Synthesis of 2-(3-hydroxypropyl)indol-3-acetic acid and 3-(2-hydroxyethyl)indole-2-propanoic acid by selective functional group transformations

Article abstract of DOI:10.1055/s-2002-33642

Hydroxyalkylindolyl acetic(propanoic) acids 1 and 2 were prepared from a common intermediate dimethyl ester 3 by chemoselective hydrolyses and reductions.

Full text of DOI:10.1055/s-2002-33642

PAPER
1689
Synthesis of 2-(3-Hydroxypropyl)indol-3-acetic Acid and 3-(2-Hydroxy-
ethyl)indole-2-propanoic Acid by Selective Functional Group
Transformations
Synthesis of
H
o
ydroxyalkyl
p
indolyl
A
ce
t
h
i
A
cidse-Isabelle Bascop, Jean-Yves Laronze, Janos Sapi*
Laboratoire de Chimie Thérapeutique, UMR 6013 du CNRS ‘Isolement, Structure, Transformations et Synthèse de Produits Naturels’, IFR
53 ‘Biomolécules’, Faculté de Pharmacie, Université de Reims-Champagne-Ardenne, 51096 Reims, Cedex, France
Fax +33(3)26918029; E-mail: janos.sapi@univ-reims.fr
Received 27 March 2002; revised 1 June 2002
of diester 3, phenylhydrazone 4, and pyridazinone 5,
Abstract: Hydroxyalkylindolyl acetic(propanoic) acids 1 and 2
whereas a two step procedure, taking advantage of the
were prepared from a common intermediate dimethyl ester 3 by
chemoselective hydrolyses and reductions.
smooth formation of pyridazinone 5,9 followed by treat-
ment with saturated HCl/MeOH solution at reflux, proved
to be efficient (73% overall yield) (Scheme 1).
Key words: chemoselectivity, hydrolysis, reduction, indol-3-acetic
acid, indole-2-propanoic acid
Spacer groups and linkers have become essential tools in
solid phase organic synthesis,1 supramolecular chemistry
and in the design of macromolecular drug delivery sys-
tems.2 In our efforts aimed at synthesizing new heterocy-
cles of biological interest, we were interested in the
preparation of indole containing linkers of structures 1
and 2 (Figure 1). Such molecules are characterized by
flexible two and three carbon side chains, bearing chemi-
cally different oxygens, i.e. alcohol or ester groups. It is
important to note that some related 2,(3)-car-
boxy(alkyl)indole derivatives were reported to be potent
thromboxane synthase,3 phospholipase-A2,4 cyclooxyge-
nase-2,5 steroid-5 -reductase6 inhibitors and glycine/
NMDA antagonists.7 Herein we describe, in full detail, a
simple access to acid alcohols 1 and 2 starting from a com-
mon intermediate diester 3 by means of selective func-
Scheme 1
tional group transformations.
As part of transformations of 3, first we tried to reduce se-
lectively one of the ester functions.10 Among the numer-
ous hydride reagents,11 only lithium aluminium hydride
and DIBAL-H mediated reductions showed some selec-
tivity, but the yield of carbinolamine 6, alcohol-ester 7,
and diol 8 remained poor, due to tedious chromatographic
purifications (Scheme 2).
Figure 1 The structures of indole containing linkers 1 and 2
For the preparation of 3, the well-known Fischer indole
synthesis8 starting from the symmetrical diethyl 4-ox-
opimelate was chosen. Direct indolisation with phenylhy-
Scheme 2
drazine hydrochloride in acidic medium led to a mixture
As the direct selective reduction of ester groups in 3
failed, we tried the differentiation by hydrolysis
(Scheme 3). Selective hydrolysis of the ester function lo-
cated on the C-2 side chain was performed by using a
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1689,1694,ftx,en;Z05202SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1690
S.-I. Bascop et al.
