A versatile synthetic methodology for the synthesis of tryptophols

Article abstract of DOI:10.1016/S0040-4020(02)01048-7

Tryptophols have been obtained in high yields by the reduction of 3-substituted-dioxindoles (obtained by the aldol condensation reaction of ketones with isatins or by a modified Knovenagel malonate condensation) using a borane tetrahydrofuran complex. The reported methodology offers distinct advantages over existing methods for the synthesis of these compounds, including consistently greater yields, diastereoselective syntheses and the possibility for the synthesis of a wide range of structurally different tryptophols. The reduction reaction was found to proceed via an intermediate 1,3-diol-oxindole, which was obtained diastereoselectively and, which was subsequently reduced to the corresponding tryptophol.

Full text of DOI:10.1016/S0040-4020(02)01048-7

Tetrahedron 58 (2002) 8399–8412
A versatile synthetic methodology for the synthesis of tryptophols
†
Simon J. Garden, Rosangela B. da Silva and Angelo C. Pinto
*
ˆ
´ ˆ ´
Departamento de Quımica Organica, Instituto de Quımica, Universidade Federal do Rio de Janeiro, Ilha do Funda˜o,
Rio de Janeiro CEP 21945-970, Brazil
Received 25 July 2002; accepted 23 August 2002
Abstract—Tryptophols have been obtained in high yields by the reduction of 3-substituted-dioxindoles (obtained by the aldol condensation
reaction of ketones with isatins or by a modified Knovenagel malonate condensation) using a borane tetrahydrofuran complex. The reported
methodology offers distinct advantages over existing methods for the synthesis of these compounds, including consistently greater yields,
diastereoselective syntheses and the possibility for the synthesis of a wide range of structurally different tryptophols. The reduction reaction
was found to proceed via an intermediate 1,3-diol-oxindole, which was obtained diastereoselectively and, which was subsequently reduced to
the corresponding tryptophol. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
or yields are variable, or that they require the synthesis of
highly reactive intermediates. One of the earliest reports
describes the obtention of tryptophol by the yeast fermen-
tation of tryptophan.2a A number of years later, Jackson7
prepared tryptophol by the reduction of indole acetic acid
esters using sodium in ethanol. Since this earlier work, there
has been a steady evolution of methodology. The introduc-
tion of LiAlH4 resulted in its use in the reduction of ethyl
indole oxoacetic acid derivatives8 as well as indole acetic
acid derivatives.9 The less powerful reducing agent NaBH4,
has also been successfully employed.6 The diastereo-
selective synthesis of 3-(2-hydroxycyclohexyl)indole
using NaBH4 or Zn(BH4)2 by reduction of the correspond-
ing ketone was reported by Freter10 and by Audia.11 Other
methods for the synthesis of tryptophols include: the Fischer
indole methodology;1b,d,5,8a,12 the ring opening of epoxides
by indolyl Grignard reagents,13 or by a 3-lithioindole;14
the reaction of indoles with diols in an autoclave;15 or by
reaction with epoxides under pressure.16 This latter method
has been further developed where the use of lanthanide
cations was found to be beneficial.17 Lithiation of ortho-
alkylphenylisocyanides and subsequent treatment with
epoxides gave moderate yields of the respective trypto-
phols.18 N,N-Diallyl-ortho-iodo- or bromo-anilines undergo
metal halogen exchange on reaction with t-BuLi at 2788C,
which upon warming cyclize to the respective lithiomethyl-
indoline which can react with an electrophile to yield
3-substituted indolines, subsequent oxidation of which
yields the respective 3-substituted indole.19 ortho-Iodo-
anilines have also found use in a synthetic sequence
involving a Heck reaction with an acrylate ester, followed
by reduction to the cinnamyl alcohol and subsequent
rhodium catalysed hydroformylation yielding tryptophol.20
The indole nucleus is widespread in both natural and
unnatural products. The interest in this skeletal structure is
reflected by the numerous methodologies that have been
devised and continue to be explored for its synthesis.1
Tryptophols are a class of indoles bearing a C-3 hydroxy-
ethyl side chain that may or may not be a- and or
b-substituted. Tryptophol and a number of its derivatives
have been isolated from a variety of natural sources.2 In
addition, some tryptophol derivatives are known to posses
biological activity. Esters of 5-methoxytryptophol posses
anticholinergic activity, whereas 5-methoxytryptophol and
other tryptophols have little or no activity.3 The production
of tryptophol, by tryptophan metabolism, has been impli-
cated as one of the pathophysiological mechanisms that
provoke sleeping sickness upon infection by trypanosomes.4
Of pharmaceutical importance is 7-ethyltryptophol as this
compound is used for the synthesis of Etodolac, an
important non-steroidal anti-inflammatory drug (NSAID).5
Whilst 2-phenyl-2-(3-indolyl)-1-ethanol has been used to
prepare Pemedolac, a compound that has been found to be
one of the most potent analgesics known and that displays
anti-inflammatory activity similar to that of Etodolac.6
A number of methods have become established for the
synthesis of tryptophols though generally these methods
present a number of limitations in that they lack generality,
Keywords: isatin; reduction; borane tetrahydrofuran complex; diastereo-
selective reduction; tryptophol.
*
Corresponding author. Tel.: þ55-21-2562-7363; fax: þ55-21-2562-7256;
e-mail: garden@iq.ufrj.br
Present address: Centro Federal de Educac¸a˜o Tecnologica de Quımica de
´ ´
Nilopolis, Nilopolis, Rio de Janeiro, Brazil.
†
An alternative method to the reduction of indolyl deriva-
tives is based upon the reduction of isatin derivatives. Isatin,
´
´
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01048-7

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S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
indol-2,3-dione, is an oxidised form of indole that may be
regarded as a masked indole or an umpoled indole
equivalent. Isatin and indole have complementary C-3
reactivity. Indole readily reacts with electrophiles whereas
isatin readily undergoes a range of C–C bond forming
reactions by nucleophilic attack at C-3.21 This comple-
mentary C-3 reactivity offers a versatile synthetic strategy
for the synthesis of indolic compounds. Tacconi22 described
a two stage reduction of an isatylidene derivative using
NaBH4 followed by sodium in propanol to obtain
a-methyltryptophol in low overall yield. Whilst David and
Doucet23 as well as Bergman24 have shown that the aldol
products, obtained by the condensation of a methylketone
with an isatin, can be reduced using LiAlH4 to give the
corresponding a-substituted tryptophol in 40–50% yield.
The use of isatin derivatives for the preparation of
3-hydroxy-2-oxindole acetic acid esters and the subsequent
reduction of these compounds using LiAlH4 has been shown
to be a general route for the obtention of tryptophols in good
to excellent yields (65–95%).6,8a,25
Equation 1. (a) Acetone, Et2NH or K2CO3; (b) BH3·THF.
reaction, during the addition of borane, resulted in the rapid
evolution of hydrogen gas. The reaction was subsequently
accompanied by TLC, which readily revealed the formation
of a product and the consumption of the starting material
over the period of a couple of hours. Isolation of the crude
product was achieved by acidic decomposition of the excess
borane, followed by neutralisation, extraction, drying of the
organic phase and removal of the solvent under reduced
pressure. The crude product was obtained as a slightly
yellow oil that was subsequently filtered through a short
column of silica, using CH2Cl2 as solvent, to remove
baseline (TLC) immobile impurities. Evaporation of the
solvent yielded a colourless oil that crystallised on storage.
GC–MS and 1H NMR analysis of this product revealed it to
be a mixture of the tryptophol 3a contaminated with a small
quantity of the respective indoline 4a (less than 5%),
Equation 1.
In ongoing investigations from our laboratory, the reduction
of isatin derivatives using borane in THF has proved to be a
versatile method for the synthesis of indole derivatives. This
relatively unknown method was successfully applied to the
reduction of N-acylisatin derivatives in excellent yields to
give N-alkylindoles26 and, more recently, to the reduction of
3,3-difluoro-2-oxindole derivatives, where either 3-fluoro-
indoles or 3,3-difluoroindolines were obtained depending
upon electronic effects of substituents on the aromatic
ring.27 Previous studies on the BH3·THF reduction of isatins
and or their derivatives include those of Sirowej,28
Wierenga and co-workers,29 as well as applications to the
synthesis of some natural products.13c,30 On the other hand,
refluxing mixtures of BH3·THF and 2-oxindolylacetic acid
derivatives in THF yielded the respective indoline ethanols
in 43–79%.31
Subsequent experiments economised the quantity of borane
resulting in the finding that the reaction proceeded equally
effectively using only 3 equiv. of borane. GC–MS and H
NMR analysis of the crude product obtained using 3 equiv.
of borane revealed the absence of the indoline 4a. The crude
product was purified as described above and the colourless
oil crystallised upon storage. The reported literature melting
points for 3a are diverse and therefore 3a was characterized
analytically and spectroscopically. In experiments using
less than 3 equiv. of borane it was found that an incomplete
1
Table 1. Compounds 2a–t, substrates for BH3·THF reduction
The ketone carbonyl of isatin derivatives is susceptible to
nucleophilic attack and aldol type condensations are readily
performed under a variety of conditions.21 It was therefore
reasoned that these aldol products should readily undergo
reduction with borane in THF to yield tryptophols. The
synthetic potential of these compounds may as of yet be
unrealised. There are few reports, with the exception of
the previously indicated studies on the synthesis of tetra-
hydropyranoindoles (Etodolac) and some recent examples
of asymmetric syntheses,32 that investigate this reactivity.
Tryptophols can be converted to tryptamines either by a
Mitsunubo reaction,11 without inversion of configuration of
the chiral center, or by Swern oxidation (yielding trypto-
phones) and subsequent NaCNBH3 reduction in the
presence of an amine.13d,33
Compound
R1
R2
R3
R4
R5
R6
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
H
Me
H
H
H
H
H
H
H
H
H
Me
Bn
H
H
H
Me
Bn
Bn
H
H
H
H
H
Br
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
I
H
H
H
H
Br
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
Br
H
H
H
H
H
H
H
H
H
Et
Et
Me
Me
Me
Me
Me
Me
Ph
NO2
H
Br
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
a
t-butyl
t-butyl
Ph
CH(OH)CH3
CH(OH)CH3
CH(OH)CH3
OMe
b
b
b
2. Results and discussion
Our investigation began with the preparation of 2a by the
reaction of isatin (1a) in acetone in the presence of a
catalytic quantity of diethylamine.34 A solution of freshly
prepared borane (1 M) in THF35 (5 equiv.) was then added
to a THF solution of 2a under a nitrogen atmosphere and
externally cooled with an ice water bath (Equation 1). Initial
OMe
OMe
OEt
2t
a
Condensation of isatin with cyclohexanone.
2n, 2 diastereoisomers (ratio 1:1), 2o (170–1718C); 2p (116–1698C).
b

