A convenient preparation of furo[2,3-b]indoles by conjugated addition of organomagnesium reagents to 2-hydroxyindolylidenemalonates

Article abstract of DOI:10.1016/S0040-4020(03)00336-3

The chelate-controlled conjugated addition of Grignard reagents to 2-hydroxyindolylidenemalonates was studied as a means of preparing 3a-alkyl-3-methoxycarbonyl-2-oxofuro[2,3-b]indoles in one or two steps. In addition to the alkylorganometallic group variation, the effects of substitution at the aromatic ring on the reaction outcome were established. The indolylidenemalonates were found to be less reactive than the analogous indolylidenecyanoacetates.

Full text of DOI:10.1016/S0040-4020(03)00336-3

Tetrahedron 59 (2003) 2843–2853
A convenient preparation of furo[2,3-b]indoles by conjugated
addition of organomagnesium reagents to
2
-hydroxyindolylidenemalonates
a,*
a
Martha S. Morales-R ´ı os, Norma F. Santos-Sanchez, M. Jonathan Fragoso-Vazquez,
a,b
´
´
David Alagille, J. Roberto Villag o´ mez-Ibarra and Pedro Joseph-Nathan
a
b
a
a
Departamento de Qu ´ı mica, Centro de Investigaci o´ n y de Estudios Avanzados del Instituto Polit e´ cnico Nacional, Apartado 14-740, M e´ xico,
D.F. 07000, Mexico
Centro de Investigaciones Qu ´ı micas, Universidad Aut o´ noma del Estado de Hidalgo, Apartado 1-622, Pachuca, Hidalgo 42001, Mexico
b
Received 27 January 2003; revised 1 March 2003; accepted 1 March 2003
Abstract—The chelate-controlled conjugated addition of Grignard reagents to 2-hydroxyindolylidenemalonates was studied as a means of
preparing 3a-alkyl-3-methoxycarbonyl-2-oxofuro[2,3-b]indoles in one or two steps. In addition to the alkylorganometallic group variation,
the effects of substitution at the aromatic ring on the reaction outcome were established. The indolylidenemalonates were found to be less
reactive than the analogous indolylidenecyanoacetates. q 2003 Published by Elsevier Science Ltd.
1
. Introduction
2-hydroxyindolylidenecyanoacetate 1 with alkylorgano-
metallic reagents resulted in the syntheses of 3-cyano-2-
3
,4
The furo[2,3-b]indole ring system is a structural unit in
1
oxofuro[2,3-b]indoles 3.
This process started by the
natural products. Due to its inherent biological activity and
the use as synthetic target of numerous natural compounds,
there is a demand for general synthetic methods for this ring
chelate-controlled conjugated Grignard addition to 1, leading
to structures 2 that cyclize to give 3. Further rearrangement
of the 3-cyano-2-oxofuro[2,3-b]indoles 3 via the g-lactone
imines 4 gave the 2-amino-3-carbomethoxyfuro[2,3-b]indoles
2
system. We have previously reported that the reaction of
Scheme 1.
Keywords: indolylidenemalonates; indolylidenecyanoacetates; furo[2,3-b]indoles; chelate-controlled conjugated Grignard addition; X-ray analysis.
*
Corresponding author. Tel.: þ52-55-5747-7112; fax: þ52-55-5747-7137; e-mail: smorales@mail.cinvestav.mx
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00336-3

2844
M. S. Morales-R ´ı os et al. / Tetrahedron 59 (2003) 2843–2853
Scheme 2.
5
3
. The acid-catalyzed hydrolysis of 5 finally afforded the
4
-methoxycarbonyl-2-oxofuro[2,3-b]indoles 6 (Scheme 1).
and requires chelate-controlled addition. This highly
ordered transition state influences the stereochemical
outcome of the process, which occurs with excellent
3
While the conjugated addition reaction of an organometallic
to a,b-unsaturated carbonyl compounds is a versatile
carbon–carbon bond forming reaction, application of this
6
method to a,b-unsaturated nitriles and esters is difficult
chemo- and stereoselectivity. In connection with our
work on the total syntheses of indole alkaloids and
5
8
related compounds,
practical procedure for an efficient preparation of
we required
a
short and
7
2
Table 1. Products and yields (%) in the reaction of 7–11, 1a and 1b with R MgX according to general procedure
Entry
Substrate
Reagent
Conditions
Temperature (8C)
Alkylation at C-3
Indolines Furoindoles
Alkylation at Ar
Indoles Oxindoles
2
R
X
Time (h)
1
2
3
4
5
6
7
8
9
7
7
Me
Me
Et
I
I
25
0
25
25
0
25
25
25
25
0
25
0
278
0
278
278
278
5
5
5
5
5
5
5
4
2
2
3
3
3
3
3
2
2
12 (49)
12 (38)
13 (48)
14 (22)
14 (19)
–
–
–
–
–
–
–
–
22 (15)
22 (16)
–
–
–
a
b
7
7
Br
Br
Br
Br
Br
I
I
I
I
Br
Br
Br
Br
Br
Br
6b (16)
6c (41)
6c (40)
6d (49)
6e (,5)
–
–
–
–
3a (60)
3a (30)
3b (64)
3b (50)
3c (58)
3d (62)
17þ18 (,2)
i-Pr
i-Pr
Bn
t-Bu
Me
Me
Me
Me
Et
19 (9)
19 (9)
c
7
c
7
20 (8)
21 (9)
–
d
7
22 (18)þ23 (18)
8
9
–
–
–
–
–
–
–
–
–
–
24 (55)
25 (48)
10
11
12
13
14
15
16
17
10
11
1a
1a
1a
1a
1b
1b
15 (58)
16 (18)
–
26 (12)
27 (6)
–
–
–
–
–
–
d
Et
Bn
Bn
Et
–
–
–
–
e
Bn
a
b
c
d
e
Unreacted starting material was recovered in 20% yield.
Yield of the isomeric mixture.
Unreacted starting material was recovered in 7% yield.
Unreacted starting material was recovered in 40% yield.
Unreacted starting material was recovered in 12% yield.

M. S. Morales-R ´ı os et al. / Tetrahedron 59 (2003) 2843–2853
2845
3
a-alkyl-3-methoxycarbonyl-2-oxofuro[2,3-b]indoles 6. In
this paper we analyze the scope and limitations of the
conjugated addition of alkylorganometallic reagents to
indolylidenemalonates 7–11, to give in one or two steps,
the desired furoindoles 6. In addition, we compare the
reactivity of indolylidenemalonates 7–11 with that of
indolylidenecyanoacetates 1a and 1b towards the Grignard
addition reaction.
2
. Results and discussion
Our interest in indolylidenemalonates 7–11 for use in the
synthesis of 3a-alkyl-3-methoxycarbonyl-2-oxofuro[2,3-b]-
indoles 6 led us to explore the regio- and stereoselectivity of
the addition of organomagnesium reagents to these
compounds (Scheme 2). The reaction could lead to addition
of the organomagnesium reagents to either the carbonyl
ester groups or to the vinylic C-3 carbon of 7–11. The
required indolylidenemalonates 7–11 were prepared by
9
reaction of 3-indolylmalonates with bromine in CCl4
followed by hydrolysis during the aqueous workup
1
0
procedure, except compound 9 which was obtained in
low yield by oxidation with NBS. Indolylidenecyano-
acetates 1a and 1b were prepared by oxidation of
3
our previous reported procedure.
-indolylcyanoacetates with CrO in AcOH according to
3
3
2
.1. Effect of alkylorganometallic group
All reactions of indolylidenemalonate 7 were carried out
under an argon atmosphere, in anhydrous THF/ether with
4
equiv. of the organomagnesium reagents (Table 1). When
the reaction mixtures were stirred at 258C for 5 h, moderated
yield of conjugated additions of methyl, ethyl, i-propyl and
benzyl groups to indolylidenemalonate 7 were obtained.
Under these conditions, the initially formed 2-hydroxy-
indolines cyclize to the corresponding g-lactones 6 in
variable yields, excepting 12, and in no case 1,2 addition
products were produced (entries 1, 3, 4, 6). The spontaneous
partial cyclization is driven by the size of the angular alkyl
substituent, which in the case of the methyl group is
meaningless. The resulting product distribution demon-
strated a significant dependence of the ratio of indolines vs
furoindoles as a function of the bulkiness of the alkyl group
of the Grignard reagent. In fact, increasing the effective size
of the alkyl group resulted in enhancement of annulation
product formation, except for the t-Bu group, for which no
2
-hydroxyindolenine is obtained. Thus, when 7 was reacted
with MeMgI only indoline 12 was isolated in 49% yield,
together with a by product identified as oxindole 22 (entry
1). Repetition of this reaction at lower temperature produced
smaller amounts of 12 and unreacted starting material was
recovered in 20% (entry 2).
