A convenient access to 1,3-disubstituted furo[3,4-b]indoles by acid ion-exchange resin-catalyzed furan formation

Article abstract of DOI:10.1016/j.tet.2011.10.022

Efficient synthesis of furo[3,4-b]indoles starting from the corresponding indole is reported. The first route involves derivatization, protection, and deprotection steps, which stretch the syntheses. The second method provides a shorter and more efficient strategy to accessing the furoindole. The innovation starts with alkylation at C-2 of the indole presenting at the C-3 position a ketone-acetal, followed by the cycloaromatization catalyzed by polymeric ion-exchange resins. The second route represents a significant improvement over other methods previously described.

Full text of DOI:10.1016/j.tet.2011.10.022

Tetrahedron 68 (2012) 356e362
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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A convenient access to 1,3-disubstituted furo[3,4-b]indoles by acid ion-exchange
resin-catalyzed furan formation
*
Joan Basset, Manel Romero, Thaïs Serra, M. Dolors Pujol
ꢀ
ꢀ
Laboratori de Química Farmaceutica (Unitat associada al CSIC), Facultat de Farmacia, Universitat de Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 August 2011
Received in revised form 5 October 2011
Accepted 7 October 2011
Available online 12 October 2011
Efficient synthesis of furo[3,4-b]indoles starting from the corresponding indole is reported. The first
route involves derivatization, protection, and deprotection steps, which stretch the syntheses. The sec-
ond method provides a shorter and more efficient strategy to accessing the furoindole. The innovation
starts with alkylation at C-2 of the indole presenting at the C-3 position a ketone-acetal, followed by the
cycloaromatization catalyzed by polymeric ion-exchange resins. The second route represents a signifi-
cant improvement over other methods previously described.
Keywords:
Acid resin
Ó 2011 Elsevier Ltd. All rights reserved.
2,3-Disubstituted furoindoles
Dienes
Hydroxyacetal cyclization
1. Introduction
alcohol and intramolecular cyclization. The alkylation of the indole
at the C-2 position of a hindered 3-imino group prepared from the
Furoindole dienes have been the subject of intense research for
many years and they are valuable tools in organic chemistry. These
intermediates have been applied in diverse inter- and intra-
molecular cycloaddition reactions. Substituted furoindoles may be
used as the starting material for the synthesis of drugs with a wide
range of pharmaceutical effects.1,2,9
corresponding aldehyde was also studied.7
In 2002, Gribble et al. described a synthesis of 1,3-dimethyl-4-
(phenylsulfonyl)-4H-furo[3,4-b]indole from the 3-acetyl-1-(phe-
nylsulfonyl)indole in 49% overall yield. The key intermediate was an
enol ether formed by treatment of the methylketone with LDA fol-
lowed by the addition of TBSOTf (tert-butyldimethylsilyl triflate).8
For the preparation of ellipticine and isoellipticine, the 1,3-
dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole was prepared
from 3-ethylindolein sixsteps(46%yield)or fromthe corresponding
indole-3-carboxaldehyde in four steps (21% yield).9 In all the
methods mentioned so far the group linked to the C-3 of the indole
was an alcohol, an aldehyde or an alkyl and there was no evidence of
alkylation of ketone acetal.10 More recently,11 the 1,3-unsubstituted
furo[3,4-b]indoles was synthesized from the N-sulfonyl-indole-3-
carboxaldehyde by a more efficient route with 48% overall yield. A
key intermediate of this original method was an ethylene acetal of
the 3-indole carbaldehyde, which unfortunately was not conducive
to a general synthesis of 1,3-disubstituted furoindoles because of the
steric hindrance. Although these routes allow us to obtain a wide
range of derivatives, they involve complex synthesis, which limits
their applicability and reduce their field of application.
Cycloaddition reactions from furoindoles offer rapid access to
polycyclic systems. Isobenzofuran derivatives are molecules of
great synthetic utility.3 Many of these rather reactive molecules
have been found to act as versatile precursors and to participle
promptly in a variety of reactions including cycloadditions.4
Due to their value as synthetic intermediates, furo[3,4-b]indoles
have attracted increasing attention.1,2,9 Many different routes have
been published for the preparation of these dienes, which in several
cases have only been prepared in situ. In general, these interesting
molecules are short-lived. A few years ago, we reported the syn-
thesis of tetracyclic compounds containing the 1,4-benzodioxin
from the appropriate furo[3,4-b][1,4]benzodioxan.5 Other authors
worked on the synthesis of furoindoles from distinct starting ma-
terials. In general, the synthesis involved lithiation of protected in-
doles followed by quenching with aldehydes, oxidation and
cyclization of the corresponding hydroxyketone.6 Gribble has re-
Results of our previous experiments indicated that the furoindole
formation occurs only if the 1-position of the indole is substituted by
a withdrawing group, such as phenylsulfonyl, which is a classical
protecting and activating group. Pursuant to our interest in novel
indole chemistry, we have developed two distinct routes to general
1,3-disubstituedfuroindolesfromthecommercialindolecompounds.
ported
a route to formylation of the N-protected hydrox-
ymethylindole via metalation and alkylation of the 2-formyl group
by Grignard reagents. This is followed by oxidation of the primarily
* Corresponding author. E-mail address: mdpujol@ub.edu (M.D. Pujol).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.022

J. Basset et al. / Tetrahedron 68 (2012) 356e362
357
2. Results and discussion
classical conditions (Scheme 3).13 N-protection of 17aec with 4-
methoxyphenylchlorosulfonyl chloride gave 18aec. The carbonyl
group of the resulting N-sulfonylindoles, without further purifica-
tion, was protected by formation of the acetal (19e21).