PAPER
nearly stoichiometric amount of KOH in boiling aqueous
methanol. After acidification acid-ester 9 and diacid 10
were obtained in 71 and 2% yield, respectively. This high
selectivity could be attributed to a lower positive induc-
tive effect (+I) on the C-2 compared to C-3 position of the
indole ring. In addition to spectroscopic data, location of
the acid function was evidenced by POCl3 assisted
cyclisation12 of 9 to lactam 11 (86%).
Scheme 4
In summary, we have developed a new synthetic pathway
for the preparation of 2- and 3-hydroxyalkylindolyl ace-
tic(propanoic) acids 1 and 2 by means of Fischer indolisa-
tion, followed by simple selective functional group
transformations. Application of compounds 1 and 2 as
spacers and linkers is under investigation.
Melting points were determined on a Reichert Thermovar hot-stage
apparatus and are uncorrected. UV spectra were recorded in MeOH
solution on a UNICAM 8700 UV/Vis spectrophotometer. IR spec-
tra were measured with a Bomem FTIR instrument. 1H NMR (300
MHz) and 13C NMR (75 MHz) spectra were acquired on a Bruker
AC 300 spectrometer using TMS as internal standard. Mass spectra
were recorded with a VG Autospec apparatus. Reactions were mon-
itored using Merck TLC aluminum sheets (Kieselgel 60 F254).
Scheme 3
Although for the selective reduction of an ester group in
the presence of an acid function lithium borohydride13 or
borane complex14 reagents have been proposed, from pre-
parative point of view only LiAlH4 reduction proved to be
Ethyl 3-[3(2H)-Oxo-2-phenyl-4,5-dihydropyridazin-6-yl]pro-
panoate (5) and Ethyl 4-Oxopimelate Phenylhydrazone (4)
A suspension of phenylhydrazine hydrochloride (4.00 g, 27.66
mmol) and diethyl 4-oxopimelate (6.44 g, 27.96 mmol) was heated
efficient. Reduction of 9 at –45 °C using 1.7 equivalents in toluene (35 mL) under N2 in a Dean–Stark apparatus until the full
consumption of the starting material. After evaporation of the sol-
vent, the residue was purified by flash chromatography on silica gel
(eluent: CH2Cl2) to afford the pyridazinone 5 (6.84 g, 90%) and the
hydrazone 4 (0.43 g, 5%).
ethereal LiAlH4 solution led to the required acid-alcohol
2, isolated in 67% yield by selective extraction, followed
by crystallisation, along with some diol 8 (14%). Treat-
ment with a larger amount of LiAlH4 at room temperature
showed no real selectivity, whereas at –78 °C reduction
became sluggish.
5
Yellowish, viscous oil.
IR (neat): 3065, 2982, 1732, 1682, 1595 cm–1.
Activation of the carboxylic acid function by formation of
mixed anhydride 12 reversed the reactivity, enabling the
acid group attached to the side chain of C-2 to be reduced
(Scheme 4).15 Acylmethyl carbonate 12 obtained without
isolation from 9 was subjected to NaBH4 reduction in
methanol to give alcohol-ester 7 in 61% yield. From the
reaction mixture variable amounts (10–14%) of diester 3
resulting from 12 by methanolysis, and starting material 9
(15–19%) were recovered. Final ester hydrolysis of 7 was
achieved using barium hydroxide assisted hydrolysis, fol-
lowed by acidification allowing the isolation of alcohol-
acid 1 in 91% yield.
1H NMR (CDCl3): = 1.23 (t, 3 H, J = 7 Hz, CH3), 2.59–2.71 (m,
8 H, 4 CH2), 4.11 (q, 2 H, J = 7 Hz, OCH2), 7.21 (t, 1 H, J = 8 Hz,
H-4), 7.36 (t, 2 H, J = 8 Hz, H-3), 7.49 (d, 2 H, J = 8 Hz, H-2).
13C NMR (CDCl3): = 14.0 (CH3), 25.5 (NCOCH2CH2), 27.7
(NCOCH2CH2),
29.8
(CH2CH2CO2CH2CH3),
31.2
(CH2CH2CO2CH2CH3), 60.4 (CH2CO2CH2CH3), 124.2 (C-2),
126.0 (C-4), 128.1 (C-3), 140.9 (C-1), 154.8 (N=C), 164.9 (NCO),
172.5 (CO2CH2CH3).
