Efficient, one-pot transformation of indoles into functionalized oxindole and spirooxindole systems under Swern conditions

Article abstract of DOI:10.1016/j.tet.2008.12.029

The reaction of indole derivatives bearing a 3- or 4-hydroxyalkyl chain with dimethylsulfoxide and oxalyl chloride under Swern conditions led to a one-pot, three-component process involving three different synthetic transformations, namely oxidation of indole to oxindole, introduction of a chlorine substituent at the oxindole C-3 position and substitution of the hydroxyl group in the side chain by chlorine, in good to excellent overall yields. The same conditions, applied to a 2-methylindole, afforded a 2-formylindole derivative oxidized at its side chain. The reaction starting from one indole with a 2-hydroxyalkyl chain furnished 3-(2-hydroxyalkyl)oxindoles. Finally, application of the Swern conditions to derivatives of indole-3-propionic or -butyric acid afforded 3-spirooxindole lactones.

Full text of DOI:10.1016/j.tet.2008.12.029

Tetrahedron 65 (2009) 1660–1672
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient, one-pot transformation of indoles into functionalized oxindole
and spirooxindole systems under Swern conditions
*
´
˜
´
Pilar Lopez-Alvarado, Judith Steinhoff, Sonia Miranda, Carmen Avendano, J. Carlos Menendez
´
´
Departamento de Qu´ımica Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of indole derivatives bearing a 3- or 4-hydroxyalkyl chain with dimethylsulfoxide and
oxalyl chloride under Swern conditions led to a one-pot, three-component process involving three
different synthetic transformations, namely oxidation of indole to oxindole, introduction of a chlo-
rine substituent at the oxindole C-3 position and substitution of the hydroxyl group in the side
chain by chlorine, in good to excellent overall yields. The same conditions, applied to a 2-methyl-
indole, afforded a 2-formylindole derivative oxidized at its side chain. The reaction starting from one
indole with a 2-hydroxyalkyl chain furnished 3-(2-hydroxyalkyl)oxindoles. Finally, application of the
Swern conditions to derivatives of indole-3-propionic or -butyric acid afforded 3-spirooxindole
lactones.
Received 10 November 2008
Received in revised form 5 December 2008
Accepted 10 December 2008
Available online 16 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
spirooxindole (5) systems, together with other synthetically valu-
able compounds (Scheme 1B). The transformation of indoles into
Dimethylsulfoxide is widely employed as an oxidant, most no-
tably in the transformation of primary alcohols into aldehydes.1 In
indole substrates where nucleophilic groups are tethered to the C-3
position, activated dimethylsulfoxide induces synthetically in-
teresting transformations. Thus, indole derivatives bearing a C-3
side chain with a nucleophilic group (1) may give tricyclic de-
rivatives 2, in a transformation that involves overall oxidation at the
C-2 position of indole. This behaviour has been found in the case of
tryptamine derivatives; for instance, the Swern reaction of N-ace-
tyltryptophan methyl ester gave 35% of compound 3, and this re-
action was rationalized as shown in Scheme 1A.2 When the same
oxindoles by dimethylsulfoxide under acidic conditions is well
known,4 although this reaction is not general due to the low sta-
bility of indole derivatives in acidic media and is not accompanied
by additional functionalization.
The transformation of indoles into highly functionalized
oxindoles is of considerable interest, since oxindole is a key
structural element in several bioactive natural products,5 in-
cluding the antifungal ascidian metabolite cynthichlorine,6 the
cell cycle inhibitor spirotryprostatin B,7 the antibiotic speradine8
and the MDR inhibitor and antimicrotubule agent N-methyl-
welwitindolinone C isothiocyanate (welwistatin)9,10 (Fig. 1). The
oxindole moiety is also present in large number of unnatural
compounds with pharmaceutical interest, including growth hor-
mone secretagogues,11 analgesic12 and antiinflammatory13 com-
pounds, and SNC active agents such as serotonergics14 and the
anti-Parkinson drug ropirinole.15 Most of these compounds bear
a variety of substituents at the oxindole C-3 position, and many of
them are 3-spirooxindoles.
reaction was performed on cyclo-(L-Trp-L-Pro), a similar cyclization
occurred but a methylthiomethyl group was introduced at C-4 of
indole; this side process could be prevented by using oxalyl chlo-
ride instead of the initially employed TFAA, and by carrying out the
reaction at ꢀ78 ꢁC, but the cyclized product was obtained in only
12% yield.
In this context, we report here in full3 our findings on the Swern
oxidation of compounds related to structures 1 where the side
chain nucleophile is an oxygen nucleophile, including
b
,
g- or
d-
2. Results and discussion
hydroxy and - or -carboxy groups. We show that a reaction
b
g
pathway alternative to that in Scheme 1A is possible, involving the
formation of highly functionalized 3-chlorooxindole (4) or 3-
The starting materials for our study were prepared according to
Scheme 2. Primary alcohol 7a was obtained from 1-methylindole-
3-carbaldehyde through a Wittig olefination–reduction sequence,
while compound 7b was prepared by the same strategy from 6b,
which was known in the literature.16 The secondary alcohols 7c–h17
came from an ytterbium triflate-catalyzed Michael reaction18 of
* Corresponding author. Tel.: þ34 91 3941840; fax: þ34 91 3941822.
´
E-mail address: josecm@farm.ucm.es (J. Carlos Menendez).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.029

P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
1661
B
This work
A
(CH2)n Cl
(CH2)n
(CH2)n
Cl
Swern
Ref. 2
N
R
Nu
N
R
HNu
N
R
O
1
2
4 (n = 3,4)
or
(CH2)n
HNu
Swern
O
CH3
N
R
H3C
H
H
S
CO2Me
Ac
CO2Me
Ac
O
Me2S-X
(CH2)n
1
HN
HN
H
N
H
N
H
Swern
n = 2
N
R
O
OH
O
CO2Me
5 (n = 2,3)
CH3
H
CO2Me
Ac
H3C
S
N
Ac
N
N
H
H
N
R
N
H
3 (35 %)
Scheme 1. Swern reactions of indoles bearing side-chain nucleophilic groups: comparison between the reactivity found for tryptamine derivatives (Ref. 2) and the results described
in this paper.
indoles 6c–f with the corresponding
a
,
b
-unsaturated ketones to
It is noteworthy that this unexpected transformation seems to
require the presence of the hydroxypropyl side chain since it was
not observed when simple indole derivatives (e.g., 3-methyl-
indole) were employed as starting materials. On this basis,
a rationalization for the formation of the observed products has
been proposed (Scheme 4). The initial reaction between the
nucleophilic C-3 position of indoles 7 and one of the sulfonium
species present in the reaction medium leads to the iminium
derivative 11, where the C-2 position is highly electrophilic and is
trapped by a second molecule of dimethylsulfoxide to give in-
termediates 12. The latter compounds would yield 13 by spi-
rocyclization, thus protecting the side chain hydroxyl group from
oxidation, and then 13 would be transformed into oxindole 14 by
reaction with a molecule of oxalyl chloride. Intermediate 14
would then undergo ring opening by attack of chloride anion to
the position adjacent to the oxonium group, giving 15,23 followed
by decarbonylation and decarboxylation of the oxalyl moiety. The
formation of minor products 10 can be explained by the possi-
bility that 12 may undergo oxidation of the secondary hydroxyl
rather than spirocyclization. This step would be followed by
displacement of a molecule of dimethyl sulfide from the C-3
position by a chloride anion and generation of the oxindole
carbonyl after elimination of HCl and SMe2.
An alternative pathway can be proposed (Scheme 5), in-
volving cyclization of the side-chain oxygen onto the iminium
cation function in 11 to give 16, followed by elimination of di-
methyl sulfide furnishing the fused pyrano[2,3-b]indole or oxe-
pino[2,3-b]indole systems 17. Further reaction of the indole C-3
position with the Swern reagent to give 18 followed by two final
steps involving nucleophilic attack by chloride with opening of
the oxygenated ring to give 19 and displacement of a second
molecule of dimethyl sulfide, would lead to the observed prod-
ucts 9.
give compounds 8c–h,19 followed by sodium borohydride re-
duction. Compound 7i was obtained by lithium aluminium hydride
reduction of commercially available 4-(3-indolyl)butyric acid, using
a slightly modified literature method.20
As shown in Scheme 3 and Table 1, the reaction between 3-(3-
hydroxyalkyl)indole derivatives 7a–g and 7i and dimethylsulf-
oxide under Swern conditions gave good to excellent yields of
oxindole derivatives 9, bearing chloro substituents at the C-3
position of both the oxindole and the side chain. In two cases (c
and d), these products were accompanied by small amounts of
the corresponding 3-chlorooxindole oxidized in the
g position of
the side chain (compounds 10c,d).21 Although we routinely
employed the standard Swern conditions, we found that addition
of triethylamine is unnecessary (for instance, compound 10f was
obtained in 88% yield in the absence of added base). In the cases
where R was different from hydrogen (c–g and i), compounds 9
were obtained as 2:1 to 3:1 diastereomeric mixtures that could
not be separated because column chromatography must be very
fast in order to avoid the hydrolysis of compounds 9. The one-pot
process leading to compounds 9 can be considered as a three-
component reaction22 because the final product incorporates
substantial structural elements from the indole substrate, oxalyl
chloride and dimethylsulfoxide (see the mechanistic discussion
below).
N
O
H
CO2CH3
O
Cl
Cl
O
N
CH3
N
H
CH3
Cl
O
N
H
H3CO
Cl
Cynthichlorine
In order to discriminate between these two mechanistic possi-
bilities, we submitted 2-(1-methyl-3-indolyl)ethanol (N-methyl
tryptophol, 20) to the Swern conditions because in this case the
intermediate corresponding to 13 would have a highly strained
spirooxetane structure, while that corresponding to 17 should be
much more easily formed and in fact it would be an analogue of the
species generated from N-acetyltryptamine, as previously men-
tioned.1 In the event, as shown in Scheme 6, this reaction did not
give a dichlorooxindole derivative, as would be expected if the
second mechanism was in operation, but instead afforded the
known24 oxindole 21 in 67% yield. This experiment leads us to
Spirotryprostatin A
H2C
H3C
H
CH3
O
SCN
CH3
H
O
N
CH3
Welwistatin
Figure 1. Structures of some biologically relevant 3-substituted oxindoles.

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P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
OH
R4
R4
CHO
i-iii
N
N
CH3
6a R4 = H
6b
4 = TBDPSOCH2
CH3
7a R4 = H
R
7b R4 = TBDPSOCH2
HO
O
R'
R'
O
H2C
R5
R5
R5
R
v
iv
R2
R2
R2
N
N
N
R1
R1 R2 R5 R'
R1
Cmpd. R1 R2 R5
6c Me
6d
6e
6f
R1
Comp. R1 R2 R5
8c Me
Yield, %
85
Comp.
7c
Yield, %
R'
H
H
Me
H
H
H
H
H
H
H
H
H
Me
Et
Me
78
82
78
83
99
72
H
H
H
H
H
Me
H
H
H
H
OMe
H
Me
H
H
H
H
H
7d Me
Me
Et 86
Me 85
Et 89
Me
Me
8d
OMe
H
7e
H
H
H
H
8e
8f
H
H
H
H
Me
H
7f
Et
8g
8h
7g
7h
OMe Me
96
73
H
Me
Me
OH
CO2H
vi
N
H
N
H
7i
Scheme 2. Synthesis of starting materials. Reagents and conditions: (i) for a: Ph3P]CHCO2Et, EtOH, rt, 90 min (98%, E/Z¼4:1); for b: same reagents, 110 ꢁC, 48 h (87%, E/Z¼6:1); (ii)
for a: H2, Pd/C, rt, 4 h (90%); for b: same reagents, 8.5 h (100%); (iii) for a: LiAlH4, THF, rt, 16 h (85%); for b: same conditions (88%); (iv) Yb(OTf)3, MeCN, rt, 16 h; (v) NaBH4, EtOH, rt,
45 min; (vi) LiAlH4, THF, rt, 14 h.
HO
nitrogen, followed by elimination of HCl, would give a fused dihy-
drofuran 24, which would be opened under the acidic workup
conditions (a similar acid-catalyzed ring opening has been de-
scribed for a 3a-hydroxy analogue of 22, presumably also through
an intermediate fused dihydrofuran,25 and also for the pyrane an-
alogue of this intermediate21b).
Cl
R
O
R4
R4
R
n
Cl
R
Cl
R5
R5
n
i
O
O
N
R1
N
N
CH3
R1
10c R = Me
7
9
10d R = Et
Cl
Scheme 3. Reagents and conditions: (i) DMSO, (COCl)2, ꢀ78 ꢁC, 10 min, then Et3N,
ꢀ78 ꢁC to rt, 1 h (method A); (ii) same conditions, without Et3N (method B).
Cl
HO
HO
CH3
CH3
H3C
R4
H3C
S
S
R
R
R4
n
n
R5
favour the first mechanism, although the second one cannot be
completely discarded since it can be argued that, due to their dif-
ferent ring sizes, intermediates 18 and 24 are not completely
equivalent in terms of their ability to react with activated DMSO.
The formation of 21 can be explained (Scheme 7) by the initial
generation of 22, analogous to 17. Elimination of dimethyl sulfide
from this intermediate to give 23, with assistance from the indoline
R5
H
CH3
CH3
CH3
CH3
N
N
O
S
O
S
R1
11
R1
Cl
Cl
12
- SMe2
Cl
R
R
O
O
(ClCO)
R4
1.
- HCl, 2
- SMe2
n
R4
2.
R5
O
Cl
n
O
Table 1
R5
H
CH3
Yields obtained in the synthesis of chlorooxindoles 9
O
N
O
S
N
R1
13 Cl
R1
R4
R5
R
n
Method
Yield
(%)
dr
CH3
Compd
R1
14
a
b
c
d
e
f
f
g
i
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
Me
Et
Me
Et
Et
Me
H
1
1
1
1
1
1
1
1
2
A
A
A
A
A
A
B
A
A
82
90
d
TBDPSOCH2
d
Cl
O
H
H
H
H
H
H
H
71a
73b
80
2:1
2:1
2:1
2:1
2:1
3:1
d
Cl
O
O
R
R4
n
R5
9
87
88
81
85
- CO
O
- CO2
N
R1
15
Scheme 4. First mechanistic proposal for the isolation of compounds 9.
a
Together with 15% of 10c.
Together with 12% of 10d.
b