As in our previous studies the synthesis of furodienes could be
accomplished by indole alkylation and subsequent intramolecular
cyclization (Scheme 1).
O
O
R1
HO
R2
ClCOR1
18a. R1 = CH3
18b. R1 = Bu
18c. R1 = Pent
R1
NaH/DMF
AlCl3
86-95%
MeOPhSO2Cl
99%
N
H
N
H
N
S
COOH
Route A
N
O
O
17a-c
16
O
S
O
R2
56-71%
HO(CH2)2OH
O
PTSA
99%
O
O
R2
R1
O
COOH
N
S
O
O
R1
OH
O
O
R1
N
S
R3
2 steps
OCH3
O
O
R1
N
S
O
O
4 steps
Route C
O
O
1) LDA
acid resin
87-92%
2 steps
Route B
N
S
R2
N
N
2) R2CHO
62-80%
R
S O
2
O
O
O
O
S O
R1
R1
CONHN(CH3)2
N
S
R1
O
O
OCH3
OCH3
OCH3
22. R1 = R2 = CH3
13. R1 = R2 = CH3
19. R1 = CH3
20. R1 = Bu
21. R1 = Pent
23. R1 = CH3, R2 = Bu
15. R1 = CH3, R2 = Bu
28. R1 = CH3, R2 = Pent
29. R1 = Bu, R2 = CH3
30. R1 = Me, R2 = Hex
31. R1 = Pent, R2 = CH3
R1
24. R1 = CH3, R2 = Pent
25. R1 = Bu, R2 = CH3
26. R1 = Me, R2 = Hex
27. R1 = Pent, R2 = CH3
Scheme 1. Synthesis of 1,3-disubstituted furo[3,4-b]indoles.
First we attempted to repeat a route we had established earlier
for the preparation of 1,3-disusbstituted furobenzodioxan com-
pounds, but with indoles this procedure was unsuccessful
(Scheme 1, route A).5d Our failure to synthesize similar compounds
can be attributed to the carboxylic group at the 2 position of the
indole.12 For this reason the derivatisation of indole-2-carboxylic
acid was attempted (Scheme 1, route B). The hydrazides 4 and 5
were prepared as follows from the indole-2-carboxylic acid (1)
(Scheme 2). Several attempts were made to convert the indole-
carboxylic acid 1 to the corresponding hydrazide and the results
demonstrated that the protection of the carboxylic acid is necessary
for the N-protection of the indole. Metalation at the position 3,
accomplished with t-BuLi in THF, was followed by oxidation of the
hydrazide, affording the tricyclic lactones 9e11.11 This procedure
requires additional alkylation and dehydration from the in-
termediate lactone to the furoindole (route B).
Scheme 3. Synthesis of furo[3,4-b]indoles by route C.
The 4-methoxyphenylsulfonic and the phenylsulfonic groups
were chosen because their withdrawing character is suitable for
diene formation. The alkylation at position 2 of the indole (19e21)
was accomplished using t-BuLi or LDA as a base and a variety of
aldehydes were used. Alcohols 22e27 were obtained as unstable
compounds joined to the acetal. On treatment of non-purified
hydroxyketals 22e27 with acid resin in polar solvent, dienes 13,
15, and 28e31 were obtained.
The second method reduces the number of steps in the syn-
thesis of 1,3-disubstituted furoindoles and, moreover, it permits the
isolation of the ethylene glycol ketals intermediates but no its pu-
rification because of the instability. Acid ion-exchange resin as solid
catalyst plays a key role in this route. The acid resin mediated the
ketal hydrolysis and intramolecular cyclization followed by de-
hydration. The use of a solid acid ion-exchange resin (Amberlyst-
15) instead of a classical acid is strong economic driving and en-
vironmentally friendly, since it is inexpensive and a recyclable
heterogeneous catalyst.14
We established that the indole ketals can be converted into the
corresponding hydroxy derivatives by alkylation. Several bases and
conditions were tested for the 2-indole alkylation (see Table 1). For
example the use of t-BuLi and TMEDA gave mixtures of the desired
compound in low yield, together with unreacted starting material
(Table 1, entries 2e4). Use of LDA in THF at ꢀ78 ꢁC gave the cor-
responding alcohol in acceptable yields (Table 1, entries 6 and 7).
Small amounts of base (<3 equiv) led to low yields of product
(Table 1, entry 5). Addition of TMEDA did not significantly affect the
yield of alkylation (Table 1, entry 8).