MS (EI): m/z (%) = 275 (M + 1, 22), 274 (M+, 100), 245 (17), 229
(18), 201 (38).
UV (MeOH): max = 204, 236, 261 nm.
Anal. Calcd for C15H18N2O3 (274.31): C, 65.67; H, 6.61; N, 10.21.
Found: C, 65.29; H, 6.83; N, 10.13.
Synthesis 2002, No. 12, 1689–1694 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Hydroxyalkylindolyl Acetic(propanoic) Acids
1691
4
in CH2Cl2 (50 mL), washed with H2O (30 mL), aq sat. Na2CO3 so-
lution (30 mL), dried (Na2SO4) and evaporated to dryness under re-
duced pressure. The residue was filtered through a short silica gel
pad (eluent: CH2Cl2) to give the diester 3 which was crystallised
from Et2O (2.54 g, 81%).
Yellow crystals; mp 65.5–66.5 °C (Et2O).
1H NMR (CDCl3): = 1.25 (t, 6 H, J = 6.7 Hz, CH3), 2.59 (m, 6 H,
CH2), 2.69 (t, 2 H, J = 6.7 Hz, N=CCH2), 4.14 (q, 4 H, J = 6.7 Hz,
OCH2), 6.80 (m, 1 H, H-4), 7.04 (d, 2 H, J = 8 Hz, H-2), 7.22 (t, 2
H, J = 8 Hz, H-3), 9.85 (s, 1 H, NH).
13C NMR (CDCl3): = 14.1 and 14.2 (CH3), 24.0 and 29.9
(CH2CH2CO2CH2CH3), 30.3 and 30.8 (CH2CH2CO2CH2CH3), 60.7
and 61.1 (CH2CO2CH2CH3), 112.8 and 119.3 (C-2), 122.6 (C-4),
128.9 and 129.0 (C-3), 146.1 (C-1), 173.3 (N=C), 173.4 and 173.5
(CO2CH2CH3).
3
White crystals; mp 73–73.5 °C (Et2O).
IR (KBr): 3395, 3028, 2953, 1738, 1732, 1462 cm–1.
MS (EI): m/z (%) = 275 (M+, 100), 243 (6), 216 (99), 202 (26).
UV (MeOH): max = 222, 282, 290 nm.
MS (EI): m/z (%) = 320 (M+, 80), 247 (10), 228 (16), 201 (24), 93
(100).
Anal. Calcd for C15H17NO4 (274.31): C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.52; H, 6.30; N, 5.10.
For 1H and 13C NMR data of compounds 1–3 and 6–11, see Table 1
and Table 2.
Methyl 3-(3-Methoxycarbonylmethyl-1H-indol-2-yl)pro-
panoate (3)
A solution of 5 (3.13 g, 11.41 mmol) in MeOH (50 mL) saturated
with HCl gas was heated under reflux with continuous bubbling of
HCl for 2 h. After evaporation of solvent, the residue was dissolved
Table 1 1H NMR Data of Compounds 1–3, and 6–11 [CDCl3, , J (Hz)]
Prod- Side Chain Protons
uct
H-4
H-5
H-6
H-7
NH
OH
–
3
6
7
8
2.68 (t, 2 H, J = 7.4, CH2CH2CO2CH3), 3.04 (t, 2
7.54
(d, 1 H,
J = 8.0)
7.13
(t, 1 H,
J = 8.0)
7.07
(t, 1 H,
J = 8.0)
7.25
(d, 1 H,
J = 8.0)
8.61