P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
1663
7h
CH3
Cl
H3C
R4
S
R4
n
n
Cl
Cl
R5
R5
HO
H
R
R
HO
CH3
CH3
H3C
H3C
O
O
S
11
S
R
CH3
- HCl
N
N
H
- SMe2
R1
R1
17
16
CH2
- Et3NH+
N
N
H
(H3C)2SCl Cl
R1
11
CH3
Cl
Et3N
O
S
Cl
CH3
26
Cl
Cl
H3C
R4
CH3
CH3
S
R
H3C
S
- SMe2
R4
n
n
R5
R5
R
HO
HO
CH3
Et3N
9
CH3
S
O
O
- SMe2
N
N
Cl
R1
R1
18
H
H
O
19
CH2
CH3
- Et3NH+Cl-
N
H
O
S
N
Scheme 5. Alternative mechanistic rationale for the isolation of 9.
H
CH3
Cl
27
- SMe2
HO
CH3
OH
i
OH
O
H
O
Swern oxidation
25
N
H
N
N
28
CH3
CH3
20
21 (67%)
Scheme 9. Rationale for the oxidation of
a C2-methyl substituent under Swern
conditions.
Scheme 6. Transformation of N-methyltryptophol into 21 under Swern conditions.
Reagents and conditions: (i) DMSO, (COCl)2, ꢀ78 ꢁC, 10 min, then Et3N, ꢀ78 ꢁC to rt, 1 h.
In order to account for the formation of 25, we propose the
mechanism outlined in Scheme 9, where the initially generated
species 11 cannot evolve by addition of a DMSO molecule to the
occupied C-2 position and hence it is deprotonated by triethyl-
amine to yield 26, which then undergoes an allylic nucleophilic
displacement of dimethyl sulfide by a molecule of DMSO to give
sulfonium salt 27. This species has the same structure as the in-
termediate of the Swern oxidation and thus it is transformed into
aldehyde 28 following the usual mechanism involving a retro
hetero-ene type process. A final oxidation of the secondary
hydroxyl by the Swern reagent affords the observed product 25.
At this stage, we became interested in studying the application
of our conditions to indole-3-propionic and indole-3-butyric acid
derivatives. Some examples of oxidative cyclization of indole-3-
propionic acids are known in the literature, often initiated by the
addition of a halogenating reagent (e.g., N-bromosuccinimide) to
Cl
OH
CH3
Cl
Cl
H3C
S
(CH3)2SCl
O
O
- S(CH3)2
N
R
H
N
N
R
H
CH3
22
23
Et3N
20
- Et3NH Cl
OH
Aqueous acidic
workup
O
O
N
N
R
CH3
21
24
Scheme 7. Proposed mechanism for the isolation of compound 21.
CO2H
n
R1= H, n = 1
29a
R1 = CH3, n = 1
29b
For comparison purposes, and also in order to contribute to the
mechanistic study, we considered it relevant to examine the re-
action of compound 7h, bearing a C-2 methyl substituent and
therefore uncapable of generating an oxindole system. Exposure of
7h to standard Swern conditions gave a rather complex mixture of
products, from which only aldehyde 25 could be isolated in
a moderate 32% yield (Scheme 8).
R1 = H, n = 2
N
29c
R1
i
O
CO2H
HO
O
n
n
+
O
O
N
N
H
O
HO
H
CH3
CH3
Comp. n Yield, %
Comp. n Yield, %
30a
30b
30c
1
1
2
52
57
95
31a
31b
31c
1
1
2
36
35
0
i
CHO
CH3
N
N
H
H
7h
ii (100 %, in all cases)
25 (32 %)
Scheme 10. Transformation of
u
-(3-indolyl)alkanoic acids 29 in the presence of
DMSO–oxalyl chloride. Reagents and conditions: (i) DMSO, (COCl)2, ꢀ78 ꢁC, 20 min; (ii)
Scheme 8. Oxidation of 2-methylindole 7h to 2-formylindole 25. Reagents and con-
ditions: (i) DMSO, (COCl)2, ꢀ78 ꢁC, 10 min, then Et3N, ꢀ78 ꢁC to rt, 1 h.
H2SO4 (trace), CHCl3, rt, 8 h.

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P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
O
Cl
CH3
Cl
Cl
Cl
HO
HO
CH3
H3C
H3C
CO2CH2SCH3
S
S
O
O
Cl
O
n
n
n
n
O
H
O
29
CH3
CH3
N
N
CH3
CH3
N
N
R1
O
S
R1
R1
R1
O
S
Cl
Cl
R1
H
CH3
n
1
1
Comp.
33a
33b
33c
R1
H
Comp.
32a
n
34
H2O
1
1
2
- SMe2,
- HCl
- SMe2,- HCl,
- DMSO
HO
MeS
Cl
32b
CH3
H
Me2SCl Cl
Et3N
O
O
O
O
Figure 2. Side products isolated when the reaction of compounds 29 with DMSO–
oxalyl chloride was performed in the presence of triethylamine.
Cl
O
HO
n
n
O
H2C SMe
n
O
O
N
N
N
the indole C-3, a clear disadvantage of the method being the often
observed concomitant halogenation of the C-5 position.26 Alter-
R1
R1
R1
31
30
Cl
native methods include the use of very strong oxidants like Fe2þ
-
tert-butyl hydroperoxide27 and the very toxic thallium trinitrate.28
To our knowledge, only a few precedents of the use of dime-
thylsulfoxide for this transformation are known. The first one was
reported by Bu¨chi during his total synthesis of tryptoquivaline G,
where exposure of two N-acyltryptophan derivatives to DMSO–
trichloromethanesulfonyl anhydride at ꢀ20 ꢁC for 5 h gave the
corresponding five-membered spirolactones in ca. 65% yields, as
mixtures of diastereomers.29 Alternatively, both Casnati and Labroo
have employed a DMSO–tert-butyl bromide mixture (40 ꢁC, 1.5–
4.5 h) to obtain 3-spirolactones from tryptophan derivatives in
moderate to good yields.30
2 Me2SCl
CO2CH2SMe
Cl
n
2 SMe2
2 HCl
O
N
O
O
R1
33
HO
O
Cl
Cl
n
O
HO
n
Cl
Cl
O
N
N
R1
R1
35
32
Scheme 11. Mechanistic explanation of the results of the Swern reaction of
dolyl)alkanoic acids 29.
u-(3-in-
As shown in Scheme 10, when indole-3-propionic acids 29a,b
were submitted to the Swern conditions in the absence of triethyl-
amine, the reactions cleanly afforded mixtures of compound hy-
droxy acids 30a,b and spirolactones 31a,b.31 Indole-3-butyric acid
29c gave hydroxy acid 30c as the only product, in an excellent 95%
yield. The three hydroxy acids 30 were transformed into the corre-
sponding lactones 3132 in quantitative yield by exposure to a trace of
sulfuric acid in chloroform solution. This method for the synthesis of
indole-3-spirolactones compares very favourably with previously
existing ones in terms of yield, experimental convenience and use of
simple, inexpensive and non-toxic starting materials and catalysts.
On the other hand, as shown in Figure 2 and Table 2, the use of
our standard conditions (i.e., DMSO–oxalyl chloride in the presence
of triethylamine) led to more complex mixtures that contained
hydroxy acids 30, the corresponding lactones 31, dichlorolactones
32 and compounds 33, bearing a methylthiomethyl ester chain.
Compounds 31 must arise by spirocyclization from an intermediate
34, related to 12 (Scheme 11). This allows the formation of hydroxy
acids 30 from 34 and traces of water in the reaction medium or
during acidic workup. In both cases this reaction is accompanied by
elimination of HCl and dimethyl sulfide with concomitant genera-
tion of the oxindole carbonyl. The hydroxy acid/lactone ratio was
altered during silica gel chromatography, which, as expected,
favoured the lactonization reaction. In the reaction starting from
indole-3-butyric acid 29c (n¼2), because the equilibrium between
hydroxy acids and lactones is more favourable for the five-mem-
bered rings than for the six-membered ones, the only product
isolated was hydroxy acid 30c. In the presence of base, the
cyclization of 34 to 31 is probably favoured and a base-catalyzed
chlorination by the Swern reagent explains the isolation of dihalo-
lactones 32. This halogenation does not take place on lactones 31,
since a separate experiment showed that neither
-butyrolactone
nor -valerolactone reacted under our conditions, while aliphatic
acids (e.g., phenylacetic acid) gave the corresponding -dichloro
derivatives. Hence, we propose that compounds 32 come from the
lactonization of the -dichlorohydroxy acids 35. Finally, the iso-
g
d
a,a
a,a
lation of methylthiomethyl esters 33 in the presence of base can be
explained by a Pummerer-type reaction of the lactone carbonyl
oxygen with S-methyl methylenesulfonium chloride, generated by
deprotonation of chlorodimethylsulfonium chloride by triethyl-
amine, followed by ring opening after attack of the chloride anion.
Finally, we started a study on the application of the chemistry
previously described in this paper to more complex starting ma-
terials in an effort to achieve the synthesis of compounds con-
taining the welwistatin ABC core (Scheme 12). To this end, the
known16 compound 36 was hydrolyzed to 37 under basic condi-
tions. Application of the Swern oxidation protocol described here
afforded an 80% yield of hydroxy acid 38, which could not be
cyclized to the corresponding lactone under acid catalysis, as pre-
viously described for compounds 30, because these conditions led
only to a low yield of the unprotected derivative of the starting
material. After some unsuccessful attempts using other methods
found in the literature,30b,33 we discovered that the desired lacto-
nization to 39 could be effected in excellent yield by heating the
hydroxy acid in vacuo. We next planned to deprotect the hydroxyl
group in compound 39 in order to prepare a suitable precursor for
the preparation of a iodide using the excellent method described by
Olah from primary alcohols, trimethylsilyl chloride and sodium
iodide,34 but in this case the conventional conditions (tetrabutyla-
mmonium fluoride in THF) afforded only a low yield of the
expected product 40, together with hydroxy acid 38, which was
isolated as a tetrabutylammonium salt and comes from hydrolysis
of the lactone ring in 39. Since the intermediate of the Olah protocol
is a trimethylsilyl ether, we attempted, albeit unsuccessfully, the
direct reaction of 39 with sodium iodide. However, treatment of 39
with trimethylsilyl chloride and sodium iodide under the
Table 2
Results obtained in the reaction of compounds 29 with DMSO–oxalyl chloride in the
presence of triethylamine
Compd
R1
n
% 30
% 31
% 32
% 33
a
b
c
H
CH3
CH3
1
1
2
40
0
43
11
11
0
22
25
0
10
17
22