The use of more sterically hindered Grignard reagents,
such as EtMgBr and i-PrMgBr, led to a mixture of
the corresponding indolines 13 and 14 along with the
furoindoles 6b and 6c, respectively (13/6b¼3:1, 64% and
1
4/6c¼1:2, 63%) (Table 1, entries 3, 4). Reaction with
Figure 1. X-Ray structures of 12 (top), 13 (center), and 15 (bottom).
i-PrMgBr showed little variation on the annulation product
ratio when conducted at 08C (entry 5). Also formed in small
amounts are the corresponding benzene ring alkylated

2846
M. S. Morales-R ´ı os et al. / Tetrahedron 59 (2003) 2843–2853
Table 2. X-Ray data collection and processing parameters for furoindoles 3b and 3d, and indolines 12, 13 and 15
Compound
3b
3d
12
13
15
Formula
C
20
H
15
N
2
O
4
F
22
C H
20
N
2
O
5
16
C H
19NO
7
C
17
H21NO
7
C
17
H
8
20NO Br
Size (mm)
Crystal system
Space group
0.16£0.42£0.60
0.20£0.30£0.45
Triclinic
P1(bar)
10.390(4)
11.184(3)
18.927(2)
104.72(2)
92.02(2)
107.52(2)
2013.5
0.45£0.32£0.20
Triclinic
P1(bar)
8.643(3)
8.861(3)
11.474(4)
84.191(15)
96.525(13)
111.339(12)
811.5
0.31£0.39£0.85
Triclinic
P1(bar)
8.617(1)
8.756(1)
13.106(2)
75.081(4)
76.278(4)
66.606(4)
866.7
0.29£0.23£0.29
Monoclinic
P2/c
14.5763(6)
10.2888(4)
13.3425(6)
90.0
112.318(1)
90.0
1851.1
1.60
Monoclinic
1
P2 /n
˚
a (A)
9.292(1)
11.267(5)
16.926(2)
90.0
91.043(9)
90.0
1771.7
1.373
4
˚
b (A)
˚
c (A)
a (8)
b (8)
g (8)
3
˚
V (A )
D
3
calcd (g/cm )
Z-value
m (mm
T (K)
1.29
4
0.77 (Mo Ka)
293
1.38
2
0.93 (Cu Ka)
293
1.35
2
0.11 (Mo Ka)
294
4
2
1
)
0.87 (Mo Ka)
295
2.27 (Mo Ka)
293
2
Total reflections
Unique reflections
u
range (8)
4.72–54.95
4269
2214
2.43–54.96
5155
4787
3.89–55.00
2001
1856
1.63–26.06
5487
3252
1.51–26.01
10022
3626
R
I$3s(I)
Parameters
int (%)
3.9
2214
293
2.4
4548
620
7.2
1644
246
2.5
2463
263
3.5
2325
324
R (%), R
rmax (e A
CCDC deposition
w
˚
(%)
3
3.9, 10.1
0.81
204984
4.9, 13.3
0.22
204985
5.2, 14.4
0.23
204986
4.8, 12.7
0.21
204987
3.3, 6.2
0.40
204988
2
)
indoles 17–19. Furoindoles 6b and 6c were formed by
intramolecular cyclization of 13 and 14, respectively.
Alternatively, conversions of 12–14 to 6a–c were con-
ducted in quantitative yields by treatment with KOH in THF
at room temperature for 20 min (Scheme 2). When a more
bulky organomagnesium reagents was used such as
BnMgBr, furoindole 6d was obtained in 49% yield,
unaccompanied by detectable amounts of the corresponding
C-3 alkylated indoline (entry 6). The reaction also yielded
the alkylated indole 20 (8%) and dibenzyl (11%), which
resulted from benzyl bromide Wurtz-type coupling. Finally,
the use of highly hindered tert-butyl magnesium bromide
was ineffective for the formation of 6e, the reaction yielded
alkylated indole 21 and a mixture of oxindoles 22 and 23
respectively (Fig. 1). Crystal data are reported in Table 2. In
1
1
agreement, MMX calculations for 12–14 predict the
stereoisomer having the C-2 hydroxyl and the C-3 alkyl
groups in a syn relationship to be 0.7, 1.4 and 0.3 kcal/mol
lower in energy than the corresponding anti isomer,
respectively. The stereoselective formation of 12–14
would be explained by a chelate-controlled addition
involving the hemiaminal hydroxyl oxygen atom. This
means that the cis fused furoindoles 6a–f arose via
intramolecular annulation of the g-hydroxyester after
inversion of the hemiaminal C-2 carbon, via a hemiaminal/
1
2
aldehyde ring-chain tautomerism.
2.2. Effect of substituents on the benzene ring
(
entry 7). The C-4 and C-6 orientation of the ring-alkylated
products is consistent with the vinylogous conjugate
addition reaction.
Substitution at the aromatic ring produced results that
differed significantly from those of the unsubstituted
indolylidenemalonate 7 (Table 1). Treatment of the 5-F
indolylidenemalonate 8 with MeMgI at 258C for 5 h,
surprisingly, gave only simple N-decarbomethoxylated
tautomeric product 24 in 55% yield, without any addition
product formation (entry 8). A similar substrate scope was
observed for reaction of 5-MeO indolylidenemalonate 9
with MeMgI affording oxindole 25 in 48% yield (entry 9).
While the NMR spectra of furoindoles 6a–c were in
4
b
accordance with published data, furoindoles 6d–f and
indolines 12–14 were fully characterized by spectroscopic
and X-ray analyses. As in the case of furoindoles 6a–c,
CDCl solutions of 6d and 6f also proved to be mixtures of
3
C-3 endo/exo epimers, at the equilibrium, the exo isomer is
favored in a 3:2 ratio, whereas 6e, carrying a highly
hindered tert-butyl group, appears as a single C-3 endo
epimer. The relative stereochemistry was determined by
1
The oxindole 25 was characterized in the H NMR spectrum
by the presence of a broad singlet at d 8.56 owing to the
N–H group, while the aliphatic C–H signals occurred at d
1
3
3
NOESY experiments. The C NMR spectrum of indoline
2, used as model compound, showed the methyl-substi-
tuted C-3 carbon at 48.9 ppm and the C-8 carbon at
4.21 and 4.05 ppm as doublets, with a J(H–H) coupling of
4.1 Hz. An intense stretching vibration at 1732 cm2 in the
IR spectrum indicates that a carbonyl group is now part of
the heterocyclic ring. Since the corresponding C-3 alkylated
indoles could not be detected in the reaction products, it
suggests that the rate of the conjugated addition to 8 and 9
would be very slow, and/or the rate of the isomerization
would be increased, resulting in complete tautomerization
under the basic reaction conditions. These products
must arise by abstraction of the hemiaminal proton
from 2-alkoxyindolylidene 28, followed by tautomerization
1
1
1
5
the presence of a C3–C8 single bond. A single exclusive
8.9 ppm, with a J(C–H) coupling of 133.4 Hz confirming
1
relative configuration in 12–14 was evidenced by H NMR.
The relative configuration between C(2) and C(3) of 12 and
1
3, established by X-ray crystal structure analysis, indicated
that the hydroxyl group at C-2 and the corresponding alkyl
group at C-3 are on the same side of the pyrrole ring with
O2–C2–C3–C15 torsion angle values of þ2.28 and 23.78,

M. S. Morales-R ´ı os et al. / Tetrahedron 59 (2003) 2843–2853
2847
Scheme 4.
that C-3 in indolylidenemalonates 8 and 9 resonates ca.
2 ppm highfield relative to C-3 of the corresponding
1
indolylidenecyanoacetates 1a and 1b. In accord with this
assertion, we found that the reaction of 5-methoxyindolyl-
idenecyanoacetate 1b with 4 equiv. of RMgX (R¼Et and
Bn) was completed after only 2 h at 2788C, even for the
somewhat hindered benzyl group. These reactions occurred
with high regioselectivity to give only the corresponding
furo[2,3-b]indoles 3c and 3d in 58 and 62% yield,
respectively (entries 16 and 17). When the 5-fluoro
derivative 1a was reacted with 4 equiv. of RMgBr (R¼Et,
Bn) at 2788C for 3 h the corresponding furo[2,3-b]indoles
3a and 3b were formed as the only products in 30 and 50%
yield, respectively (Table 1, entries 13 and 15). In both
cases the presence of the fluorine atom retards the
addition reaction, and unreacted 5-fluoroindolylidene 1a
was recovered in 40 and 12%, respectively. However, with
increased reaction temperature the yields of 3a and 3b
increased to 60 and 64%, respectively (entries 12 and 14).
Scheme 3.
to 29, driving the reaction toward oxindoles 22–27,
Scheme 3.
A similar treatment of 6-bromo-5-methoxyindolylidene-
malonate 11 with MeMgI gave the corresponding con-
jugated addition product 16, along with the
N-decarbomethoxylated oxindole 27 in low yields (18 and
6
% yields, respectively, entry 11). When the same reaction
was conducted at 08C, only unreacted starting material was
recovered. In contrast, reaction of the 4-bromo-5-methoxyl
congener 10, under similar reaction conditions, gave the
conjugated addition product 15 in a substantially increased
yield (58%, entry 10). Thus, the 4-bromine substituent plays
a pivotal role in the addition reaction, the effect being
believed to be due to a transition state in which a cyclic
chelate involves the hemiaminal hydroxyl group and the
bromine atom. X-Ray diffraction analysis of 15 (Fig. 1)
indicated that this compound exhibits the C-2 hydroxyl
group and the C-3 alkyl groups in a syn relationship, with a
O2–C2–C3–C-15 torsion angle value of 219.28.
Attempted cyclization reactions of indolines 15 and 16,
using KOH in THF at room temperature for 20 min, yielded
recovered starting material 15 and the corresponding
furoindole 6f, in quantitative yield, respectively. These
results suggest that the failure of indolylmalonate 15 to
undergo annulation is due to the steric inhibition of the
hemiaminal/aldehyde ring-chain tautomerism posed by
the bromine atom at C-4, thereby preventing the inversion
of the hemiaminal C-2 carbon.