(s, 1 H)
H, J = 7.4, CH2CH2CO2CH3), 3.63 (s, 3 H,
CH2CO2CH3), 3.68 (s, 3 H, CH2CH2CO2CH3),
3.69 (s, 2 H, CH2CO2CH3)
2.34–2.80 (m, 2 H, HOCHCH2CH2), 3.03–3.33
(m, 2 H, HOCHCH2CH2), 3.66 (s, 3 H,
CH2CO2CH3), 3.74 (s, 2 H, CH2CO2CH3), 5.93
(m, 1 H, HOCH)
7.50
(d, 1 H,
J = 8.0)
7.02
(t, 1 H,
J = 8.0)
7.02
(t, 1 H,
J = 8.0)
7.39
(d, 1 H,
J = 8.0)
–
2.80
(br, 1 H)
1.87 (m, 2 H, CH2CH2CH2OH), 2.85 (t, 2 H, J =
6.4, CH2CH2CH2OH), 3.58 (t, 2 H, J = 6.4,
CH2CH2CH2OH), 3.66 (s, 3 H, CH2CO2CH3), 3.71 J = 8.1)
(s, 2 H, CH2CO2CH3)
7.53
(d, 1 H,
7.11
(t, 1 H,
J = 8.1)
7.10
(t, 1 H,
J = 8.1)
7.23
(d, 1 H,
J = 8.1)
8.41
(s, 1 H)
2.70
(br, 1 H)
1.88 (m, 2 H, CH2CH2CH2OH), 2.89 (t, 2 H, J =
6.2, CH2CH2CH2OH), 2.99 (t, 2 H, J = 6.2,
CH2CH2OH), 3.62 (t, 2 H, J = 6.2,
CH2CH2CH2OH), 3.88 (t, 2 H, J = 6.2,
CH2CH2OH)
7.51
(d, 1 H,
J = 8.2)
7.13
(t, 1 H,
J = 8.2)
7.08
(t, 1 H,
J = 8.2)
7.28
(d, 1 H,
J = 8.2)
8.27
(s, 1 H)
1.95
(br, 1 H)
2.39
(br, 1 H)
9
10
11
2
2.64 (t, 2 H, J = 7.8, CH2CH2CO2H), 2.98 (t, 2 H, 7.43
7.05
(t, 1 H,
J = 8.1)
6.98
(t, 1 H,
J = 8.1)
7.31
(d, 1 H,
J = 8.1)
10.88
(s, 1 H)
12.22
(br, 2 H)
J = 7.8, CH2CH2CO2H), 3.61 (s, 3 H,
CH2CO2CH3), 3.74 (s, 2H, CH2CO2CH3)
(d, 1 H,
J = 8.1)
2.64 (t, 2 H, J = 7.7, CH2CH2CO2H), 2.98 (t, 2 H, 7.45
7.06
(t, 1 H,
J = 8.0)
6.98
(t, 1 H,
J = 8.0)
7.31
(d, 1 H,
J = 8.0)
10.84 (s, 12.47
1 H)
J = 7.7, CH2CH2CO2H), 3.65 (s, 2 H, CH2CO2H)
(d, 1 H,
(br, 2 H)
J = 8.0)
3.06–3.18 (m, 4 H, CH2CH2CON), 3.66 (s, 2 H,
CH2CO2CH3), 3.72 (s, 3 H, CO2CH3),
7.48
(d, 1 H,
J = 7.7)
7.30
(t, 1 H,
J = 7.7)
7.28
(t, 1 H,
J = 7.7)
8.06
(d, 1 H,
J = 7.7)
-
–
2.65 (t, 2 H, J = 7.1, CH2CH2CO2H), 2.85 (t, 2 H, 7.44
7.02
(t, 1 H,
J = 8.0)
6.95
(t, 1 H,
J = 8.0)
7.28
(d, 1 H,
J = 8.0)
10.71 (s, 5.40
1 H) (br, 1 H)
J = 7.1, CH2CH2CO2H), 2.98 (t, 2 H, J = 7.2,
CH2CH2OH), 3.57 (t, 2 H, J = 7.2, CH2CH2OH)
(d, 1H,
J = 8.0)
12.52
(br, 1 H)
1a
1.84 (m, 2 H, CH2CH2CH2OH), 2.81 (t, 2 H, J =
6.1, CH2CH2CH2OH), 3.40 (t, 2 H, J = 6.1,
CH2CH2CH2OH), 3.42 (s, 2 H, CH2COOH)
7.58
(d, 1 H,
J = 7.8)
6.94
(t, 1 H,
J = 7.8)
6.87
(t, 1 H,
J = 7.8)
7.22
(d, 1 H,
J = 7.8)
10.65 (s, 4.10
1 H) (br, 1 H)
11.81
(br, 1 H)
a Recorded in DMSO-d6.