P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
1665
O
CO2H
CO2Et
i
TBDPSO
TBDPSO
TBDPSO
TBDPSO
CO2H
iii
O
HO
ii
O
O
N
N
N
N
CH3
CH3
CH3
CH3
37 (77 %)
36
39(91 %)
38 (80 %)
iv
O
v
O
O
O
O
CH3
O2N
I
N
O2N
HO
OCH3
HO
O
O
vii
vi
O
+
O
40 (48 %)
O
O
viii
N
N
N
N
CH3
43 (75 %)
CH3
CH3
41 (46 %)
CH3
42 (60 %)
40 (26 %)
+
38 as nBu4N salt (47 %)
Scheme 12. Reagents and conditions: (i) KOH, CH3OH, rt, 12 h; (ii) DMSO, (COCl)2, ꢀ78 ꢁC, 20 min; (iii) 110 ꢁC, 0.1 Torr, 8 h; (iv) TBAF, THF, rt, 16 h; (v) TMSCl, NaI, CH3CN, ꢀ78 ꢁC to rt,
7 h; (vi) NaNO2, urea, DMF, ꢀ38 ꢁC to ꢀ20 ꢁC, 2 h; (vii) MeONHMe$HCl, Me2AlCl, CH2Cl2, rt, 4 h; (viii) DBU, THF, t.a., 3 h (80%).
conditions normally employed for alcohols afforded equimolecular
amounts of the desired iodide 41 and alcohol 40, which was gen-
erated from the iodide during the purification process as verified by
examination of the NMR spectra of the crude reaction product.
Although the yield of 41 was only moderate and it could not be
further improved, the reaction did provide a sufficient amount of
the iodide to continue with our study. Treatment of this iodide 41
with sodium nitrite in DMF in the presence of urea to increase the
solubility of the nitrite35 afforded nitro derivative 42 in 60% yield,
accompanied again by a small amount of alcohol 40. Unfortunately,
all attempts to cyclize 42 to a compound related to the welwistatin
ABC fragment were unsuccessful. As an alternative, compound 42
was transformed into the Weinreb amide 43 by treatment with
O,N-dimethylhydroxylamine hydrochloride in the presence of
chlorodimethyl-aluminium,36 but again all attempts at the cycli-
zation of this material were unsuccessful. These failures at the cy-
clization stage notwithstanding the results summarized in Scheme
12 prove that the chemistry described in this paper is suitable for
the preparation of C-4 functionalized 3-spirooxindole systems.
Elmer Paragon 1000 FT-IR spectrophotometer, with all com-
pounds examined as films on a NaCl disk. NMR spectra were
obtained on
a
Bruker Avance instrument (250 MHz for 1H,
62.9 MHz for 13C), maintained by the Servicio de RMN, Uni-
versidad Complutense, with CDCl3 as solvent. Combustion ele-
mental analyses were determined by the Servicio de
´
Microanalisis Elemental, Universidad Complutense, using a Leco
932 CHNS microanalyzer.
4.2. 3-(1-Methyl-3-indolyl)propanol (7a)
To
a solution of 1-methylindole-3-carbaldehyde (1.333 g,
8.37 mmol) in ethanol (20 ml) was added carbethoxymethylene-
triphenylphosphorane (5.83 g, 16.7 mmol). The solution was heated
for 90 min in an oil bath at 90 ꢁC, under an argon atmosphere. The
ethanol was evaporated under reduced pressure and the residue was
dissolved in ethyl acetate (40 ml), which was washed with water
(3ꢂ20 ml). The organic phase was dried (Na2SO4) and evaporated,
and the residue was chromatographed on silica gel, eluting with
petroleum ether–ethyl acetate (gradient from 8:1 to 4:1), yielding
1.521 g (79%) of (E)-ethyl 3-(1-methyl-3-indolyl)prop-2-enoate and
0.369 g (19%) of the corresponding Z isomer. Data for the (E) isomer:
3. Conclusions
In conclusion, we have shown that Swern conditions, involving
the use of very simple and inexpensive reagents, allow the one-pot
transformation of indole derivatives with a C-3 alkyl chain bearing
mp 96 ꢁC. IR (NaCl): 1698.3 (C]O),1617.3 (C]C),1284.0 (C–O) cmꢀ1
.
1H NMR (CDCl3) 8.05–8.20 (m, 2H, H-4, H-10); 7.65–7.40 (m, 3H, H-
d
5,6,7); 7.44 (s, 1H, H-2); 6.62 (d, 1H, J¼15.9 Hz, H-20); 4.48 (q, 2H,
J¼7.1 Hz, CO2CH2CH3); 4.02 (s, 3H, NCH3); 1.56 (t, 3H, J¼7.1 Hz,
g- or d-hydroxy and b- or g-carboxy groups into synthetically
valuable, highly functionalized oxindole and spirooxindole sys-
tems. These findings constitute a significant addition to the grow-
ing list37 of non-conventional synthetic applications of activated
dimethylsulfoxide.
CO2CH2CH3) ppm. 13C NMR (CDCl3)
d 168.8 (CO2CH2CH3); 138.4 (C-
7a); 134.3 (C-10); 133.5 (C-20); 126.4 (C-3a); 123.3 (C-5); 121.6 (C-4);
121.0 (C-6); 112.9 (C-2); 112.5 (C-3); 110.3 (C-7); 60.4 (CO2CH2CH3);
33.6 (NCH3); 14.9 (CO2CH2CH3) ppm. Anal. Calcd for C14H15NO2: C,
73.36; H, 6.55; N, 6.11. Found:C, 73.02; H, 6.57; N, 5.96. Data for the (Z)
isomer: mp 94–96 ꢁC. IR (NaCl): 1699.7 (C]O),1623.9 (C]C), 1280.2
4. Experimental
4.1. General
(C–O) cmꢀ1. 1H NMR (CDCl3)
d
8.89 (s, 1H, H-2); 7.76 (d, 1H, J¼7.6 Hz,
H-4); 7.45–7.20 (m, 4H, H-5,6,7,10); 5.85 (d,1H, J¼12.5 Hz, H-20); 4.32
(q, 2H, J¼7.1 Hz, CO2CH2CH3); 3.80 (s, 3H, NCH3); 1.42 (t, 3H, J¼7.1 Hz,
All reagents were of commercial quality (Aldrich, Fluka, SDS,
Probus) and were used as received. Solvents (from SDS) were
dried and purified using standard techniques. Reactions were
monitored by thin layer chromatography, on aluminium plates
coated with silica gel with fluorescent indicator (SDS
CCM221254). Separations by flash chromatography were per-
formed on silica gel (SDS 60 ACC, 40–230 mesh). Melting points
were measured with a Reichert 723 hot stage microscope, and
are uncorrected. Infrared spectra were recorded on a Perkin
CO2CH2CH3) ppm. 13C NMR (CDCl3)
d 168.0 (CO2CH2CH3); 136.8
(C-7a); 135.8 (C-C-10); 135.3 (C-20); 129.6 (C-3a); 122.8 (C-5); 121.2
(C-4); 118.3 (C-6); 111.1 (C-2); 110.7 (C-3); 110.1 (C-7); 60.1
(CO2CH2CH3); 33.6 (NCH3); 14.9 (CO2CH2CH3). Anal. Calcd for
C14H15NO2: C, 73.36; H, 6.55; N, 6.11. Found: C, 73.63; H, 6.85; N, 5.91.
To
a solution of the E isomer described above (1.521 g,
6.64 mmol) in methanol (20 ml) was added 10% Pd–C (152 mg). The
suspension was stirred at room temperature for 4 h under a balloon
filled with hydrogen. Filtration through Celite and evaporation gave

1666
P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
1.525 g (100%) of ethyl 3-(1-methyl-3-indolyl)propanoate. The re-
4.3.4. 5-(3-Indolyl)-3-pentanone (8f)
action starting from the Z isomer or from an E–Z mixture gave an
Starting from 500 mg (4.27 mmol) of indole, a yield of 764 mg
(89%) of 8d was obtained. Spectral data were identical to those
published in Ref. 19c.
identical result. 1H NMR (CDCl3)
d
7.65 (d, 1H, J¼7.8 Hz, H-4); 7.35–
7.15 (m, 2H, H-6,7); 7.14 (t, 1H, J¼7.8 Hz, H-5); 6.89 (s, 1H, H-2); 4.16
(q, 2H, J¼7.1 Hz, CO2CH2CH3); 3.75 (s, 3H, NCH3); 3.12 (t, 2H,
J¼7.4 Hz, H-10); 2.72 (t, 2H, J¼7.5 Hz, H-20); 1.27 (t, 3H, J¼7.1 Hz,
4.3.5. 4-(5-Methoxy-3-indolyl)-2-butanone (8g)
CO2CH2CH3) ppm. 13C NMR (CDCl3)
d
173.9 (CO2CH2CH3); 137.4 (C-
Starting from 500 mg (3.39 mmol) of 5-methoxyindole, a yield
of 707 mg (96%) of compound 8g was obtained. Mp 110–112 ꢁC. IR
7a); 128.0 (C-3a); 126.7 (C-2); 121.9 (C-5); 119.1 (C-6); 113.9 (C-3);
109.6 (C-7); 60.7 (CO2CH2CH3); 35.7 (C-20); 32.9 (NCH3); 20.9 (C-
10); 14.6 (CO2CH2CH3) ppm. Anal. Calcd for C14H17NO2: C, 72.13; H,
7.36; N, 6.66. Found: C, 72.81; H, 7.52; N, 6.30.
(NaCl): 3365.9 (NH), 1703.5 (C]O) cmꢀ1. 1H NMR (CDCl3)
d 7.88 (br
s, 1H, NH); 7.23 (d, 1H, J¼7.8 Hz, H-40); 7.03 (d, 1H, J¼2.0 Hz, H-70);
6.97 (s, 1H, H-20); 6.85 (dd, 1H, J¼7.7 and 1.9 Hz H-60); 3.87 (s, 3H,
OCH3); 3.02 (t, 2H, J¼7.1 Hz, H-1); 2.84 (t, 2H, J¼7.1 Hz, H-2); 2.16 (s,
A
suspension of LiAlH4 (402 mg, 6.93 mmol) in dry THF
(10 ml), under an argon atmosphere, was externally cooled in an
ice bath. A solution of ethyl 3-(1-methyl-3-indolyl)propanoate
(400 mg, 1.73 mmol) in dry THF (6 ml) was added via cannula,
and the suspension thus obtained was stirred at room temper-
ature overnight. Excess LiAlH4 was destroyed by successive ad-
dition of ethyl acetate, water and solid NaHCO3. The suspension
obtained was filtered and the solid was washed with ethyl ace-
tate. The combined filtrates were dried (Na2SO4) and evaporated,
yielding 279 mg (85%) of compound 7a. IR (NaCl): 3364.2 (OH),
3H, H-4) ppm. 13C NMR (CDCl3) 209.6 (C-3); 154.2 (C-50); 131.8
d
(C-7a0); 127.9 (C-3a0); 122.7 (C-20); 115.0 (C-40); 112.5 (C-60); 112.4
(C-30); 100.9 (C-70); 56.3 (OCH3); 44.3 (C-2); 30.5 (NCH3); 19.7 (C-
10) ppm. Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45.
Found: C, 71.66; H, 6.79; N, 6.40.
4.3.6. 4-(2-Methyl-3-indolyl)-2-butanone (8h)
Starting from 500 mg (3.81 mmol) of 2-methylindole, a yield of
559 mg (73%) of compound 8h was obtained. Spectral data were
identical to those published in Ref. 19d.
1613.8 (C]C), 1471.9 (C]C), 1247.9 (C–O) cmꢀ1 1H NMR (CDCl3)
.
d
7.61 (d, 1H, J¼7.8 Hz, H-4); 7.45–7.20 (m, 2H, H-6,7); 7.10 (t, 1H,
J¼7.8 Hz, H-5); 6.87 (s, 1H, H-2); 3.75 (m, 2H, H-30); 3.73 (s, 3H,
NCH3); 2.89 (t, 2H, J¼7.3 Hz, H-10); 1.98 (quint, 2H, J¼7.5 Hz, H-
4.4. Reduction of Michael adducts (8). General procedure
20); 1.58 (br s, 1H, OH) ppm. 13C NMR (CDCl3)
d
137.4 (C-7a);
To a solution or suspension of the suitable compound 8 in eth-
anol (1 ml per 100 mg of substrate) was added an equimolecular
amount of sodium borohydride, in small portions, over 15 min. The
reaction mixture was stirred at room temperature for 30 min. It was
then poured on a mixture of water (10 ml) and 1 M aqueous HCl
(2 ml) and stirring was continued for another 10 min. The aqueous
phase was extracted with ethyl acetate (3ꢂ50 ml), which was dried
(Na2SO4) and evaporated, yielding the pure secondary alcohols 7c–
h. Compounds 7e17a and 7g17b were known in the literature. Data
for other compounds and previously unpublished characterization
data are given below.
128.1 (C-3a); 126.6 (C-2); 121.9 (C-5); 119.4 (C-4); 119.0 (C-6);
114.8 (C-3); 109.5 (C-7); 63.1 (C-30); 33.5 (C-20); 33.0 (NCH3); 21.6
(C-10) ppm. Anal. Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40.
Found: C, 75.89; H, 7.64; N, 7.14.
Compound 7b was prepared by a very similar route, which has
been described in Ref. 16.
4.3. Michael additions to indole derivatives. General
procedure
To a solution of the starting indole derivative and the suitable
enone (2.2 equiv) in CH3CN (1 ml per mmol of indole), under an
argon atmosphere, was added ytterbium(III) triflate (0.02 equiv).
The solution was stirred at room temperature for 14 h and filtered
through silica gel, eluting with a 10:1 petroleum ether–ethyl ace-
tate mixture or with CH2Cl2. Data for compounds 8c,19a 8e,19a 8f19c
and 8h19d were known in the literature. Characterization data for
previously unknown compounds are given below.
4.4.1. 4-(1-Methyl-3-indolyl)-2-butanol (7c)
Starting from 762 mg (3.8 mmol) of 8c, a yield of 874 mg (78%) of
compound 7c was obtained. IR (NaCl): 3379.3 (OH) cmꢀ1. 1H NMR
(CDCl3)
d
7.62 (d, 1H, J¼7.8 Hz, H-40); 7.35–7.20 (m, 2H, H-60,70); 7.11
(t, 1H, J¼6.9 Hz, H-50); 6.87 (s, 1H, H-20); 3.90 (q, 1H, J¼6.1 Hz, H-3);
3.75 (s, 3H, NCH3); 2.98–2.72 (m, 2H, H-4); 1.87 (q, 2H, J¼6.6 Hz, H-
2); 1.41 (br s, 1H, OH); 1.25 (d, 3H, J¼6.2 Hz, H-1) ppm. 13C NMR
(CDCl3) d
137.4 (C-7a0); 128.2 (C-3a0); 126.5 (C-20); 121.9 (C-50); 119.4
4.3.1. 4-(1-Methyl-3-indolyl)-2-butanone (8c)
(C-60); 119.0 (C-60); 115.0 (C-30); 109.6 (C-70); 68.2 (C-2); 40.0 (C-3);
33.0 (NCH3); 24.0 (C-4); 21.8 (C-1) ppm. Anal. Calcd for C13H17NO: C,
76.81; H, 8.43; N, 6.89. Found: C, 76.50; H, 8.42; N, 6.75.
Starting from 590 mg (4.5 mmol) of 1-methylindole, a yield of
762 mg (85%) of compound 8c was obtained. Spectral data were
identical to those published in Ref. 19a.
4.4.2. 5-(1-Methyl-3-indolyl)-3-pentanol (7d)
4.3.2. 1-(1-Methyl-3-indolyl)-3-pentanone (8d)
Starting from 500 mg (3.81 mmol) of 1-methylindole, a yield of
705 mg (86%) of compound 8b was obtained. IR (NaCl): 1713
Starting from 300 mg (1.40 mmol) of 8d, a yield of 247 mg (82%)
of compound 7d was obtained. IR (NaCl): 3382.2 (OH) cmꢀ1 1H
.
NMR (CDCl3)
d
7.56 (d, 1H, J¼7.0 Hz, H-50); 7.35–7.20 (m, 2H, H-
(C]O) cmꢀ1.1H NMR (CDCl3)
d
7.39 (d,1H, J¼7.0 Hz, H-40); 7.15–7.00
60,70); 7.06 (t, 1H, J¼6.6 Hz, H-50); 6.82 (s, 1H, H-20); 3.70 (s, 3H,
NCH3); 3.60–3.52 (m, 1H, H-3); 2.95–2.70 (m, 2H, H-1); 1.85–1.55
(m, 2H, H-2); 1.60–1.30 (m, 2H, H-4); 0.90 (t, 3H, J¼7.5 Hz, H-
(m, 2H, H-60,70); 6.91 (t,1H, J¼6.6 Hz, H-50); 6.65 (s,1H, H-20); 3.52 (s,
3H, NCH3); 2.85 (t, 2H, J¼7.6 Hz, H-1); 2.62 (t, 2H, J¼7.6 Hz, H-2);
2.22 (q, 2H, J¼7.3 Hz, H-4); 0.86 (t, 3H, J¼7.2 Hz, H-5) ppm. 13C NMR
5) ppm. 13C NMR (CDCl3) 137.4 (C-7a0); 128.2 (C-3a0); 126.5 (C-20);
d
(CDCl3)
d
211.9 (C-3); 137.4 (C-7a0); 127.9 (C-3a0); 126.8 (C-20); 121.9
121.9 (C-50); 119.4 (C-60); 119.0 (C-60); 115.1 (C-30); 109.6 (C-70); 73.4
(C-3); 37.8 (C-2); 33.0 (NCH3); 30.7 (C-4); 21.7 (C-1); 10.3 (C-
5) ppm. Anal. Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found:
C, 77.01; H, 8.72; N, 6.20.
(C-50); 119.2 (C-40); 119.1 (C-60); 114.2 (C-30); 109.6 (C-70); 43.4 (C-2);
36.5 (C-4); 32.9 (NCH3); 19.7 (C-1); 8.2 (C-5) ppm. Anal. Calcd for
C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found: C, 77.91; H, 8.12; N, 6.20.
4.3.3. 4-(3-Indolyl)-2-butanone (8e)
4.4.3. 4-(3-Indolyl)-2-butanol (7e)
Starting from 500 mg (4.27 mmol) of indole, a yield of 686 mg
(85%) of compound 8c was obtained. Spectral data were identical to
those published in Ref. 19a.
Starting from 606 mg (3.24 mmol) of 8e, a yield of 479 mg (78%)
of compound 7e was obtained. IR (NaCl): 3541.0, 3414.4, 3200 cmꢀ1
.
1H NMR (CDCl3)
d
7.96 (br s, 1H, NH); 7.63 (d, 1H, J¼7.7 Hz, H-40);