S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
8401
reaction occurred, vide infra. It was also found that
maintaining the reaction at temperatures below zero
(<2158C) inhibited the reaction, but the reaction
recommenced on warming. Temperatures above those of
room temperature were not investigated as it was known
that 2-oxindole acetic acid derivatives can be reduced to
indoline ethanols when refluxed with borane in THF.31
Indolines have also been obtained by the reaction of the
BH3·NMe3 complex with indoles under acidic conditions
via the 3-H-indolium ion.36
(8:1). Preferential formation of the trans isomer is
consistent with previously observed results of the reduction
of a-substituted cyclohexanones using BH3·THF.11,38 The
isomers were readily separated by column chromatography
and individually characterized. The trans configuration of
the major isomer was confirmed by comparison with data
from the literature.13d
The reduction of 2m also required 4 equiv. of BH3·THF in
order to completely consume the substrate and to give the
respective tryptophol 3m in 80% yield. When the same
reaction was conducted using only 3 equiv. of BH3·THF, the
tryptophol 3m was obtained in 63% yield along with a 25%
yield of 5m (Equation 3). Compound 5m was unambigu-
ously characterized as the intermediate diol by spectro-
scopic and elemental analyses. As in the case of 5a, 5m was
also obtained as essentially a single diastereoisomer.
A closer investigation of the effect of reducing the reaction
temperature revealed the formation of an intermediate
during the reduction of 2a. This intermediate was consumed
when the reaction was allowed to warm to room
temperature. The intermediate (5a), Equation 2, was
subsequently isolated in 21% yield, along with 72% of the
tryptophol 3a, when the reaction was run using a deficiency
of BH3·THF (2 mol equiv.).
Equation 3. (a) 3 equiv. of BH3·THF (,1:2.5 mixture of 5m/3m).
Equation 2. (a) 2 mol equiv. of BH3·THF.
Having observed and characterised the formation of
intermediate single diastereoisomer diols (5a and 5m), it
was of interest to investigate the origin of this diastereo-
selectivity. At first the possibility of a directed reduction of
the keto-carbonyl group was considered.39,40 The alterna-
tive hypothesis being that reduction of the exocyclic keto-
carbonyl group was not diastereoselective, thus generating
an approximately one to one mixture of syn/anti diol
diastereoisomers (5) which were subsequently reduced at
different rates (kinetic resolution) to give the tryptophol 3a
or 3m and, in essence, the single diastereomer 5a or 5m as a
consequence of the deficiency of reducing agent. In order to
investigate these hypotheses, the reduction of 2a was
performed using 1 mol equiv. of BH3·THF. Spectroscopic
analysis of the crude product by 1H and 13C NMR revealed
the product to be a mixture of starting material (2a) and
diastereomeric diols (5a), though it was not possible to
determine a diastereomeric excess with any certainty.
Further experiments to investigate the diastereoselective
reduction of 2a using triacetoxyborohydride salts in THF
were unsuccessful, no reaction occurred.41 Attempts to
produce a mixture of the syn/anti 5a using sodium
borohydride (in protic or aprotic solvents) were unsuccess-
ful and resulted in complex mixtures of products.42
In an independent experiment, the reduction of 5a using an
excess of BH3·THF yielded 3a quantitatively. Spectroscopic
1
investigation of 5a by H and 13C NMR revealed it to be
structurally related to the starting dioxindole 2a. The
1
following differences were observed: the H methyl signal
was now a doublet; the methylene hydrogens were now
doublets of doublets; a new multiplet corresponding to one
hydrogen at 3.97 ppm (CH methine) and a doublet at
4.44 ppm (OH). The 13C NMR revealed the absence of the
keto-carbonyl and a new methine signal at 62 ppm. The
adjacent methyl and methylene signals were shifted upfield
by 7 and 5 ppm (d 23.2 and d 44.5) with respect to the
substrate 2a, whereas the other 13C signals were largely
unaffected. The most notable changes in the infra-red
spectrum of the product (5a) in comparison with the
substrate (2a), were the disappearance of the keto-carbonyl
stretching vibration (1721 cm21) and a broadening of the
absorption in the region 3400 cm21. The spectroscopic data
are entirely consistent with the reduction of the exocyclic
keto-carbonyl group and no reduction of the dioxindole
1
nucleus. Further, the H and 13C NMR data indicated that
the product had a greater than 95% diastereomeric excess.
The successful synthesis of the tryptophol 3a prompted the
investigation of the reduction of various isatin aldol
condensation products (2b–t, Table 1). These substrates
were prepared analogously to 2a or by using a modified
methodology. Subsequent treatment with borane resulted in
smooth reduction to give excellent yields of the respective
tryptophol in all experiments; the results are summarised in
Table 2. In a number of cases, it was found that 3 equiv. of
BH3·THF were insufficient for the complete reduction of the
substrate to the respective tryptophol. For example, the
reduction of the cyclohexanone derivative (2j)37 required
4 equiv. of borane in THF. The reduction occurred
stereoselectively yielding principally the trans isomer
As the reduction of 2a using only 1 equiv. of BH3·THF was
found to give a mixture of the diols 5a, but determination of
the diastereomeric excess of 5a had proven to be difficult,
and in order to further investigate the possibility of a
diastereoselective reduction, the N-methyl derivative 2b
was reduced with 1 equiv. of BH3·THF. After workup of the
reaction in the manner described previously, or utilising
an aqueous ammonium chloride workup, spectroscopic
investigation of the crude reaction product revealed it to be a
2:1 mixture of the diastereomeric diols (5b) with no other
product present (93% yield). This mixture was readily

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S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
Table 2. Tryptophol products obtained in this study
Table 2 (continued)
Product
Yield (%),
mp (8C)
Product
Yield (%),
mp (8C)
a
87,
oil
90,
53–54
a
90,
oil
89,
74–75
a
82,
oil
86,
93–95
a
78,
47–48
66,
155–157
All compounds gave satisfactory analytical and/or spectroscopic data.
A typical experimental procedure: dioxindole (1 mmol) was solubilised in
anhydrous THF (5 ml). To this was added a solution of BH3·THF (1 M,
3 ml) under a nitrogen atmosphere. The reaction mixture was stirred at
room temperature until TLC indicated complete consumption of the
substrate (typically a few hours). The reaction was subsequently quenched
with aqueous HCl (2N) and neutralised with aqueous NaOH (2N). Dilution
of the reaction mixture with water and extraction with ethyl acetate gave the
crude product. Pure tryptophols were obtained by filtration through a short
column of silica with CH2Cl2.
90,
125–126
92,
128–130
a
Four mole equivalents of BH3·THF were required for complete
consumption of the substrate.
trans/cis, 8:1; cis 110–1128C.
The same 4:1 mixture of diol indole diastereoisomers was obtained in all
b
c
85,
oil
three reactions irrespective of the starting material [2n, 2 diastereoi-
somers (1:1), 2o (170–1718C); 2p (116–1198C)]. The relative stereo-
chemistry of the major diastereoisomer has not been unambiguously
determined.
88,
151–152
reduced to the tryptophol 3b in 94% yield upon treatment
with 3 equiv. of borane, Equation 4.
90,
120–121
a
80 (trans),
157–160b
Equation 4. (a) 1 mol BH3·THF; (b) 3 mol BH3·THF.
In a similar manner, the reduction of 2m was conducted
using 1 mol equiv. of BH3·THF. This experiment furnished
a 3:1 mixture of the diastereomeric diols (5m) in 97% yield.
Comparison of the spectral data for the single diastereo-
isomer, obtained when 3 mol of BH3·THF were used
(Equation 3), with that of the mixture of the two
diastereoisomers, revealed it to have the same structure as
the major diastereoisomer. Therefore, the origin of the
single diol diastereoisomer in the preceding experiments,
where a deficiency of borane was utilised during the
synthesis of the respective tryptophols, lies in a mildly
diastereoselective reduction of the keto-carbonyl group and
not in a kinetic resolution of the diols (although differences
in the rates of reduction of the diols may have a minimal
role).
82,
121–122
80,
49–50
80,
oil
a
83–85,
oilc
Compound 2n was first prepared by condensation of
3-hydroxy-2-butanone with isatin in methanol at room

S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
8403
temperature in the presence of a catalytic quantity of
diethylamine yielding a 1:1 mixture of the diastereoisomers
2o and 2p. On workup it was found that one of the
diastereomers (2o, the isomer with the higher melting point)
was reasonably insoluble in ethyl acetate, thus separation of
the diastereoisomers could be achieved by fractional
crystallisation. Subsequently, the synthesis of 2n was
performed in ethyl acetate under otherwise equivalent
conditions, but in this case the ethyl acetate insoluble
isomer 2o precipitated during the reaction. The isomer 2p
was obtained as a crystalline solid by the slow evaporation
of the ethyl acetate solution enriched with the soluble
isomer. The reduction of compounds 2n–p was realized
using 4 equiv. of BH3·THF and in each case it was found
that the reactions yielded the same mixture (4:1) of
diastereomeric tryptophol diols (3n).These diastereo-
isomeric diols have been recently isolated from a
Streptomyces broth.43
Scheme 1. Simplified reaction mechanism for the obtention of tryptophols
by the BH3·THF reduction of isatin aldol adducts.
The foregoing results are consistent with a mechanism that
involves diastereoselective reduction of the ketone to the
secondary alcohol due to the presence of the b-asymmetric
tertiary alcohol. The diastereoselective reduction can be
envisaged to occur either by external or internal hydride
delivery.45 The amide carbonyl is subsequently reduced to
the amine in a two step process via a carbinolamine borate
ester.46 Subsequent elimination of the leaving group bonded
to C-3 with concomitant deprotonation of C-2 would yield
the tryptophol (Scheme 1).
In addition, tryptophols without a- or b-substituents can be
prepared by the reduction of (3-hydroxy-2-oxindol-3-yl)-
acetates.8a Examples of these compounds have been
prepared by the Reformatsky reaction.8a,44 As an alternative
method, the reaction of N-alkylisatin derivatives and
malonic acid (1.1 equiv.) in a 1:3 mixture of pyridine and
ethanol was conducted under reflux for 20 h resulting in the
obtention of (3-hydroxy-2-oxindol-3-yl)-acetic acids which
were isolated by evaporation of the solvent and addition of
dilute aqueous HCl followed by filtration, washing with
water, and air drying (Equation 5). The intermediate acids
were of sufficiently good quality that they could be used in
the next step without further purification. Esterification was
performed by the dropwise addition of SOCl2 to a
methanolic solution of the acid (Equation 5). The resulting
esters (2q–s) were subsequently purified by filtration
through a short column of silica. Esters 2q–s were reduced
with 4 equiv. of BH3·THF to give excellent yields of the
respective tryptophols (Table 2, 3q–s). However, this
procedure was found to be incompatabile with isatin
derivatives that were not N-alkylated. These substrates
yielded the respective quinolone derivatives upon esterifi-
cation via ring opening and ring closure. Therefore, an
alternative procedure employing the potassium salt of the
mono-ethyl malonyl ester with 7-ethylisatin in a mixture of
pyridine, acetic acid and ethanol under reflux was
investigated. This modified Knovenagel reaction gave
the b-hydroxyester (2t) in good yield. Ester 2t was
subsequently reduced with BH3·THF to give the corre-
sponding tryptophol after acidic workup (Equation 5). The
use of an aqueous ammonium chloride workup resulted in
the isolation of substantial quantities (<20%) of the ethyl
ether of the respective tryptophol.
3. Conclusion
In conclusion, we have found that the use of BH3·THF
solutions for the reduction of isatin aldol or Knovenagel
products (2a–t) to be not only a very convenient method,
but also to be a readily reproducible and high yielding
method for the synthesis of a diverse range of tryptophols
(3a–t). We have also found that the reduction of
compounds 2 proceeds via diol intermediates (5) that may
be obtained with limited stereoselectivity when a 1 mol
equiv. of borane is used. However, reduction of 2, using an
insufficient quantity of borane for complete reduction to
give 3, does allow isolation, in low yields, of what was
identified as being the major diol diastereoisomer of 5 along
with the corresponding tryptophol 3 as the principle
product.
4. Experimental
General. 1H and 13C NMR spectra were recorded using 300
and 200 MHz (1H) Bruker spectrometers and are referenced
to CHCl3. Coupling constants are quoted in Hz. 1H and 13
C
NMR assignments, where given, were based upon 2D
experiments (COSY, HMQC, and HMBC) or by compari-
son with related structures. Primary (p), secondary (s),
tertiary (t) and quaternary (q) assignments in 13C spectra
were based upon analysis of PENDANT spectra. Mass
spectra were recorded using a Hewlett–Packard GC–MS or
by direct insertion using a VG Autospec. Infra-red spectra
were recorded using a Perkin–Elmer 1600 FT-IR as either
KBr or KCl discs. Melting points were recorded using a
Meltemp II capillary melting point apparatus and are
reported as uncorrected values. THF was dried by refluxing
with a Na/K alloy and benzophenone. BF3·Et2O, purified
and redistilled, (Aldrich) was used as received. Isatin was
Equation 5. For R1¼Me or Bn; R2¼H a (1) CH2(CO2H), pyridine, EtOH
(1:3 v/v), K, (2) SOCl2, MeOH (R3¼Me); (b) BH3·THF; for R1¼H; R2¼Et.
(a) EtO2CCH2CO2K, pyridine, AcOH, EtOH (5:2:15 v/v/v), K; R3¼Et;
(b) BH3·THF.