The cyclization reactiondid notoccur incertainconditions. The use
of trifluoroacetic acid in toluene at reflux did not give the diene. Al-
though the useof PTSA in toluene affordeddegradationproducts of the
starting hydroxyketal (Table 2, entry 3), the mixture of trifluoroacetic
acid and sodium sulfate at room temperature in CH2Cl2 led pre-
dominantly to the recovery of unreacted starting material (Table 2,
entry 1). The use of HCl in isopropanol provided the diene in 52%yield.
Moreover, the intermediate hydroxyketal was converted directly, in
a one-pot reaction, to the diene by treatment with acid resin in iso-
propanol, without previous hydrolysis to the corresponding aryl alkyl
ketone. Thus, stirring the hydroxyketal in isopropanol/H2O (99:1) in
Scheme 2. Synthesis of furo[3,4-b]indoles using route B.
Subsequently our attention has been directed to alkylation at
the C-2 or C-3 position of indoles and cyclization to the expected
furoindoles. We attempted the alkylation of ketone ethylene acetals
(route C), which to our knowledge has not been reported. Com-
pounds 17aec are available from acylation of indole 16 under

358
J. Basset et al. / Tetrahedron 68 (2012) 356e362
Table 1
H3C
N
CH3
H3C
N
X
Y
X
Y
Alkylation of the indoleketal 19
Fe2(CO)9
O
O
benzene
15 h
O
O
O
O
N
N
S
CH3
1) base
CH3
CH3
CH3
CH3
CH3
O
O
S
O
O
THF, -78 ºC, time
O
S
O
N
S
2) CH3CHO
overnight
N
S
OH
O
O
O
O
OCH3
OCH3
OCH3
19
22
33a. X = N, Y = CH
33b. X = CH, Y = N
[(CH3)3Si]2NLi
THF
-15 ºC to reflux
13
32a. X = N, Y = CH
32b. X = CH, Y = N
OCH3
OCH3
NaOt-Bu/dioxane
sealed tube 80 ºC
5 h
Br
N
Entry
Base
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
LiHMDS 3.0 equiv
3
1
1
3
3
3
3
3
d
d
5
33
18
62
63
68
H3C
t-BuLi 1.5 equivþTMEDA 1.5 equiv
t-BuLi 3.0 equivþTMEDA 3.0 equiv
t-BuLi 3.0 equivþTMEDA 3.0 equiv
LDA 1.5 equiv
LDA 3.0 equiv
LDA 4.0 equiv
X
Y
N
H
CH3
34a. X = N, Y = CH (Ellipticine) (46%)
34b. X = CH, Y = N (Isoellipticine) (26%)
LDA 3.0 equivþTMEDA 3.0 equiv
Scheme 4. Synthesis of ellipticine.
a
Isolated yield.
of 1,3-disubstituted furo[3,4-b]indoles from the corresponding 3-
alkylketones. The dienes obtained are more stable and less re-
active than the corresponding benzo[c]furans. These furoindoles
could be synthesized by alkylation of protected ketones and sub-
sequent intramolecular cyclization. This is a mild efficient method
for the synthesis of furoindoles, and different alkyl substituents
were tolerated. This procedure is simple and broadly applicable.
Route B, starting from the indole-2-carboxylic acid, led to the diene
in eight steps with yields between 24 and 40%, while route C pro-
vide the same dienes in four steps from the corresponding ketone-
indole in overall yields of 65e70%. This furo[3,4-b]indole may be
a versatile precursor for the preparation of molecules with high
biological activity. More detailed applications are under in-
vestigation in our laboratory and will be reported in due course.
the presence of acid resin afforded the diene in 92% yield (Table 2,
entry 5). Acid ion-exchange resins are effective catalysts for furan
formationfromhydroxyketals, suchas 23. The diene13 was up-scaled,
and 20 g was easily prepared using the method described above.
Finally, to show the synthetic interest of the dienes obtained, we
synthesized the ellipticine, a natural compound with anticancer
properties.15,16 The optimized process route is shown in Scheme 4.
The diene 13 was successfully converted to the mixture of isomeric
DielseAlder adducts 32a and 32b (100% conversion) by cycload-
dition with 3,4-pyridyne as the dienophile, obtained from 3-
bromopyridine. These adducts were deoxygenated with Fe2(CO)9
without previous purification as described elsewhere.17
Table 2
Intramolecular cyclization of hydroxylketals
4. Experimental section
4.1. Materials
O
CH3
O
O
CH3
(CH2)3CH3
Conditions
N
S
Commercial reagents and solvents were purchased from
SigmaeAldrich and SDS-Carlo Erba.
N
S
(CH2)3CH3
OH
O
O
O
O
4.2. General methods
15
23
OCH3
OCH3
Melting points were obtained on an MFB-595010M Gallenkamp
apparatus with digital thermometer in open capillary tubes and are
uncorrected. IR spectra were obtained using an FTIR PerkineElmer
1600 Infrared Spectrophotometer. Only noteworthy IR absorptions
are listed (cmꢀ1). 1H and 13C NMR spectra were recorded on a Varian
Gemini-200 (200 and 50.3 MHz, respectively) or Varian Gemini-300
(300 and 75.5 MHz) instrument using CDCl3 as solvent with tetra-
Entry
Conditions
Solvent
Products (yield)a
1
2
3
4
5
CF3COOH, Na2SO4
CF3COOH, (CF3CO)2O
PTSA
HCl
Acid resin
CH2Cl2
15 (<10%)
Trace
d
Toluene
Toluene
Isopropanol
15 (52%)
15 (92%)
i-PrOH/1% H2O
methylsilaneasinternalstandard, (CD3)2COor(CD3)2SO. Other1H,13
C
a
Isolated yield.