P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
1667
7.37 (d, 1H, J¼7.9 Hz, H-70); 7.21 (t, 1H, J¼7.6 Hz, H-60); 7.12 (t, 1H,
J¼7.0 Hz, H-50); 7.02 (s, 1H, H-20); 3.91 (sext, 1H, J¼6.2 Hz, H-3);
3.00–2.78 (m, 2H, H-1); 1.89 (q, 2H, J¼7.6 Hz, H-2); 1.26 (t, 3H,
The solution was stirred for ca. 10 min, until effervescence ceased. A
solution of the suitable alcohol 7 (0.77 mmol) in dry CH2Cl2 (3 ml)
was added dropwise via cannula, and the red solution was stirred
for 10 min at ꢀ78 ꢁC. Triethylamine (10 equiv) was then added and
the solution was left to warm to room temperature for 20 min,
while stirred. The reaction mixture was diluted with CH2Cl2 (20 ml)
and washed with saturated aqueous NH4Cl (3ꢂ20 ml). The organic
layer was dried (Na2SO4) and evaporated, and the residue was
purified by rapid chromatography on silica gel, eluting with pe-
troleum ether–ethyl acetate mixtures. Slower chromatographic
separation may lead to considerable amounts of decomposition
products, specially from hydrolysis of the terminal chloro-
methylene moiety.
J¼6.2 Hz, H-1) ppm. 13C NMR (CDCl3)
d
136.7 (C-7a0); 127.8 (C-3a0);
122.3 (C-20); 121.5 (C-50); 119.6 (C-40); 119.3 (C-60); 116.5 (C-30);
111.5 (C-70); 68.3 (C-2); 39.8 (C-3); 24.0 (C-1); 21.8 (C-4) ppm. Anal.
Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 75.91; H,
7.82; N, 7.20.
4.4.4. 1-(3-Indolyl)-3-pentanol (7f)
Starting from 660 mg (3.28 mmol) of 8f, a yield of 552 mg (83%)
of compound 7f was obtained. IR (NaCl): 3568.2, 3412.0,
3340.9 cmꢀ1 1H NMR (CDCl3)
. d 8.20 (br s, 1H, NH); 7.85 (d, 1H,
J¼7.7 Hz, H-40); 7.46 (d, 1H, J¼7.6 Hz, H-70); 7.37 (t, 1H, J¼7.8 Hz, H-
60); 7.32 (t, 1H, J¼7.4 Hz, H-50); 7.22 (s, 1H, H-20); 3.92–3.80 (m, 1H,
H-3); 3.20–2.95 (m, 2H, H-1); 2.20–2.00 (m, 2H, H-2); 1.85–1.60 (m,
4.5.1. 3-Chloro-3-(30-chloropropyl)-1-methylindolin-2-one (9a)
Starting from 143 mg (0.76 mmol) of alcohol 7a, a yield of
160 mg (82%) of compound 9a was obtained. IR (NaCl): 1728.5
2H, H-4); 1.18 (t, 3H, J¼7.4 Hz, H-5) ppm. 13C NMR (CDCl3)
d 136.7
(C-7a0); 127.8 (C-3a0); 122.3 (C-20); 121.5 (C-50); 119.6 (C-40); 119.3
(C-60); 116.7 (C-30); 111.5 (C-70); 73.4 (C-3); 37.5 (C-2); 30.7 (C-4);
21.8 (C-1); 10.3 (C-5) ppm. Anal. Calcd for C13H17NO: C, 76.81; H,
8.43; N, 6.89. Found: C, 76.62; H, 8.21; N, 6.71.
(C]O), 1613.6 (C]C) cmꢀ1. 1H NMR (CDCl3)
d 7.40–7.25 (m, 2H, H-
4,6); 7.08 (t, 1H, J¼7.4 Hz, H-5); 6.80 (d, 1H, J¼6.8 Hz, H-7); 3.42 (t,
2H, J¼6.5 Hz, H-30); 3.18 (s, 3H, NCH3); 2.33 (t, 2H, J¼8.3 Hz, H-10);
1.75–1.55 (m, 2H, H-20) ppm. 13C NMR (CDCl3)
d 173.9 (CO); 142.9
(C-7a); 130.7 (C-4); 129.5 (C-3a); 124.6 (C-6); 123.9 (C-5); 109.2 (C-
7); 64.6 (C-3); 44.5 (C-30); 37.0 (C-10); 27.8 (C-20); 27.1 (NCH3) ppm.
Anal. Calcd for C12H13Cl2NO: C, 55.83; H, 5.08; N, 5.43. Found: C,
55.53; H, 5.34; N, 5.46.
4.4.5. 4-(5-Methoxy-3-indolyl)-2-butanol (7g)
Starting from 500 mg (2.30 mmol) of 8g, a yield of 504 mg (99%)
of compound 7g was obtained. IR (NaCl): 3541.2, 3409.3, 3335.6
(OH, NH) cmꢀ1. 1H NMR (CDCl3)
d 8.21 (br s, 1H, NH); 7.22 (d, 1H,
J¼7.9 Hz, H-40); 7.07 (d, 1H, J¼2.1 Hz, H-70); 6.94 (s, 1H, H-20); 6.86
(dd, 1H, J¼7.8 and 2.1 Hz, H-60); 4.48–4.32 (m, 1H, H-2); 3.86 (s, 3H,
OCH3); 2.90–2.62 (m, 2H, H-4); 1.95–1.70 (m, 2H, H-3); 1.25 (d, 3H,
4.5.2. 4-tert-Butyldiphenylsilyloxy-3-chloro-3-(30-chloropropyl)-1-
methylindolin-2-one (9b)
Starting from 100 mg (0.22 mmol) of alcohol 7b, a yield of
120 mg (90%) of compound 9b was obtained. IR (NaCl): 1731.6
J¼6.5 Hz, H-1) ppm. 13C NMR (CDCl3)
d
154.1 (C-50); 132.0 (C-3a0);
128.2 (C-7a0); 122.6 (C-20); 112.3 (C-30); 112.1 (C-70); 101.1 (C-40,60);
69.8 (C-2); 56.3 (OCH3); 38.2 (C-3); 23.6 (C-1); 21.8 (C-4) ppm. Anal.
Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.06; H,
7.79; N, 6.40.
(C]O), 1112.9 (C–O) cmꢀ1. 1H NMR (CDCl3)
d 7.73–7.67 (m, 4H, H-
200,600); 7.50–7.35 (m, 8H, H-5,6,300,400,500); 6.77 (d,1H, J¼7.6 Hz, H-7);
5.07 (d, 1H, J¼14.2 Hz, CH2O); 4.90 (d, 1H, J¼14.2 Hz, CH2O); 3.31–
3.13 (m, 2H, H-30); 3.21 (s, 3H, NCH3); 2.40–2.17 (m, 2H, H-10); 1.43–
1.28 (m, 2H, H-20); 1.12 (s, 9H, C(CH3)3) ppm. 13C NMR (CDCl3)
4.4.6. 4-(2-Methyl-3-indolyl)-2-butanol (7h)
d
173.2 (C-2); 142.4 (C-7a); 139.1 (C-4); 135.5 (C-200,600); 133.0 (C-
Starting from 559 mg (2.78 mmol) of 8h, a yield of 405 mg (72%)
of compound 7h was obtained. IR (NaCl): 3568.2, 3399.8, 3224.8
100); 130.5 (C-6); 129.9 (C-400); 127.8 (C-300,500); 123.2 (C-3a); 121.6
(C-5); 107.4 (C-7); 64.4 (C-3); 60.9 (CH2O); 43.6 (C-30); 35.6 (C-10);
27.7 (C-20); 26.85 (NCH3); 26.75 (C(CH3)3); 19.3 (C(CH3)3) ppm.
Anal. Calcd for C29H33Cl2NO2Si: C, 66.15; H, 6.32; N, 2.66. Found: C,
65.97; H, 6.02; N, 2.36.
(NH and OH) cmꢀ1. 1H NMR (CDCl3)
d 7.74 (br s, 1H, NH); 7.53 (d, 1H,
J¼7.1 Hz, H-40); 7.28 (d, 1H, J¼6.4 Hz, H-70); 7.17–7.02 (m, 2H, H-
50,60); 3.84 (sext, 1H, J¼6.2 Hz, H-3); 2.81 (t, 1H, J¼7.6 Hz, H-1); 1.78
(q, 2H, J¼7.1 Hz, H-2); 2.40 (s, 3H, CH3); 1.23 (d, 3H, J¼6.2 Hz, H-
4) ppm. 13C NMR (CDCl3)
d
135.6 (C-7a0); 131.2 (C-20); 128.9 (C-3a0);
4.5.3. 3-Chloro-3-(30-chlorobutyl)-1-methylindolin-2-one (9c)
Starting from 193 mg (0.95 mmol) of alcohol 7c, a yield of
184 mg (71%) of compound 9c was obtained, as a 2:1 mixture of
diastereomers (major diastereomer, 9ca; minor diastereomer, 9cb),
together with 35 mg (15%) of 3-chloro-3-(30-oxobutyl)-1-methyl-
indolin-2-one (10c).
121.3 (C-50); 119.5 (C-40); 118.4 (C-60); 111.8 (C-30); 110.6 (C-70); 68.2
(C-3); 40.2 (C-2); 24.1 (C-4); 20.8 (C-1); 12.0 (C2-CH3) ppm. Anal.
Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.51; H,
8.16; N, 6.71.
4.4.7. 4-(3-Indolyl)butanol (7i)
Data for 9c: IR (NaCl): 1729.4 (C]O) cmꢀ1 1H NMR (CDCl3)
.
A suspension of LiAlH4 (1.143 g, 30 mmol, 6.1 equiv) in dry
THF (20 ml), under an argon atmosphere, was externally cooled
in an ice bath. A solution of 4-(3-indolyl)butanoic acid (1 g,
4.92 mmol) in dry THF (5 ml) was added via cannula, and the
suspension thus obtained was stirred at room temperature
overnight. Excess LiAlH4 was destroyed by successive addition of
ethyl acetate, water and solid NaHCO3. The suspension obtained
was filtered and the solid was washed with ethyl acetate. The
combined filtrates were dried (Na2SO4) and evaporated, yielding
790 mg (85%) of compound 7i.20
d
7.45–7.32 (m, 2H, H-4,6); 7.20 (t, 1H, J¼6.7 Hz, H-5); 6.88 (d,
1H, J¼7.8 Hz, H-7); 4.05–3.85 (m, 1H, H-30); 3.26 (m, 3H, NCH3);
2.55–2.21 (m, 2H, H-10); 1.80–1.70 (m, 2H, H-20); 1.49 (d, 3H,
J¼6.6 Hz, CH3, 9ca); 1.47 (d, 3H, J¼6.6 Hz, CH3, 9cb) ppm. 13C
NMR (CDCl3)
d 174.0 (CO); 142.9 (C-7a); 130.7 (C-4); 129.7 (C-3a,
9ca); 129.4 (C-3a, 9cb); 124.6 (C-6); 124.0 (C-5, 9cb); 123.9 (C-5,
9ca); 109.2 (C-7); 64.6 (C-3); 58.2 (C-30, 9cb); 58.0 (C-30, 9ca);
36.9 (C-10, 9cb); 36.5 (C-10, 9ca); 35.1 (C-20, 9cb); 34.8 (C-20, 9ca);
27.1 (NCH3); 25.7 (CH3, 9cb); 25.5 (CH3, 9ca) ppm. Anal. Calcd for
C13H15Cl2NO: C, 57.37; H, 5.56; N, 5.15. Found: C, 57.68; H, 5.88;
N, 5.17.
4.5. Reaction of 3-(3-indolyl)propanol and 4-(3-indolyl)-
butanol derivatives with the Swern reagent. General
procedure for the synthesis of compounds (9)
Data for 10c: IR (NaCl): 3422.0 (OH), 1728.2 and 1717.0
(2C]O) cmꢀ1. 1H NMR (CDCl3)
d
7.39 (d, 1H, J¼7.6 Hz, H-4); 7.37 (t,
1H, J¼7.6 Hz, H-6); 7.15 (t, 1H, J¼6.9 Hz, H-5); 6.87 (d, 1H, J¼7.6 Hz,
H-2); 3.25 (s, 3H, NCH3); 2.65–2.40 (m, 4H, H-10,20); 2.11 (s, 3H,
To a solution of oxalyl chloride (5 equiv) in dry CH2Cl2 (10 ml),
at ꢀ78 ꢁC under an argon atmosphere, was added DMSO (7 equiv).
COCH3) ppm. 13C NMR (CDCl3) 206.9 (C-30); 173.9 (C-2); 142.7 (C-
d
7a); 130.8 (C-4); 129.8 (C-3a); 124.5 (C-6); 123.9 (C-5); 109.2 (C-7);