The furo[2,3-b]indoles 3a–d were obtained as mixtures of
two equilibrated epimers at the C-3 chiral center. The
relative stereochemistry at the three chiral centers C-3, C-3a
and C-8a was elucidated mainly on the basis of NOESY
correlations. Thus, NOESY cross-peaks for H-3/(C3a)R
(R¼Et, Bn) indicated a 1,2-anti relationship of (C3a)R/
(C3)CN, while for H-8a/(C3a)R the corresponding NOESY
peaks indicated a cis B/C ring fusion. The epimeric C-3
endo/exo ratio (at 258C) was determined by comparing the
1
respective H-3 signals in the H NMR spectra (CDCl
)
3
whose chemical shift values are larger for the endo isomers
than for the exo isomers. At equilibrium, the endo isomer is
favored in a 7:3 ratio for 3a and 3c, and 9:2 for 3b and 3d, in
13
Table 3. C NMR chemical shifts of the exocyclic double bond of
indolenines 1a, 1b, 7–11
13
2.3. Reactions of indolylidenecyanoacetates with
organomagnesium reagents
Compound
C (d)
C-3
C-8
At this point, of particular interest was to compare the
reactivity of indolylidenemalonates with that of indolyl-
idenecyanoacetates towards the Grignard addition reaction.
Indolylidenecyanoacetates 1a and 1b (Scheme 4) were
expected to be better substrates than the corresponding
indolylidenemalonates 8 and 9 for the nucleophilic addition,
because the ethylenic b carbon atom in the former
compounds is more electron-deficient, due to a more
extensive delocalization of the p-electrons, than in the
a
1
1b
a
162.4
163.6
149.2
150.0
151.4
148.6
148.6
97.3
96.0
a,b
c,d
7
8
9
1
1
118.8
119.6
118.4
123.4
118.9
a,d
a
c,d
c,d
0
1
a
b
c
d
In CDCl
From Ref. 3.
In DMSO-d
From Ref. 10.
3
.
6
.
1
3
latter compounds. In fact, inspection of Table 3 reveals

2848
M. S. Morales-R ´ı os et al. / Tetrahedron 59 (2003) 2843–2853
hydroxyl and bromine atoms. A study of substituent effects
has provided information as to the scope as well the utility
of the reaction. Less reactive or highly hindered Grignard
reagents showed greater propensity for oxindole formation.
4. Experimental
4.1. General
All reactions were carried out under an argon atmosphere
with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Tetrahydrofuran and
ethyl ether were distilled from sodium using benzo-
phenone as indicator. Yields refer to chromatographically
1
and spectroscopically ( H) homogeneous materials. All
reagents were purchased at highest commercial quality and
used without further purification.
Melting points are uncorrected. IR spectra were recorded on
1
13
a Perkin–Elmer 16F PC FT spectrophotometer. H and
C
NMR spectra were measured on Varian XL-300GS and
Mercury spectrometers working at 300 and 75 MHz,
respectively. Chemical shifts are reported in ppm downfield
from tetramethylsilane. EIMS were obtained on Hewlett–
Packard 5989A or Varian Saturn 2000 mass spectrometers.
HRMS were measured on a Jeol JMS-SX 102A spectro-
meter. Analytical thin-layer chromatography was performed
on silica gel F254 coated aluminum sheets. Flash chroma-
tography was performed using silica gel 60 (230–400 mesh)
from Aldrich. X-Ray data for 3a, 3d, 13 and 15 were
collected on a Bruker Smart 6000 CCD diffractometer using
crystals grown from DMSO. The structures were solved and
refined by using SHELX97. X-Ray data for 12 were
collected on a Nicolet R3m diffractometer. The structure
was solved by direct methods using SHELX86. Crystal data,
collection and refinement parameters are given in Table 2.
Figure 2. X-Ray structures of 3b (top), and 3d (bottom).
contrast to that observed for furoindoles 6a–d and 6f in
which the exo epimer is the preferred one.
4.1.1. Methyl 2-(Z-1-carbomethoxy-5-fluoro-2-hydroxy-
1,2-dihydroindol-3-ylidene)cyanoacetate (1a). The title
Very slow crystallization of furoindoles 3b and 3d from
methyl sulfoxide provided the endo isomers shown in
Figure 2. Several features of the structures deserve
comment. First, the crystal structures of 3b and 3d are
characterized by a folded shape along the C3a–C8a bond,
with a cis-like fusion of the two five-membered rings. The
s-trans to H4 conformation of the benzyl group of 3b may
be readily observed from the C3b–C3a–C12–C13 torsion
angle of 217398 whereas for 3d the C3b–C3a–C14–C15
torsion angle of 258.88 indicates a s-cis conformation for
the same group. In addition, in 3d the 5-O-methyl group is
oriented s-trans to H4, and the carbamate N8–C10 bond
shows an s-cis geometry, which in 3b is s-trans oriented.
compound was prepared from methyl 2-(1-carbomethoxy-5-
1
4,15
fluoro-1H-indol-3-yl)cyanoacetate
gous to the previously described synthesis of 1b in 67%
yield. Yellow crystals, mp 173–1758C (CHCl ); R 0.24
by a method analo-
3
3
f
(EtOAc–hexane 2:3); IR (CHCl ) n
3
3566, 3022, 2224,
max
1728 cm2
1
;
1
H NMR (CDCl ) d 8.15 (1H, dd, J¼8.6,
3
2.7 Hz, H4), 8.00 (1H, br s, H7), 7.32 (1H, ddd, J¼9.0, 8.4,
2.7 Hz, H6), 6.81 (1H, br s, H2), 4.46 (1H, br s, OH), 3.96
(3H, s, CO Me), 3.94 (3H, s, NCO Me); C (CDCl ) d
1
3
2
2
3
162.9 (CO Me), 162.4 (C3), 158.8 (d, J¼244.8 Hz, C5),
2
151.6 (NCO Me), 144.1 (C7a), 124.4 (d, J¼23.8 Hz, C6),
2
122.2 (C3a), 116.8 (d, J¼7.7 Hz, C7), 114.8 (CN), 112.5 (d,
J¼25.5 Hz, C4), 97.3 (C8), 83.4 (C2) 53.7 (CO Me), 53.5
2
þ
þ
(NCO Me); EIMS m/z 306 (M , 43), 247 (100), 215 (44);
HRMS m/z 306.0656 (M , C H N O F requires
2
3. Conclusions
1
4 11 2 5
306.0652).
The synthesis of 3a-alkyl-3-methoxycarbonyl-2-oxo-
furo[2,3-b]indoles has been accomplished in moderated
yield with complete regio- and stereoselectivity. The yield
of the initial conjugated addition of the organomagnesium
reagents to the indolylidenemalonate derivative is strongly
dependent not only on electronic effects but also on the
chelation of the Grignard reagent to the neighboring
4.1.2. Dimethyl 2-(1-carbomethoxy-2-hydroxy-5-meth-
oxy-1,2-dihydroindol-3-ylidene)malonate (9). To a solu-
tion of dimethyl 2-(1-carbomethoxy-5-methoxy-1H-indol-
3-yl)malonate (70 mg, 0.21 mmol) in CCl (12 mL) was
4
added N-nitroso-N-methylurea (5 mg, 0.05 mmol) and NBS
(80 mg, 0.45 mmol) at room temperature. The mixture was
1
0

M. S. Morales-R ´ı os et al. / Tetrahedron 59 (2003) 2843–2853
2849
stirred at this temperature for 2 h, diluted with CH Cl
2
53.4 (NCO Me), 52.6 (C3, CO Me), 43.3 (CH Ph); EIMS
2
2
2
2
þ
(M , C H NO requires 381.1212).
(
Na SO and evaporated. The residue was purified by flash
100 mL), washed with brine (3£20 mL), dried over
m/z 381 (M , 88), 264 (33), 246 (100); HRMS m/z 381.1214
þ
2
4
21 19
6
chromatography on silica gel to give dimethyl 2-(4-bromo-
1
0
1
1
-carbomethoxy-5-methoxy-1H-indol-3-yl)malonate (15 mg,
7%) and the oxidized product 9 (10 mg, 13%). Starting
4.2.2. Dimethyl 3a-tert-butyl-2-oxo-2,3,3a,8a-tetrahydro-
8H-furo[2,3-b]indole-3,8-dicarboxylate (6e). Prepared
from 7 as colorless oil; R 0.59 (EtOAc–hexane 2:3); IR
material was also recovered from the chromatography
45 mg, 64%). Compound 9, a yellow solid, showed mp
46–1488C (EtOAc); R 0.19 (EtOAc–hexane 2:3); IR
f
3020, 1788, 1734 cm2 ; H NMR (CDCl ) d
1
1
(
1
(CHCl ) n
3
max
3
7.90 (1H, br, H7), 7.33 (1H, td, J¼7.8, 1.4 Hz, H6), 7.11
(1H, dd, J¼7.8, 1.4 Hz, H4), 7.02 (1H, td, J¼7.8, 1.1 Hz,
H5), 6.29 (1H, br s, H8a), 4.06 (1H, s, H3), 3.94 (3H, br s,
f
2
1
1
(
CHCl ) n
3
3572, 3012, 1720, 1238 cm
max
; H NMR
(CDCl ) d 7.94 (1H, br s, H7), 7.05 (1H, dd, J¼9.0, 2.6 Hz,
H6), 6.85 (1H, br s, H4), 6.68 (1H, br s, H2), 4.34 (1H, br s,
3
1
3
NCO Me), 3.37 (3H, s, CO Me), 1.07 (9H, s, 3 Me);
2
C
2
OH), 3.91 (3H, br s, NCO Me), 3.96 and 3.87 (6H, 2s,
2
(CDCl ) d 170.5 (C2), 167.1 (CO Me), 152.4 (NCO Me),
3 2 2
1
3
2
1
1
CO Me), 3.77 (3H, s, OMe); C (CDCl ) d 166.1 and
2
141.8 (C7a), 129.8 (C6), 128.2 (C3b), 125.7 (C4), 123.1
(C5), 115.3 (C7), 93.7 (C8a), 62.0 (C3a), 53.7 (C3), 53.5
(NCO Me), 52.5 (CO Me), 36.8 (CMe ), 25.4 (CMe );
3
64.6 (2CO Me), 155.8 (C5), 152.3 (NCO Me), 151.4 (C3),
2
2
40.6 (C7a), 122.8 (C3a), 121.3 (C6), 118.4 (C8), 116.5
2
2
3
3
þ
(
5
(
C7), 108.8 (C4), 83.0 (C2), 55.6 (OMe), 53.1 (NCO Me),
2
EIMS m/z 347 (M , 10), 305 (65), 246 (100), 188 (89);
þ
þ
100); HRMS m/z 351.0958 (M , C H NO requires
2.9 (2CO Me); EIMS m/z 351 (M , 12), 292 (30), 232
2
HRMS m/z 347.1369 (M , C H NO requires 347.1361).