NMR spectra and heterocorrelation 1He13C (HSQC and HMBC) ex-
periments were recorded on a Varian Gemini-400 (400 MHz and
100.6 MHz). Chemical shifts (d scale) are reported in parts per million
The last step, basic desulfonylation using NaOt-Bu in dioxane in
a sealed tube,18 afforded the ellipticine (34a) in 46% overall yield
and the regioisomer isoellipticine (34b) was obtained in 26% after
separation by column chromatography over silica gel (hexane/ethyl
acetate). These compounds were identical with commercial sam-
ples purchased from SigmaeAldrich.
(ppm) relative to the central peak of the solvent (
d
¼7.26 ppm for
CDCl3 in 1H NMR and
d
¼77.16 ppm for CDCl3 in 13C NMR). Mass
spectra were taken on a HewlettePackard 5988-A. Column chroma-
tography was performed with silica gel (E. Merck, 70e230 mesh).
Reactions were monitored by TLC using 0.25 mm silica gel F254 (E.
Merck). Elemental analysis for C, H, and N were determined on a Carlo
Erba-1106analyzer. Allreagentswereofcommerciallyqualityorwere
purified before use. Organic solvents were of analytical grade or were
purifiedbystandardprocedures. Commercialproductswereobtained
from SigmaeAldrich. Reactions were carried out under argon.
3. Conclusions
In summary, we report two synthetic routes to furoindoles. In
particular, the shorter route proved to be of value for the synthesis

J. Basset et al. / Tetrahedron 68 (2012) 356e362
359
4.3. Preparation of 1,3-disubstituted furo[3,4-b]indoles. Route
B
(s, 1H, H-3); 7.28e7.52 (m, 8H, Ar); 8.04 (s, 1H, NH); 8.10 (d,
J¼8.9 Hz, 1H, H-4). NMR 13C (CDCl3, 75.5 MHz)
d (ppm): 46.2 (CH3);
47.4 (CH3); 111.5 (CH, C-3); 114.4 (CH, C-7); 122.3 (CH, C-6); 124.2
(CH, C-5); 126.0 (CH, C-4); 127.3 (CH, C-20, C-60); 129.4 (CH, C-40);
129.6 (CH, C-30, C-50); 134.5 (CH, C-3a); 134.6 (C, C-10); 135.0 (C, C-
2); 135.4 (C, C-7a); 158.7 (C, C]O). C17H17N3O3S (343.09): calcd C
59.46, H 4.99, N 12.24; found C 59.88, H 4.78, N 11.98. Compound
4.3.1. Preparation
of
methyl
indole-2-carboxylate. Indole-2-
carboxylic acid (1.99 g, 12.3 mmol) was dissolved in a flask by dis-
tilled DMF. Then, 2 equiv of both, NaHCO3 (1.59 g) and CH3I (3 mL),
were added to the flask. The mixture was stirred overnight at room
temperature. The crude product was extracted with ether/purified
water (3ꢂ20 mL). The organic layer was dried over anhydrous
Na2SO4 and the solvent was removed under reduced pressure. This
procedure gave the ester as white solid in 94% of average yield. The
analytical data is in agreement with the reported data.2,9
(5) mp 126e128 ꢁC (hexane/AcOEt). IR (KBr)
1664 (C]O); 1594 (C]C); 1265 (AreO); 1211 (AreS); 1169 (CeO);
1092 (CeO). NMR 1H (CDCl3, 200 MHz)
(ppm): 2.76 (s, 6H,
n
cmꢀ1: 3202 (NH);
d
CH3eN); 3.77 (s, 3H, CH3eO); 6.87 (s, 3H, H-3); 6.86 (d, J¼9.0 Hz,
2H, H-30, H-50); 6.97 (s, 1H, NH); 7.23 (t, J¼7.4 Hz, 1H, H-5); 7.38 (t,
J¼7.0 Hz, 1H, H-6); 7.47 (d, J¼7.8 Hz, 1H, H-4); 7.99 (d, J¼9.0 Hz, 2H,
H-20, H-60); 8.08 (d, J¼8.2 Hz, 1H, H-7). C18H19N3O4S (373.11): calcd
C 57.89, H 5.13, N 11.25; found C 58.34, H 5.09, N 11.43.