1668
P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
64.4 (C-3); 38.4 (C-20); 33.2 (C-10); 30.4 (CH3); 27.0 (NCH3) ppm. MS
(m/z, %): 251 (Mþ). Anal. Calcd for C13H14ClNO2: C, 62.03; H, 5.61; N,
5.56. Found: C, 62.35; H, 5.81; N, 5.62.
4.5.7. 3-Chloro-3-(30-chlorobutyl)-5-methoxyindolin-2-one (9g)
Starting from 200 mg (0.91 mmol) of alcohol 7g, a yield of
212 mg (81%) of compound 9g was obtained, as a 3:1 diastereomer
mixture (major diastereomer, 9ga; minor diastereomer, 9gb). IR
4.5.4. 3-Chloro-3-(30-chloropentyl)-1-methylindolin-2-one (9d)
Starting from 160 mg (0.74 mmol) of alcohol 7d, a yield of
155 mg (73%) of compound 9d was obtained, as a 2:1 mixture of
diastereomers (major diastereomer, 9da; minor diastereomer,
9db), together with 22 mg (12%) of 3-chloro-3-(30-oxopentyl)-1-
methylindolin-2-one (10c).
(NaCl): 3296.0 (N–H), 1718.7 (C]O) cmꢀ1. 1H NMR (CDCl3)
d 8.96 (s,
1H, NH, 9ga); 8.90 (s, 1H, NH, 9gb); 6.96 (d, 1H, J¼2.4 Hz, H-4); 6.88
(d, 1H, J¼8.5 Hz, H-6); 6.82 (dd, 1H, J¼8.5 and 2.4 Hz, H-7); 4.05–
3.85 (m, 1H, H-30); 3.81 (s, 3H, OCH3); 2.60–2.40 (m, 2H, H-10);
2.40–2.20 (m, 2H, H-20); 1.48 (d, 3H, J¼6.5 Hz, CH3 9ga); 1.46 (d, 3H,
J¼6.3 Hz, CH3 9gb) ppm. 13C NMR (CDCl3)
d 177.1 (CO); 156.3 (C-5);
Data for 9d: IR (NaCl): 1729.0 (C]O) cmꢀ1
.
1H NMR (CDCl3)
141.1 (C-7a); 134.1 (C-3a, 9gb); 133.8 (C-3a, 9ga); 115.7 (C-7, 9gb);
115.5 (C-7, 9ga); 111.8 (C-4, 9ga); 111.5 (C-4, 9gb); 111.3 (C-6); 68.0
(C-3); 58.2 (C-30, 9gb); 58.0 (C-30, 9ga); 56.2 (OCH3); 36.9 (C-10,
9gb); 36.5 (C-10, 9ga); 35.1 (C-20, 9gb); 34.8 (C-20, 9ga); 25.7 (CH3,
9gb); 25.5 (CH3, 9ga) ppm. Anal. Calcd for C13H15Cl2NO2: C, 54.18;
H, 5.25; N, 4.86. Found: C, 53.95; H, 5.12; N, 4.75.
d
7.35–7.25 (m, 2H, H-4,6); 7.07 (t, 1H, J¼7.6 Hz, H-5); 6.80 (d, 1H,
J¼7.8 Hz, H-7); 3.75–3.60 (m, 1H, H-30); 3.18 (m, 3H, NCH3); 2.70–
2.10 (m, 2H, H-10); 1.80–1.35 (m, 2H, H-20); 0.95–0.80 (m, 3H, H-
40) ppm. 13C NMR (CDCl3)
d 174.1 (C-2); 143.0 (C-7a, 9da); 142.9
(C-7a, 9db); 130.7 (C-4); 129.7 (C-3a, 9da); 129.5 (C-3a, 9db); 124.6
(C-6); 124.0 (C-5, 9db); 123.9 (C-5, 9da); 109.1 (C-7); 65.1 (C-30,
9db); 64.9 (C-30, 9da); 64.7 (C-3); 36.8 (C-10, 9db); 36.3 (C-10, 9da);
33.1 (C-20, 9db); 32.7 (C-20, 9da); 31.8 (C-40, 9da); 31.5 (C-40, 9db);
27.1 (NCH3); 11.3 (C-50) ppm. Anal. Calcd for C14H17Cl2NO: C, 58.75;
H, 5.99; N, 4.89. Found: C, 58.80; H, 5.91; N, 4.99.
4.5.8. 3-Chloro-3-(40-chlorobutyl)indolin-2-one (9i)
Starting from 500 mg (2.65 mmol) of alcohol 7i, a yield of
580 mg (85%) of compound 9i, which is very sensitive to chro-
matography, was obtained. IR (NaCl): 3257.4 (NH), 1731.8
Data for 10d: IR (NaCl): 3420.1 (OH), 1727.8 and 1718.1
(C]O) cmꢀ1 1H NMR (CDCl3)
. d 9.54 (s, 1H, NH); 7.37 (d, 1H,
(2C]O) cmꢀ1.1H NMR (CDCl3)
d
7.35–7.15 (m, 2H, H-4,6); 7.09 (t,1H,
J¼7.5 Hz, H-4); 7.29 (t, 1H, J¼7.6 Hz, H-6); 7.14 (t, 1H, J¼7.6 Hz, H-
5); 6.99 (d, 1H, J¼7.6 Hz, H-7); 3.45 (t, 2H, J¼6.6 Hz, H-40); 2.29
(t, 2H, J¼6.6 Hz, H-10); 1.85–1.55 (m, 2H, H-30); 1.50–1.25 (m, 2H,
J¼6.6 Hz, H-5); 6.79 (d, 1H, J¼8.0 Hz, H-2); 3.17 (s, 3H, NCH3); 2.50–
2.05 (m, 4H, H-10,20); 1.40–1.10 (m, 2H, C-40); 0.80 (t, 3H, J¼7.5 Hz, C-
50) ppm. 13C NMR (CDCl3)
d
210.4 (C-30); 173.1 (C-2); 142.9 (C-7a);
H-20) ppm. 13C NMR (CDCl3)
d 177.1 (CO); 140.4 (C-7a); 130.7 (C-
131.8 (C-3a); 130.7 (C-4); 124.6 (C-6); 123.9 (C-5); 109.1 (C-7); 59.2
(C-3); 37.1 (C-20); 36.4 (C-40); 33.3 (C-10); 27.0 (NCH3); 8.1 (C-
50) ppm. MS (m/z, %): 265 (Mþ). Anal. Calcd for C14H16ClNO2: C,
63.28; H, 6.07; N, 5.27. Found: C, 62.98; H, 5.79; N, 4.95.
4); 129.9 (C-3a); 124.8 (C-6); 123.9 (C-5); 111.4 (C-7); 65.6 (C-3);
44.7 (C-40); 38.7 (C-10); 32.5 (C-30); 22.2 (C-20) ppm. Anal. Calcd
for C12H13Cl2NO: C, 55.83; H, 5.08; N, 5.43. Found: C, 55.45; H,
4.86; N, 5.34.
4.5.5. 3-Chloro-3-(30-chlorobutyl)indolin-2-one (9e)
4.5.9. 3-(20-Hydroxyethyl)-1-methylindolin-2-one (21)
Starting from 275 mg (1.46 mmol) of alcohol 7e, a yield of
310 mg (80%) of compound 9e was obtained, as a 2:1 mixture of
diastereomers (major diastereomer, 9ea; minor diastereomer, 9eb).
To a solution of tryptophol (1.2 g, 7.4 mmol) in CH2Cl2 (20 ml)
was added tetrabutylammonium bisulfate (223 mg, 0.67 mmol,
0.09 equiv). A 50% aqueous solution of KOH (1 ml) was added and
the biphasic system was vigorously stirred for 5 min. Methyl iodide
(0.55 ml, 1.26 g, 8.88 mmol) was added and vigorous stirring was
maintained for 14 h. The reaction mixture was poured onto a satu-
rated aqueous NH4Cl solution and the resulting mixture was
extracted with CH2Cl2 (3ꢂ25 ml). The combined organic layers
were dried (Na2SO4) and evaporated and the residue was chro-
matographed on silica gel, eluting with CH2Cl2, to yield 1.21 g (93%)
of 1-methyltryptophol 20, whose spectral data were identical to
those found in the literature.38
IR (NaCl): 3257.8 (NH), 1731.5 (C]O) cmꢀ1. 1H NMR (CDCl3)
d 7.72
(br s, 1H, NH); 7.32 (d, 1H, J¼7.5 Hz, H-4); 7.21 (t, 1H, J¼6.6 Hz, H-6);
7.07 (t, 1H, J¼7.6 Hz, H-5); 6.84 (d, 1H, J¼7.8 Hz, H-7); 3.95–3.78 (m,
1H, H-30); 2.60–2.10 (m, 2H, H-10); 1.75–1.55 (m, 2H, H-20); 1.42 (d,
3H, J¼6.5 Hz, H-40, 9ea); 1.38 (d, 3H, J¼6.5 Hz, H-40, 9eb) ppm. 13C
NMR (CDCl3)
d 176.8 (CO); 140.2 (C-7a); 130.8 (C-4); 130.0 (C-3a,
9ea); 129.8 (C-3a, 9eb); 124.9 (C-6); 124.0 (C-5, 9ea); 123.9 (C-5,
9eb); 111.4 (C-7); 65.4 (C-3, 9ea); 65.2 (C-3, 9eb); 58.2 (C-30, 9eb);
58.0 (C-30, 9ea); 36.9 (C-10, 9eb); 36.5 (C-10, 9ea); 35.1 (C-20, 9eb);
34.9 (C-20, 9ea); 25.7 (H-40, 9eb); 25.5 (H-40, 9ea) ppm. Anal. Calcd
for C12H13Cl2NO: C, 55.83; H, 5.08; N, 5.43. Found: C, 55.55; H. 4.82;
N, 5.12.
To a solution of oxalyl chloride (0.38 ml, 4.28 mmol) in dry
CH2Cl2 (10 ml), at ꢀ78 ꢁC under an argon atmosphere, was added
DMSO (0.42 ml, 6.0 mmol). The solution was stirred for ca. 10 min,
until effervescence ceased.
A solution of 1-methyltryptophol
4.5.6. 3-Cloro-3-(30-chloropentyl)indolin-2-one (9f)
(150 mg, 0.857 mmol) in dry CH2Cl2 (3 ml) was added dropwise via
cannula, and the red solution was stirred for 10 min at ꢀ78 ꢁC.
Triethylamine (1.22 ml, 8.57 mmol) was then added and the solu-
tion was left to warm to room temperature for 20 min, while stir-
red. The reaction mixture was diluted with CH2Cl2 (20 ml) and
washed with saturated aqueous NH4Cl (3ꢂ20 ml). The organic layer
was dried (Na2SO4) and evaporated, and the residue was purified by
chromatography on silica gel, eluting with CH2Cl2, to yield 109 mg
(67%) of compound 21, whose spectral data were identical to those
found in the literature.24
Starting from 200 mg (0.98 mmol) of alcohol 7f, a yield of
230 mg (87%) of compound 9f was obtained, as a 2:1 mixture of
diastereomers (major diastereomer, 9fa; minor diastereomer, 9fb).
IR (NaCl): 3261.3 (NH), 1727.9 (C]O) cmꢀ1. 1H NMR (CDCl3)
d 8.92
(s, 1H, NH, 9fa); 8.85 (s, 1H, NH, 9fb); 7.38 (d, 1H, J¼7.4 Hz, H-4);
7.29 (t, 1H, J¼7.7 Hz, H-6); 7.11 (t, 1H, J¼7.5 Hz, H-5); 6.95 (d, 1H,
J¼7.7 Hz, H-7); 3.61–3.39 (m, 1H, H-30); 2.58–2.40 (m, 2H, H-10);
2.38–2.15 (m, 2H, H-20); 1.55–1.15 (m, 4H, H-40); 0.88 and 0.86 (2 t,
6H, J¼7.4 Hz, H-50) ppm. 13C NMR (CDCl3)
d 175.6 (CO, 9fa); 175.0
(CO, 9fb); 139.4 (C-7a, 9fb); 139.2 (C-7a, 9fa); 129.3 (C-4, 9fa); 129.1
(C-4, 9fb); 128.7 (C-3a, 9fa); 128.5 (C-3a, 9fb); 123.5 (C-6, 9fb);
123.3 (C-6, 9fa); 122.4 (C-5, 9fa); 122.3 (C-5, 9fb); 110.0 (C-7, 9fa);
109.8 (C-7, 9fb); 71.6 (C-3, 9fa); 71.4 (C-3, 9fb); 64.6 (C-30, 9fa); 64.5
(C-30, 9fb); 34.4 (C-10, 9fa); 34.2 (C-10, 9fb); 30.2 (C-20, 9fa); 30.0 (C-
20, 9fb); 28.8 (C-40, 9fa); 28.7 (C-40, 9fb); 9.2 (C-50, 9fb); 8.9 (C-50,
9fa) ppm. Anal. Calcd for C13H15Cl2NO: C, 57.37; H, 5.56; N, 5.15.
Found: C, 57.13; H, 5.32; N, 4.97.
4.5.10. 3-(30-Oxobutyl)indole-2-carbaldehyde (25)
To a solution of oxalyl chloride (0.56 ml, 6.45 mmol) in dry
CH2Cl2 (15 ml), at ꢀ78 ꢁC under an argon atmosphere, was added
DMSO (0.64 ml, 9.03 mmol). The solution was stirred for ca.
10 min, until effervescence ceased. A solution of alcohol 7h
(262 mg, 1.29 mmol) in dry CH2Cl2 (3 ml) was added dropwise via
cannula, and the red solution was stirred for 10 min at ꢀ78 ꢁC.

