Investigation of the selective reduction of isatin derivatives. Synthesis of α-hydroxyacetophenone derivatives and ethyl spiro-3,3-(ethylenedioxy)-2-hydroxyindoline carboxylates

Article abstract of DOI:10.1016/j.tetlet.2003.08.058

The product from the reduction of ethyl spiro-3,3-(ethylenedioxy)-2-oxindole carboxylates (1) using borohydride salts has been found to be dependant upon both solvent and metal ion. With polar solvents and lithium bromide/sodium borohydride, spiro-3,3-(ethylenedioxy)-2-hydroxyindole carboxylates (2) are obtained in high yields whilst [2-(2-hydroxymethyl-[1,3]dioxolan-2-yl)-phenyl]-carbamic acid ethyl esters (3) are obtained using sodium borohydride in less polar solvents.

Full text of DOI:10.1016/j.tetlet.2003.08.058

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7617–7621
Investigation of the selective reduction of isatin derivatives.
Synthesis of a-hydroxyacetophenone derivatives and ethyl
spiro-3,3-(ethylenedioxy)-2-hydroxyindoline carboxylates
Simon J. Garden,* Marilza B. Coˆrrea and Angelo C. Pinto
Departamento de Qu´ımica Orgaˆnica, Universidade Federal do Rio de Janeiro, Ilha do Funda˜o, Rio de Janeiro CEP 21945-970,
Brazil
Received 5 June 2003; revised 7 August 2003; accepted 15 August 2003
Abstract—The product from the reduction of ethyl spiro-3,3-(ethylenedioxy)-2-oxindole carboxylates (1) using borohydride salts
has been found to be dependant upon both solvent and metal ion. With polar solvents and lithium bromide/sodium borohydride,
spiro-3,3-(ethylenedioxy)-2-hydroxyindole carboxylates (2) are obtained in high yields whilst [2-(2-hydroxymethyl-[1,3]dioxolan-2-
yl)-phenyl]-carbamic acid ethyl esters (3) are obtained using sodium borohydride in less polar solvents.
© 2003 Elsevier Ltd. All rights reserved.
Isatin and its derivatives have proved to be versatile
starting materials for the synthesis of heterocyclic, and
non-cyclic, natural products, and analogues, as well as
for the synthesis of potentially important compounds
with biological activity.1 We have been interested in the
reduction of isatin derivatives as a means for the syn-
thesis of indoles, as isatin can be considered to be an
umpoled indole equivalent. We have shown that
acylisatins are reduced to the N-alkylindoles,2 3,3-
difluoro-2-oxindoles are reduced to 3-fluoroindoles,3
and isatin Aldol adducts are reduced to tryptophols in
excellent yields using THF solutions of BH3·THF.4
intermediates for the synthesis of 1,2-diols, 1,2-aminoal-
cohols, phenethylalcohols, or phenethylamines, many
of which posses important biological activities or
are used as, or in the preparation of, asymmetric lig-
ands.9–15
Our study began with the preparation of 1a by reaction
of isatin with ethylene glycol mixed with toluene and a
catalytic quantity of H2SO4, under conditions of
azeotropic removal of water using a Dean–Stark
apparatus. Compound 4 was subsequently treated with
a mixture of Et3N and ethyl chloroformate in CH2Cl2
to give 1a in 88% yield after workup (Scheme 2). The
In this present study, we have investigated the reduc-
tion of ethyl spiro-3,3-(ethylenedioxy)-2-oxindole carb-
oxylates (1) under various conditions. This study has
resulted in the determination of methodology for the
selective preparation of either ethyl spiro-3,3-(ethylene-
dioxy)-2-hydroxyindole carbamates (2) or [2-(2-hydroxy-
methyl-[1,3]dioxolan-2-yl)-phenyl]-carbamic acid ethyl
esters (3) (Scheme 1).
Scheme 1. Reduction of compounds 1.
Compounds 2 are potentially useful intermediates for
the synthesis of N-acyliminium ions and subsequent
reactions with nucleophilic species5–8 whilst a-hydroxy-
acetophenones (of which 3 are derivatives) are potential
Keywords: hydroxylactam; a-hydroxyacetophenone; isatin; reduction;
N-acyliminium precursor.