4.3.2. Preparation of methyl N-benzenesulfonylindole-2-carboxylate
(2) and methyl N-(4-methoxybenzenesulfonyl)indole-2-carboxylate
(3). Methyl indole-2-carboxylate (1.86 g, 10.6 mmol) was dis-
solved in a flask by distilled DMF. NaH (0.50 g,1.1 equiv) and PhSO2Cl
(1.6 mL,1.2 equiv) or MeOSO2Cl (2.62 g,1.2 equiv) were slowlyadded
to the flask on a pre-cooled bath of ice. The mixture was stirred
overnight at room temperature. The crude product was extracted
with ethyl ether/purified water (3ꢂ20 mL), the organic layer was
dried over anhydrous Na2SO4, and the solvent was removed under
reduced pressure to obtain the desired product as a white solid in
90e99% of average yield. Compounds (2)19 and (3) mp: 116e118 ꢁC
4.3.4. Preparation
of
N-benzenesulfonyl-2-(N,N-dimethylhy-
drazinecarbonyl)-3-(1-hydroxyalkyl)-indoles (6, 8) and 3-(1-
hydroxymethyl)-2-(N,N-dimethylhydrazinecarbonyl)-N-(4-
methoxybenzenesulfonyl)indole (7). The compound (1.5 mmol) dis-
solved in THF (10 mL) was transferred to a three-necked anhydrous
flask equipped with stirrer and cooled to ꢀ78 ꢁC by a solid carbon
dioxideeacetone bath. Then, 3 equiv of TMEDA (0.7 mL, 4.5 mmol)
and t-BuLi 1.5 M (3.0 mL, 4.5 mmol) were added dropwise. The
mixture was stirred at controlled temperature for 3 h. After that,
5 equiv of the corresponding aldehyde (7.5 mmol) were added. The
mixture was stirred overnight at room temperature. The crude
product was treated with NH4Cl and then extracted with purified
water/mixture of ethyl ether and drops of ethyl acetate (3ꢂ15 mL).
The organic layer was dried over Na2SO4 and the solvent was re-
moved under reduced pressure, giving the desired compound as
yellow oil in 60e65% of gross average yield. Compound (6) oil. IR
(methanol). IR (KBr)
n
cmꢀ1: 1731 (C]O); 1594 (C]C); 1260 (AreO);
(ppm): 3.71
1205 (AreS); 1087 (CeO). NMR 1H (CDCl3, 200 MHz)
d
(s, 3H CH3eOC6H4); 3.92 (s, 3H, CH3eOOC); 6.85 (d, J¼9.0 Hz, 2H, H-
30, H-50); 7.12 (s,1H, H-3); 7.22 (t, J¼7.8 Hz,1H, H-5); 7.39 (t, J¼7.0 Hz,
1H, H-6); 7.51 (d, J¼7.6 Hz, 1H, H-4); 7.96 (d, J¼9.0 Hz, 2H, H-20, H-
60); 8.10 (d, J¼8.4 Hz, 1H, H-7). NMR 13C (CDCl3, 50.3 MHz)
d (ppm):
52.6 (CH3eOOC); 55.4 (CH3eOC6H4); 113.9 (CH, C-30, C-50); 115.1
(CH, C-3); 116.4 (CH, C-7); 122.3 (CH, C-6); 123.8 (CH, C-5); 126.7
(CH, C-4); 127.1 (C, C-2); 127.9 (C, C-10); 129.5 (C, C-20, C-60); 131.2 (C,
C-3a); 137.8 (C, C-7a); 161.6 (C, C-40); 163.5 (C, C]O). C17H15NO5S
(345.07): calcd C 59.12, H 4.38, N 4.06; found C 59.43, H 4.68, N 3.87.
(KBr)
n
cmꢀ1: 3512 (OH, NH); 1653 (C]O); 1202 (CeO); 1175 (CeN).
NMR 1H (CDCl3, 300 MHz)
d
(ppm): 1.53 (d, J¼8.5 Hz, 3H, CH3N);
2.71 and 2.78 (s, 3H, CH3); 5.20 (q, J¼8.5 Hz, 1H, CHeO); 7.27e7.53
(m, 7H, Ar); 7.98 (d, J¼9 Hz, 1H, H-7); 8.17 (d, J¼9.0 Hz, 1H, H-4).
4.3.3. Preparation of N-benzenesulfonylindole-2-carboxylic acid and
N-(4-methoxybenzenesulfonyl)indole-2-carboxylic acid. Preparation
of N-benzenesulfonyl-2-chlorocarbonylindole, N-benzenesulfonyl-2-
(N,N-dimethylhydrazinecarbonyl)indole (4), 2-chlorocarbonyl-N-
(4-methoxybenzenesulfonyl)indole, and 2-(N,N-dimethylhydrazine-
carbonyl)-N-(4-methoxybenzenesulfonyl)indole (5). The N-pro-
tected ester (6.37 mmol) dissolved in ethanol (20 mL) was treated
with NaOH 2 N (30 mL). The resulting mixture was stirred over-
night at room temperature. Then, ethanol was removed under re-
duced pressure and the remaining ester was extracted with
a mixture of ethyl ether and drops of ethyl acetate (3ꢂ20 mL). Fi-
nally, the addition of HCl 1 N let us extract the N-protected acid
with the same solvent mixture indicated above. The latter organic
layer was dried over anhydrous Na2SO4 and the solvent was re-
moved under reduced pressure. This gave the desired carboxylic
acid as a white solid in 95e99% of average yield. Alternatively, these
carboxylic acids can be crystallized from MeOH. The carboxylic acid
(2.34 mmol) and an excess of SOCl2 (1.2 mL) were added in a flask
dissolved in toluene (20 mL). The mixture was heated at reflux
temperature and stirred for 2 h. After removing the toluene under
reduced pressure, the obtained solid was dissolved in CH2Cl2 and
N,N-dimethylhydrazine (1.5 equiv) was added. The mixture was
stirred overnight at room temperature. The crude product was
washed with NaOH 2 N (3ꢂ10 mL), the organic layer was dried over
Na2SO4, and the solvent was removed under reduced pressure.