Synthesis 2002, No. 12, 1689–1694 ISSN 0039-7881 © Thieme Stuttgart · New York

1692
S.-I. Bascop et al.
PAPER
Table 2 13C NMR Data of Compounds 1–3 and 6–11 (CDCl3, )
Prod- Side Chain Carbons
uct
C-2
C-3
C-3a
C-4
C-5
C-6
C-7
C-7a
C=O
3
6
7
8
20.7 (CH2CH2CO2CH3), 30.1
135.6
104.4
127.9
121.5
119.4
118.2
110.6
135.1
172.4,
174.4
(CH2CO2CH3), 33.7
(CH2CH2CO2CH3),
51.8, 51.9 (CO2CH3)
20.9 (HOCHCH2CH2), 30.3
(CH2CO2CH3), 37.6
(HOCHCH2CH2), 51.89
(CO2CH3), 80.2 (HOCHCH2)
133.0
136.4
136.2
103.2
104.3
107.7
131.4
128.2
128.4
120.9
121.3
121.2
119.9
119.4
119.2
118.4
118.1
118.1
109.9
110.5
110.5
141.8
135.3
135.5
172.8
173.4
-
22.0 (CH2CH2CH2OH), 30.1
(CH2CO2CH3), 31.5
(CH2CH2CH2OH), 52.0
(CO2CH3), 60.9 (CH2CH2OH)
22.1 (CH2CH2CH2OH), 27.5
(CH2CH2OH), 31.9
(CH2CH2CH2OH), 61.3, 62.6
(CH2CH2OH)
9
10
11
2
21.4 (CH2CH2CO2H), 29.6
(CH2CO2CH3), 34.0
(CH2CH2CO2H), 51.7 (CO2CH3)
136.4
136.1
134.8
135.6
103.6
104.4
105.7
107.7
128.2
128.4
130.2
128.5
120.7
120.7
124.0
120.4
118.7
118.6
123.6
118.3
118.0
118.1
118.6
117.9
110.9
110.9
113.7
110.8
135.5
135.5
141.3
135.4
172.3,
173.8
21.5 (CH2CH2CO2H), 30.1
(CH2CO2H), 34.0
(CH2CH2CO2H)
173.5,
173.9
18.8 (CH2CH2CON), 29.8
(CH2CO2CH3), 34.7
(CH2CH2CON), 52.1 (CO2CH3)
171.2,
171.4
21.6 (CH2CH2OH), 28.2
(CH2CH2CO2H), 34.5
(CH2CH2CO2H), 62.0
(CH2CH2OH)
174.1
1a
22.7 (CH2CH2CH2OH), 32.5
(CH2CH2CH2OH), 34.7
(CH2CO2H), 59.7
136.1
107.9
129.2
119.8
119.2
117.8
110.2
135.6
178.7
(CH2CH2CH2OH)
a Recorded in DMSO-d6.
Reduction of Diester 3 with LiAlH4
MS (EI): m/z (%) = 245 (M+, 25), 227 (42), 200 (16), 194 (11).
To a –70 °C cooled solution of 3 (550 mg, 2.00 mmol) in anhyd
THF (10–12 mL) was added dropwise a 1 M ethereal solution of
LiAlH4 (2.2 mL, 2.20 mmol) and the reaction mixture was stirred at
the same temperature under N2 for 2.5 h.
UV (MeOH): max = 223, 271, 291 nm.
Methyl [2-(3-Hydroxypropyl)-1H-indol-3-yl]acetate (7)
Amorphous solid.