* Corresponding author. Tel.: +55-21-2562-7363; fax: +55-21-2562-
7256; e-mail: garden@iq.ufrj.br
Scheme 2. Synthesis of compound 1a. Reagents: a (CH2OH)2,
toluene, cat. H2SO4; b CH2Cl2, Et3N, ClCO2Et.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.058

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S. J. Garden et al. / Tetrahedron Letters 44 (2003) 7617–7621
Table 1. Reduction of compound 1a with metal borohydrides in solvents with different polarities
Table entry NaBH4
+additivea
Solventb
Ratio of
Mass
balance (%)
Table entry NaBH4
+additivea
Solventb
Ratio of
Mass
balance (%)
2a:3ac
2a:3ac
1
2
3
4
5
6
MeOH
EtOH
Et2O
THF
CH3CN
CH3CN
94:6
79
76
83
87
76
72
10
11
12
13
14
15
LiBr
LiBr
LiBr
CaCl2
CaCl2
CaCl2
EtOH
THF
CH3CN
MeOH
EtOH
23:77
42:58
100:0
90:10
38:62
91:9
90
73
80
72
90
70
20:80
12:88
12:88
75:25
93:7
1 mol.
equiv.
Li2CO3
Li2CO3
LiBr
THF, reflux
7
8
9
EtOH
THF
MeOH
40:60
40:60
75:25
76
82
83
16
17
18
ZnCl2
ZnCl2
ZnCl2
MeOH
EtOH
THF, reflux
28:72
19:81
99:1
82
84
69
a General experimental procedure: NaBH4 (2.0 mmol) was added to the respective solvent (20 ml) containing additive (2.0 mmol) whilst being
cooled on an ice water bath. After a few minutes the substrate (1.0 mmol) was added and the ice bath was removed. The reactions were allowed
to warm to room temperature and after two hours were hydrolysed with a small quantity of sat. aqueous NH4Cl, concentrated to remove the
volatile organic solvent and the residue extracted with ethyl acetate and sat. aqueous NaCl solution. The organic extract was dried over Na2SO4,
filtered and evaporated under reduced pressure.
b Room temperature unless otherwise stated.
c Ratios were determined by GC and GC–MS analysis of the crude products.
pyroglutarimide derivative with NaBH4 in EtOH in the
presence of HCl, standard conditions for the synthesis
of a-hydroxylactams.18 Chamberlin, in studies of
cationic cyclizations, reported that the use of MeOH as
solvent for the preparation of hydroxylactams was
superior to the EtOH/H2SO4 procedure.19 The addition
of various metal salt additives, but not lithium salts, to
the reduction of cyclic N-imidotryptamines in EtOH
using NaBH4 has been reported and the authors high-
lighted the use of CuCl2, CoCl2 and HgCl2 for the
obtention of tryptamine hydroxylactam derivatives.20
Evans and co-workers, as part of a synthesis of histri-
onicotoxin, found that the use of CH2Cl2 as solvent for
the Grignard addition to the magnesate of glutarimide
gave a quantitative yield of the hydroxyamide on
workup. In the absence of CH2Cl2 and using Et2O as
solvent they obtained a 1:1 mixture of the hydroxylac-
tam and the ring opened ketoamide.21 Quirion and
co-workers as part of work aimed at the synthesis of
bicyclic lactams also found the NaBH4/EtOH/HCl
methodology to be unsatisfactory whilst the use of the
NaBH4/MeOH method gave the desired product in
good yield.22
reduction of 1a was investigated using a number of
borohydride salts in various solvents. Table 1 details
these results.
A first analysis of the results presented in Table 1
reveals a reversal in reaction selectivity on changing the
solvent from methanol to ethanol (Table 1 entries 1/2,
9/10 and 13/14), with the exception of the use of ZnCl2
(Table 1 entries 16 and 17). Changing the solvent from
MeOH to acetonitrile continued the observed trend,
with respect to increasing the solvent polarity, and
greater yields of ring-closed product 2a were obtained.