Purification by silica gel column chromatography, using hexane/
ethyl acetate as eluent gave the desired compound as a white solid
in 80e84% of average yield. Compound (4) mp: 170e173 ꢁC (hex-
9.42 (br s, 1H, NH). NMR 13C (CDCl3, 75.5 MHz)
d (ppm): 23.1 (CH3);
46.9 (CH3 (ꢂ2)); 105.4 (CH, C-7); 115.8 (CH, C-4); 121.4 (CH, C-6);
124.5 (CH, C-5); 127.5 (CH, C-20 and C-60); 128.8 (CH, C-30, C-50);
129.0 (C, C-3); 132.1 (C, C-3); 137.0 (C, C-10); 145.5 (C, C-7a); 160.8
(C, C]O). C19H21N3O4S (387.13): calcd C 58.90, H 5.46, N 10.85;
found C 59.88, H 5.78, N 10.65. Compound (7) mp: 144e146 ꢁC
(hexane/AcOEt). IR (KBr)
(C]C); 1265 (AreO); 1210 (AreS); 1170 (CeO); 1070 (CeO). NMR
1H (CDCl3, 200 MHz)
n
cmꢀ1: 3268 (OH, NH); 1645 (C]O); 1594
d
(ppm): 1.51 (d, J¼6.8 Hz, 3H, CH3eC); 2.70 (s,
6H, CH3eN); 3.70 (s, 3H, CH3eO); 5.13 (q, J¼6.6 Hz,1H, CHeO); 6.80
(d, J¼9.0 Hz, 2H, H-30, H-50); 7.19 (t, J¼8.0 Hz, 1H, H-5); 7.34 (t,
J¼8.0 Hz, 1H, H-6); 7.70 (d, J¼7.8 Hz, 1H, H-4); 7.91 (d, J¼9.0 Hz, 2H,
H-20, H-60); 8.02 (d, J¼7.8 Hz, 1H, H-7); 9.81 (s, 1H, NH).
C20H23N3O5S (417.14): calcd C 57.54, H 5.55, N 10.97; found C 57.32,
H 5.89, N 10.76. Compound (8) oil. IR (KBr)
n
cmꢀ1: 3299 (OH, NH);
(ppm): 0.97
1657 (C]O); 1175 (CeN). NMR 1H (CDCl3, 300 MHz)
d
(t, J¼7.8 Hz, 3H, CH3N); 1.20e1.34 (m, 4H, CH2); 2.53 (s, 6H,
CH3eN); 4.62 (t, J¼7.8 Hz, 1H, CHeO); 5.24 (br s, 1H, OH); 7.27e7.62
(m, 4H, Ar); 7.70e7.82 (m, 2H, Ar); 7.99 (d, J¼8.2 Hz, 2H, H-20, H-60).
NMR 13C (CDCl3, 75.5 MHz)
d (ppm): 16.2 (CH2); 22.1 (CH2); 24.1
(CH2); 30.2 (CH2); 46.9 (CH3); 68.9 (CH, CHeO); 113.9 (CH, C-7);
126.3 (CH, C-4); 127.4 (CH, C-6); 127.7 (CH, C-5); 128.4 (CH, C-20 and
C-60); 128.9 (CH, C-30, C-50); 123.8 (C, C-4a); 133.9 (C, C-3); 136.1 (C,
C-10); 136.9 (C, C-2); 137.2 (C, C-7a); 162.1 (C, C]O). C22H27N3O4S
(429.17): calcd C 61.52, H 6.34, N 9.78; found C 61.23, H 6.68, N 9.55.
4.3.5. Preparation of 1-alkyl-N-benzenesulfonyl-3-oxo-(1H)-furo
[3,4-b]indoles (9, 11) and N-(4-methoxybenzenesulfonyl)-1-methyl-
ane/AcOEt). IR (KBr)
n
cmꢀ1: 1658 (C]O); 1455; 1174 (CeN); 1191
(ppm): 2.74 (s, 6H, CH3N); 6.93
3-oxo-(1H)-furo[3,4-b]indole
(10). The
starting
material
(AreS). NMR 1H (CDCl3, 300 MHz)
d
(2.24 mmol), dissolved in anhydrous CH2Cl2 (20 mL), 10 equiv of

360
J. Basset et al. / Tetrahedron 68 (2012) 356e362
MnO2 (2.51 g, 28.87 mmol) and 10 equiv of glacial acetic acid
(1.4 mL, 22.4 mmol) were added in an anhydrous flask and stirred
overnight at room temperature. The crude product was filtered and
washed with NaHCO3/CH2Cl2 (3ꢂ10 mL). The organic layer was
dried over anhydrous Na2SO4 and the solvent was removed under
reduced pressure. Purification by silica gel column chromatogra-
phy, using hexane/ethyl acetate as eluent, allowed us to obtain the
intermediate lactone as yellow oil in 60e95% of average yield.