The excess of reducing agent was destroyed under cooling by cau-
tious addition of sat. aq Na2SO4 solution, and the precipitate was fil-
tered and washed with THF (5 10 mL). The filtrate was
concentrated to 10–12 mL, diluted with H2O (15 mL) and extracted
with CH2Cl2 (4 15 mL). The combined organic layers were dried
(MgSO4), filtered, evaporated to dryness and the residue was sepa-
rated by chromatography on silica gel (eluent: CH2Cl2–MeOH
98:2) to give pure 6 (93 mg, 19%), 7 (79 mg, 16%), and 8 (30 mg,
7%).
IR (KBr): 3398, 3057, 2951, 1725, 1622, 1462 cm–1.
MS (EI): m/z (%) = 247 (M+, 72), 216 (7), 203 (6), 188 (70).
UV (MeOH): max = 223, 282, 290 nm.
3-[3-(2-Hydroxyethyl)-1H-indol-2-yl]propan-1-ol (8)
White crystals; mp 100–101.5 °C (Et2O).
IR (KBr): 3397, 3327, 3059, 2940, 1620, 1462 cm–1.
MS (EI): m/z (%) = 219 (M+, 49), 188 (77), 170 (7), 144 (100).
UV (MeOH): max = 226, 284, 291 nm.
Methyl (3-Hydroxy-2,3-dihydro-1H-3a-azacyclopenta[a]inden-
8-yl)acetate (6)
Amorphous solid.
IR (KBr): 3406, 3055, 2953, 1732, 1620, 1459 cm–1.
Anal. Calcd for C13H17NO2 (219.28): C, 71.21; H, 7.81; N, 6.39.
Found: C, 70.90; H, 7.83; N, 6.40.
Synthesis 2002, No. 12, 1689–1694 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Hydroxyalkylindolyl Acetic(propanoic) Acids
1693
3-(3-Methoxycarbonylmethyl-1H-indol-2-yl)propanoicAcid(9)
and 3-(3-Carboxymethyl-1H-indol-2-yl)propanoic Acid (10)
A solution of diester 3 (3.80 g, 13.8 mmol) and KOH (0.99 g, 17.7
mmol) in MeOH (40 mL) and H2O (2 mL) was refluxed for 2 h. Af-
ter evaporation of the MeOH, the residue was dissolved in H2O (20
mL), and extracted with Et2O (3 10 mL). The Et2O extracts were
dried (MgSO4) and evaporated to afford some (0.34 g, 9%) recov-
ered starting material 3. The aqueous layer was acidified (pH 1–2)
with 10% aq HCl under cooling and extracted with CHCl3 (4 15
mL). The organic extracts were dried (MgSO4), filtered, evaporated
to dryness and the residue was purified by flash chromatography on
silica gel (eluent: CH2Cl2–MeOH, 99:1 90:10) to afford the acid-
ester 9 (2.56 g, 71%) and the diacid 10 (0.07 g, 2%).
(3 8 mL). The Et2O extracts were washed with H2O (5 mL), dried
(MgSO4) and evaporated to dryness affording the diol 8. The aque-
ous phase after elimination of the traces of Et2O was acidified with
30% HCl under cooling and the acid-alcohol 2 was isolated by crys-
tallisation.
3-[3-(2-Hydroxyethyl)-1H-indol-2-yl]propanoic Acid (2)
White powder; mp 126–128 °C (Et2O).
IR (KBr): 3482, 3374, 2953, 1724, 1462 cm–1.
MS (EI): m/z (%) = 233 (M+, 51), 215 (9), 202 (100), 184 (29), 143
(24).
UV (MeOH): max = 226, 284, 291 nm.
HRMS-EI: m/z calcd for C13H15NO3: 233.1052; found: 233.1064.
9
White crystals; mp 112–114 °C (Et2O).
Mixed Anhydride Reduction of Acid-Ester 9
IR (KBr): 3398, 3037, 2957, 1732, 1694, 1462 cm–1.
MS (EI): m/z (%) = 261 (M+, 73), 216 (2), 202 (100), 184 (34).
UV (MeOH): max = 222, 282, 290 nm.