The yield of 2a could be increased by decreasing the
number of mole equivalents of NaBH4 when using
acetonitrile as solvent (Table 1 entries 5 and 6). In the
case of LiBr, as an additive in acetonitrile, compound
2a was obtained exclusively (entry 12). It is also seen
that the use of less polar solvents (THF and Et2O)
generally had little effect upon the ratio of 2a:3a (com-
pare Table 1 entries: 2, 3, and 4, as well as 7 and 8, and,
10 and 11) with the exception of the use of ZnCl2, or
CaCl2, where a greater yield of ring closed product 2a
was observed (Table 1 entries 15 and 18). It should be
noted that the use of ZnCl2 or CaCl2 in THF required
that the reaction be refluxed in order to observe con-
sumption of the starting material.
The reduction of 1a is found to be highly regioselective
with the reduction of the endo carbonyl group to give
2a and 3a. This regioselectivity may be attributed to the
presence of the Lewis basic oxygen atoms of the spiro-
1,3-dioxolane ring which provide a unique co-ordinat-
ing environment for Lewis acidic cations. Thus, the
coordination of a Lewis acidic species to the endocyclic
amide carbonyl, facilitated by the neighbouring 1,3-
dioxolane ring, would serve to activate this carbonyl
group for regioselective reduction. This hypothesis was
tested in two separate reactions (Schemes 3 and 4). The
addition of compound 4 to a solution of NaBH4 in
EtOH resulted in a quantitative yield of 5 (Scheme 3).23
Similarly, with compound 6,24 reduction with NaBH4
and LiBr in acetonitrile resulted in 7 (Scheme 4). In
So far as we are aware there is no reported systematic
survey of solvent or metal ion effects on the reduction
of cyclic imides.5,16 There are however, various reports
that suggest that certain solvents, or methods, are
better than others for the obtention of the a-hydroxy-
lactams, precursors for the synthesis of N-acyliminium
ions.
Speckamp and co-workers reported the use of EtOH
with portion wise addition of HCl as a means for the
selective preparation of hydroxylactams.17 Altmann and
co-workers observed ring opening on treating a hydroxy-

S. J. Garden et al. / Tetrahedron Letters 44 (2003) 7617–7621
7619
group, that may play important roles in deciding the
reaction outcome, include complexation of Lewis acidic
species with the carbamate group. Such complexation
would be expected to facilitate solvolysis in protic
media or fragmentation of the respective alkoxides in
non-protic media, although in the latter case a more
polar non-protic solvent (CH3CN versus THF) could
help to stabilize the alkoxide metal ion pair. Ring
opening could be favoured by the formation of more
stable aggregates in less polar solvents due to relief of
ring strain and/or due to a more stable anion as a
consequence of resonance through the carbamate
structure.
Scheme 3. Reagents: a EtOH, NaBH4.
Based upon our findings, compounds 2b–d and 3b–c
were prepared from compounds 1b–d. The results are
summarized in Table 2 (Scheme 5).30 Under all condi-
tions tested, compound 1d gave only compound 2d
upon reduction. The bromine atom bonded to the
aromatic C-4 position may exert a steric interaction
with the dioxolane ring, thus favouring the a-hydroxy-
lactam structure of compound 2d.
Scheme 4. Reagents: a CH3CN, LiBr, NaBH4.
both cases, the reaction with borohydride salts resulted
in the cleavage of the exocyclic carbonyl group.
Our results (Table 1) indicate that the ratio of 2a to 3a
is both solvent and metal ion dependent. The effect of
temperature was minimized by performing all reactions
under equivalent conditions. Reduction of 1 by borohy-
dride in the alcoholic solution would be expected to
yield initially the respective metal alkoxide or borate
ester of 2.25,26 As there should be little difference
between the pKa values for the solvent and the product
then an equilibrium reaction with protonation of the
alkoxide of 2, or transesterification of the borate ester,
by the solvent will result in the formation of 2. Com-
pound 3 can be considered to be the result of ring
opening of product 2, or fragmentation of the metal
alkoxide of 2, and subsequent reduction of the exposed
aldehyde group. Both of these processes would be
expected to be dependent upon the stability of the
interaction with a Lewis acidic species in a given
solvent.27–29
In conclusion we have developed a method for the
regioselective synthesis of spiro-3,3-(ethylenedioxy)-2-
hydroxyindole carbamates (2) and [2-(2-hydroxymethyl-
[1,3]dioxolan-2-yl)-phenyl]-carbamates (3) from readily
available isatin derivatives.31 The regioselective reduc-
tion of the endocyclic carbonyl group is attributed to
assistance from the neighbouring dioxolane ring which
participates in the co-ordination of the Lewis acid thus
activating the carbonyl group and directing the reduc-
tion reaction. Compounds 2 are C-3 protected indoxyls,
analogous to compounds prepared from the oxidation
of indoles.32,33
Acknowledgements
Other factors, in addition to the electron withdrawing
inductive effect of the dioxolane ring, which would
increase the reactivity of the endocyclic amide carbonyl
The authors wish to thank FAPERJ and CNPq for
financial assistance in the development of this work.
