH), 7.31(d, J = 7.0 Hz, 1H), 7.04 (m, 2H), 4.28, 4.02
(each m, 2H, ArCH2CH2O),3.33 (m, 2H, CH2Br),2.92, 2.68 (each m, 2H, ArCH2CH2), 2.80 (q, J= 7.5 Hz,
2H), 2.39, 2.25 (each m, 2H), 2.03, 1.87 (each m, 2H),1.30 (t, J = 7.5 Hz, 3H), 13C-NMR (CDCl3): 135.38
(0), 127.40 (0), 127.16 (0), 125.92 (0),122.07 (1), 120.70 (1),118.93 (0), 116.54 (1), 111.39 (0), 71.66 (0),
64.30 (2), 37.71(2), 33.15 (2), 26.33 (2), 23.94 (2), 21.59 (2), 13.79 (3). MS (EI) m/z (%) : 348 (M+, 20),
225 (100). Anal. Calcd for C17H19N2OBr : C, 58.80; H, 5.51; N, 8.07. Found : C, 58.76; H, 5.26; N, 8.46.
8-Ethyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carbonitrile (22). To a solution of 21 (0.08
g, 0.23 mmol) in methanol (6 mL) were added catalytical amounts of 10 % Pd-C and triethylamine (0.023
g, 0.23 mmol). After being stirred under hydrogen for 15 h (hydrogen balloon), the reaction mixture was
filtered through Celite and evaporated. Purification by silica gel column chromatography (eluent : ethyl
o
acetate/hexane = 1/15) provided 22 as a white powder (0.04 g, 65.0 %), mp 136-138 C (1/4 ethyl
1
acetate-hexane). IR (KBr) νmax : 3344, 2235, 1695, 1042 cm-1. H-NMR (CDCl3) : 8.00 (br s, 1H, NH),
7.30 (d, J = 7.4 Hz, 1H), 7.02 (m, 2H), 4.28, 4.00 (each m, 2H, ArCH2CH2O), 2.90, 2.69 (each m, 2H,
ArCH2CH2), 2.78 (q, J = 7.5 Hz, 2H), 2.18, 1.98 (each m, 2H),1.53, 1.42 (each m, 2H),1.28 (t, J = 7.5 Hz,
13
3H), 0.88 (t, J = 7.4 Hz, 3H). C-NMR (CDCl3) : 135.27 (0), 128.32 (0), 127.02 (0), 125.97 (0), 121.83
(1), 120.55 (1), 119.29 (0), 116.49 (1), 110.89 (0), 72.20 (0), 64.21 (2), 41.58 (2), 23.92 (2), 21.66 (2),
16.73 (2), 13.37 (3, overlapping CH3). Ms (EI) m/z (%) : 268 (M+, 26), 225 (100). Anal. Calcd for
C17H20N2O : C, 76.09; H, 7.51; N, 9.92. Found : C, 76.26; H, 7.26; N, 9.66.
ACKNOWLEDGEMENT
The author would like to thank the Ministry of Economic Affairs, R.O.C. for financially supporting this

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HETEROCYCLES, Vol. 60, No. 5, 2003
research. The author also appreciate the helpful comments and suggestions of one of the referees in the
chain extension reaction.
REFERENCES
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8.
A related skeletal rearrangement of a benzazepine skeleton, in which a tertiary amine acts as the
nucleophilic center has been reported, see: H. Irie, S. Tani and H. Yamane. J. Chem. Soc., Perkin
Trans. 1, 1972, 2986.
9. The corresponding α- and β-methylene protons of the alcohol (20) and the bromide (21) also reveal
comparable chemical shifts (see EXPERIMENTAL). The corresponding ring expansion skeleton
would not show comparable signals.
10. Phenyl-substituted tryptophols are prepared by refluxing the corresponding phenylhydrazines and
2-ethoxytetrahydrofuran in 95 % ethanol, this process, is a modification of one in the literature,
wherein 2-ethoxytetrahydrofuran is employed as the substitute for the highly acid-sensitive
2,3-dihydrofuran, see: B. Mckittrick, A. Failli, R. J. Steffan, R. M. Soll, P. Hughes, J. Schmid, A. A.
Asselin, C. C. Shaw, R. Noureldin, and G. Gavin, J. Heterocycl. Chem., 1990, 27, 2151.