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S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
´
purchased from Merck and NaBH4 from Grupo Quımica
and Merck. The isatin derivatives were prepared using
literature procedures.47
380 (59), 320 (13), 304 (10), 277 (15), 249 (5), 170 (7), 120
(10), 105 (100), 77 (76). 1H NMR (300 MHz, CDCl3,
DMSO-d6): d 2.95 [1H, d, H-8, J¼18.0 Hz], 3.30 [1H, d,
H-80, J¼18.0 Hz], 4.76 [1H, s, OH], 6.66 [1H, d, H-6,
J¼1.8 Hz], 6.69 [2H, t, H-12, J¼7.5 Hz], 6.71 [1H, d, H-4,
J¼1.8 Hz], 6.82 [1H, t, H-13, J¼7.5 Hz], 7.11 [2H, d, H-11,
J¼7.5 Hz], 9.90 [1H, bs, NH]. 13C NMR (75.5 MHz,
CDCl3, DMSO-d6): d 44.7 [s, C-8], 72.6 [q, C-3], 101.4
[q, C-7], 112.2 [q, C-5], 124.3 [t, C-6], 126.5p [t, C-11],
127.2p [t, C-12], 132.1 [t, C-13], 132.1 [t, C-4], 134.0 [q,
C-3a], 134.4 [q, C-10], 140.6 [q, C-7a], 176.5 [q, C-2],
194.80 [q, C-9]. The assignments for the signals marked p
may be interchanged.
4.1. General method for the synthesis of the acetone aldol
adducts
Isatin (10 mmol) was solubilised/suspended in acetone
(50 ml) to which was added a few drops of Et2NH. The
reaction mixture was left stirring at room temperature until
complete consumption of the respective isatin had occurred.
The excess acetone was removed by rotary evaporation
under reduced pressure. The crude product was extracted
with hot ethyl acetate, filtered and the ethyl acetate solution
evaporated to yield the respective product which was used
without further purification.
4.2.3. 4,6-Dibromo-3-hydroxy-3-(2-phenyl-2-oxoethyl)-
2-oxindole (2h). Recrystallised from CH2Cl2/hexane.
Yield 80%; mp 195–2008C. IR (cm21): 3382, 3170, 1715,
Alternatively, K2CO3 (10 mol%) was used as the basic
catalyst. The reactions were filtered through a pad of
diatomaceous earth and evaporated under reduced pressure.
The crude product was used without further purification.
1683, 1609, 1576, 1355, 1216, 1066, 839, 687. Mass,
81
11
m/z (%): 427 (Mþz, C16H Br2NO3, 9), 425 (Mþz,
79,81
11
79
11
C16H
Br2NO3, 21), 423 (Mþz, C16H Br2NO3, 10), 407
(4), 380 (6), 328 (6), 316 (13), 306 (16), 277 (9), 120 (70),
105 (100), 77 (50). 1H NMR (300 MHz, CDCl3, DMSO-d6):
d 3.76 [1H, d, H-8, J¼18.0 Hz], 4.56 [1H, d, H-80, J¼
18.0 Hz], 6.20 [1H, bs, OH], 7.05 [1H, d, H-7, J¼1.6 Hz],
7.15 [1H, d, H-5, J¼1.6 Hz], 7.45 [1H, t, H-12, J¼7–8 Hz],
7.58 [1H, t, H-13, J¼7–8 Hz], 7.89 [1H, d, H-11, J¼
8.0 Hz], 10.45 [1H, bs, NH]. 13C NMR (75.5 MHz, CDCl3,
DMSO-d6): d 43.2 [s, C-8], 73.6 [q, C-3], 111.6 [t, C-7],
117.9 [q, C-6], 122.0 [q, C-4], 126.4 [t, C-5], 126.8p [t,
C-11], 127.3 [q, C-3a], 127.5p [t, C-12], 132.4 [t, C-13],
134.7 [C-10], 145.2 [C-7a], 177.0 [C-2], 195.4 [C-9]. The
assignments for the signals marked p may be interchanged.
4.1.1. 3-Hydroxy-3-(2-oxopropyl)-2-oxindole (2a). Yield
85%; mp 166–1688C; lit.34 166–1678C.
4.1.2. N-Methyl-3-hydroxy-3-(2-oxopropyl)-2-oxindole
(2b). Yield 70%; mp 146–1488C; lit.34 1458C.
4.1.3. 5-Iodo-3-hydroxy-3-(2-oxopropyl)-2-oxindole (2c).
Yield 80%; mp 232–2348C; lit.48 233–2358C.
4.1.4. 5-Nitro-3-hydroxy-3-(2-oxopropyl)-2-oxindole
(2d). Yield 55%; mp 237–2398C; lit.48 239–2408C.
4.2.4. N-Benzyl-3-hydroxy-3-(2-phenyl-2-oxoethyl)-2-
oxindole51 (2m). The title compound was crystallised
from the reaction medium and isolated by filtration and
washed with small portions of cold MeOH. More product
was obtained by concentration of the filtrate. Yield 82%; mp
192–1968C. IR (cm21): 3323, 3075, 3030, 2897, 1697,
1682, 1618, 1496, 1389, 1348, 1216, 1180, 1070, 1008, 767,
733, 685, 643. Mass, m/z (%): 357 (Mþz, 17), 312 (4), 238
(8), 237 (13), 209 (6), 180 (10), 146 (35), 120 (10), 105 (81),
4.1.5. 4,6-Dibromo-3-hydroxy-3-(2-oxopropyl)-2-oxin-
dole (2e). Yield 77% (recryst. CHCl3); mp 198–2028C
(decomp.);47a lit.49 190–1958C.
4.1.6. 5,7-Dibromo-3-hydroxy-3-(2-oxopropyl)-2-oxin-
dole (2f). Yield 83%; mp 173–1758C.47a
4.2. Acetophenone and pinacolone condensation
products. General condensation procedure
1
91 (100), 77 (56), 65 (25), 51 (19). H NMR (200 MHz,
CDCl3, DMSO-d6): d 3.84 [1H, d, H-8, J¼17.4 Hz], 4.04
[1H, d, H-80, J¼17.4 Hz], 4.95 [2H, s, H-14, CH2 benzyl],
6.18 [1H, s, OH], 6.69 [1H, d, H-7, J¼7.6 Hz], 6.94 [1H, t,
H-5, J¼7.6 Hz], 7.15 [1H, td, H-6, J¼1.2, 7.6 Hz], 7.2–7.6
[9H, m], 7.88 [2H, d, H-11, J¼7.8 Hz]. 13C NMR (50 MHz,
CDCl3, DMSO-d6): d 45.5 [s,C-8], 43.1 [s, C-14], 72.7 [q,
C-3], 108.6 [t, C-7], 121.8 [t, C-5], 122.7 [t, C-6], 126.7 [t,
C-16], 126.8 [t, C-17], 127.4p [t, C-11], 127.9p [t, C-12],
128.0 [t, C-18], 128.7 [t, C-4], 130.3 [q, C-3a], 132.8 [t,
C-13], 135.4# [q, C-10], 135.7# [q, C-15], 143.0 [q, C-7a],
176.6 [q, C-2], 195.8 [q, C-9]. The assignments for the
signals marked p or # may be interchanged.
Isatin derivative (10 mmol) was solubilised/suspended in
MeOH (30 ml). To this was added 2 equiv. of methyl ketone
(acetophenone or pinacolone) followed by a few drops of
Et2NH. The reaction mixture was stirred at room tempera-
ture (or refluxed) until complete consumption of the starting
material as judged by TLC. The reaction mixtures were
evaporated under reduced pressure to yield the crude
products which were subsequently recrystallised.
4.2.1. 3-Hydroxy-3-(2-phenyl-2-oxoethyl)-2-oxindole
(2g). Recrystallised from EtOAc/hexane. Yield 80%; mp
175–1778C; lit.50 173–1758C.
4.2.5. 3-Hydroxy-3-(3,30-dimethyl-2-oxobutyl)-2-oxin-
dole52 (2k). The title compound was prepared by refluxing
the reagents in MeOH and purified by filtration through a
column of silica eluting with CH2Cl2. Yield 53%; mp 158–
1618C. IR (cm21): 3362, 3272, 2966, 1735, 1698, 1627,
1474, 1340, 1185, 1045, 752. Mass, m/z (%): 247 (Mþz, 16),
202 (6), 190 (7), 162 (46), 148 (100), 147 (18), 120 (27),
4.2.2. 5,7-Dibromo-3-hydroxy-3-(2-phenyl-2-oxoethyl)-
2-oxindole (2i). Recrystallised from CH2Cl2/hexane.
Yield 89%; mp 162–1658C. IR (cm21): 3330, 3192, 1730,
1708, 1678, 1619, 1462, 1349, 1218, 1158, 1082, 996, 859,
752, 691. Mass, m/z (%): 427 (Mþz, C16H Br2NO3, 3), 425
81
11
(MþzC, C16H
Br2NO3, 8), 423 (Mþz, C16H Br2NO3, 4),
79
79,81
11
11