To a cooled solution of 9 (200 mg, 0.77 mmol) and Et3N (123 L,
0.88 mmol) in anhyd THF (5 mL) was added dropwise methyl chlo-
roformate (70 L, 0.91 mmol) and the reaction mixture was stirred
at –10 °C under N2 for 1 h. The precipitate was filtered, washed with
THF (2 2 mL) and to the combined filtrates MeOH (1 mL) and
NaBH4 (96 mg, 2.54 mmol) were added. The mixture was stirred at
0–5 °C for 1 h. After acidification with 10% AcOH, the solvent was
evaporated, the residue was diluted with H2O (8 mL), and extracted
with CHCl3 (4 15 mL). The organic layers were dried (MgSO4),
filtered, evaporated to dryness and the residue was purified by chro-
matography on silica gel (eluent: CH2Cl2–MeOH, 97:3) to give the
alcohol-ester 7 (116 mg, 61%), diester 3 (23 mg, 11%) and some re-
covered starting material 9 (30 mg, 15%).
Anal. Calcd for C13H17NO2 (261.28): C, 64.36; H, 5.79; N, 5.36.
Found: C, 64.19; H, 5.62; N, 5.38.
10
Glossy white crystals; mp 186–188 °C (H2O).
IR (KBr): 3387, 3030, 2917, 1717, 1460 cm–1.
MS (EI): m/z (%) = 247 (M+, 87), 202 (100), 188 (15), 184 (34), 156
(62).
UV (MeOH): max = 224, 281, 291 nm.
2-[2-(3-Hydroxypropyl)-1H-indol-3-yl]acetic Acid (1)
A suspension of 7 (0.37 g, 1.50 mmol) and Ba(OH)2 8H2O (1.36 g,
4.31 mmol) in MeOH–H2O (4/4 mL) was stirred under N2 at r.t. for
2 h. After bubbling CO2 through the reaction mixture, the BaCO3
formed was filtered on Celite and washed with MeOH–H2O (50
mL). After evaporation of MeOH, the aqueous layer was extracted
with CH2Cl2 (2 10 mL) and then evaporated to dryness to obtain
1 (0.41 g, 91%).
Anal. Calcd for C13H13NO4 (247.25): C, 63.15; H, 5.30; N, 5.67.
Found: C, 62.92; H, 5.20; N, 5.69.
Methyl (3-Oxo-2,3-dihydro-1H-3a-azacyclopenta[a]inden-8-
yl)acetate (11)
A solution of 9 (2.0 g, 7.65 mmol) in freshly distilled POCl3 (20
mL) was stirred at r.t. for 40 h. After evaporation of POCl3 under
reduced pressure, the residue was triturated with ice-water, ren-
dered alkaline with aq 10% NaOH under cooling and extracted with
CH2Cl2 (4 10 mL). The combined organic layers were washed
with brine, dried (MgSO4), filtered and evaporated to dryness. The
residue was filtered through a short silica gel pad (eluent: CH2Cl2),
evaporated and crystallised from Et2O to afford the lactam 11 (1.6
g, 86%).
1
White crystalline powder; mp 159–162 °C (dec.)
IR (KBr): 3391, 3297, 2961, 1680, 1568 cm–1.
MS (EI): m/z (%) = 233 (M+, 31), 215 (10), 202 (4), 18 (36), 170
(11), 156 (13), 14 (100).
HRMS-EI: m/z calcd for C13H15NO3: 233.1052; found: 233.1052.
11
White crystals; mp 113–113.5 °C (Et2O).
UV (MeOH): max = 226, 284, 291 nm.
IR (KBr): 3443, 3030, 2951, 1731, 1719, 1624, 1462 cm–1.
MS (EI): m/z (%) = 243 (M+, 71), 213 (3), 184 (100), 170 (11), 156
(42), 142 (11).
Acknowledgement
An Europol Agro doctoral fellowship to S.-I. B. is gratefully ack-
nowledged.
UV (MeOH): max = 238, 261, 297, 302 nm.
Anal. Calcd for C14H13NO3 (243.26): C, 69.12; H, 5.39; N, 5.76.
Found: C, 68.92; H, 5.19; N, 5.66.