P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
1669
Triethylamine (1.31 ml, 13 mmol) was then added and the solution
was left to warm to room temperature for 20 min, while stirred.
The reaction mixture was diluted with CH2Cl2 (20 ml) and washed
with saturated aqueous NH4Cl (3ꢂ20 ml). The organic layer was
dried (Na2SO4) and evaporated, and the residue was purified by
chromatography on silica gel, eluting with a 10:1 petroleum
ether–ethyl acetate to yield 88 mg (32%) of compound 25. IR
40); 7.30 (t, 1H, J¼7.6 Hz, H-60); 7.12 (t, 1H, J¼7.4 Hz, H-50); 6.95 (d,
1H, J¼7.4 Hz, H-70); 5.07 (d, 1H, J¼11.7 Hz, CH2S); 5.03 (d, 1H,
J¼11.7 Hz, CH2S); 2.70–2.35 (m, 4H, H-1,2); 2.19 (s, 3H, SCH3) ppm.
13C NMR (CDCl3)
d
176.6 and 176.0 (2C]O); 140.1 (C-7a0); 130.9
(C-40); 129.5 (C-3a0); 124.9 (C-60); 124.0 (C-50); 111.2 (C-70); 69.0
(CH2S); 64.6 (C-30); 34.2 (C-2); 29.6 (C-1); 15.8 (SCH3) ppm. Anal.
Calcd for C13H14NO3SCl: C, 52.09; H, 4.71; N, 4.67. Found: C, 52.45;
H, 4.45; N, 4.97.
(NaCl): 3316.1 (NH), 1715.3 (C]O), 1651.5 (CHO) cmꢀ1
.
1H NMR
(CDCl3) 10.04 (s, 1H, CHO); 8.19 (br s, 1H, NH); 7.60 (d, 1H,
d
J¼7.2 Hz, H-4); 7.35–7.21 (m, 2H, H-6,7); 7.12–7.00 (m, 1H, H-5);
4.6.2. Swern reaction of 29b
3.31 (t, 2H, J¼7.3 Hz, H-10); 2.85 (t, 2H, J¼7.3 Hz, H-20); 2.06 (s, 3H,
Starting from carboxylic acid 29b (200 mg, 0.98 mmol) and us-
ing Method A, the following products were isolated after chroma-
tography eluting with petroleum ether–ethyl acetate (gradient
from 10:1 to 4:1): 24 mg (11%) of 31b, 70 mg (25%) of 32b and
51 mg (17%) of 33b.
H-40) ppm. 13C NMR (CDCl3)
d 207.6 (C-3); 181.4 (CHO); 132.3 (C-
7a); 127.9 (C-6); 127.7 (C-3a); 127.6 (C-2); 126.9 (C-3); 121.6 (C-5);
121.1 (C-4); 112.8 (C-7); 45.0 (C-20); 30.6 (C-40); 17.8 (C-10) ppm.
Anal. Calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C,
72.15; H, 5.72; N, 6.17.
4.6.2.1. 3-[30-Hydroxy-10-methyl-20-oxoindolin-30-yl]propanoic acid
lactone (31b). Spectral data were identical to those published in the
literature.31b
4.6. Reaction of 3-(3-indolyl)propanoic acid and 4-
(3-indolyl)butanoic acid derivatives with the Swern
reagent. General procedures
4.6.2.2. 2,2-Dichloro-3-[30-hydroxy-10-methyl-20-oxoindolin-3-yl]-
Method A. To a solution of oxalyl chloride (5 equiv) in dry CH2Cl2
(10 ml), at ꢀ78 ꢁC under an argon atmosphere, was added DMSO
(7 equiv). The solution was stirred for ca.10 min, until effervescence
ceased. A solution of the suitable acid in dry CH2Cl2 (3 ml) was
added dropwise via cannula, and the red solution was stirred for
10 min at ꢀ78 ꢁC. Triethylamine (10 equiv) was then added and the
solution was left to warm to room temperature for 20 min, while
stirred. The reaction mixture was diluted with CH2Cl2 (20 ml) and
washed with saturated aqueous NH4Cl (3ꢂ20 ml). The organic layer
was dried (Na2SO4) and evaporated, and the residue was purified by
rapid chromatography on silica gel, eluting with petroleum ether–
ethyl acetate mixtures.
propanoic acid lactone (32b). IR (NaCl): 1794.8, 1734.7 (C]O) cmꢀ1
.
1H NMR (CDCl3)
d
7.57 (d, 1H, J¼7.6 Hz, H-40); 7.41 (t, 1H, J¼7.8 Hz,
H-60); 7.09 (t, 1H, J¼7.8 Hz, H-50); 6.86 (d, 1H, J¼7.8 Hz, H-70); 3.56
(d, 1H, J¼15.4 Hz, H-1); 3.34 (d, 1H, J¼15.4 Hz, H-1); 3.17 (s, 3H,
NCH3) ppm. 13C NMR (CDCl3)
d 172.0 (C]O); 168.0 (C]O); 144.4
(C-7a0); 132.5 (C-40); 125.9 (C-3a0); 125.3 (C-60); 124.3 (C-50); 109.7
(C-70); 80.3 (C-30); 75.9 (C-2); 51.3 (C-1); 27.2 (NCH3) ppm. Anal.
Calcd for C12H9Cl2NO3: C, 50.38; H, 3.17; N, 4.90. Found: C, 50.63; H,
3.49; N, 4.64. MS (m/z): 285, 287 and 289 (Mþ); 251 and 253
(MþꢀCl); 222 and 224; 206 and 208.
4.6.2.3. Methylthiomethyl 3-[30-chloro-10-methyl-20-oxoindolin-30-
Method B. Same procedure as in Method A, without the addition
of triethylamine.
yl]propionate (33b). IR (NaCl): 3445.9 (OH), 1730.4 (C]O),
1613.3 cmꢀ1. 1H NMR (CDCl3)
d
7.33 (d, 1H, J¼6.8 Hz, H-40); 7.31 (t,
1H, J¼6.8 Hz, H-60); 7.07 (t, 1H, J¼6.8 Hz, H-50); 6.80 (d, 1H,
J¼7.7 Hz, H-70); 5.03 (d, 1H, J¼11.8 Hz, CH2S); 4.95 (d, 1H, J¼11.8 Hz,
CH2S); 3.18 (s, 3H, NCH3); 2.58–2.32 (m, 4H, H-1,2); 2.14 (s, 3H, S–
4.6.1. Swern reaction of 29a
Starting from carboxylic acid 29a (150 mg, 0.79 mmol), trie-
thylamine (1.13 ml, 7.93 mmol, 10 equiv) and dimethylsulfoxide
(0.1 ml) (method A), the following products were obtained: 70 mg
(40%) of 30a, 17 mg (11%) of 31a, 47 mg (22%) of 32a and 23 mg
(10%) of 33a.
When the reaction was performed in the absence of triethyl-
amine (method B), starting from 150 mg (0.79 mmol) of 29a, the
products obtained were hydroxy acid 30a (91 mg, 52%) and lactone
31a (55 mg, 36%).
CH3) ppm. 13C NMR (CDCl3)
d 173.4 (C]O); 172.0 (C]O); 142.9
(C-7a0); 130.9 (C-40); 129.2 (C-3a0); 124.6 (C-60); 123.9 (C-50); 109.2
(C-70); 68.9 (CH2S); 64.2 (C-30); 34.3 (C-2); 27.1 (C-1); 27.1 (NCH3);
15.8 (SCH3) ppm. Anal. Calcd for C14H16ClNO3S: C, 53.59; H, 5.14; N,
4.46; S, 11.48. Found: C, 53.25; H, 5.53; N, 4.79; S, 11.19.
4.6.3. Swern reaction of 29c
Starting from 500 mg (2.46 mmol) of carboxylic acid 29c, the
following compounds were obtained: 30c (250 mg, 43%) and 33c
(150 mg, 20%). When the reaction was performed in the absence of
triethylamine (Method B), a yield of 50 mg (95%) of compound 30c
was obtained.
4.6.1.1. 3-[30-Hydroxy-20-oxoindolin-30-yl]propanoic acid (30a).
Spectral data were identical to those published in the literature.30b
4.6.1.2. 3-[30-Hydroxy-20-oxoindolin-30-yl]propanoic acid lactone
(31a). Spectral data were identical to those published in the
literature.30b
4.6.3.1. 4-[30-Hydroxy-20-oxoindolin-30-yl]butanoic acid (30c). IR
(NaCl): 3208.7 (NH, OH), 1731.6, 1713.9 (2C]O), 1694.0 cmꢀ1 1H
.
NMR (CDCl3)
d 9.63 (s, 1H, CO2H); 8.24 (s, 1H, NH); 7.35 (d, 1H,
4.6.1.3. 2,2-Dichloro-3-[30-hydroxy-20-oxoindolin-3-yl]propanoic acid
J¼7.9 Hz, H-40); 7.25 (t, 1H, J¼7.8 Hz, H-60); 7.08 (t, 1H, J¼7.8 Hz, H-
lactone (32a). IR (NaCl): 1806.9, 1745.9 (C]O) cmꢀ1 1H NMR
.
50); 6.95 (d, 1H, J¼7.8 Hz, H-70); 2.42–2.18 (m, 4H, H-1,3); 1.67–1.45
(CDCl3)
d
8.11 (s, 1H, NH); 7.55 (d, 1H, J¼7.6 Hz, H-4); 7.31 (t, 1H,
(m, 2H, H-2) ppm. 13C NMR (CDCl3)
d 178.2 (C]O); 177.4 (C]O);
J¼7.7 Hz, H-6); 7.06 (t, 1H, J¼7.6 Hz, H-5); 6.88 (d, 1H, J¼7.8 Hz, H-
140.3 (C-7a0); 129.8 (C-40); 129.0 (C-3a0); 124.8 (C-60); 124.0 (C-50);
111.5 (C-70); 65.5 (C-30); 38.6 (C-1); 33.8 (C-3); 20.0 (C-2) ppm. Anal.
Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C, 60.98; H,
5.31; N, 5.58.
7); 3.60 (d, 1H, J¼15.5 Hz, H-10); 3.36 (d, 1H, J¼15.6 Hz, H-10) ppm.
13C NMR (CDCl3)
d 172.0 and 168.1 (2C]O); 141.7 (C-7a); 132.5
(C-4); 126.4 (C-3a); 125.5 (C-6); 124.4 (C-5); 111.5 (C-7); 80.4 (C-3);
75.8 (C-20); 51.3 (C-10) ppm. Anal. Calcd for C11H7NO3Cl2: C, 48.56;
H, 2.59; N, 5.15. Found: C, 48.23; H, 2.23; N, 4.89.
4.6.3.2. Methylthiomethyl 4-[30-chloro-10-methyl-20-oxoindolin-30-
yl]butanoate (33c). IR (NaCl): 3215.1 (NH), 1731.8, 1715.0 (C]O),
4.6.1.4. Methylthiomethyl 3-[30-chloro-20-oxoindolin-30-yl]propionate
1694.1, 1682.1 cmꢀ1. 1H NMR (CDCl3)
d 9.46 (s, 1H, NH); 7.34 (d, 1H,
(33a). 1H NMR (CDCl3)
d
8.90 (s, 1H, NH); 7.35 (d, 1H, J¼7.5 Hz, H-
J¼7.7 Hz, H-40); 7.28 (t, 1H, J¼7.7 Hz, H-60); 7.08 (t, 1H, J¼7.7 Hz,