18 21
6
þ
1
6
17
8
3
51.0954).
4.2.3. Dimethyl 2-(1-carbomethoxy-2-hydroxy-3-methyl-
,3-dihydro-1H-indol-3-yl)malonate (12). Prepared from
7 as colorless crystals, mp 142–1448C (Et O); R 0.38
2
4
.2. General procedure using Grignard reagents
2
f
(EtOAc–hexane 2:3); IR (CHCl ) n
1734 cm ; H NMR (CDCl ) d 7.75 (1H, br s, H7), 7.49
3594, 3020,
max
3
2
1 1
To a stirred suspension (at the temperature indicated in
Table 1) of the Grignard reagent, prepared from the
corresponding alkyl halide (14.0 mmol) and Mg turnings
3
(1H, br s, OH), 7.23 (1H, td, J¼7.6, 0.9 Hz, H6), 7.12 (1H,
dd, J¼7.6, 0.9 Hz, H4), 7.01 (1H, td, J¼7.6, 0.9 Hz, H5),
(
0.34 g, 14 mmol) in dry ether (50 mL) under argon, was
6.32 (1H, d, J¼4.3 Hz, H2), 3.90 (3H, br s, NCO Me), 3.68
2
added dropwise a solution of the appropriate indolylidene-
malonate 7–11 (3.5 mmol) or indolylidenecyanoacetate 1a
and 1b (3.5 mmol) in THF (50 mL) over a 0.5 h period.
After the reaction mixture was left for the reaction time and
temperature indicated in Table 1, the resulting suspension
and 3.49 (6H, 2s, 2CO Me), 3.61 (1H, s, H8), 1.56 (3H, s
2
1
3
C3–Me); C (CDCl ) d 167.6 and 167.3 (2CO Me), 153.0
3
2
(NCO Me), 139.7 (C7a), 133.8 (C3a), 128.8 (C6), 123.4
2
(C4), 123.1 (C5), 114.6 (C7), 86.9 (C2), 58.9 (C8), 52.9
(NCO Me), 52.4 (2CO Me), 48.9 (C3), 18.0 (Me); EIMS
2
2
þ
HRMS m/z 337.1160 (M , C H NO requires 337.1162).
was quenched with saturated NH Cl solution (10 mL),
4
m/z 337 (M , 8), 305 (34), 287 (41), 260 (97), 202 (100);
þ
and diluted with EtOAc (150 mL). The organic layer was
separated, washed with brine (2£15 mL), dried over
Na SO and evaporated. The reaction products were then
1
6
19
7
4.2.4. Dimethyl 2-(1-carbomethoxy-3-ethyl-2-hydroxy-
2,3-dihydro-1H-indol-3-yl)malonate (13). Prepared from
7 as colorless crystals, mp 117–1188C (Et O–hexane); Rf
2
2
4
purified by flash column chromatography on silica gel
EtOAc–hexane 1:4). Products and yields are reported in
Table 1. Compounds 6b and 6c were identical in all respects
(
0.22 (EtOAc–hexane 1:3); IR (CHCl ) n
3
1734 cm ; H NMR (CDCl ) d 7.64 (1H, br s, H7), 7.22
3
3594, 3012,
max
4
b
21 1
to the products previously obtained.
(
1H, td, J¼7.6, 1.2 Hz, H6), 7.10 (1H, br d, J¼7.6 Hz, H4),
4
8
.2.1. Dimethyl 3a-benzyl-2-oxo-2,3,3a,8a-tetrahydro-
H-furo[2,3-b]indole-3,8-dicarboxylate (6d). Prepared
7.00 (1H, td, J¼7.6, 1.1 Hz, H5), 6.49 (1H, d, J¼3.8 Hz,
H2), 3.90 (3H, s, NCO Me), 3.85 (1H, s, H8), 3.73 and 3.47
2
from 7 as a C-3 diastereomeric mixture (2:3 endo–exo
1
(6H, 2s, 2CO Me), 2.24 and 1.76 (2H, 2 dq, J¼14.5, 7.2 Hz,
2
13
ratio by H NMR analysis), colorless solid; mp 127–1298C
Et O–hexane); R 0.28 (EtOAc–hexane 1:3); IR (CHCl )
CH ), 0.83 (3H, t, J¼7.2 Hz); C (CDCl ) d 167.6 and
167.3 (2CO Me), 153.7 (NCO Me), 140.6 (C7a), 131.7
2 2
2
3
(
nmax 3020, 1792, 1732, 1444 cm ; (major exo-isomer) H
2
f
3
2
1
1
(C3a), 128.5 (C6), 123.5 (C4), 122.7 (C5), 114.2 (C7), 87.3
(C2), 58.0 (C8), 52.8 (NCO Me), 52.5 and 52.2 (2CO Me),
NMR (CDCl ) d 7.58 (1H, br s, H7), 7.35–7.00 (7H, m, Ar),
3
2
2
þ
(6), 219 (100), 187 (53), 160 (34); HRMS m/z 351.1320
6
s, H3), 3.95 (3H, s, CO Me), 3.77 (3H, s, NCO Me), 3.14
.62 (1H, d, J¼6.9 Hz, H4), 6.47 (1H, br s, H8a), 4.00 (1H,
51.9 (C3), 26.5 (CH ), 9.7 (Me); EIMS m/z 351 (M , 9), 319
2
2
2
1
3
þ
and 2.94 (2H, dd, J¼13.0 Hz, CH Ph); C (CDCl ) d 169.0
(M , C H NO requires 351.1318).
17 21 7
2
3
(
(
C2), 167.0 (CO Me), 151.4 (NCO Me), 140.5 (C7a), 133.4
2 2
Ci), 130.3 (C6), 130.2 (C3b), 129.3 (C4, Co), 128.9 (Cm),
4.2.5. Dimethyl 2-(1-carbomethoxy-2-hydroxy-3-iso-pro-
pyl-2,3-dihydro-1H-indol-3-yl)malonate (14). Prepared
from 7 as colorless crystals, mp 121–1228C (Et O–hex-
1
5
27.9 (Cp), 124.3 (C5), 115.7 (C7), 95.4 (C8a), 57.1 (C3),
6.0 (C3a), 53.3 (CO Me), 53.2 (NCO Me), 39.8 (CH Ph);
2
1
2
2
2
(
minor endo-isomer) H NMR (CDCl ) d 7.88 (1H, br s,
3
ane); R 0.20 (EtOAc–hexane 1:3); IR (CHCl ) n
f
3594,
max
3
3010, 1734 cm2 ; H NMR (CDCl ) d 7.64 (1H, br s, H7),
1 1
H7), 7.35–7.00 (7H, m, Ar), 6.62 (1H, d, J¼6.9 Hz, H4),
3
6
.34 (1H, br s, H8a), 4.04 (1H, s, H3), 3.88 (3H, s,
7.21 (1H, td, J¼7.4, 1.2 Hz, H6), 7.06 (1H, dd, J¼7.4,
NCO Me), 3.77 (3H, s, CO Me), 3.26 and 3.11 (2H, dd, J¼
1.2 Hz, H4), 6.95 (1H, td, J¼7.4, 1.1 Hz, H5), 6.64 (1H, d,
2
2
1
3
1
4.0 Hz, CH Ph);
2
C (CDCl ) d 168.5 (C2), 166.2
3
J¼3.6 Hz, H2), 4.0 (1H, s, OH), 3.91 (3H, s, NCO Me), 4.20
2
(
CO Me), 151.4 (NCO Me), 140.5 (C7a), 134.0 (Ci),
2
(1H, s, H8), 3.80 and 3.44 (6H, 2s, 2CO Me), 2.58 (1H, sept,
2
2
1
1
30.5 (C6), 130.2 (C3b), 129.3 (C4, Co), 128.9 (Cm),
27.9 (Cp), 123.9 (C5), 115.7 (C7), 92.3 (C8a), 56.2 (C3a),
J¼6.7 Hz, CH), 1.08 and 0.71 (6H, 2 d, J¼6.7 Hz, 2
1
3
Me); C (CDCl ) d 167.9 and 167.6 (2CO Me), 154.2
3
2

2850
M. S. Morales-R ´ı os et al. / Tetrahedron 59 (2003) 2843–2853
(
NCO Me), 141.0 (C7a), 130.1 (C3a), 128.5 (C6), 123.4 (C4),
2
22.2 (C5), 113.9 (C7), 87.7 (C2), 55.2 (C8), 52.8 (NCO Me),
2
4.2.9. Dimethyl 2-(1-carbomethoxy-6-iso-propyl-1H-
indol-3-yl)malonate (19). Prepared from 7 as colorless
1
5
1
2.7 and 52.3 (2CO Me), 54.0 (C3), 29.5 (CH), 19.7 and
2
oil; R 0.40 (EtOAc–hexane 1:3); IR (CHCl ) n
f
1738, cm ; H NMR (CDCl ) d 8.08 (1H, br s, H7), 7.74
3
3010,
max
3
þ
21 1
7.7 (2 Me); EIMS m/z 365 (M , 6), 233 (100), 218 (33);
þ
HRMS m/z 365.1492 (M , C H NO requires 365.1475).