S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
8405
1
119 (22), 92 (23), 57 (57). H NMR (300 MHz, CDCl3,
(20 mmol) and a few drops of Et2NH. The reaction mixture
was stirred at room temperature during 24 h. The complete
consumption of the isatin was verified by TLC. The reaction
mixture was evaporated under reduced pressure and the
crude product was filtered through a short column of
silica using CH2Cl2/EtOAc (1:4 v/v) as eluent. Evaporation
of the solvent gave the diastereomeric mixture (2n) as a
colourless solid (73% yield). The initial ratio of the
diastereoisomers (3:1) was determined from analysis of
the 1H NMR spectrum. The H-11 (CH3) and the H-9
(CH–OH) signals were sufficiently resolved permitting
comparison of the integrated peak areas.
DMSO-d6): d 1.05 [9H, s, H-11, CH3, t-butyl], 3.19 [1H, d,
H-8, J¼17.6 Hz], 3.44 [1H, d, H-80, J¼17.6 Hz], 5.68 [1H,
bs, OH], 6.87 [1H, d, H-7, J¼7.7 Hz], 6.94 [1H, td, H5,
J¼0.9, 7.3 Hz], 7.18 [1H, td, H-6, J¼1.2, 7.7 Hz], 7.24 [1H,
d, H-4, J¼7.3 Hz], 9.71 [1H, bs, NH]. 13C NMR (75.5 MHz,
CDCl3, DMSO-d6): d 25.6 [p, C-11], 43.5 [s, C-8], 43.8
[q, C-10], 73.6 [q, C-3], 110.0 [t, C-7], 121.6 [t, C-5], 123.1
[t, C-6], 129.1 [t, C-4], 130.7 [q, C-3a], 142.0 [q, C-7a],
178.6 [q, C-2], 213.1 [q, C-9].
4.2.6. N-Methyl-3-hydroxy-3-(3,30-dimethyl-2-oxobutyl)-
2-oxindole (2l). Prepared as for compound 2k. Yield: 50%;
mp 150–1528C. IR (cm21): 3350, 3168, 2970, 1731, 1698,
1614, 1473, 1379, 1349, 1112, 1090, 1061, 1000, 805, 764,
748. Mass, m/z (%): 261 (Mþz, 22), 239 (6), 217 (4), 176
(32), 162 (100), 160 (27), 134 (10), 130 (9), 104 (14), 91
(31), 77 (27), 57 (56). 1H NMR (200 MHz, CDCl3, DMSO-
d6): d 1.08 [9H, s, H-11, CH3, t-butyl], 3.03 [1H, d, H-8,
J¼17.5 Hz], 3.21 [3H, s, NCH3], 3.34 [1H, d, H-80, J¼
17.5 Hz], 4.69 [1H, bs, OH], 6.84 [1H, d, H-7, J¼8.0 Hz],
7.04 [1H, td, H-5, J¼0.8, 7.5 Hz], 7.27–7.34 [2H, m, H-4
and H-6]. 13C NMR (50 MHz, CDCl3, DMSO-d6): d 26.1 [p,
C-11], 26.4 [p, C-12, CH3N], 43.0 [s, C-8], 44.8 [q, C-10],
74.6 [q, C-3], 108.7 [t, C-7], 123.1 [t, C-5], 123.7 [t, C-6],
130.1 [t, C-4], 130.2 [q, C-3a], 143.9 [q, C-7a], 176.5 [q,
C-2], 215.3 [q, C-9].
The diastereomeric mixture was solubilised in hot EtOAc,
on cooling a product crystallized. The product was removed
by filtration and washed with small portions of cold EtOAc.
This product, compound 2o, was determined to be the
diastereoisomer of higher melting point (40% yield). The
filtrate was allowed to slowly evaporate. During this
process, a colourless product crystallized. The solid was
separated by filtration and determined to be the diastereo-
isomer (2p) of lower melting point (14% yield).
Alternatively, the reaction may be performed in EtOAc as
solvent. This results in the precipitation of a colourless
product in 68% yield (a further 20–25% of product can be
obtained from the filtrate) that was found to be a 3:1 mixture
of diastereoisomers. Recrystallisation from EtOAc gave the
diastereoisomer of higher melting point in 48% yield.
4.3. Condensation with cyclohexanone
4.3.1. 3-Hydroxy-3-(2-oxocyclohexyl)-2-oxindole (2j).
Isatin (10 mmol) was suspended in EtOAc (20 ml) to
which was added cyclohexanone (30 mmol) and a few drops
of Et2NH. The reaction mixture was left stirring at room
temperature until complete consumption of the isatin had
occurred (24 h). The product partially precipitated during
the reaction. The precipitate was removed by filtration and
the filtrate concentrated under reduced pressure. The
combined solids were recrystallised from acetone/hexane
to give a 4:1 mixture of diastereoisomers in 72% yield, mp
167–1758C; lit.53 198–1998C. A similar procedure using
MeOH as the solvent gave a 1.6:1 mixture of diastereo-
isomers in 64% yield. IR (cm21): 3339, 3293, 3203, 3169,
3027, 2944, 2868, 1723, 1688, 1619, 1470, 1381, 1215,
1047, 757. Mass, m/z (%): 245 (Mþz, 39), 227 (8), 172 (7),
162 (10), 148 (90), 147 (15), 120 (29), 119 (22), 98 (100), 92
4.4.1. Characterization data for the less soluble diastereo-
isomer (2o). Yield: 48%; mp 170–1728C; lit.23 172–1808C.
IR (cm21): 3504, 3331, 3185, 2987, 1731, 1703, 1620,
1477, 1399, 1334, 1307, 1216, 1187, 1018, 775, 756. Mass,
m/z (%): 235 (Mþz, 4), 207 (6), 191 (4), 162 (100), 148 (95),
1
147 (9), 146 (34), 120 (23), 119 (14), 92 (20), 65 (14). H
NMR (300 MHz, CDCl3, DMSO-d6): d 1.23 [3H, d, H-11,
J¼6.9 Hz], 3.17 [1H, d, H-8, J¼17.1 Hz], 3.49 [1H, d, H-80,
J¼17.1 Hz], 4.08 [1H, m, H-10], 4.83 [1H, d, C10–OH,
J¼5.1 Hz], 5.96 [1H, s, C3–OH], 6.87 [1H, d, H-7, J¼
7.7 Hz], 6.94 [1H, t, H-5, J¼7.5 Hz], 7.18 [1H, t, H-6,
J¼7.6 Hz], 7.26 [1H, d, H-4, J¼7.3 Hz], 9.97 [1H, sl, NH].
13C NMR (75.5 MHz, CDCl3, DMSO-d6): d 18.2 [p, C-11],
43.8 [s, C-8], 71.8 [t, C-10], 72.4 [q, C-3], 109.0 [t, C-7],
120.8 [t, C-5], 122.6 [t, C-6], 128.2 [t, C-4], 129.9 [q, C-3a],
141.2 [q, C-7a], 177.7 [q, C-2], 209.7 [q, C-9]. Elemental
analysis: C12H13NO4, calcd: C: 61.27, H: 5.57, N: 5.95,
obs.: C: 61.25, H: 5.66, N: 5.76.
1
(22), 70 (25). H NMR (300 MHz, CDCl3, DMSO-d6): d
1.4–2.6 [8H, m], 3.14 [1H, dd, H-8, J¼5.3, 12.9 Hz], 5.80
[1H, s, OH], 6.88 [2H, m, H-7 and H-5], 7.17 [1H, t, H-6,
J¼7.4 Hz], 7.25 [1H, d, H-4, J¼7.4 Hz], 10.07 and 10.10
[1H, s, NH diastereoisomers]. 13C NMR (75.5 MHz, CDCl3,
DMSO-d6): d Major diastereoisomer 23.8 [s, C-12], 25.8 [s,
C-11], 26.0 [s, C-10], 56.4 [t, C-8], 73.8 [q, C-3], 108.9 [t,
C-7], 120.3 [t, C-5], 123.7 [t, C-6], 127.9 [t, C-4], 129.5 [q,
C-3a], 142.3 [q, C-7a], 178.3 [q, C-2], 208.7 [q, C-9].
4.4.2. Characterization data for the EtOAc soluble
diastereoisomer (2p). Yield 14%; mp 116–1698C. IR
(cm21): 3420, 3357, 3263, 2988, 2918, 1729, 1704, 1622,
1472, 1347, 1186, 1115, 999, 779, 756. Mass, m/z (%): 235
(Mþz, 5), 207 (5), 191 (5), 162 (100), 148 (84), 147 (10), 146
(54), 120 (28), 119 (17), 92 (28), 65 (22). 1H NMR
(300 MHz, CDCl3, DMSO-d6): d 1.26 [3H, d, H-11, J¼
7.0 Hz], 3.17 [1H, d, H-8, J¼16.7 Hz], 3.42 [1H, d, H-80,
J¼16.7 Hz], 4.13 [1H, qd, H-10, J¼4.8, 7.0 Hz], 4.66 [1H,
d, C10–OH, J¼4.8 Hz], 5.92 [1H, s, C3–OH], 6.87 [1H, d,
H-7, J¼7.7 Hz], 6.95 [1H, t, H-5, J¼7.6 Hz], 7.19 [1H, td,
H-6, J¼1.2, 7.7 Hz], 7.27 [1H, dl, H-4, J¼7.1 Hz], 9.87
[1H, sl, NH]. 13C NMR (75.5 MHz, CDCl3, DMSO-d6): d
18.6 [p, C-11], 44.2 [s, C-8], 72.5 [t, C-10], 73.0 [q, C-3],
4.4. Condensation of 3-hydroxybutan-2-one. Synthesis
and isolation of the diastereoisomers of 3-hydroxy-3-(3-
hydroxy-2-oxobutyl)-2-oxindole (2n—the mixture, 2o
and 2p—the individual diastereoisomers)
Isatin (10 mmol) was solubilised/suspended in MeOH
(20 ml). To this was added 3-hydroxybutan-2-one