indole-2-carboxylic acid). Compounds (12)10 and (13). Mp:
166e168 ꢁC (hexane/AcOEt). IR (ATR) cmꢀ1: 1594 (C]C); 1262
(AreO); 1184 (AreS); 1167 (CeO). NMR 1H (CDCl3, 400 MHz)
n
d
(ppm): 2.43 (s, 3H, CH3eAr); 2.68 (s, 3H, CH3eAr); 3.74 (s, 3H,
CH3eO); 6.75 (d, J¼9.0 Hz, 2H, H-30, H-50); 7.13e7.32 (m, 2H, H-6, H-
7); 7.40 (d, J¼7.5 Hz,1H, H-5); 7.56 (d, J¼9.0 Hz, 2H, H-20, H-60); 8.03
(d, J¼8.4 Hz, 1H, H-8). NMR 13C (CDCl3, 100.6 MHz)
d (ppm): 13.1
(CH3, CH3eAr); 14.3 (CH3, CH3eAr); 55.6 (CH3, CH3eO); 114.1 (CH,
C-30, C-50); 116.8 (CH, C-5); 118.7 (C, C-8b); 121.1 (CH, C-8); 123.8 (C,
C-3a); 124.6 (CH, C-6); 126.5 (CH, C-7); 128.2 (C, C-10); 128.4 (C, C-
8a); 129.3 (CH, C-20, C-60); 132.6 (C, C-4a); 138.1 (C, C-3); 145.2 (C,
C-1); 163.6 (C, C-40). C19H17NO4S (355.09): calcd C 64.21, H 4.82, N
3.94; found C 64.45, H 4.78, N 3.65. Compound (14) mp: 110e112 ꢁC
Compound (9) mp¼164e166 ꢁC (hexane/AcOEt). IR (KBr)
n :
cmꢀ1
1762 (C]O); 1377; 1183 (CeN); 1039 (CeO). NMR 1H (CDCl3,
200 MHz)
d
(ppm): 1.67 (d, J¼6.6 Hz, 3H, CH3N); 5.59 (q, J¼6.6 Hz,
1H, CHeCH3); 7.27e7.45 (m, 3H, Ar); 7.48 (d, J¼7.8 Hz, 1H, H-7);
7.54 (d, J¼7.4 Hz, 2H, H-30, H-50); 8.12 (d, J¼7.4, 2H, H-20, H-60); 8.42
(d, J¼7.8 Hz, 1H, H-4). NMR 13C (CDCl3, 50.4 MHz)
d
(ppm): 19.9
(hexane/AcOEt). IR (KBr)
1180 (AreS). NMR 1H (CDCl3, 300 MHz)
3H, CH3CH2CH2CH2eAr); 1.44
n
cmꢀ1: 1678 (C]C); 1455; 1362 (AreO);
(ppm): 0.98 (t, J¼7.3 Hz,
(sext, 2H,
J¼7.3 Hz,
(CH3); 73.9 (CHeO); 115.7 (CH, C-5); 120.9 (CH, C-8); 121.4 (C, C-
8b); 124.5 (CH, C-6); 127.3 (C, C-8a); 127.4 (CH, C-30 and C-50); 128.9
(CH, C-7); 129.4 (CH, C-20, C-60); 134.4 (C, C-40); 137.9 (C, C-10);
142.4 (C, C-3a); 148.0 (C, C-4a); 160.7 (C, C]O). C17H13NO4S
(327.06): calcd C 62.37, H 4.00, N 4.28; found C 62.12, H 4.44, N 3.98.