8
(1H, s, H2), 7.48 (1H, d, J¼8.0 Hz, H4), 7.17 (1H, dd,
J¼8.0, 1.5 Hz, H5), 4.87 (1H, s, H8), 4.02 (3H, br s,
NCO Me), 3.77 (6H, s, 2CO Me), 3.04 (1H, m, CHMe ),
1
23
7
4
5
.2.6. Dimethyl 2-(4-bromo-1-carbomethoxy-2-hydroxy-
-methoxy-3-methyl-2,3-dihydro-1H-indol-3-yl)malo-
2
2
2
1
3
1.31 (6H, d, CHMe2); C (CDCl ) d 167.9 (CO Me), 151.1
3 2
nate (15). Prepared from 10 as colorless crystals, mp 145–
468C (EtOAc–hexane); R 0.20 (EtOAc–hexane 2:3); IR
(NCOMe), 146.4 (C6), 135.6 (C7a), 127.0 (C3a), 124.5
(C2), 122.1 (C5), 118.9 (C4), 112.8 (C7), 112.7 (C3), 53.8
(NCOMe), 53.0 (CO Me), 49.1 (C8), 34.7 (CHMe ), 24.4
1
f
2
1
1
(
CHCl ) n
3
3596, 3026, 1734, 1058 cm
; H NMR
max
2
2
þ
(
CDCl ) d 7.69 (1H, br s, H7), 6.77 (1H, d, J¼8.8 Hz, H6),
(CHMe ); EIMS m/z 347 (M , 100), 333 (20), 289 (80);
2
3
þ
6
s, NCO Me), 3.84 (3H, s, OMe), 3.43 (6H, 2s, 2CO Me),
1
.41 (1H, d, J¼3.9 Hz, H2), 4.63 (1H, br s, H8), 3.88 (3H, br
HRMS m/z 347.1364 (M , C H NO requires 347.1369).
1
8
21
6
2
2
1
3
.67 (3H, s C3–Me); C (CDCl ) d 167.0 and 166.6
3
4.2.10. Dimethyl 2-(1-carbomethoxy-6-benzyl-1H-indol-
3-yl)malonate (20). Prepared from 7 as colorless oil; Rf
(
2CO Me), 152.0 (NCO Me), 151.2 (C5), 135.0 (C7a),
2 2
1
5
32.9 (C3a), 113.5 (C7), 111.3 (C6), 108.4 (C4), 85.9 (C2),
6.9 (OMe), 56.0 (C8), 53.2 (NCO Me), 52.9 and 52.6
0.35 (EtOAc–hexane 1:3); IR (CHCl ) n
3
3014, 1738,
max
1446, cm2 ; H NMR (CDCl ) d 8.09 (1H, br s, H7), 7.75
1 1
2
3
þ
0/20), 313/315 (100/98), 281/283 (49/48); HRMS m/z
(
2CO Me), 51.2 (C3), 18.1 (Me); EIMS m/z 445/447 (M ,
2
(1H, d, J¼0.8 Hz, H2), 7.47 (1H, d, J¼8.0 Hz, H4), 7.30–
2
4
7.16 (5H, m, Ar), 7.12 (1H, dd, J¼8.0, 1.5 Hz, H5), 4.86
þ
45.0369 (M , C H NO Br requires 445.0372).
8
(1H, d, J¼0.8 Hz, H8), 4.11 (2H, s, CH Ph), 4.01 (3H, br s,
1
7
20
2
1
3
NCO Me), 3.77 (6H, s, 2CO Me); C (CDCl ) d 168.0
2
2
3
4
5
.2.7. Dimethyl 2-(6-bromo-1-carbomethoxy-2-hydroxy-
-methoxy-3-methyl-2,3-dihydro-1H-indol-3-yl)malo-
(CO Me), 151.2 (NCOMe), 141.4 (Ci), 138.5 (C6), 135.7
2
(C7a), 128.8 (Co), 128.4 (Cm), 127.3 (C3a), 126.0 (Cp),
124.8 (C2), 124.5 (C5), 119.2 (C4), 115.6 (C7), 112.8 (C3),
53.8 (NCOMe), 53.0 (CO Me), 49.1 (C8), 42.3 (CH Ph);
nate (16). Prepared from 11 as colorless crystals, mp 138–
408C (EtOAc–hexane); R 0.21 (EtOAc–hexane 2:3); IR
1
f
2
2
2
1
1
þ
(
(
CHCl ) n 3588, 3020, 1734, 1056 cm
CDCl ) d 8.05 (1H, br s, H7), 7.61 (1H, br s, OH), 6.73 (1H,
;
H NMR
EIMS m/z 395 (M , 100), 336 (91), 200 (17); HRMS m/z
þ
3
max
395.1366 (M , C H NO requires 395.1369).
22 21
3
6
s, H4), 6.27 (1H, d, J¼3.7 Hz, H2), 3.91 (3H, br s,
NCO Me), 3.86 (3H, s, OMe), 3.70 and 3.57 (6H, 2s,
2
4.2.11. Dimethyl 2-(1-carbomethoxy-6-tert-butyl-1H-
indol-3-yl)malonate (21). Prepared from 7 as colorless
1
3
2
(
CO Me) 3.60 (1H, br s, H8), 1.55 (3H, s, C3–Me);
C
CDCl ) d 167.5 and 167.2 (2CO Me), 152.9 (NCO Me),
2
oil; R 0.66 (EtOAc–hexane 2:3); IR (CHCl ) n
f
3012,
max
3
2
2
3
1738 cm2 ; H NMR (CDCl ) d 8.27 (1H, br s, H7), 7.75
1 1
1
52.3 (C5), 134.4 (C7a), 133.4 (C3a), 119.4 (C7), 111.7
C6), 107.9 (C4), 87.4 (C2), 58.6 (C8), 56.8 (OMe), 53.1
3
(
(
(1H, s, H2), 7.50 (1H, d, J¼8.4 Hz, H4), 7.36 (1H, dd, J¼
13
NCO Me), 52.6 and 52.5 (2CO Me), 49.2 (C3), 17.9 (Me);
2
8.4, 1.8 Hz, H5), 4.87 (1H, s, H8), 4.03 (3H, br s, NCO Me),
2
2
þ
100/96); HRMS m/z 445.0367 (M , C H NO Br requires
EIMS m/z 445/447 (M , 84/90), 313/315 (56/58), 254/256
þ
3.78 (6H, s, 2CO Me), 1.39 (9H, s, CMe ); C (CDCl ) d
168.1 (CO Me), 151.3 (NCOMe), 148.7 (C6), 135.7 (C7a),
2
3
3
(
1
7
20
8
2
4
45.0372).
126.7 (C3a), 124.8 (C2), 121.2 (C5), 118.7 (C4), 112.6 (C3),
111.9 (C7), 53.8 (NCOMe), 53.0 (CO Me), 49.1 (C8), 35.1
(CMe ), 31.7 (CMe ); EIMS m/z 361 (M , 20), 346 (100);
2
þ
HRMS m/z 361.1522 (M , C H NO requires 361.1525).