8406
S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
109.6 [t, C-7], 121.4 [t, C-5], 123.1 [t, C-6], 128.8 [t, C-4],
130.0 [q, C-3a], 141.4 [q, C-7a], 178.1 [q, C-2], 210.1 [q,
C-9]. Elemental analysis: C12H13NO4, calcd: C: 61.27, H:
5.57, N: 5.95, obs.: C: 61.46, H: 5.62, N: 5.73.
yl)-acetate (2s). The title compound was purified by silica
gel column chromatography using hexane/EtOAc (1:1 v/v)
as eluent. Yield 82%; mp 138–1398C. IR (cm21): 3312,
3032, 2974, 1744, 1701, 1605, 1454, 1387, 1358, 1297,
1270, 1165, 1046, 809, 753, 729, 698. Mass, m/z (%): 339
(Mþz, 6), 174 (38), 91 (100). 1H NMR (300 MHz, CDCl3): d
1.06 [3H, t, H12, J¼7.5 Hz], 2.56 [2H, q, H11, J¼7.5 Hz],
2.97 [1H, d, H8, J¼15.7 Hz], 3.08 [1H, d, H80, J¼15.7 Hz],
3.69 [3H, s, H10], 4.61 [1H, bs, OH], 5.14 [2H, s, H13], 7.06
[2H, m, CH aromatic], 7.22–7.35 [6H, m, CH aromatic].
13C NMR (75.5 MHz, CDCl3): d 16.6 [p, C-12], 24.6 [s,
C-11], 41.5 [s, CH2], 45.6 [s, CH2], 52.4 [p, C-10], 72.8 [q,
C-3], 121.9 [CH], 123.8 [CH], 125.9 [CH], 127.3 [C], 127.5
[CH], 129.1 [CH], 130.3 [C], 132.7 [CH], 137.1 [C], 140.0
[C], 171.0 [q, CvO ester], 178.0 [q, CvO amide].
4.5. Synthesis of compounds 2q, 2r and 2s, methyl
(1-alkyl-3-hydroxy-2-oxindol-3-yl)-acetates. General
procedure
The 1-alkylisatin derivatives (5.0 mmol) were solubilised in
a mixture of pyridine and EtOH (20 ml, 1:3 v/v), to which
was added a slight excess of malonic acid (6–7 mmol). The
reaction mixture was refluxed for 20 h, after which time
TLC revealed the complete consumption of the starting
material. The reaction mixture was evaporated under
reduced pressure to give a solid. This was washed with
dilute aqueous HCl (25 ml, 0.25 M), filtered and air-dried.
The crude product was solubilised in MeOH (20 ml) and
cooled on an ice water bath. Thionyl chloride (2 ml) was
added dropwise to the solution. The reaction mixture was
allowed to warm to room temperature and left stirring
overnight. The crude products were isolated by evaporation
of the reaction mixtures under reduced pressure.
4.5.4. Ethyl (3-hydroxy-7-ethyl-2-oxindol-3-yl)-acetate
(2t). The general procedure for the synthesis of compounds
2q, 2r and 2s was adapted by using the mono-potassium
ethyl malonate salt (10% excess) in place of malonic acid.
The solvent used was a mixture of EtOH, pyridine and
acetic acid (15:5:2 v/v/v). Reflux was maintained until
complete consumption of the respective isatin derivative
was observed. The crude reaction product was isolated as
described for compounds 2q, 2r and 2s.
4.5.1. Methyl (N-methyl-3-hydroxy-2-oxindol-3-yl)-acetate
(2q). The title compound was purified by filtration through a
column of silica using hexane/EtOAc (1:1 v/v) as eluent.
Yield: 80%; mp 191–1938C. IR (cm21): 3297, 2959, 1742,
1695, 1617, 1473, 1434, 1388, 1349, 1203, 1098, 787, 760.
Mass, m/z (%): 235 (Mþz, 39), 175 (18), 162 (100), 146 (10),
The title compound was purified by silica gel column
chromatography using hexane/EtOAc (1:1 v/v) as eluent.
Yield 78%; mp 115–1168C. IR (cm21): 3354, 3201, 3078,
2983, 2938, 2905, 1737, 1703, 1629, 1607, 1456, 1258,
1187, 1034, 820, 807, 752, 709. 1H NMR (200 MHz,
CDCl3): d 1.15 [3H, t, H-11, J¼7.1 Hz], 1.23 [3H, t, H-13,
J¼7.5 Hz], 2.61 [2H, q, H-12, J¼7.5 Hz], 2.94 [2H, s, H-8],
4.13 [2H, q, H-10, J¼7.1 Hz], 7.01 [1H, t, H-5, J¼7.3 Hz],
7.13 [1H, d, H-4 or 6, J¼7.2 Hz], 7.23 [1H, d, H-4 or 6,
J¼7.3 Hz], 9.12 [1H, bs, NH]. 13C NMR (50 MHz, CDCl3):
d 14.1 [CH3], 14.2 [CH3], 23.8 [CH2], 41.3 [CH2], 61.3
[CH2O], 74.5 [C-3], 121.8 [CH], 123.5 [CH], 126.4 [C],
129.6 [C], 129.8 [CH], 138.9 [C], 170.6 [CvO, ester], 179.4
[CvO, amide].
1
134 (15), 105 (13), 104 (10), 77 (16). H NMR (300 MHz,
CDCl3, DMSO-d6): d 3.05 [1H, d, H-8, J¼15.7 Hz], 3.13
[1H, d, H-80, J¼15.7 Hz], 3.19 [3H, s, H-11, N–CH3], 3.46
[3H, s, H-10, O–CH3], 6.15 [1H, s, OH], 6.86 [1H, d, H-7,
J¼7.8 Hz], 7.04 [1H, t, H-5, J¼7.8 Hz], 7.31 [1H, td, H-6,
J¼1.1, 7.8 Hz], 7.36 [1H, d, H-4, J¼7.8 Hz]. 13C NMR
(75.5 MHz, CDCl3, DMSO-d6): d 25.3 [p, C-11], 41.0 [s,
C-8], 50.7 [p, C-10], 72.0 [q, C-3], 107.4 [t, C-7], 121.7 [t,
C-5], 122.8 [t, C-6], 128.8 [t, C-4], 129.2 [q, C-3a], 143.1 [q,
C-7a], 168.6 [q, C-9], 175.9 [q, C-2].
4.5.2. Methyl (N-benzyl-3-hydroxy-2-oxindol-3-yl)-acetate
(2r). The title compound was purified by filtration through a
column of silica using hexane/EtOAc (1:1 v/v) as eluent.
Yield 84%; mp 137–1398C. IR (cm21): 3316, 3054, 2953,
1737, 1698, 1617, 1495, 1468, 1429, 1352, 1210, 1183,
1074, 1010, 761, 734, 645. Mass, m/z (%): 311 (Mþz, 62),
293 (8), 238 (18), 234 (13), 220 (10), 180 (8), 146 (100), 91
4.6. Synthesis of tryptophol derivatives (3), general
experimental procedure
The appropriate aldol derivative (10 mmol) was solubilised
in dry THF (20 ml) under a nitrogen atmosphere. To the
solution/suspension was added via a syringe a solution of
BH3·THF (1 M, 3 or 4 mol equiv.). The reaction mixture
was stirred at room temperature until TLC revealed
complete consumption of the starting material (generally 2
to 3 h). The reaction mixture was added to ethyl acetate
(50 ml) and dilute aqueous HCl (0.3 M, 50 ml). The phases
were mixed and separated. The aqueous phase was extracted
with more ethyl acetate (50 ml). The combined organic
phases were further washed with aqueous HCl (0.3 M,
50 ml) and water (50 ml), then dried over Na2SO4, filtered
and evaporated under reduced pressure to yield the crude
product.
1
(97), 65 (11). H NMR (300 MHz, CDCl3, DMSO-d6): d
3.11 [1H, d, H-8, J¼15.7 Hz], 3.20 [1H, d, H-80, J¼
15.7 Hz], 3.42 [3H, s, H-10, OCH3], 4.85 [1H, d, H-11,
J¼15.8 Hz], 4.92 [1H, d, H-110, J¼15.8 Hz], 6.35 [1H, bs,
OH], 6.70 [1H, d, H-7, J¼7.8 Hz], 7.00 [1H, t, H-5,
J¼7.8 Hz], 7.18 [1H, td, H-6, J¼1.1, 7.8 Hz], 7.2–7.4 [6H,
m]; 13C13C NMR (75.5 MHz, CDCl3, DMSO-d6): d 40.7 [s,
C-8], 42.4 [s, C-11], 50.4 [p, C-10], 71.7 [q, C-3], 108.0 [t,
C-7], 121.4 [t, C-5], 122.7 [t, C-6], 126.3p [t, C-13], 126.4p
[t, C-14], 127.5p [t, C-15], 128.4 [t, C-4], 129.1 [q, C-3a],
134.8 [q, C-12], 142.1 [q, C-7a], 168.2 q, C-9], 175.7 [q,
C-2]. The assignments of the signals marked by an p may
be interchanged.
Alternatively, 6 M HCl was added dropwise with caution to
the reaction mixture whilst being cooled on an ice water
bath until no further effervescence was observed. The
reaction mixture was neutralised by dropwise addition of
4.5.3. Methyl (N-benzyl-3-hydroxy-7-ethyl-2-oxindol-3-

S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
8407
3 M NaOH. The product was isolated by partitioning the
reaction between water and ethyl acetate, then dried over
Na2SO4, filtered and evaporated under reduced pressure to
yield the crude product.
4.6.4. 3-(2-Hydroxypropyl)-5-nitroindole (3d). Purified
by filtration through a short column of silica using CH2Cl2
and EtOAc (3:2 v/v) as eluent, 66% yield. Mp 155–1578C.
IR (cm21): 3504, 3228, 2965, 2924, 1619, 1518, 1474,
1327, 1074, 935, 808, 738. Mass, m/z (%): 220 (Mþz, 34),
175 (81), 159 (48), 146 (4), 129 (100), 117 (7), 102 (15), 89
(5), 75 (7), 63 (6). 1H NMR (300 MHz, CDCl3, DMSO-d6):
d 1.11 [3H, d, H-10, J¼6.1 Hz], 2.79 [2H, d, H-8 and H-80,
J¼6.2 Hz], 3.14 [1H, sl, OH], 3.98 [1H, m, H-9], 7.11 [1H,
d, H-2, J¼1.2 Hz], 7.27 [1H, d, H-7, J¼9.0 Hz], 7.89 [1H,
dd, H-6, J¼2.0, 9.0 Hz], 8.46 [1H, d, H-4, J¼2.0 Hz], 10.47
[1H, sl, NH]. 13C NMR (75.5 MHz, CDCl3, DMSO-d6): d
22.9 [p, C-10], 34.8 [s, C-8], 67.5 [t, C-9, CHOH], 111.3
[t, C-7], 114.9 [q, C-3], 116.3 [t, C-2], 116.8 [t, C-4], 126.3
[t, C-6], 127.1 [q, C-3a], 139.6 [q, C-7a], 140.9 [q, C-5,
C–NO2].
Subsequent purification of the tryptophols was achieved by
filtration through short columns of silica as indicated for
each compound.
4.6.1. 3-(2-Hydroxypropyl)-indole (3a). Purified by fil-
tration through a short column of silica using CH2Cl2 as
eluent. Yield 90%; mp 53–548C; lit. 52–55;12a 44–45;54
40–418C.24b IR (cm21): 3521, 3443, 3300, 3248, 3057,
2970, 2925, 2901, 1439, 1355, 1338, 1249, 1228, 1099,
1047, 926, 800, 739. Mass, m/z (%): 175 (Mþz, 21), 130
(100), 103 (8), 77 (14). 1H NMR (300 MHz, CDCl3): d 1.32
[3H, d, H-10, J¼6.15 Hz], 1.79 [1H, bs, OH], 2.83 [1H, ddd,
H-8, J¼0.6, 8.3, 14.3 Hz], 3.01 [1H, ddd, H-80, J¼0.9, 4.4,
14.3 Hz], 4.14 [1H, m, H-9, CHOH], 7.08 [1H, d, H-2,
J¼2.3 Hz], 7.15 [1H, td, H-5, J¼1.2, 7.0 Hz], 7.23 [1H, td,
H-6, J¼1.2, 7.0 Hz], 7.38 [1H, dt, H-7, J¼0.9, 8.0 Hz], 7.64
[1H, d, H-4, J¼7.8 Hz], 8.14 [1H, bs, NH]. 13C NMR
(75.5 MHz, CDCl3): d 22.6 [p, C-10], 35.2 [s, C-8], 67.6
[t, C-9, CHOH], 111.1 [t, C-7], 112.3 [q, C-3], 118.9
[t, C-5], 119.4 [t, C-4], 122.1 [t, C-6], 122.7 [t, C-2], 127.5
[q, C-3a], 136.3 [q, C-7a]. Elemental analysis: C11H13NO,
calcd: C: 75.40, H: 7.48, N: 7.99, obs.: C: 75.29, H: 7.69, N:
7.91.
4.6.5. 3-(2-Hydroxypropyl)-4,6-dibromoindole (3e).
Purified by filtration through a short column of silica
using CH2Cl2 as eluent, 90% yield. Mp 125–1268C. IR
(cm21): 3417, 3259, 2965, 2924, 1638, 1612, 1399, 1261,
1122, 1049, 935, 819. Mass, m/z (%): 335 (Mþz,
C11H Br2NO, 18), 333 (Mþz, 38), 331 (Mþz, 17), 288
81
11
(100), 209 (15), 128 (29), 101 (7), 75 (8). 1H NMR
(300 MHz, CDCl3): d 1.31 [3H, d, H-10, J¼6.1 Hz], 1.79
[1H, bs, OH], 2.84 [1H, dd, H-8, J¼8.5, 14.5 Hz], 3.31 [1H,
ddd, H-80, J¼0.75, 4.0, 14.5 Hz], 4.18 [1H, m, H-9], 7.04
[1H, bd, H-2, J¼2.4 Hz], 7.37 [1H, d, H-5, J¼1.6 Hz], 7.41
[1H, d, H-7, J¼1.6 Hz], 8.42 [1H, bs, NH]. 13C NMR
(75.5 MHz, CDCl3): d 22.8 [p, C-10], 35.9 [s, C-8], 68.7
[t, C-9, CHOH], 113.8 [t, C-7], 114.1 [q, C-3], 114.8 [q,
C-4], 115.2 [q, C-6], 124.7 [q, C-3a], 125.5 [t, C-2], 126.8 [t,
C-5], 138.4 [q, C-7a]. Elemental analysis: C11H11Br2NO,
calcd: C: 39.67, H: 3.33, N: 4.21, obs.: C: 39.40, H: 3.15, N:
3.95.
4.6.2. 3-(2-Hydroxypropyl)-N-methylindole (3b). Purified
by filtration through a short column of silica using CH2Cl2
as eluent, 89% yield. Mp 74–758C; lit.55 75–768C. IR
(cm21): 3326, 3051, 2959, 2919, 2866, 1615, 1475, 1372,
1328, 1250, 1080, 938, 735. Mass, m/z (%): 189 (Mþz, 17),
144 (100), 129 (4), 115 (3), 102 (5), 77 (5). 1H NMR
(300 MHz, CDCl3): d 1.27 [3H, d, H-10, J¼6.1 Hz], 1.79
[1H, bs, OH], 2.77 [1H, dd, H-8, J¼8.2, 14.3 Hz], 2.95 [1H,
dd, H-80, J¼4.3, 14.3 Hz], 3.73 [3H, s, H-11, N–CH3], 4.07
[1H, m, H-9], 6.91 [1H, s, H-2], 7.11 [1H, t, H-5, J¼7.9 Hz],
7.20–7.30 [2H, m, H-6 and H-7], 7.59 [1H, d, H-4,
J¼7.9 Hz]. 13C NMR (75.5 MHz, CDCl3): d 22.6 [p, C-10],
32.5 [p, C-11, NCH3], 35.0 [s, C-8], 67.6 [t, C-9, CHOH],
109.1 [t, C-7], 110.6 [q, C-3], 118.8 [t, C-5], 118.9 [t, C-4],
121.6 [t, C-6], 127.5 [t, C-2], 127.9 [q, C-3a], 137.0 [q,
C-7a]. Elemental analysis: C12H15NO, calcd: C: 76.16, H:
7.99, N: 7.40, obs.: C: 75.72, H: 8.26, N: 7.30.
4.6.6. 5,7-Dibromo-3-(2-hydroxypropyl)-indole (3f).
Purified by filtration through a short column of silica
using CH2Cl2 as eluent, 92% yield. Mp 128–1308C. IR
(cm21): 3529, 3451, 3253, 2964, 1638, 1611, 1399, 1320,
1261, 1180, 1123, 1049, 935, 835, 819. Mass, m/z (%): 335
(Mþz, C11H Br2NO, 19), 333 (Mþz, C11H
Br2NO, 40),
81
79,81
11
79
11
331 (Mþz, C11H Br2NO, 20), 288 (100), 207 (18), 128 (31),
11
101 (9), 75 (9). 1H NMR (300 MHz, CDCl3): d 1.28 [3H, d,
H-10, J¼6.2 Hz], 1.67 [1H, sl, OH], 2.76 [1H, ddd, H-8,
J¼0.6, 7.9, 14.5 Hz], 2.89 [1H, ddd, H-80, J¼0.8, 4.5,
14.5 Hz], 4.09 [1H, m, H-9], 7.15 [1H, d, H-2, J¼2.3 Hz],
7.47 [1H, d, H-6, J¼1.6 Hz], 7.70 [1H, dd, H-4, J¼0.6,
1.6 Hz], 8.34 [1H, bs, NH]. 13C NMR (75.5 MHz, CDCl3): d
23.2 [p, C-10], 35.3 [s, C-8], 67.9 [t, C-9, CHOH], 105.4 [q,
C-7], 112.7 [q, C-5], 113.9 [q, C-3], 121.3 [t, C-4], 124.8 [t,
C-2], 126.1 [t, C-6], 130.2 [q, C-3a], 134.2 [q, C-7a].
Elemental analysis: C11H11Br2NO, calcd: C: 39.67, H: 3.33,
N: 4.21, obs.: C: 39.50, H: 3.21, N: 4.03.
4.6.3. 3-(2-Hydroxypropyl)-5-iodoindole (3c). Purified by
filtration through a short column of silica using CH2Cl2 as
eluent, 86% yield. Mp 93–958C. IR (cm21): 3519, 3252,
2964, 2910, 1458, 1233, 1101, 1042, 931, 872, 795. Mass,
1
m/z (%): 301 (Mþz, 46), 256 (100), 129 (48), 102 (12). H
NMR (300 MHz, CDCl3): d 1.28 [3H, d, H-10, J¼6.15 Hz],
1.73 [1H, s, 0OH], 2.75 [1H, dd, H-8, J¼8.2, 14.4 Hz], 2.90
[1H, dd, H-8 , J¼4.3, 14.4 Hz], 4.08 [1H, m, H-9], 7.02 [1H,
d, H-2, J¼2.0 Hz], 7.13 [1H, d, H-7, J¼8.5 Hz], 7.43 [1H,
dd, H-6, J¼1.4, 8.5 Hz], 7.94 [1H, sl, H-4], 8.22 [1H, bs,
NH]. 13C NMR (75.5 MHz, CDCl3): d 23.1 [p, C-10], 35.2
[s, C-8], 67.9 [t, C-9, CHOH], 83.1 [q, C-5, C-I], 112.1 [q,
C-3], 113.4 [t, C-7], 123.8 [t, C-2], 128.1 [t, C-4], 130.4 [q,
C-3a], 130.6 [t, C-6], 135.6 [q, C-7a]. Elemental analysis:
C11H12INO, calcd: C: 43.88, H: 4.02, N: 4.65, obs.: C:
43.74, H: 4.08, N: 4.42.
4.6.7. 3-(2-Phenyl-2-hydroxyethyl)-indole23 (3g). Purified
by filtration through a short column of silica using CH2Cl2
as eluent, 85% yield. Obtained as a slightl yellow oil. IR (n,
cm21): 3405, 3057, 3026, 2933, 2897, 1453, 1420, 1335,
1093, 1061, 1005, 745, 670. Mass, m/z (%): 237 (Mþz,5),
219 (12), 130 (100), 77 (18). 1H NMR (300 MHz, CDCl3): d
2.17 [1H, bs, OH], 3.10 [1H, ddd, H-8, J¼0.5, 8.8, 14.5 Hz],
3.23 [1H, ddd, H-80, J¼0.8, 4.4, 14.5 Hz], 4.99 [1H, dd,