1670
P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
H-50); 6.93 (d, 1H, J¼7.7 Hz, H-70); 5.05 (s, 2H, CH2S); 2.42–2.18 (m,
and the red solution was stirred for 20 min at ꢀ78 ꢁC and left to
warm to room temperature for 45 min, while stirred. The reaction
mixture was diluted with CH2Cl2 (20 ml) and washed with satu-
rated aqueous NH4Cl (3ꢂ20 ml). The organic layer was dried
(Na2SO4) and evaporated, and the reddish oily residue (682 mg,
80%) was identified as hydroxy acid 38. IR (NaCl): 3500 (broad
4H, H-1,3); 2.19 (s, 3H, SCH3); 1.68–1.45 (m, 2H, H-2) ppm. 13C NMR
(CDCl3)
d
176.9 (C]O); 172.8 (C]O); 140.4 (C-7a0); 130.7 (C-40);
129.8 (C-3a0); 124.9 (C-60); 123.9 (C-50); 111.4 (C-70); 68.7 (C-30);
65.4 (CH2S); 38.6 (C-3); 33.9 (C-1); 20.1 (C-2); 15.8 (SCH3) ppm.
Anal. Calcd for C14H16NO3ClS: C, 53.59; H, 5.14; N, 4.46. Found: C,
53.32; H, 4.92; N, 4.22.
signal, OH), 1731.6 (C]O), 1112.6 (Si–O) cmꢀ1 1H NMR (CDCl3)
.
d
7.82–7.66 (m, 4H, H-200,600); 7.48–7.33 (m, 8H, H-50,60,300,400,500);
4.7. Lactonization on hydroxy acids 30
6.83–6.76 (m, 1H, H-70); 4.95 (m, 2H, J¼12.5 Hz, TBDPSOCH2); 3.22
(s, 3H, NCH3); 2.58 (t, 2H, J¼7.5 Hz, H-3); 2.44 (t, 2H, J¼7.5 Hz, H-2);
4.7.1. Lactonization of 30a
1.25 (s, 1H, OH); 1.09 (s, 9H, C(CH3)3) ppm. 13C NMR (CDCl3)
d 174.7
To a solution of the hydroxy acid 30a (70 mg, 0.32 mmol) in
CHCl3 (1 ml) was added 96% H2SO4 (one drop). The solution was
stirred at room temperature for 8 h. After addition of solid NaHCO3
(200 mg), the solution was filtered and evaporated, yielding 64 mg
(100%) of lactone 31a.
(C-20); 172.0 (CO2H); 141.4 (C-7a0); 138.0 (C-40); 134.6 and 134.5 (C-
200,600); 133.8 (C-100); 129.6 (C-60); 128.9 (C-400); 126.8 (C-300,500);
122.4 (C-3a0); 121.3 (C-50); 106.6 (C-70); 63.1 (C-30); 59.9
(TBDPSOCH2); 32.0 (C-2); 27.9 (C-3); 25.5 (C(CH3)3); 25.4 (NCH3);
14.1 (C(CH3)3) ppm. Anal. Calcd for C29H33NO5Si: C, 69.16; H, 6.60;
N, 2.78. Found: C, 68.81; H, 6.46; N, 2.59.
4.7.2. Lactonization of 30c
To a solution of the hydroxy acid 30c (275 mg, 1.1 mmol) in
CHCl3 (1 ml) was added 96% H2SO4 (one drop). The solution was
stirred at room temperature for 24 h and the precipitated solid
was filtered, giving 240 mg (100%) of 4-[30-hydroxy-20-oxoindo-
lin-30-yl]butanoic acid lactone (31c). Mp 132–133 ꢁC (CHCl3);
lit.31a 134–135 ꢁC (ethyl acetate–hexane). IR (NaCl): 3255.9 (NH),
4.8.3. 3-[40-(tert-Butyldimethylsilyloxymethyl)-30-hydroxy-10-
methyl-20-oxoindolin-30-yl]propanoic acid lactone (39)
The neat hydroxy acid 38 (50 mg, 0.1 mmol) was heated at 110 ꢁC
and 0.1 Torr for 8 h, affording lactone 39 as a pale brown syrup
(44 mg, 91%). IR (NaCl): 1790.0 (C]O), 1731.7 (C]O), 1690.4 (C]O),
1160.4 (C–O),1111.9 (Si–O) cmꢀ1.1H NMR (CDCl3)
d 7.77–7.58 (m, 4H,
1723.5 (C]O), 1619.0 cmꢀ1
.
1H NMR (acetone-d6, 250 MHz)
H-200,600); 7.47–7.37 (m, 7H, H-60,300,400,500); 7.23 (d, 1H, J¼7.5 Hz, H-
50); 6.79 (d,1H, J¼7.5 Hz, H-70); 4.89–4.56 (m, 2H, TBDPSOCH2); 3.18
(s, 3H, NCH3); 3.12–2.96 (m, 1H); 2.81–2.71 (m, 1H); 2.56–2.31 (m,
d
9.81 (s, 1H, NH); 7.50 (d, 1H, J¼7.6 Hz, H-40); 7.30 (t, 1H,
J¼7.7 Hz, H-60); 7.05 (t, 1H, J¼7.7 Hz, H-50); 6.95 (t, 1H, J¼7.7 Hz,
H-70); 2.50–2.25 (m, 4H, H-1,3); 1.60–1.30 (m, 2H, H-2) ppm. 13C
2H) (H-2,3); 1.08 (s, 9H, C(CH3)3) ppm. 13C NMR (CDCl3)
d 176.3
NMR (acetone-d6)
d
174.7 (C]O); 173.7 (C]O); 141.6 (C-7a0);
(C]O); 175.0 (C]O); 144.0 (C-7a0); 139.1 (C-40); 136.0 and 135.9 (C-
200,600); 133.3 and 133.0 (C-100); 131.5 (C-60); 130.4 (C-400); 128.4 and
128.3 (C-300,500); 123.6 (C-50); 123.0 (C-3a0); 108.3 (C-70); 83.2 (C-30);
61.9 (TBDPSOCH2); 30.0 (C-2); 27.9 (C-3); 27.2 (C(CH3)3); 26.9
(NCH3); 19.7 (C(CH3)3) ppm. Anal. Calcd for C29H31NO4Si: C, 71.72; H,
6.43; N, 2.88. Found: C, 71.36; H, 6.28; N, 2.78.
130.7 (C-40); 129.9 (C-3a0); 124.9 (C-60); 123.1 (C-50); 110.8 (C-
70); 65.7 (C-30); 38.4 (C-3); 33.1 (C-1); 20.3 (C-2) ppm. Anal.
Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.02;
H, 4.82; N, 6.21.
4.8. Subsequent transformations of 3,4-difunctionalized
oxindoles
4.8.4. Removal of silicon protection from spirolactone (39)
To a solution of spirolactone 39 (1.628 g, 3.35 mmol) in dry
CH2Cl2 (20 ml) was added a 1 M solution of tetrabutylammonium
fluoride in THF (12 ml, 12 mmol). The solution was stirred at room
temperature for 16 h, poured onto pH 7 aqueous buffer (65 ml) and
extracted with CH2Cl2 (3ꢂ30 ml). The combined organic layers
were dried over anhydrous Na2SO4 and evaporated, and the residue
was chromatographed on silica gel, eluting with 1:2 ethyl acetate–
petroleum ether (1:2), followed by ethyl acetate–methanol (9:1)
and methanol, affording 215 mg (26%) of 3-[30-hydroxy-40-hydrox-
ymethyl-10-methyl-20-oxoindolin-30-yl]propanoic acid lactone (40)
as a white solid. The aqueous layer from the first extraction was
acidified with 2 M aqueous HCl and submitted to continuous ex-
traction with ethyl acetate over 24 h. The ethyl acetate was dried
over anhydrous Na2SO4 and evaporated, affording 778 mg (47%) of
the tetrabutylammonium salt of compound 38. Characterization
data for 40: mp 60 ꢁC. IR (NaCl): 3415.2 (OH), 1788.1 (C1]O), 1726.9
0
4.8.1. 3-[40-(tert-Butyldimethylsilyloxymethyl)-10-methylindol-30-
yl]propanoic acid (37)
To a solution of compound 36 (400 mg, 0.80 mmol) in 5%
methanolic KOH (7 ml) was added water (three drops) and the
reaction mixture was stirred at room temperature for 16 h. The
solvent was evaporated under reduced pressure and the residue
was dissolved in water (10 ml), which was acidified with 1 M
aqueous HCl to pH 1–2 and extracted with ethyl acetate (3ꢂ20 ml).
The combined organic layers were dried (Na2SO4) and evaporated,
affording compound 37 as a white solid (292 mg, 77%). IR (NaCl):
3500–2700 (CO2H), 1708.5 (CO2H), 1111.9 (Si–O) cmꢀ1
.
1H NMR
(CDCl3)
d
7.83–7.72 (m, 4H, H-200,600); 7.44–7.31 (m, 6H, H-300,400,500);
7.25–7.12 (m, 3H, H-50,60,70); 6.85 (s, 1H, H-20); 5.15 (s, 2H,
TBDPSOCH2); 3.73 (s, 3H, NCH3); 3.20 (t, 2H, J¼7.5 Hz, H-3); 2.64 (t,
2H, J¼7.5 Hz, H-2); 1.11 (s, 9H, C(CH3)3) ppm. 13C NMR (CDCl3)
d
179.7 (CO2H); 137.9 (C-7a0); 136.1 (C-200,600); 135.2 (C-40); 134.0 (C-
(C2 ]O), 1163.5 (C–O), 1051.6 (Si–O) cmꢀ1. 1H NMR (CDCl3)
d 7.40 (t,
100); 130.1 (C-400); 128.1 (C-300,500); 127.0 (C-20); 125.0 (C-3a0); 121.8
(C-50); 118.5 (C-60); 113.9 (C-30); 109.1 (C-70); 65.0 (TBDPSOCH2);
35.8 (C-2); 33.18 (NCH3); 27.3 (C(CH3)3); 22.2 (C-3); 19.7
(C(CH3)3) ppm. Anal. Calcd for C29H33NO3Si: C, 73.85; H, 7.05; N,
2.97. Found: C, 73.68; H, 7.21; N, 3.08.
1H, J¼7.5 Hz, H-60); 7.15 (d,1H, J¼7.5 Hz, H-50); 6.82 (d,1H, J¼7.5 Hz,
H-70); 4.78–4.66 (m, 2H, CH2OH); 3.20 (s, 3H, NCH3); 3.22–3.14 (m,
1H); 2.82–2.70 (m, 2H); 2.69–2.48 (m, 1H) (H-2,3); 1.26 (t, 1H,
J¼7.5 Hz, OH) ppm. 13C NMR (CDCl3)
d
174.5 (C-20); 144.6 (C-7a0);
139.1 (C-40); 131.7 (C-60); 124.3 (C-3a0); 123.7 (C-50); 108.8 (C-70);
83.4 (C-30); 62.1 (CH2OH); 30.6 (C-2); 28.3 (C-3); 26.9 (NCH3) ppm.
Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.67. Found: C,
62.94; H, 5.45; N, 5.38.
4.8.2. 3-[40-(tert-Butyldimethylsilyloxymethyl)-30-hydroxy-10-
methyl-20-oxoindolin-30-yl]propanoic acid (38)
To a solution of oxalyl chloride (0.51 ml, 5.85 mmol) in dry
CH2Cl2 (4 ml), at ꢀ78 ꢁC under an argon atmosphere was added
DMSO (0.58 ml, 8.19 mmol). The solution was stirred for ca. 10 min,
4.8.5. 3-[30-Hydroxy-40-iodomethyl-10-methyl-20-oxoindolin-30-
yl]propanoic acid lactone (41)
until effervescence ceased.
1.17 mmol) in dry CH2Cl2 (3 ml) was added dropwise via cannula,
A
solution of acid 37 (500 mg,
To a solution of spirolactone 39 (34 mg, 0.07 mmol) and so-
dium iodide (74 mg, 0.49 mmol) in dry acetonitrile (1 ml),