S.J.G. also acknowledges the Fundac¸a˜o Oswaldo Cruz,
Farmanguinhos, Rio de Janeiro, for financial support
from the PAPES II program.
Table 2. Preparation of 2b–d and 3b,c
Entry
Substrate
Product 2 (%)a
Product 3 (%)b
1
2
3
1b
1c
1d
90
80
83
94
89
–
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7620
S. J. Garden et al. / Tetrahedron Letters 44 (2003) 7617–7621
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[CH2O], 65.2 [CH2O], 66.7 [CH2O], 86.5 [CH], 115.3
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m/z (%): 391 (M , 22), 335 (36), 275 (100), 245 (34). H
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7.1]; 13C NMR Pendant (50.32 MHz): l 14.7 [CH3], 62.6
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109.5 [C], 117.6 [CH], 128.8 [C], 133.7 [CH], 140.8 [CH],
141.9 [C], 153.0 [C]. Compound 2d, 2-Hydroxy-3,3-
(ethylenedioxy) - 4,6 - dibromo - 2,3 - dihydro - indole - 1 - car-
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Recrystallized
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30. Spectroscopic data: Compound 2a, 2-Hydroxy-3,3-
[ethylenedioxy]-2,3-dihydro-indole-1-carboxylic acid ethyl
ester: Recrystallized from hexane:CH2Cl2 (2:1); Colour-
less needle crystals, mp 99–100°C; IR (cm−1): 3433, 2978,
hexano:CH2Cl2; pale yellow cubes, mp 128–129°C; IR
(cm−1): 3435, 3130, 3083, 2974, 2898, 1716, 1592, 1571;
Mass m/z (%): 423 (M, 12), 367 (12), 307 (100), 277 (20);
1H NMR (200 MHz, CDCl3): l 8.01 [1H, bs], 7.39 [1H, d,
J 1.7], 5.35 [1H, s], 4.10–4.50 [6H, m], 1.40 [3H, t, J 7.1];
13C NMR Pendant (50.32 MHz): l 14.6 [CH3], 62.9
[CH2O], 66.1 [CH2O], 67.3 [CH2O], 86.9 [CH] 110.3 [C],
117.9 [CH], 120.0 [C], 123.3 [C], 126.5 [C], 130.2 [CH],
145.0 [C], 152.7 [C]. Compound 3a, [2-(2-Hydroxymethyl-
[1,3]dioxolan - 2 - yl) - phenyl] - carbamic acid ethyl ester:
Recrystallized from hexane:CH2Cl2; colourless needle
crystals, mp 115°C; IR (cm−1): 3467, 3365, 2990, 2961,
2909, 1713, 1593, 1541, 1241, 1032, 767; Mass m/z (%):
267 (M , 5), 236 (100), 190 (15), 146 (70); HRMS:
+
’
calculated for C13H17NO5: 267.1107, observed: 267.1104;
1H NMR (200 MHz, CDCl3): l 8.54 [1H, bs, NH], 8.07
[1H, d, J 8.1], 7.47 [1H, d, J 8.1], 7.33 [1H, t, J 8.1], 7.04
[1H, t, J 8.1], 4.22 [4H, m], 3.98 [2H, m], 3.76 [2H, d, J
6.1], 2.17 [1H, bt, OH], 1.32 [3H, t, J 7.0]; 13C NMR
Pendant (50.32 MHz): l 14.7 [CH3], 61.3 [CH2O], 65.39
[CH2O], 65.51 [CH2O], 110.1 [C], 121.0 [CH], 123.1 [CH],
126.5 [C], 127.3 [CH], 130.0 [CH], 136.8 [C], 154.0 [CꢀO].