8408
S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
H-9, CHOH, J¼4.4, 8.8 Hz], 6.98 [1H, d, H-2, J¼2.3 Hz],
7.12–7.43 [8H, m, H-5, 6, 7, 11, 110, 12, 120, 13], 7.60 [1H,
dd, H-4, J¼0.6, 7.8 Hz], 8.05 [1H, bs, NH]. 13C NMR
(75.5 MHz, CDCl3): d 36.1 [s, C-8], 74.1 [t, C-9, CHOH],
111.4 [t, C-7], 112.2 [q, C-3], 119.1 [t, C-5], 119.8 [t, C-4],
122.4 [t, C-6], 123.3 [t, C-2], 126.1 [t, C-11], 127.7 [t, C-13],
128.6 [t, C-12], 136.6 [q, C-3a], 144.3 [q, C-7a]. Elemental
analysis: C16H15NO, calcd: C: 80.98, H: 6.32, N: 5.90, obs.:
C: 80.72, H: 6.59, N: 5.71.
7.74 [1H, bd, H-4, J¼7.5 Hz], 8.27 [1H, bs, NH]. 13C NMR
(75.5 MHz, CDCl3): d 25.0 [s, C-11], 26.1 [s, C-12], 32.5 [s,
C-13], 34.1 [s, C-10], 44.3 [t, C-8], 74.6 [t, C-9, CHOH],
111.2 [t, C-7], 117.4 [q, C-3], 119.3 [t, C-5], 119.4 [t, C-4],
121.2 [t, C-6], 122.1 [t, C-2], 126.9 [q, C-3a], 136.4 [q,
C-7a]. HRMS: C14H17NO, calcd: 215.1311, obs.: 215.1288.
4.6.11. cis-3-(2-Hydroxycyclohexyl)-indole (cis-3j). Puri-
fied by filtration through a short column of silica using
CH2Cl2 as eluent, 10% yield. Mp 110–1128C; lit.10 1158C.
IR (cm21): 3529, 3316, 3060, 2928, 2858, 1452, 1433,
1341, 1219, 984, 955, 767, 737, 681. Mass, m/z (%): 215
(Mþz, 98), 156 (55), 143 (16), 130 (100), 117 (11). 1H NMR
(300 MHz, CDCl3): d 1.4–2.1 [9H, m, CH2, OH], 3.14 [1H,
dt, H-8, J¼1.2, 11.4 Hz], 4.19 [1H, bs, H-9, CHOH], 7.03
[1H, dd, H-2 indole, J¼0.8, 2.4 Hz], 7.11 [1H, td, H-5,
J¼1.1, 7.0 Hz], 7.20 [1H, td, H-6, J¼1.1, 7.0 Hz], 7.35 [1H,
m, H-7], 7.62 [1H, m, H-4], 8.15 [1H, bs, NH]. 13C NMR
(75.5 MHz, CDCl3): d 19.7 [s, C-11], 25.0 [s, C-12], 26.2 [s,
C-13], 31.8 [s, C-10], 39.5 [t, C-8], 68.2 [t, C-9, CHOH],
111.1 [t, C-7], 118.2 [q, C-3], 118.8 [t, C-5], 119.2 [t, C-4],
121.5 [t, C-6], 122.2 [t, C-2], 126.3 [q, C-3a], 136.4 [q, C-7a].
4.6.8. 3-(2-Phenyl-2-hydroxyethyl)-4,6-dibromoindole
(3h). Purified by filtration through a short column of silica
using CH2Cl2 as eluent, 88% yield. Mp 151–1528C. IR
(cm21): 3501, 3233, 3024, 2940, 1610, 1537, 1395, 1319,
1191, 1167, 1049, 999, 804, 746, 699. Mass, m/z (%): 397
(Mþz, C16H Br2NO, 5), 395 (Mþz, C16H
Br2NO, 11),
81
79,81
13
79
13
13
393 (Mþz, C16H Br2NO, 6), 377 (46), 288 (100), 217 (21),
207 (10), 189 (7), 128 (22), 107 (26), 79 (18). H NMR
1
(300 MHz, CDCl3): d 2.08 [1H, bs, OH], 3.15 [1H, dd, H-8,
J¼9.0, 14.6 Hz], 3.60 [1H, dd, H-80, J¼4.1, 14.6 Hz], 5.11
[1H, dd, H-9, J¼4.1, 9.0 Hz], 7.02 [1H, 0d, H-2, J¼2.2 Hz],
7.29–7.50 [7H, m, H-5, 7, 11, 110, 12, 12 , 13], 8.18 [1H, bs,
NH]. 13C NMR (75.5 MHz, CDCl3): d 36.4 [s, C-8], 74.6 [t,
C-9, CHOH], 113.7 [q, C-3], 113.8 [t, C-7], 114.9 [q, C-4],
115.4 [q, C-6], 124.7 [q, C-10], 125.9 [t, C-2], 126.2 [t, C-5],
127.0 [t, C-11], 127.8 [t, C-13], 128.6 [t, C-12], 138.3 [q,
C-3a], 144.2 [q, C-7a]; FAB-MS: C16H13Br2NO, calcd:
392.9364, 394.9343, 396.9323, obs.: 396.9360, 392.9352,
394.9345. Elemental analysis: C16H13Br2NO, calcd: C:
48.64, H: 3.32, N: 3.55, obs.: C: 48.35, H: 3.35, N: 3.39.
4.6.12. 3-(3,3-Dimethyl-2-hydroxybutyl)-indole (3k).
Purified by filtration through a short column of silica
using CH2Cl2 as eluent, 82% yield. Mp 121–1228C; lit.
125–126;22 120–1228C.24a IR (cm21): 3537, 3419, 3266,
2922, 2862, 1619, 1456, 1234, 1100, 1064, 1003, 737. Mass,
m/z (%): 217 (Mþz, 15), 130 (100), 118 (4), 103 (4), 77 (6).
1H NMR (300 MHz, CDCl3): d 1.05 [9H, s, H-11, t-butyl],
1.67 [1H, s, OH], 2.63 [1H, dd, H-8, J¼10.9, 14.3 Hz], 3.10
[1H, bd, H-80, J¼14.3 Hz], 3.56 [1H, dd, H-9, J¼1.8,
10.9 Hz], 7.07 [1H, d, H-2, J¼1.5 Hz], 7.12 [1H, td, H-5,
J¼1.0, 7.4 Hz], 7.21 [1H, td, H-6, J¼1.0, 7.5 Hz], 7.29 [1H,
bd, H-7, J¼8.0 Hz], 7.60 [1H, bd, H-4, J¼7.8 Hz], 8.07
[1H, bs, NH]. 13C NMR (75.5 MHz, CDCl3): d 26.1 [p,
C-11, t-butyl], 28.1 [s, C-8], 34.9 [q, C-10], 78.9 [t, C-9,
CHOH], 111.5 [t, C-7], 113.5 [q, C-3], 119.1 [t, C-5], 119.6
[t, C-4], 122.4 [t, C-6], 122.9 [t, C-2], 127.6 [q, C-3a], 136.8
[q, C-7a]. Elemental analysis: C14H19NO, calcd: C: 77.38,
H: 8.81, N: 6.45, obs.: C: 77.47, H: 8.99, N: 6.20.
4.6.9. 3-(2-Phenyl-2-hydroxyethyl)-5,7-dibromoindole
(3i). Purified by filtration through a short column of silica
using CH2Cl2 as eluent, 90% yield. Mp 120–1218C. IR
(cm21): 3502, 3416, 3329, 3065, 3029, 2922, 2879, 1638,
1556, 1463, 1188, 1111, 1053, 700. Mass, m/z (%): 397
(Mþz, C16H Br2NO, 6), 395 (Mþz, C16H
Br2NO, 13),
81
79,81
13
79
13
393 (Mþz, C16H Br2NO, 7), 377 (13), 288 (100), 207 (19),
13
128 (32), 107 (41), 79 (39). 1H NMR (300 MHz, CDCl3): d
2.10 [1H, bs, OH], 3.11 [1H, bd, H-8, J¼3.0 Hz], 3.13 [1H,
bs, H-80], 4.96 [1H, t, H-9, J¼6.5 Hz],0 7.05 [1H, d, H-2,
J¼2.3 Hz], 7.31–7.38 [5H, m, H-11, 11 , 12, 120, 13], 7.47
[1H, d, H-6, J¼1.5 Hz], 7.58 [1H, d, H-4, J¼1.5 Hz], 8.25
[1H, bs, NH]. 13C NMR (75.5 MHz, CDCl3): d 35.8 [s, C-8],
74.3 [t, C-9, CHOH], 105.3 [q, C-7], 112.7 [q, C-5], 113.4
[q, C-3], 121.2 [t, C-4], 125.0 [t, C-2], 126.1 [t, C-6], 126.9
[t, C-11], 128.0 [t, C-13], 128.7 [t, C-12], 130.1 [q, C-10],
134.0 [q, C-3a], 144.0 [q, C-7a, CN]. Elemental analysis:
C16H13Br2NO, calcd: C: 48.64, H: 3.32, N: 3.55, obs.: C:
48.35, H: 3.35, N: 3.39.
4.6.13. 3-(3,3-Dimethyl-2-hydroxybutyl)-N-methylindole
(3l). Purified by filtration through a short column of silica
using CH2Cl2 as eluent, 80% yield. Mp 49–508C. IR
(cm21): 3564, 3057, 2953, 2863, 1482, 1358, 1327, 1252,
1153, 1122, 1069, 1005, 821, 735. Mass, m/z (%): 231 (Mþz,
9), 144 (100), 84 (6), 77 (6). 1H NMR (300 MHz, CDCl3): d
1.04 [9H, s, H-11, t-butyl], 1.65 [1H, s, OH], 2.65 [1H, dd,
H-8, J¼10.9, 14.3 Hz], 3.08 [1H, dd, H-80, J¼1.5, 14.3 Hz],
3.53 [1H, dd, H-9, J¼1.5, 10.9 Hz], 3.75 [3H, s, H-12,
NCH3], 6.96 [1H, s, H-2], 7.11 [1H, td, H-5, J¼1.1, 7.6 Hz],
7.24 [1H, td, H-6, J¼1.0, 7.6 Hz], 7.30 [1H, bd, H-7,
J¼7.6 Hz], 7.59 [1H, bd, H-4, J¼7.6 Hz]. 13C NMR
(75.5 MHz, CDCl3): d 26.1 [p, C-11, t-butyl], 28.0 [s,
C-8], 32.8 [p, C-12], 34.9 [q, C-10], 79.1 [t, C-9, CHOH],
109.5 [t, C-7], 111.9 [q, C-3], 119.0 [t, C-5], 119.2 [t, C-4],
122.0 [t, C-6], 127.7 [t, C-2], 128.3 [q, C-3a], 137.5 [q,
C-7a, C–N]. Elemental analysis: C15H21NO, calcd: C:
77.88, H: 9.15, N: 6.05, obs.: C: 77.74, H: 8.93, N: 5.88.
4.6.10. trans-3-(2-Hydroxycyclohexyl)-indole (trans-3j).
Purified by filtration through a short column of silica using
CH2Cl2 as eluent, 80% yield. Mp 157–1608C; lit. 157;54
160–162;13d 166–1698C.10 IR (cm21): 3488, 3249, 3057,
2925, 2853, 1442, 1221, 1106, 1026, 947, 868, 797, 734.
Mass, m/z (%): 215 (Mþz, 62), 197 (10), 168 (8), 156 (49),
143 (17), 130 (100), 117 (14). 1H NMR (300 MHz, CDCl3):
d 1.43–2.08 [8H, m, CH2 cyclohexanol], 2.18 [1H, bs, OH],
2.75 [1H, ddd, H-8 cyclohexanol, J¼3.5, 10.0, 12.2 Hz],
3.78 [1H, td, H-9, CHOH, J¼4.3, 10.0 Hz], 7.06 [1H, d, H-2
indole, J¼2.4 Hz], 7.14 [1H, td, H-5, J¼1.1, 7.5 Hz], 7.22
[1H, td, H-6, J¼1.1, 7.5 Hz], 7.36 [1H, bd, H-7, J¼7.5 Hz],
4.6.14. 3-(2-Phenyl-2-hydroxyethyl)-N-benzylindole
(3m). Purified by filtration through a short column of silica