References
Reduction of Acid-Ester 9
(1) James, I. W. Tetrahedron 1999, 55, 4855.
(2) Soyez, H.; Schacht, E.; Vanderkerken, S. Adv. Drug
Delivery Rev. 1996, 21, 81.
(3) Bhagvat, S. S.; Gude, C. Tetrahedron Lett. 1994, 35, 1847.
(4) Lehr, M. Ger. Offen. DE 4 338 770, 1995; Chem. Abstr.
1995, 123, 32958.
(5) Lau, C.; Black, C.; Guay, D.; Gauthier, J.-Y.; Leblanc, Y.;
Roy, P.; Ducharme, Y.; Hamel, P. PCT Int. Appl. WO 96 37
467, 1996; Chem. Abstr. 1997, 126, 89261.
To a –45 °C cooled solution of 9 (300 mg, 1.15 mmol) in anhyd
THF (10–12 mL) was added dropwise a 1 M ethereal solution of
LiAlH4 (2.0 mL, 2.00 mmol) and the reaction mixture was stirred at
the same temperature under N2 for 4 h.
After destruction of the excess of LiAlH4 by adding a mixture of
MeOH (3 mL) and H2O (1 mL), the precipitate was filtered, washed
with THF (2 5 mL) and MeOH–H2O (10 5mL). The combined
filtrates were concentrated to 10–12 mL and extracted with Et2O
Synthesis 2002, No. 12, 1689–1694 ISSN 0039-7881 © Thieme Stuttgart · New York

1694
S.-I. Bascop et al.
PAPER
(6) Sawada, K.; Okada, S.; Golden, P.; Kayakiri, N.; Sawada,
Y.; Hashimoto, M.; Tanaka, H. Chem. Pharm. Bull. 1999,
47, 481.
(10) (a) Ireland, R. E.; Thompson, W. J. Tetrahedron Lett. 1979,
4705. (b) Prugh, J. D.; Deana, A. Tetrahedron Lett. 1988, 29,
37. (c) Ayers, T. A. Tetrahedron Lett. 1999, 40, 5467.
(11) Seyden-Penne, J. Reduction by the Alumino- and
Borohydrides in Organic Synthesis; VCH-Inc. Lavoisier:
New York, 1991.
(12) (a) Szabo, L.; Kalaus, G.; Szantay, C. Arch. Pharm.
(Weinheim, Ger.) 1983, 316, 629. (b) Szabo, L.; Sapi, J.;
Nogradi, K.; Kalaus, G.; Szantay, C. Tetrahedron 1983, 39,
3749.
(7) (a) Rowley, M.; Leeson, P. D.; Grimwood, S.; Foster, A.;
Saywell, K. Bioorg. Med. Chem. Lett. 1992, 2, 1627. (b) Di
Fabio, R.; Capelli, A. M.; Conti, N.; Cugola, A.; Donati, D.;
Feriani, A.; Gastaldi, P.; Gaviraghi, G.; Hewkin, C. T.;
Micheli, F.; Missio, A.; Mugnaini, M.; Pecunioso, A.;
Quaglia, A. M.; Ratti, E.; Rosssi, L.; Tedesco, G.; Trist, D.
G.; Reggiani, A. J. Med. Chem. 1997, 40, 841.
(8) (a) Robinson, B. The Fischer Indole Synthesis; Wiley:
Chichester, 1982. (b) Hughes, D. L. Org. Prep. Proced. Int.
1993, 25, 609.
(13) Ozegowski, R.; Kunath, A.; Schick, H. Tetrahedron:
Asymmetry 1993, 4, 695.
(14) Fadel, A.; Canet, J.-L.; Salaün, J. Tetrahedron Lett. 1989,
30, 6687.
(9) Robinson, B. The Fischer Indole Synthesis; Wiley:
Chichester, 1982, Chap. VII E, 760.
(15) Soai, K.; Yokoyama, S.; Mochida, K. Synthesis 1987, 647.
Synthesis 2002, No. 12, 1689–1694 ISSN 0039-7881 © Thieme Stuttgart · New York