4.2.8. Dimethyl 2-(1-carbomethoxy-4-ethyl-1H-indol-3-
yl)malonate (17) and dimethyl 2-(1-carbomethoxy-6-
3
3
þ
1
9
23
6
ethyl-1H-indol-3-yl)malonate (18). Prepared from 7 as
1
an inseparable (2:3, H NMR analysis) isomeric mixture;
colorless oil; R 0.40 (EtOAc–hexane 1:3); IR (CHCl ) n
max
4.2.12. Dimethyl 2-(2-oxo-2,3-dihydro-1H-indol-3-yl)-
malonate (22). Prepared from 7 as colorless crystals, mp
109–1108C (EtOAc–hexane); Rf 0.19 (EtOAc–hexane
f
3
2
1 1
3
018, 1738, 1444 cm ; H NMR (DMSO-d ) 17 (minor
6
3440, 1734 cm2
1
;
1
H NMR
4
-ethyl-isomer) d 8.05 (1H, d, J¼7.9 Hz, H7), 7.64 (1H, s,
2:3); IR (CHCl ) n
3
max
H2), 7.32 (1H, t, J¼7.9 Hz, H6), 7.11 (1H, d, J¼7.9 Hz,
(CDCl ) d 8.69 (1H, br s, NH), 7.29 (1H, br d, J¼7.8 Hz,
3
H5), 5.30 (1H, s, H8), 3.99 (3H, br s, NCO Me), 3.74 (6H, s,
2
H4), 7.20 (1H, td, J¼7.8, 1.0 Hz, H6), 6.98 (1H, td, J¼7.8,
1.0 Hz, H5), 6.86 (1H, br d, J¼7.8 Hz, H7), 4.21 (1H, d,
J¼4.2 Hz, H8), 4.06 (1H, d, J¼4.2 Hz, H3), 3.80 and 3.58
1
3
2CO Me), 2.87 (2H, q, CH ), 1.21 (3H, t, Me); C (DMSO-
2 2
d ) d 168.2 (CO Me), 150.4 (NCOMe), 136.5 (C7a), 135.1
6
2
1
3
(
(
2
C4), 126.3 (C3a), 125.0 (C2), 124.6 (C6), 123.2 (C5), 112.9
C7), 112.6 (C3), 54.3 (NCOMe), 53.1 (CO Me), 49.6 (C8),
5.0 (CH ), 15.4 (Me); 18 (major 6-ethyl-isomer) H NMR
2
(6H, 2s, 2CO Me); C NMR (CDCl ) d 177.2 (C2), 168.1
2 3
and 167.2 (2CO Me), 141.7 (C7a), 128.6 (C6), 125.9 (C3a),
2
2
1
124.7 (C4), 122.4 (C5), 109.8 (C7), 52.9 and 52.7
(2CO Me), 52.0 (C8), 45.1 (C3); EIMS m/z 263 (M , 66),
þ
231 (48), 204 (85), 172 (100); HRMS m/z 263.0799 (M ,
(
(
5
DMSO-d ) d 7.96 (1H, br s, H7), 7.71 (1H, s, H2), 7.52
6
2
þ
1H, t, J¼8.1 Hz, H4), 7.15 (1H, dd, J¼8.1, 1.5 Hz, H5),
.32 (1H, s, H8), 3.99 (3H, br s, NCO Me), 3.69 (6H, s,
2
C H NO requires 263.0794).
13 13 5
1
3
2
d ) d 168.1 (CO Me), 150.7 (NCOMe), 140.9 (C6), 136.5
CO Me), 2.73 (2H, q, CH ), 1.22 (3H, t, Me); C (DMSO-
2
2
4.2.13. Dimethyl 2-(2-carbomethoxy-2-oxo-2,3-dihydro-
1H-indol-3-yl)malonate (23). Prepared from 7 as colorless
6
2
(
C7a), 126.8 (C3a), 125.0 (C2), 123.3 (C5), 120.0 (C4),
13.6 (C7), 113.1 (C3), 54.2 (NCOMe), 52.8 (CO Me), 48.4
1
oil, R 0.4 (EtOAc–hexane 2:3); IR (CHCl ) n
3
3020,
max
2
f
þ
100), 214 (34); HRMS m/z 333.1212 (M , C H NO
21 1
(
C8), 28.7 (CH ), 16.2 (Me); EIMS m/z 333 (M , 77), 274
2
1734, cm ; H NMR (CDCl ) d 7.94 (1H, d, J¼7.7 Hz,
3
þ
(
requires 333.1212).
H7), 7.35 (1H, td, J¼7.7, 1.0 Hz, H6), 7.34 (1H, d, J¼
7.7 Hz, H4), 7.16 (1H, td, J¼7.7, 1.0 Hz, H5), 4.26 (1H, d,
1
7
19
6

M. S. Morales-R ´ı os et al. / Tetrahedron 59 (2003) 2843–2853
2851
J¼3.9, Hz, H8), 4.23 (1H, d, J¼3.9 Hz, H3), 4.03 (3H, s,
126.2 (C3a), 114.4 (C7), 111.5 (C6), 110.7 (C4), 56.9
(OMe), 53.1 and 52.8 (2CO Me), 51.8 (C8), 45.4 (C3);
1
3
NCO Me), 3.77 and 3.64 (6H, 2s, 2CO Me); C NMR
2
2
2
þ
(90/90); HRMS m/z 370.9997 (M , C H NO Br requires
371.0004).
(
(
(
5
2
CDCl ) d 173.4 (C2), 167.7 and 167.1 (2CO Me), 151.3
3
NCO Me), 140.2 (C7a), 129.1 (C6), 124.8 (C5), 124.3
2
EIMS m/z 371/373 (M , 60/61), 339/341 (35/36), 280/282
þ
2
14 14
6
C3a), 123.9 (C4), 115.2 (C7), 54.0 (NCO Me), 53.0 and
2
þ
3), 289 (54), 257 (100), 230 (60); HRMS m/z 321.0834
2.9 (2CO Me), 52.6 (C3), 45.3 (C8); EIMS m/z 321 (M ,
2
4.2.18. Methyl 3-cyano-3a-ethyl-5-fluoro-2-oxo-2,3,3a,
8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate (3a).
Prepared from 1a as a C-3 diastereomeric mixture (7:3
þ
(
M , C H NO requires 321.0849).
7
1
5
15
1
4.2.14. Dimethyl 2-(5-fluoro-2-oxo-2,3-dihydro-1H-
indol-3-yl)malonate (24). Prepared from 8 as yellow
crystals, mp 108–1098C (EtOAc–hexane); R 0.12 (EtOAc–
f
endo–exo ratio by H NMR analysis), colorless crystals, mp
155–1568C (EtOAc–hexane); Rf 0.39 (EtOAc–hexane
1
2:3); IR (CHCl ) n
3
3018, 2360, 1732, 1206 cm2
(major endo-isomer) H NMR (CDCl ) d 7.91 (1H, br s,
;
max
1
2
1
1
hexane 2:3); IR (CHCl ) n
3
3024, 1734, 1218 cm ; H
NMR (CDCl ) d 8.35 (1H, br s, NH), 7.12 (1H, br dd, J¼8.3,
max
3
H7), 7.37 (1H, dd, J¼7.9, 2.6 Hz, H4), 7.14 (1H, td, J¼8.8,
3
2
.9 Hz, H4), 6.93 (1H, td, J¼8.8, 2.9 Hz, H6), 6.80 (1H, dd,
2.6 Hz, H6), 6.27 (1H, br s, H8a), 4.08 (1H, s, H3), 3.94 (3H,
br s, NCO Me), 2.06 and 1.95 (2H, dq, J¼15.8, 7.5 Hz,
J¼8.8, 4.2 Hz, H7), 4.22 (1H, d, J¼3.9 Hz, H8), 4.04 (1H,
2
1
3
13
br d, J¼3.9 Hz, H3), 3.83 and 3.60 (6H, 2s, 2CO Me);
C
NMR (CDCl ) d 176.7 (C2), 168.0 and 167.0 (2CO Me),
CH ), 0.94 (3H, t, J¼7.5 Hz, Me); C NMR (CDCl ) d
2
2
3
164.6 (C2), 159.6 (C5), 151.9 (NCO Me), 136.6 (C7a),
2
3
2
1
58.8 (C5), 137.5 (C7a), 127.5 (C3a), 115.0 (C4), 113.2
C6), 110.2 (C7), 53.1 and 52.9 (2CO Me), 51.9 (C8), 45.5
128.6 (C3b), 117.6 (C6), 116.8 (C7), 113.2 (C4), 112.3
(CN), 95.4 (C8a), 54.2 (NCO Me), 53.8 (C3a), 42.1 (C3),
(
2
2
þ
100); HRMS m/z 281.0692 (M , C H NO F requires
1
(
C3); EIMS m/z 281 (M , 23), 249 (24), 222 (47), 190
þ
31.1 (CH ), 8.5 (Me); (minor exo-isomer) H NMR (CDCl )
2
3
(
d 7.91 (1H, br s, H7), 7.14 (1H, td, J¼8.8, 2.6 Hz, H6), 6.92
1
3
12
5
2
81.0699).
(1H, dd, J¼7.9, 2.6 Hz, H4), 6.33 (1H, br s, H8a), 3.99 (1H,
s, H3), 3.94 (3H, br s, NCO Me), 2.06 and 1.95 (2H, dq,
2
1
3
4.2.15. Dimethyl 2-(5-methoxy-2-oxo-2,3-dihydro-1H-
indol-3-yl)malonate (25). Prepared from 9 as brown
J¼15.8, 7.5 Hz, CH ), 0.91 (3H, t, J¼7.5 Hz, Me);
C
2
NMR (CDCl ) d 164.6 (C2), 159.6 (C5), 151.9 (NCO Me),
3 2
crystals, mp 161–1638C (EtOAc–hexane); R 0.11 (EtOAc–
f
136.6 (C7a), 132.2 (C3b), 117.5 (C6), 117.1 (C7), 111.8
(CN), 111.1 (C4), 96.4 (C8a), 54.2 (NCO Me), 53.8 (C3a),
2
1 1
hexane 2:3); IR (CHCl ) n
3032, 1732, 1222 cm ; H
NMR (CDCl ) d 8.56 (1H, br s, NH), 6.96–6.70 (3H, m,
3
max
2
þ
231 (45), 187 (41), 162 (32); HRMS m/z 304.0853 (M ,
42.4 (C3), 28.6 (CH ), 8.2 (Me); EIMS m/z 304 (M , 100),
2
3
þ
Ar), 4.21 (1H, d, J¼4.1 Hz, H8), 4.05 (1H, d, J¼4.1 Hz,
H3), 3.83 and 3.76 (6H, 2s, 2CO Me), 3.61 (3H, s, OMe);
2
C H N O F requires 304.0859).