S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
8409
using CH2Cl2 as eluent, 80% yield. Obtained as an oil. IR
(cm21): 3547, 3404, 3060, 3029, 2914, 1614, 1495, 1467,
1454, 1357, 1333, 1200, 1182, 1047, 1028, 1014, 740, 700.
Mass, m/z (%): 327 (Mþz, 7), 309 (28), 279 (10), 220 (81),
1454, 1357, 1333, 1177, 1044, 740, 700. Mass, m/z (%): 251
(Mþz, 20), 220 (43), 129 (15), 102 (10), 91 (100), 65 (15). 1H
NMR (300 MHz, CDCl3): d 1.73 [1H, bs, OH], 3.00 [2H, t,
H-8, J¼6.4 Hz], 3.85 [2H, t, H-9, J¼6.4 Hz], 5.22 [2H, s,
H-10, CH2 benzyl], 6.96 [1H, s, H-2], 7.07–7.26 [8H, m,
CH aromatic], 7.61 [1H, bd, H-4, J¼6–7 Hz]. 13C NMR
(75.5 MHz, CDCl3): d 28.9 [s, C-8], 50.0 [s, C-10], 62.8 [s,
C-9, CH2OH], 109.9 [t, C-7], 111.6 [q, C-3], 119.2 [t, C-5],
119.3 [t, C-4], 122.1 [t, C-6], 126.8 [t, C-12], 127.0 [t,
C-13], 127.8 [t, C-2], 128.3 [q, C-3a], 128.9 [t, C-14], 137.0
[q, C-11], 137.7 [q, C-7a].
1
167 (22), 149 (84), 91 (100), 71 (34). H NMR (300 MHz,
CDCl3): d 2.13 [1H, d, OH, J¼2.7 Hz], 3.11 [1H, dd, H-8,
J¼8.6, 14.5 Hz], 3.23 [1H, dd, H-80, J¼4.6, 14.5 Hz], 5.00
[1H, dd, H-9, J¼4.6, 8.6 Hz], 5.26 [2H, s, H-14, CH2
benzilic], 6.92 [1H, s, H-2], 7.07–7.41 [13H, m, CH
aromatic], 7.63 [1H, d, H-4, J¼7.4 Hz]. 13C NMR
(75.5 MHz, CDCl3): d 36.1 [s, C-8], 50.1 [s, C-14], 74.2
[t, C-9, CHOH], 110.0 [t, C-7], 111.2 [q, C-3], 119.3 [t,
C-5], 119.5 [t, C-4], 122.2 [t, C-6], 126.1 [t, C-11], 127.0 [t,
C-16], 127.4 [t, C-17], 127.7 [t, C-13], 127.8 [t, C-2], 128.4
[q, C10], 128.6 [t, C-12], 129.0 [t, C-18], 136.9 [q, C-15],
137.7 [q, C-3a], 144.3 [q, C-7a]. Elemental analysis:
C23H21NO, calcd: C: 84.37, H: 6.46, N: 4.28, obs.: C:
83.95, H: 6.28, N: 4.03.
4.6.18. 3-(N-Benzyl-2-hydroxyethyl)-7-ethylindole (3s).
Purified by filtration through a short column of silica using
1
CH2Cl2 as eluent, 82% yield. Obtained as an oil. H NMR
(300 MHz, CDCl3): d 1.28 [3H, t, H-11, J¼7.5 Hz], 2.88
[2H, q, H-10, J¼7.5 Hz], 3.06 [2H, t, H-8, J¼6.4 Hz], 3.94
[2H, t, H-9, J¼6.4 Hz], 5.53 [2H, s, CH2 benzyl], 6.96 [3H,
m, CH aromatic], 7.02 [1H, d, H-2, J¼7.5 Hz], 7.12 [1H, t,
CH, J¼7.5 Hz], 7.28 [3H, m, CH aromatic], 7.54 [1H, d,
H-4, J¼7.5 Hz]. 13C NMR (75.5 MHz, CDCl3): d 16.2 [p,
C-11], 25.4 [s, C-10], 28.8 [s, C-8], 52.3 [s, C-12], 62.7 [s,
C-9], 111.7 [q, C-3], 117.1 [t, CH], 119.8 [t, CH], 123.3 [t,
CH], 125.7 [t, CH], 127.5 [t, CH], 127.9 [q, C-3a], 128.9 [t,
CH], 129.0 [t, CH], 129.6 [q, C-7], 134.9 [q, C-13], 139.6 [q,
C-7a].
4.6.15. 3-(2,3-Dihydroxybutyl)-indole (3n). Purified by
filtration through a short column of silica using CH2Cl2 as
eluent, 83–5% yield. Obtained as a colourless oil. IR
(cm21): 3411, 3057, 2972, 2924, 1705, 1619, 1457, 1339,
1230, 1050, 743. Mass, m/z (%): 205 (Mþz, 21), 160 (3), 130
(100), 118 (5), 103 (3), 77 (4). 1H NMR (300 MHz, CDCl3):
d 1.29 [3H, d, H-11, J¼6.1 Hz, major isomer], 1.29 [3H, d,
H-11, J¼6.3 Hz, minor isomer], 2.39 [1H, bs, OH], 2.64
[1H, bs, OH], 2.82 [1H, dd, H-8, J¼8.2, 14.6 Hz, major
isomer], 2.85 [1H, d, H-8, J¼10.2 Hz, minor isomer], 3.01
[1H, d, H-80, J¼3.2 Hz, minor isomer], 3.05 [1H, dd, H-80,
J¼3.8, 14.6 Hz, major isomer], 3.65–3.77 [2H, m, H-9 and
H-10, major isomer], 3.88–3.92 [2H, m, H-9 and H-10,
minor isomer], 7.04 [1H, d, H-2, J¼2.4 Hz], 7.16 [1H, td,
H-5, J¼1.2, 7.5 Hz], 7.22 [1H, td, H-6, J¼1.2, 7.5 Hz], 7.36
[1H, bd, H-7, J¼7.5–8.0 Hz], 7.62 [1H, bd, H-4, J¼7.5–
8.0 Hz], 8.25 [1H, bs, NH]. 13C NMR (75.5 MHz, CDCl3): d
major isomer 19.3 [p, C-11], 29.4 [s, C-8], 70.1 [CHOH],
75.3 [CHOH], minor isomer 17.2 [p, C-11], 27.3 [s, C-8],
69.7 [CHOH], 74.4 [CHOH], aromatic carbons 111.2 [t,
C-7], 111.4 [q, C-3], 118.7 [t, C-5], 119.4 [t, C-4], 122.1 [t,
C-6], 122.8 [t, C-2, CH minor isomer], 122.9 [t, C-2, CH
major isomer], 127.3 [q, C-3a], 136.2 [q, C-7a, CN]. HRMS:
C12H15NO2, calcd: 205.1103, obs.: 205.1120.
4.6.19. 3-(2-Hydroxyethyl)-7-ethylindole8a (3t). Purified
by filtration through a short column of silica using CH2Cl2
as eluent, 78% yield. Obtained as an oil that solidified, mp
47–488C. IR (cm21): 3399, 3057, 2960, 2926, 2865, 1613,
1494, 1436, 1344, 1221, 1094, 1048, 1006, 820, 797, 747.
1H NMR (200 MHz, CDCl3): d 1.39 [3H, t, H-11, J¼
7.6 Hz], 2.88 [2H, q, H-10, J¼7.6 Hz], 3.06 [2H, t, H-8,
6.3], 3.93 [2H, t, H-9, J¼6.3 Hz] 7.12 [3H, m, CH], 7.51
[1H, dd, CH, J¼1.6, 7.0 Hz], 8.12 [1H, bs, NH]. 13C NMR
(50 MHz, CDCl3): d 14.0 [p, C-11], 24.2 [s, C-10], 29.0 [s,
C-8], 62.8 [s, C-9], 112.8 [q, C-3], 116.7 [t, CH], 119.9 [t,
CH], 120.9 [t, CH], 122.4 [t, CH], 126.8 [q, C], 127.3 [q, C],
135.5 [q, C-7a].
4.7. Isolation of the intermediate diols (5a and 5m)
4.7.1. 3-(2-Hydroxypropyl)-3-hydroxy-2-oxindole (5a).
Compound 5a was obtained when the aldol derivative 2a
was treated with a deficiency of BH3·THF (2 mol equiv.)
in anhydrous THF. The crude product was isolated as
described in the general tryptophol synthesis procedure and
the mixture of products was separated by silica gel
chromatography. The tryptophol 3a and the diol 5a were
separated using a solvent gradient of CH2Cl2/EtOAc (9:1,
8:2, 7:3 v/v) where 3a was eluted first in 72% yield followed
by 5a in 21% yield, mp 194–1958C. IR (cm21): 3417, 3239,
2972, 2934, 2909, 1708, 1624, 1475, 1189, 619. Mass, m/z
(%): 207 (Mþz, 34), 189 (11), 174 (28), 162 (27), 149 (79),
4.6.16. 3-(2-Hydroxyethyl)-N-methylindole56 (3q). Puri-
fied by filtration through a short column of silica using
CH2Cl2 as eluent, 87% yield. Obtained as a slight yellow oil.
IR (cm21): 3363, 3053, 2928, 1726, 1642, 1473, 1378,
1328, 1248, 1045, 740. Mass, m/z (%): 175 (Mþz, 24), 144
(100), 115 (4), 102 (4), 77 (5). 1H NMR (200 MHz, CDCl3):
d 1.69 [1H, bs, OH], 2.99 [2H, t, H-8, J¼6.35 Hz], 3.72 [3H,
s, H-10, N–CH3], 3.86 [2H, t, H-9, O–CH2, J¼6.35 Hz],
6.91 [1H, s, H-2], 7.10 [1H, ddd, H-5, J¼1.6, 6.5, 7.0 Hz],
7.24 [2H, m, H-6 e H-7], 7.58 [1H, d, H-4, J¼7.0 Hz]. 13C
NMR (50 MHz, CDCl3): d 28.8 [s, C-8], 32.7 [p, C-10,
N–CH3], 62.9 [s, C-9, CH2OH], 109.4 [t, C-7], 110.8 [q,
C-3], 119.0 [t, C-5], 119.1 [t, C-4], 121.9 [t, C-6], 127.4 [t,
C-2], 128.0 [q, C-3a], 137.3 [q, C-7a].
1
146 (100), 120 (81), 92 (38), 77 (17), 65 (32). H NMR
(300 MHz, CDCl3, DMSO-d6): d 0.99 [3H, d, H-10,
J¼6.2 Hz], 1.69 [1H, dd, H-8, J¼2.8, 14.1 Hz], 2.03 [1H,
dd, H-80, J¼9.7, 14.1 Hz], 3.97 [1H, m, H-9], 4.44 [1H, d,
C9–OH, J¼4.2 Hz], 6.05 [1H, bs, C3–OH], 6.74 [1H, d,
H-7, J¼7.7 Hz], 6.91 [1H, td, H-5, J¼1.2, 7.7 Hz], 7.09
[1H, td, H-6, J¼1.2, 7.7 Hz], 7.19 [1H, d, H-4, J¼7.7 Hz],
9.90 [1H, bs, NH]. 13C NMR (75.5 MHz, CDCl3,
4.6.17. 3-(2-Hydroxyethyl)-N-benzylindole56 (3r). Puri-
fied by filtration through a short column of silica using
CH2Cl2 as eluent, 90% yield. Obtained as an oil. Lit.57 538C.
IR (cm21): 3368, 3056, 3029, 2927, 1614, 1496, 1467,