Compound 3b, [2-(2-Hydroxymethyl-[1,3]dioxolan-2-yl)-4-
methylphenyl]-carbamic acid ethyl ester: Recrystallized
from hexane:CH2Cl2; pale yellow needles, mp 68–69°C;
IR (cm−1): 3375, 2981, 2957, 2921, 2900, 1732, 1596, 1525,
1234, 1062; Mass m/z (%): 281 (M , 5), 250 (100), 222
(10), 204 (30), 160 (60); H NMR (200 MHz, CDCl3): l
+
’
1
8.42 [1H, bs, NH], 7.94 [1H, d, J 8.6], 7.28 [1H, s, J 8.6],
7.16 [1H, d, J 8.6], 4.15 [4H, m], 4.10 [2H, m], 3.75 [2H,
s], 2.30 [3H, s], 2.14 [1H, bs, OH], 1.32 [3H, t, J 7.2]; 13C
NMR Pendant (50.32 MHz): l 14.7 [CH3], 20.9 [CH3],
61.2 [CH2], 65.3 [CH2], 65.5 [CH2], 110.1 [C], 121.2 [CH],
126.5 [C], 127.6 [CH], 130.5 [CH], 132.6 [C], 134.1
[C], 154.0 [C]. Compound 3c, [2-(2-Hydroxymethyl-
[1,3]dioxolan-2-yl)-4-iodophenyl]-carbamic acid ethyl ester:
Recrystallized from hexane:CH2Cl2; pale yellow
needles, mp 142°C; IR (cm−1): 3453, 3326, 3069, 2995,
2906, 1709, 1611, 1488, 1406, 1312, 1257, 992, 776; Mass
+
’
m/z (%): 265 (M , 12), 209 (18), 149 (100), 119 (55);
HRMS: calculated for C13H15NO5 265.0950, observed
1
265.0947; H NMR (200 MHz, CDCl3): l 7.72 [1H, d, J
8.1], 7.35 [2H, m], 7.05 [1H, t, J 8.1], 5.54 [1H, s],
4.05–4.40 [6H, m], 1.45 [3H, t, J 7.1]; 13C NMR Pendant
(50.32 MHz): l 14.7 [CH3], 62.4 [CH2], 65.2 [CH2O], 66.7
[CH2O], 86.3 [CH], 110.2 [C], 115.5 [CH], 123.6 [CH],
124.7 [CH], 126.2 [C], 132.1 [CH], 142.0 [C], 153.4 [C].
Compound 2b, 2-Hydroxy-3,3-(ethylenedioxy)-5-methyl-
2,3-dihydro-indole-1-carboxylic acid ethyl ester: Yellow
2957, 2902, 1715, 1583, 1530, 1244, 1080, 1039;
+
’
Mass m/z (%): 393 (M , 4), 362 (100), 316 (16), 272
oil. IR (cm−1): 3406, 2983, 2906, 1694, 1499, 1140, 1055,
(48); 1H NMR (200 MHz, CDCl3): l 8.49 [1H, bs,
NH], 7.77 [1H, d, J 8.7], 7.69 [1H, d, J 2.1], 7.50 [1H, dd,
J 8.7, 2.1], 4.10 [4H, m], 3.93 [2H, m], 3.61 [2H, s],
+
’
829, 771; Mass m/z (%): 279 (M , 22), 223 (24), 163
1
(100), 133 (34); H NMR (200 MHz, CDCl3): l 7.65 [1H,

S. J. Garden et al. / Tetrahedron Letters 44 (2003) 7617–7621
7621
3.03 [1H, bs, OH], 1.22 [3H, t, J 7.1]; 13C NMR Pendant
(50.32 MHz): l 14.5 [CH3], 61.1 [CH2], 65.3 [CH2], 86.0
[C], 109.2 [C], 122.4 [CH], 129.3 [C], 135.8 [CH], 136.5
[C], 138.2 [CH], 153.5 [C-12].
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