15 13 2 4
1
3
C NMR (CDCl ) d 177.1 (C2), 168.3 and 167.3
3
(
(
(
2CO Me), 155.7 (C5), 135.2 (C7a), 127.3 (C3a), 113.3
2
4.2.19. Methyl 3a-benzyl-3-cyano-5-fluoro-2-oxo-2,3,3a,
8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate (3b).
Prepared from 1a as a C-3 diastereomeric mixture (9:1
C7), 112.1 (C6), 110.1 (C4), 55.7 (OMe), 52.9 and 52.7
2CO Me), 52.0 (C8), 45.5 (C3); EIMS m/z 293 (M , 42),
þ
33 (83), 202 (100), 174 (22); HRMS m/z 293.0884 (M ,
2
þ
1
2
C H NO requires 293.0899).
endo–exo ratio by H NMR analysis), colorless crystals, mp
173–1748C (EtOAc–hexane); Rf 0.46 (EtOAc–hexane
1
4
15
6
1
2
:3); IR (CHCl ) n
3
3020, 2360, 1734, 1206 cm2
(major endo-isomer) H NMR (CDCl ) d 7.85 (1H, br s,
;
max
1
4
.2.16. Dimethyl 2-(4-bromo-1-carbomethoxy-5-meth-
oxy-2-oxo-2,3-dihydro-1H-indol-3-yl)malonate (26).
Prepared from 10 as colorless crystals, mp 174–1758C
3
H7), 7.41–6.79 (7H, m, Ar), 6.72 (1H, s, H8a), 6.36 (1H, br
s, H8a), 4.12 (1H, s, H3), 3.90 (3H, br s, NCO Me), 3.10
2
1
3
(
(
(
EtOAc–hexane); Rf 0.27 (EtOAc–hexane 2:3); IR
1
(2H, s, CH Ph); C NMR (CDCl ) d 164.2 (C2), 159.6
2 3
2
1
CHCl ) n
3
3018, 1734, 1216, 1074 cm
;
H NMR
(C5), 150.3 (NCO Me), 136.3 (C7a,), 132.8 (Ci), 129.9
2
max
CDCl ) d 7.92 (1H, d, J¼9.0 Hz, H7), 7.07 (1H, d, J¼
(Cm), 129.5 (Co), 128.6 (Cp), 128.0 (C3b), 117.8 (C6),
117.1 (C7), 113.2 (C4), 112.1 (CN), 93.9 (C8a), 55.1 (C3a),
53.8 (NCO Me), 42.2 (CH Ph), 40.3 (C3); EIMS m/z 366
3
9
.0 Hz, H6), 5.04 (1H, d, J¼3.9 Hz, H8), 4.29 (1H, br d,
J¼3.9 Hz, H3), 4.00 (3H, s NCO Me), 3.89 and 3.61 (6H,
2
2
2
1
3
þ
þ
2
s, 2CO Me), 3.89 (3H, s, OMe); C NMR (CDCl ) d 172.1
2
(M , 82), 231 (58), 187 (35), 91 (100); HRMS m/z 366.1009
(M , C H N O F requires 366.1016).
20 15 2 4
3
(
(
(
C2), 167.5 and 167.1 (2CO Me), 153.0 (C5), 151.3
2
NCO Me), 135.0 (C7a), 125.7 (C3a), 114.9 (C7), 111.6
2
C6), 108.5 (C4), 56.6 (OMe), 54.1 (2 NCO Me), 53.3 and
2
4.2.20. Ethyl 3-cyano-3a-ethyl-5-methoxy-2-oxo-2,3,3a,
8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate (3c).
Prepared from 1b as a C-3 diastereomeric mixture (7:3
5
2.9 (2CO Me), 50.6 (C8), 47.2 (C3); EIMS m/z 429/431
2
þ
m/z 429.0058 (M , C H NO Br requires 429.0059).
(
M , 30/31), 365/367 (97/100), 352/354 (52/53); HRMS
þ
1
endo–exo ratio by H NMR analysis), colorless crystals, mp
135–1368C (EtOAc–hexane); Rf 0.43 (EtOAc–hexane
2:3); IR (CHCl ) n
1
6
16
8
3036, 2358, 1800, 1724 cm2
(major endo-isomer) H NMR (CDCl ) d 7.82 (1H, br s,
1
;
4.2.17. Dimethyl 2-(6-bromo-5-methoxy-2-oxo-2,3-dihy-
dro-1H-indol-3-yl)malonate (27). Prepared from 11 as
3
max
1
3
colorless crystals, mp 166–1678C (EtOAc–hexane); R 0.15
f
H7), 7.19 (1H, d, J¼2.6 Hz, H4), 6.94 (1H, dd, J¼8.8,
(
EtOAc–hexane 2:3); IR (CHCl ) n
3
3030, 1736, 1232,
2.6 Hz, H6), 6.28 (1H, br s, H8a), 4.36 (2H, br s, OCH ),
2
max
1
042 cm2 ; H NMR (CDCl ) d 7.89 (1H, br s, NH), 7.09
1
1
4.15 (1H, s, H3), 3.82 (3H, s, OMe), 2.06 and 1.95 (2H, dq,
3
(
1H, s, H7), 7.08 (1H, s, H4), 4.26 (1H, d, J¼3.5 Hz, H8),
J¼14.1, 7.4 Hz, C3a–CH ), 1.41 (3H, br t, J¼7.0 Hz,
2
1
3
3
and 3.59 (6H, 2s, 2CO Me); C NMR (CDCl ) d 176.5
.98 (1H, dd, J¼3.5, 1.0 Hz, H3), 3.86 (3H, s, OMe), 3.85
OCH Me), 0.91 (3H, t, J¼7.4 Hz, C3a–CH Me); C NMR
(CDCl ) d 165.2 (C2), 156.8 (C5), 151.3 (NCO Et), 134.0
3 2
2
2
1
3
2
3
(
C2), 168.5 and 167.1 (2CO Me), 152.0 (C5), 135.7 (C7a),
2
(C7a), 128.0 (C3b), 116.4 (C7), 116.1 (C6), 112.7 (CN),

2852
M. S. Morales-R ´ı os et al. / Tetrahedron 59 (2003) 2843–2853
1
11.2 (C4), 95.6 (C8a), 62.9 (OCH Me), 55.8 (OMe), 54.3
2
br s, H7), 7.37 (1H, s, H4), 6.33 (1H, s, H8a), 4.38 (1H, s,
H3), 3.85 (3H, s, OMe), 3.84 (3H, br s, NCO Me), 3.81 (3H,
(
C3a), 42.3 (C3), 31.1 (C3a–CH Me), 14.4 (OCH Me) 8.6
2
2
2
1
13
(
C3a–CH Me); (minor exo-isomer) H NMR (CDCl ) d
2
s, CO Me), 1.31 (3H, s, Me); C NMR (DMSO-d ) d 169.3
2
3
6
7
.46 (1H, br s, H7), 6.89 (1H, dd, J¼8.8, 2.6 Hz, H6), 6.74
(C2), 166.5 (CO Me), 152.4 (C5), 152.0 (NCO Me), 134.3
2 2
(1H, d, J¼2.6 Hz, H4), 6.34 (1H, br s, H8a), 4.36 (2H, br s
OCH ), 4.06 (1H, s, H3), 3.80 (3H, s, OMe), 2.06 and 1.95
(C7a), 131.9 (C3b), 118.3 (C7), 110.7 (C6), 109.4 (C4), 96.3
(C8a), 56.6 (OMe), 55.5 (C3), 53.5 (NCO Me), 53.2
2
2
þ
94/100), 310/312 (64/62), 187 (20); HRMS m/z 413.0110
(
7
1
2H, dq, J¼14.1, 7.4 Hz, C3a–CH ), 1.41 (3H, br t, J¼
(CO Me), 51.8 (C3a), 19.8 (Me); EIMS m/z 413/415 (M ,
2
2
.0 Hz, OCH Me), 0.91 (3H, t, J¼7.4 Hz, C3a–CH Me);
2
2
3
þ
C NMR (CDCl ) d 165.2 (C2), 157.1 (C5), 151.3
3
(M , C H NO Br requires 413.0100).
16 16
7
(
NCO Et), 134.0 (C7a), 128.0 (C3b), 116.7 (C7), 115.2
2
(
C6), 112.3 (CN), 109.7 (C4), 96.6 (C8a), 62.9 (OCH Me),
2
5
1
1
5.8 (OMe), 54.7 (C3a), 42.6 (C3), 28.6 (C3a–CH Me),
2
þ
00), 258 (13), 213 (45), 174 (70); HRMS m/z 330.1201
4.4 (OCH Me) 8.2 (C3a–CH Me); EIMS m/z 330 (M ,
2
Acknowledgements
2
þ
(
M , C H N O requires 330.1216).
17 18 2 5
This research was supported by CONACYT-M e´ xico
34405-N, G-32631-N). The authors thank I. Q. Luis
(
4
8
.2.21. Ethyl 3a-benzyl-3-cyano-5-methoxy-2-oxo-2,3,3a,
a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate (3d).