8410
S. J. Garden et al. / Tetrahedron 58 (2002) 8399–8412
DMSO-d6): d 23.2 [p, C-10], 44.5 [s, C-8], 61.9 [t, C-9],
74.2 [q, C-3], 108.5 [t, C-7], 120.3 [t, C-5], 122.6 [t, C-6],
127.6 [t, C-4], 131.0 [q, C-3a], 140.5 [q,C-7a], 178.6 [q,
C-2]. Elemental analysis: C11H13NO3, calcd: C: 63.76, H:
6.32, N: 6.76, obs.: C: 63.93, H: 6.11, N: 6.20. HRMS:
C11H13NO3, calcd: 207.0896, obs.: 207.0872.
J¼2.1, 14.9 Hz], 2.07 [major 1H, dd, H-8, J¼10.1,
14.8 Hz], 2.23 [major 1H, dd, H-8, J¼10.7, 14.8 Hz], 3.16
[minor 3H, s, N–CH3], 3.18 [major 3H, s, N–CH3], 4.44
[both isomers 1H, m, H-9], 6.82 [1H, t, J¼7.5 Hz], 7.11
[1H, m], 7.30–7.48 [2H, m]. 13C NMR (50 MHz, CDCl3): d
22.8, 23.2 [CH3], 26.4, 26.5 [CH3], 45.1, 45.2 [CH2], 64.6,
64.8 [CH], 76.3, 76.5 [C3], 108.5, 108.8 [CH], 123.4 [CH],
124.0, 124.4 [CH], 129.7, 129.8 [CH], 131.0, 131.4 [C3a],
142.9 [C7a], 178.5, 178.7 [CvO].
4.7.2. 3-(2-Phenyl-2-hydroxyethyl)-3-hydroxy-N-benzyl-
2-oxindole (5m). Compound 5m was obtained in a similar
manner to compound 5a when the aldol derivative 2m was
treated with a deficiency of BH3·THF. The products were
purified by silica gel column chromatography using a
CH2Cl2/EtOAc gradient (9:1, 8:2, 7:3 v/v) as eluent. The
tryptophol 3m was eluted first in 63% yield followed by
compound 5m, 25% yield, mp 143–1448C. IR (cm21):
3443, 3360, 3030, 2940, 1694, 1615, 1468, 1371, 1351,
1176, 1056, 756, 699. Mass, m/z (%): 359 (Mþz, 1), 252 (2),
239 (60), 162 (8), 161 (16), 146 (13), 133 (6), 105 (7), 92
(11), 91 (100), 77 (19), 65 (17). 1H NMR (200 MHz,
CDCl3): d 1.96 [1H, dd, H-8, J¼2.5, 15.5 Hz], 2.59 [1H, dd,
H-80, J¼11.0, 15.1 Hz], 3.40 [1H, d, C9–OH, J¼2.5 Hz],
4.84 [1H, d, H-14, J¼15.7 Hz], 4.95 [1H, d, H-140, J¼
15.7 Hz], 5.45 [1H, sl, C3–OH], 5.50 [1H, dd, H-9, J¼2.5,
11.0 Hz], 6.69 [1H, dd, H-7, J¼0.6, 7.7 Hz], 7.03 [1H, td,
H-5, J¼1.5, 7.7 Hz], 7.17 [1H, td, H-6, J¼1.5, 7.7 Hz],
7.2–7.4 [11H, m, CH aromatic]. 13C NMR (50 MHz,
CDCl3): d 43.9 [s, C-8], 45.9 [s, C-14], 70.8 [t, C-9, CHOH],
76.2 [q, C-3, COH], 109.6 [t, C-7], 123.4 [t, C-5], 123.9 [t,
C-6], 125.7 [t, C-16], 127.4 [t, C-17], 127.9 [t, C-11], 127.9
[t, C-12], 128.8 [t, C-18], 129.0 [t, C-4], 129.7 [t, C-13],
131.2 [q, C-3a], 135.7 [q, C-15], 142.1 [q, C-10], 144.1 [q,
C-7a], 178.5 [q, C-2, CvO, amide]. Elemental analysis:
C23H21NO3, calcd: C: 76.86, H: 5.89, N: 3.90, obs.: C:
76.90, H: 5.72, N: 3.79.
4.8.2. 3-Hydroxy-3-(2-hydroxy-2-phenylethyl)-N-benzyl-
2-oxindole (5m). Yield 97%, diastereomeric ratio 2:1; mp
120–1258C. IR (cm21): 3347, 3030, 2940, 1697, 1614,
1
1468, 1371, 1351, 1176, 755, 699. H NMR (200 MHz,
CDCl3): d 1.98 [major 1H, dd, H-8, J¼2.5, 15.0 Hz], 2.05
[minor 1H, dd, H-8, J¼2.5, 14.9 Hz], 2.49 [minor 1H, dd,
H-80, J¼10.5, 14.9 Hz], 2.61 [major 1H, dd, H-80, J¼11.1,
15.0 Hz], 4.76 [minor 1H, d, NCH2 benzylic, J¼15.5 Hz],
4.86 [major 1H, d, NCH2 benzylic, J¼15.6 Hz], 4.96 [major
1H, d, NCH2 benzylic, J¼15.6 Hz], 5.32 [minor 1H, dd,
H-9, J¼2.5, 10.5 Hz], 5.49 [major 1H, dd, H-9, J¼2.5,
11.1 Hz], 6.6–7.6 [14H, CH aromatic]. 13C NMR (50 MHz,
CDCl3): d 43.9, 44.1 [CH2], 45.8, 46.0 [CH2], 70.7, 71.3
[CH], 76.4, 76.6 [C3], 109.6, 109.9 [CH], 123.4, 123.5
[CH], 123.9, 124.5 [CH], 125.7, 126.1 [CH], 127.4 [CH],
127.85, 127.92 [CH], 128.68, 128.73 [CH], 129.00, 129.04
[CH], 129.7, 129.9 [CH], 130.7, 131.2 [C], 135.5, 135.7 [C],
142.1 [C], 143.8, 144.1 [C], 178.2, 178.5 [CvO].
Acknowledgements
We would like to thank Professors Vitor F. Ferreira
(Universidade Federal Fluminensce, Rio de Janeiro),
Francis J. Schmitz (University of Oklahoma) for the FAB
mass spectra, Marcus Eberlin (University of Campinas, Sa˜o
4.8. General experimental procedure for the synthesis of
the dioxindole diols (5b and 5m)
´
Paulo) for HRMS and Mario Vasconcellos (Nucleo de
Pesquisas em Produtos Naturais, Universidade Federal do
Rio de Janeiro) for the sample of 7-ethylisatin. In addition,
we would like to thank the CNPq (Brazilian National
The respective aldol derivatives (3.0 mmol) were solubilised/
suspended in anhydrous THF (10 ml) and cooled on an ice
water bath. A solution of BH3·THF (1 mol equiv.) was
slowly added to the reaction mixtures. The substrate was
observed to completely solubilise after a couple of minutes.
The reactions were left stirring in the cooling bath for an
hour after which time TLC (ethyl acetate/hexane) revealed
the consumption of the substrate with the formation of a
product of similar polarity and the absence of the respective
tryptophol.
`
Research Council), and the Fundac¸a˜o a Apoio de
Pesquisa do Estado de Rio de Janeiro, FAPERJ. SJG also
acknowledges the Fundac¸a˜o Fiocruz, Farmanguinhos
(PAPES II) for financial support.
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