P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
1671
at ꢀ78 ꢁC and under an argon atmosphere, was added trime-
124.5 (C-3a0); 108.6 (C-70); 74.9 (CH2NO2); 60.2 (C-30); 33.2 (C-3);
28.9 (C-2); 29.3 (NOCH3); 25.3 (2NCH3) ppm.
thylsilyl chloride (24 ml, 0.19 mmol). The reaction was left to warm
to room temperature and the reaction mixture was stirred for 7 h
at this temperature. The reaction was then poured 10% aqueous
sodium thiosulfate and extracted with diethyl ether (3ꢂ10 ml),
and then with CH2Cl2 (3ꢂ10 ml). The combined ether layers were
dried over anhydrous Na2SO4 and evaporated, affording 8 mg
(48%) of alcohol 40. Similarly, evaporation of the CH2Cl2 extracts
afforded 11 mg (46%) of iodide 41, as a yellow solid with the
following characterization data: mp 143 ꢁC. IR (NaCl): 1790.3
0
d 7.27
Acknowledgements
We thank MEC (grant CTQ2006-10930), UCM-CAM (Grupos de
´
Investigacion, grant 920234) and CAM (predoctoral fellowship to
S.M.) for financial support. The stay of J.S. in Madrid was funded by
an Erasmus fellowship, which is also gratefully acknowledged. We
also thank Lucia Dicorato for assistance with some experiments
related to the mechanistic studies.
(C1]O), 1727.2 (C2 ]O), 1159.8 (C–O) cmꢀ1. 1H NMR (CDCl3)
(t, 1H, J¼7.9 Hz, H-60); 7.02 (d, 1H, J¼7.9 Hz, H-50); 6.67 (d, 1H,
J¼7.8 Hz, H-70); 4.47 (d, 1H, J¼10.2 Hz, CH2I); 4.30 (d, 1H,
J¼10.2 Hz, CH2I); 3.20–3.13 (m, 1H); 3.08 (s, 3H, NCH3); 2.99–2.86
(m, 1H); 2.80–2.73 (m, 1H); 2.49–2.40 (m, 1H) (H-2,3) ppm. 13C
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.12.029.
NMR (CDCl3)
d
177.2 (C-1); 175.6 (C-20); 143.4 (C-7a0); 139.0
(C-40); 132.9 (C-60); 127.3 (C-50); 124.2 (C-3a0); 109.7 (C-70); 84.1
(C-30); 29.6 (C-2); 28.9 (C-3); 27.8 (NCH3); 0.00 (CH2I) ppm. Anal.
Calcd for C13H12INO3: C, 43.72; H, 3.39; N, 3.92. Found: C, 43.40;
H, 3.73; N, 3.61.
References and notes
1. For a review of the Swern oxidation, see: Tidwell, T. T. Synthesis 1990, 857.
2. Bailey, P. D.; Cochrane, P. J.; Irvine, F.; Morgan, K. M.; Pearson, D. P. J.; Veal, K. T.
Tetrahedron Lett. 1999, 40, 4593.
3. For a preliminary communication dealing with the synthesis of compounds 9a–h,
see: Lo´pez-Alvarado, P.; Steinhoff, J.; Miranda, S.; Avendan˜o, C.; Mene´ndez, J. C.
Synlett 2007, 2792.
4. For representative examples, see: (a) Szabo-Pusztay, K.; Szabo, L. Synthesis
1979, 276; (b) Underwood, R.; Prasad, K.; Repic, O.; Hardtmann, G. Synth.
Commun. 1992, 22, 343; (c) Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M. J.
Am. Chem. Soc. 1993, 115, 9323. For a review of the synthesis of 2-oxindoles, see:
(d) Karp, G. M. Org. Prep. Proced. Int. 1993, 25, 481.
5. For early surveys of oxindole alkaloids, see: (a) Cordell, G. A. An Introduction to
Alkaloids: A Biogenetic Approach; Wiley-Interscience: New York, NY, 1981; (b)
Bindra, J. S. In Oxindole Alkaloids; Manske, R. H. F., Ed.; The Alkaloids-Chemistry
and Physiology; Academic: New York, NY, 1973; Vol. 14, p 83.
6. Abourriche, A.; Abboud, Y.; Maoufoud, S.; Mohou, H.; Seffaj, T.; Charrouf, M.;
Chaib, N.; Benamara, A.; Bontemps, N.; Francisco, C. Farmaco 2003, 58, 1351.
7. (a) Isolation: Cui, C. B.; Kakeya, H.; Okada, G.; Onose, R.; Osada, H. J. Antibiot.
1996, 49, 527; (b) Structure: Cui, C.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52,
12651; (c) Cytotoxic activity: Edmondson, S. E.; Danishefsky, S. J.; Sepp-Lor-
enzino, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147.
8. Tsuda, M.; Mugishima, T.; Komatsu, K.; Sone, T.; Tanaka, M.; Mikami, Y.; Shiro,
M.; Hirai, M.; Ohizumie, Y.; Kobayashi, J. Tetrahedron 2003, 59, 3227.
9. (a) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.; Moore, R. E. Mol.
Pharmacol. 1995, 47, 241; (b) Zhang, X.; Smith, C. D. Mol. Pharmacol. 1996, 49,
288.
10. For reviews of the chemistry of the welwitindolinones, see: (a) Avendan˜o, C.;
Mene´ndez, J. C. Curr. Org. Synth. 2004, 1, 65; (b) Mene´ndez, J. C. In Bioactive
Heterocycles V; Khan, M. T. H., Ed.; Topics in Heterocyclic Chemistry; Springer:
Berlin, Heidelberg, 2007; Vol. 11, p 63.
11. Tokunaga, T.; Hume, W. E.; Nagamine, J.; Kawamura, T.; Taiji, M.; Nagata, R.
Bioorg. Med. Chem. Lett. 2005, 15, 1789.
4.8.6. 3-[30-Hydroxy-10-methyl-40-nitromethyl-20-oxoindolin-30-
yl]propanoic acid lactone (42)
A mixture of sodium nitrite (48 mg, 0.69 mmol) and urea
(53 mg, 0.88 mmol), pre-dried in an oven at 90 ꢁC for 24 h, was
dissolved in dry dimethylformamide (4 ml), which required
a slight heating. To this solution, cooled to ꢀ38 ꢁC, was dropwise
added a solution of iodide 41 (142 mg, 0.40 mmol) in dry dime-
thylformamide (3 ml). The reaction mixture was stirred at ꢀ20 ꢁC
for 2 h, poured on water (10 ml) and with ethyl acetate (3ꢂ10 ml).
The combined organic layers were dried over anhydrous Na2SO4
and evaporated. The residue was chromatographed on silica gel,
eluting with
a 8:1 petroleum ether–ethyl acetate mixture,
affording 56 mg (60%) of nitro compound 42 and 19 mg (18%) of
alcohol 40, both as pale yellow oils. Characterization data for 42:
0
IR (NaCl): 1791.3 (C1]O), 1726.8 (C2 ]O), 1557.5 and 1373.1 (NO2),
1159.8 (C–O) cmꢀ1
.
1H NMR (CDCl3)
d
7.50 (t, 1H, J¼7.5 Hz, H-60);
7.23 (d, 1H, J¼7.5 Hz, H-50); 6.95 (d, 1H, J¼7.5 Hz, H-70); 5.57 (d, 1H,
J¼12.5 Hz, CH2NO2); 5.45 (d, 1H, J¼12.5 Hz, CH2NO2); 3.30–3.22
(m, 1H); 3.22 (s, 3H, NCH3); 2.86–2.58 (m, 3H) (H-2,3) ppm. 13C
NMR (CDCl3)
d
176.0 (C-1); 174.6 (C-20); 144.9 (C-7a0); 132.3 (C-60);
127.7 (C-40); 126.3 (C-50); 125.7 (C-3a0); 110.9 (C-70); 82.8 (C-30);
75.5 (CH2NO2); 31.7 (C-2); 27.7 (C-3); 27.0 (NCH3) ppm. Anal. Calcd
for C13H12N2O5: C, 56.52; H, 4.38; N, 10.14. Found: C, 56.23; H,
4.02; N, 9.87.
12. Zaveri, N. T.; Jiang, F.; Olsen, C. M.; Deschamps, J. R.; Parrish, D.; Polgar, W.; Toll,
L. J. Med. Chem. 2004, 47, 2973.
13. Alcaraz, M.; Atkinson, S.; Cornwall, P.; Foster, A. C.; Gill, D. M.; Humphries, L. A.;
Keegan, P. S.; Kemp, R.; Merifield, E.; Nixon, R. A.; Noble, A. J.; O’Beirne, D.;
Patel, Z. M.; Perkins, J.; Rowa, P.; Sadler, P.; Singleton, J. T.; Tornos, J.; Watts, A. J.;
Woodland, I. A. Org. Process Res. Dev. 2005, 9, 555.
14. Kikuchi, C.; Hiranuma, T.; Koyama, M. Bioorg. Med. Chem. Lett. 2002, 12, 2549.
15. Gallagher, G.; Lavanchi, P. G.; Wilson, J. W.; Hieble, J. P.; DeMarinis, R. M. J. Med.
Chem. 1985, 28, 1533.
16. Miranda, S.; Avendan˜o, C.; Mene´ndez, J. C. Open Org. Chem. J. 2007, 1, 1.
17. Some compounds 7 have been described in the literature: (a) Compound 7e:
Novikov, A. V.; Sabahi, A.; Nyong, A. M.; Rainier, J. D. Tetrahedron: Asymmetry
2003, 14, 911; (b) Compound 7g: Francis, P.; Smith, I.; Finnie, M. D. A. Biomed.
Mass Spectrom. 1980, 7, 294.
4.8.7. 3-(30-Hydroxy-10-methyl-40-nitromethyl-20-oxoindolin-30-
yl)-N-methyl-N-methoxypropanamide (43)
To a stirred suspension of N-methoxy-N-methylamine hydro-
chloride (25 mg, 0.26 mmol) in dry CH2Cl2 (8 ml), at 0 ꢁC and under
an argon atmosphere, was added a 1 M dimethylaluminium chloride
solution in hexanes (260 ml, 0.26 mmol). The reaction mixture left to
warm toroomtemperatureover1 h, while stirred. A solution ofnitro
lactone 42 (24 mg, 0.087 mmol) in dry CH2Cl2 (4 ml) was added and
stirring at 0 ꢁC was maintained for 4 h. The reaction mixture was
then poured onto pH 8 aqueous buffer (0.78 ml, 0.26 mmol) and was
filtered through Celite, which was washed with CHCl3. The com-
bined organic layers were dried over anhydrous Na2SO4 and evap-
orated, yielding 21 mg (75%) of Weinreb amide 43, as a pale yellow
oil. IR (NaCl): 1731.6 (C]O), 1557.2 and 1373.5 (NO2), 1260.3 (C–
18. Harrington, P. E.; Kerr, M. A. Synlett 1996, 1047.
19. Some compounds 8 have been described in the literature: (a) Compound 8c:
Harrington, P. E.; Kerr, M. A. Can. J. Chem. 1998, 76, 1256; (b) Compound 8e:
Bartoli, G.; Bartolacci, M.; Bosco, M.; Foglia, G.; Giuliani, A. J. Org. Chem. 2003,
68, 4594; (c) Compound 8f: Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem.dEur. J.
2004, 10, 484; (d) Compound 8h: Yadav, J. S.; Abraham, S.; Reddy, B. V. S.;
Sabitha, G. Synthesis 2001, 2165.
20. Wuest, F. R.; Kniess, T. J. Labelled Compd. Radiopharm. 2005, 48, 31.
21. The N-demethyl analogue of compound 9a has been previously obtained in 7%
yield by treatment of the corresponding alcohol with NCS in CH2Cl2 followed by
addition of aqueous NH4Cl. See: (a) Hino, T.; Miura, H.; Nakagawa, T.; Murata,
R.; Nakagawa, M. Heterocycles 1975, 3, 805; (b) Hino, T.; Miura, H.; Murata, R.;
Nakagawa, M. Chem. Pharm. Bull. 1978, 26, 3695.
O) cmꢀ1. 1H NMR (CDCl3)
d
7.37 (t, 1H, J¼7.5 Hz, H-60); 7.12 (d, 1H,
J¼7.5 Hz, H-50); 6.87 (d, 1H, J¼7.5 Hz, H-70); 6.01 (d, 1H, J¼12.5 Hz,
CH2NO2); 5.61 (d,1H, J¼12.5 Hz, CH2NO2); 3.69 (s, 3H, NOCH3); 3.21
(s, 3H, NCH3); 3.19 (s, 3H, NCH3); 3.10–2.95 (m, 1H); 2.50–2.40 (m,
1H); 2.10–1.95 (m, 2H) (H-2,3) ppm. 13C NMR (CDCl3)
173.6 (C-20); 134.7 (C-7a0); 129.0 (C-60); 126.0 (C-40); 124.5 (C-50);
d
176.5 (C-1);
22. For selected reviews and monographs on multicomponent reactions, see: (a)
Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (b) Bienayme´, H.;

1672
P. Lo´pez-Alvarado et al. / Tetrahedron 65 (2009) 1660–1672
Hulme, C.; Oddon, G.; Schmitt, P. Chem.dEur. J. 2000, 6, 3321; (c) Ugi, A. Pure
Appl. Chem. 2001, 73, 187; (d) Ugi, A. Molecules 2003, 8, 53; (e) Orru, R. V. A.; de
Greef, M. Synthesis 2003, 1471; (f) Zhu, J. Eur. J. Org. Chem. 2003, 1133; (g) Ra-
31. (a) For a synthesis of 31a from the corresponding 3-bromooxindole-3-pro-
pionic acid, see: Hinman, R. L.; Bauman, C. P. J. Org. Chem. 1964, 29, 2431.
Compound 31a has also been obtained in 54% yield by oxidative lactonization of
29a in the presence of thallium trinitrate in the course of work aimed at the
synthesis of tryptoquivaline G30; (b) For an alternative, experimentally more
complex synthesis of 31b involving a Ru3(CO)12-catalyzed intermolecular cy-
clocoupling of isatin, ethylene and carbon monoxide, see: Tobisu, M.; Chatani,
N.; Asaumi, T.; Amako, K.; Ie, Y.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2000,
122, 12663.
´
mon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (h) Multicomponent
Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, 2005; (i) Do¨mling,
A. Chem. Rev. 2006, 106, 17; (j) For a symposium in print on this topic, see:
Marek, I., Ed. Tetrahedron 2005, 67, 11299.
23. For a mechanistic proposal involving an intermediate related to 15, see: Raina,
S.; Singh, V. K. Tetrahedron 1995, 51, 2467.
24. Nozoye, T.; Shibanuma, Y.; Nakai, T.; Hatori, H. Chem. Pharm. Bull. 1988, 36, 4980.
25. McComas, C. C.; Perales, J. B.; Van Vranken, D. L. Org. Lett. 2002, 3, 2337.
26. See, for instance: (a) Lawson, W. B.; Patchornik, A.; Witkop, B. J. Am. Chem. Soc.
1960, 82, 5918; (b) Kornet, M. J.; Thio, A. P.; Thornstenson, J. H. J. Pharm. Sci.
1977, 66, 1022.
32. Compound 31c has been previously obtained in two steps (31% overall yield)
by oxidation of non-commercially available 1-hydroxy-1,2,3,4-tetrahydrocar-
bazole with iodine pentoxide (I2O5) to a lactol, followed by PCC oxidation. See:
Yoshida, K.; Goto, J.; Ban, Y. Chem. Pharm. Bull. 1987, 35, 4700.
33. Labroo, R. B.; Cohen, L. A. J. Org. Chem. 1990, 55, 4901.
27. Sto¨hrer, G. J. Heterocycl. Chem. 1976, 13, 157.
34. (a) Olah, G. A.; Narang, S. C.; Balaram Gupta, B. G.; Malhotra, R. J. Org. Chem.
1979, 44, 1247; (b) Olah, G. A.; Balaram Gupta, B. G.; Malhotra, R.; Narang, S. C.
J. Org. Chem. 1980, 45, 1638.
28. (a) Ohnuma, T.; Kasuya, H.; Kimura, Y.; Ban, Y. Heterocycles 1982, 17, 377; (b)
Ohnuma, T.; Kimura, Y.; Ban, Y. Tetrahedron Lett. 1981, 22, 4969. However data
for 31a are not reported in these references.
35. Kornblum, N. Org. React. 1962, 12, 101.
29. Bu¨ chi, G.; DeShong, P. R.; Katsumura, S.; Sagimura, Y. J. Am. Chem. Soc. 1979,
101, 5084.
30. (a) Palla, G.; Marchelli, R.; Casnati, G.; Dossena, A. Gazz. Chim. Ital.1982, 112, 535;
(b) Labroo, R. B.; Labroo, V. M.; King, M. M.; Cohen, L. A. J. Org. Chem.1991, 56, 3637.
36. Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685.
37. For some recent examples, see: (a) Brewer, M. Tetrahedron Lett. 2006, 47, 7731;
(b) Javed, M. I.; Brewer, M. Org. Lett. 2007, 9, 1789.
38. Garden, S. J.; da Silva, R. B.; Pinto, A. C. Tetrahedron 2002, 58, 8399.