Velasco Ibarra (Instituto de Qu ´ı mica, UNAM) for recording
the HRMS and Dr Oscar R. Su a´ rez Castillo (Universidad
Aut o´ noma del Estado de Hidalgo) for providing raw X-ray
data.
Prepared from 1b as a C-3 diastereomeric mixture (9:1
1
endo–exo ratio by H NMR analysis), colorless crystals, mp
1
2
61–1638C (EtOAc–hexane); Rf 0.51 (EtOAc–hexane
:3); IR (CH Cl ) n
max
3006, 2360, 1798, 1724 cm2
;
1
2
2
1
(major endo-isomer) H NMR (CDCl ) d 7.75 (1H, br s,
3
H7), 7.35–6.79 (7H, m, Ar), 6.36 (1H, br s, H8a), 4.32 (2H,
References
br q, J¼6.8 Hz, OCH ), 4.16 (1H, s, H3), 3.82 (3H, s, OMe),
2
1
3
3.12 (2H, s, CH Ph), 1.37 (3H, t, J¼6.8 Hz, OCH Me);
NMR (CDCl ) d 164.7 (C2), 156.8 (C5), 150.8 (NCO Me),
C
1. (a) Joule, J. A. In Indoles Part IV: The Monoterpenoid Indole
Alkaloids; Saxtone, J. E., Ed.; Wiley: New York, 1983; pp
244–259. (b) Salway, A. H. J. Chem. Soc. 1911, 99,
2148–2159. (c) Robinson, B. J. Chem. Soc. 1964, 1503.
(d) Bohrmann, H.; Lau-Cam, C.; Tashiro, J.; Youngken, H. W.,
Jr. Phytochemistry 1969, 8, 645–652.
2
2
3
2
1
(
33.2 (Ci), 132.9 (C7a), 129.9 (Co), 129.5 (C3b), 129.3
Cm), 128.3 (Cp), 116.6 (C7), 116.0 (C6), 112.5 (CN), 111.0
(
C4), 94.1 (C8a), 62.9 (OCH ), 55.8 (OMe), 55.2 (C3a),
2
4
2.3 (CH Ph), 40.7 (C3), 14.4 (OCH Me); EIMS m/z 392
2 2
þ
(M , 100), 275 (30), 185 (24), 91 (39); HRMS m/z 392.1364
(M , C H N O requires 392.1372).
22 20 2 5
2. Morales-R ´ı os, M. S.; Su a´ rez-Castillo, O. R.; Joseph-Nathan, P.
Trends Heterocycl. Chem. 1999, 6, 111–124.
þ
3
. Morales-R ´ı os, M. S.; Bucio, M. A.; Joseph-Nathan, P.
Tetrahedron 1996, 52, 5339–5348.
4
.3. General lactonization procedure
4
. (a) Su a´ rez-Castillo, O. R.; Garc ´ı a-Velgara, M.; Morales-R ´ı os,
M. S.; Joseph-Nathan, P. Can. J. Chem. 1997, 75, 959–964.
(b) Morales-R ´ı os, M. S.; Su a´ rez-Castillo, O. R.; Joseph-
Nathan, P. J. Chem. Soc., Perkin Trans. 2 2000, 769–775.
To a precooled (08C) stirred solution of the appropriate
-hydroxyindoline 12–14, and 16, (0.19 mmol) in THF
5 mL) was added 6% aqueous KOH (0.2 mL) at once. The
resulting mixture was stirred at room temperature for
2
(
5. Perlmutter, P. Conjugated Addition Reactions in Organic
Synthesis; Pergamon: Oxford, 1992.
2
4
0 min, then treated with 10% aqueous HCl to reach pH
–5, and extracted with EtOAc (2£20 mL). The organic
6. (a) Fleming, F. F.; Wang, Q.; Zhang, Z.; Steward, O. W. J. Org.
Chem. 2002, 67, 5953–5956. (b) Fleming, F. F.; Wang, Q.;
Steward, W. Org. Lett. 2000, 2, 1477–1479.
layer was washed with brine (2£15 mL) and dried over
Na SO . The resultant crude product was purified by flash
4
2
chromatography on silica gel eluting with CH Cl to give
2
7. (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C.
Tetrahedron 1999, 55, 6231–6242. (b) Fang, C.; Ogawa, T.;
Suemune, H.; Sakai, K. Tetrahedron: Asymmetry 1991, 2,
389–398.
2
the corresponding furoindoles 6a–c and 6f, respectively, in
quantitative yields. Compound 6a was identical in all
4
b
respects to the product previously obtained.
8
. (a) Morales-R ´ı os, M. S.; Su a´ rez-Castillo, O. R.; Joseph-
Nathan, P. J. Org. Chem. 1999, 64, 1086–1087. (b) Morales-
R ´ı os, M. S.; Su a´ rez-Castillo, O. R.; Trujillo-Serrato, J. J.;
Joseph-Nathan, P. J. Org. Chem. 2001, 66, 1186–1192.
(c) Morales-R ´ı os, M. S.; Santos-S a´ nchez, N. F.; Joseph-
Nathan, P. J. Nat. Prod. 2002, 65, 136–141. (d) Morales-R ´ı os,
M. S.; Su a´ rez-Castillo, O. R.; Joseph-Nathan, P. Tetrahedron
2002, 58, 1479–1484.
4
3
.3.1. Dimethyl 6-bromo-5-methoxy-3a-methyl-2-oxo-2,
,3a,8a-tetrahydro-8H-furo[2,3-b]indole-3,8-dicarboxyl-
ate (6f). Prepared from 16 as a C-3 diastereomeric mixture
1
(
0
2:3 endo–exo ratio by H NMR analysis), colorless oil; Rf
.24 (EtOAc–hexane 2:3); IR (CHCl ) n
3030, 1742,
max
3
206, 1096 cm2 ; (minor endo-isomer) H NMR (DMSO-
1
1
1
d6) d 7.82 (1H, br s, H7), 6.68 (1H, s, H4), 6.23 (1H, s, H8a),
.32 (1H, s, H3), 3.82 (3H, br s, NCO Me), 3.77 (3H, s,
4
OMe), 3.67 (3H, s, CO Me), 1.61 (3H, s, Me); C NMR
9. (a) Rozhkov, V. S.; Smushkevich, Y. I.; Suvorov, N. N. Khim.
Geterotsikl. Soedin. 1980, 55–58, Chem. Abstr. 1980, 93,
8124j. (b) Gibe, R.; Kerr, M. A. J. Org. Chem. 2002, 67,
6247–6249.
10. Morales-R ´ı os, M. S.; Santos-S a´ nchez, N. F.; Su a´ rez-Castillo,
O. R.; Joseph-Nathan, P. J. Org. Chem. 2003, 68, 305–311.
11. Burket, U.; Allinger, N. L. Molecular Mechanics; ACS
2
1
3
2
(
(
(
(
(
DMSO-d6) d 169.1 (C2), 166.2 (CO Me), 152.0
2
NCO Me), 151.8 (C5), 134.3 (C7a), 131.9 (C3b), 118.3
2
C7), 110.9 (C6), 108.7 (C4), 95.6 (C8a), 56.5 (OMe), 55.5
C3), 53.5 (NCO Me), 52.6 (CO Me), 51.8 (C3a), 24.5
Me); (major exo-isomer) H NMR (DMSO-d ) d 7.82 (1H,
6
2
2
1

M. S. Morales-R ´ı os et al. / Tetrahedron 59 (2003) 2843–2853
2853
Monograph 177, American Chemical Society: Washington,
DC, 1983.
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P. Can. J. Chem. 1999, 77, 130–137. (c) Morales-R ´ı os, M. S.;
Mora-P e´ rez, Y.; Joseph-Nathan, P. Magn. Reson. Chem. 1992,
30, 1153–1157.
1
3
621–3624. (b) Derrick, S. D.; Boehme, R.; Wong, K. M.;
14. Schut, R. N.; Safdy, M. E.; Hong, E. US Patent 4,283,410,
August 11, 1981.
Nemeth, F.; Tanaka, K.; Rumberg, B.; Beekman, R. A.; Dibbe,
P. W. Tetrahedron 1996, 52, 7679–7690. (c) Harrison, D. M.
Tetrahedron Lett. 1984, 25, 6063–6064. (d) Rees, C. W.;
Sabet, C. R. J. Chem. Soc. 1965, 870–875. (e) Buchardt, O.;
Lohse, C. Tetrahedron Lett. 1966, 4355–4361.
15. Pale green crystals of methyl 2-(1-carbomethoxy-5-fluoro-1H-
indol-3-yl)cyanoacetate (C14
11 2 4
H N O F) were grown from
EtOAc–hexane. Data collection was conducted at 293 K on
˚
˚
a monoclinic crystal P2
˚
1
/n; a¼10.661(1) A, b¼8.098(1) A,
1
3. (a) Morales-R ´ı os, M. S.; Garc ´ı a-Velgara, M.; Cervantes-
Cuevas, H.; Alvarez-Cisneros, C.; Joseph-Nathan, P. Magn.
Reson. Chem. 2000, 38, 172–176. (b) Morales-R ´ı os, M. S.;
Su a´ rez-Castillo, O. R.; Alvarez-Cisneros, C.; Joseph-Nathan,
˚
3
c¼16.281(2) A, b¼107. 292(3)8 V¼1342.1(3) A , Z¼4;
R ¼4.2%, wR ¼10.3%, GOF¼0.954. CCDC deposition
1
2
number 204989.