d
CH3CH2CH2CH2eAr); 1.75 (qt, J¼7.3 Hz, 2H, CH3CH2CH2CH2eAr);
2.44 (s, 3H, CH3eAr); 3.11 (t, J¼7.3 Hz, 2H, CH3CH2CH2CH2eAr); 7.18
(dt, J1¼1.1 Hz, J2¼7.5 Hz,1H, H-6); 7.20e7.24 (m,1H, H-7); 7.25e7.33
(dt, J1¼1.3 Hz, J2¼7.3 Hz, 2H, H-30, H-50); 7.39 (dd, J1¼1.1 Hz,
J2¼7.5 Hz, 1H, H-5); 7.44 (m, 1H, H-40); 7.64 (dd, J1¼1.4 Hz, J2¼8.4,
2H, H-20, H-60); 8.03 (dt, J1¼0.4 Hz, J2¼8.3 Hz, 1H, H-8). NMR 13C
Compound (10) mp: 139e141 ꢁC (hexane/AcOEt). IR (KBr)
1768 (C]O); 1594 (C]C); 1263 (AreO); 1221 (AreS); 1171 (CeO);
1084 (CeO). NMR 1H (CDCl3, 200 MHz)
n :
cmꢀ1
d
(ppm): 1.67 (d, J¼6.8 Hz,
3H, CH3eC); 3.81 (s, 3H, CH3eO); 5.56 (q, J¼6.8 Hz, 1H, CHeO); 6.92
(d, J¼9.0 Hz, 2H, H-30, H-50); 7.37 (t, J¼7.0 Hz, 1H, H-5); 7.58 (m, 2H,
H-4, H-6); 8.10 (d, J¼9.0 Hz, 2H, H-20, H-60); 8.36 (d, J¼8.8 Hz,1H, H-
(CDCl3, 75.5 MHz) d (ppm): 13.5 (CH3, CH3CH2CH2CH2eAr); 14.0
(CH3, CH3eAr); 22.5 (CH2, CH3CH2CH2CH2eAr); 26.6 (CH2,
CH3CH2CH2CH2eAr); 31.0 (CH2, CH3CH2CH2CH2eAr); 116.7 (CH, C-
5); 118.3 (C, C-8b); 120.9 (CH, C-8); 123.7 (C, C-3a); 124.6 (CH, C-6);
126.3 (CH, C-7); 126.9 (CH, C-20, C-60); 127.5 (C, C-4a); 128.7 (CH, C-
30, C-50); 133.4 (CH, C-40); 136.6 (C, C-8a); 137.2 (C, C-10); 138.1 (C, C-
1); 144.9 (C, C-3). Compound (15) mp: 94e96 ꢁC (hexane/AcOEt). IR
7). NMR 13C (CDCl3, 50.3 MHz)
d (ppm): 19.9 (CH3eC); 55.7
(CH3eO); 73.8 (CH, CHeO); 114.5 (CH, C-30, C-50); 115.7 (CH, C-5);
120.8 (CH, C-6); 121.3 (C, C-8b); 123.3 (C, C-10); 124.2 (CH, C-7);
127.3 (C, C-8a); 128.7 (C, C-8); 129.8 (CH, C-20, C-60); 142.8 (C, C-3a);
147.5 (C, C-40); 143.2 (C, C-3a); 149.3 (C, C-4a); 164.1 (C, C]O).
C18H15NO5S (357.07): calcd C 60.49, H 4.23, N 3.92; found C 60.34, H
(ATR)
n
cmꢀ1: 1594 (C]C); 1264 (AreO); 1180 (AreS); 1161 (CeO).
(ppm): 0.98 (t, J¼7.2 Hz, 3H,
NMR 1H (CDCl3, 200 MHz)
d
4.54, N 3.76. Compound (11) oil. IR (KBr)
n
cmꢀ1: 1764 (C]O); 1379;
(ppm): 0.85
CH3CH2CH2CH2eAr); 1.41e1.43 (m, 2H, CH3CH2CH2CH2eAr);
1.72e1.76 (m, 2H, CH3CH2CH2CH2eAr); 2.44 (s, 3H, CH3eAr); 3.10
(t, J¼7.3 Hz, 2H, CH3CH2CH2CH2eAr); 3.73 (s, 3H, CH3eO); 6.74 (d,
J¼9.0 Hz, 2H, H-30, H-50); 7.17 (td, J1¼1.3 Hz, J2¼7.4 Hz, 1H, H-7);
7.27 (td, J1¼1.5 Hz, J2¼7.5 Hz, 1H, H-6); 7.39 (dd, J1¼1.0 Hz,
J2¼7.2 Hz, 1H, H-5); 7.55 (d, J¼9.0 Hz, 2H, H-20, H-60); 8.02 (d,
1187 (CeN); 1064 (CeO). NMR 1H (CDCl3, 300 MHz)
d
(t, J¼6.7 Hz, 3H, CH3N); 1.29 (m, 4H, CH2); 1.97 (m, 4H, CH2e); 5.41
(q, J¼6.7 Hz, 1H, CHeO); 7.21e7.61 (m, 5H, Ar); 8.05 (d, J¼6.9 Hz,
2H, H-20, H-60); 8.21 (d, J¼6.9 Hz, 1H, H-8). NMR 13C (CDCl3,
75.5 MHz)
d (ppm): 13.8 (CH3); 22.3 (CH2); 26.6 (CH2); 33.8 (CH2);
77.4 (CH, CHeO); 115.5 (CH, C-7); 121.1 (CH, C-8); 121.8 (CH, C-8b);
124.5 (CH, C-6); 127.5 (CH, C-30 and C-50); 128.9 (CH, C-7); 129.3 (C,
C-8a); 129.9 (CH, C-20, C-60); 134.3 (C, C-40); 138.1 (C, C-10); 143.0 (C,
C-3a); 147.2 (C, C-4a); 158.2 (C, C]O). C20H19NO4 (369.11): calcd C
65.02, H 5.18, N 3.79; found C 65.34, H 4.99, N 3.65.
J¼7.5 Hz, 1H, H-8). NMR 13C (CDCl3, 75.5 MHz)
d
(ppm): 13.7 (CH3,
CH3CH2CH2CH2eAr);
14.1
(CH3,
CH3eAr); 22.7 (CH2,
CH3CH2CH2CH2eAr); 26.8 (CH2, CH3CH2CH2CH2eAr); 31.1 (CH2,
CH3CH2CH2CH2eAr); 55.6 (CH3, CH3eO); 114.0 (CH, C-30, C-50);
117.0 (CH, C-5); 118.6 (C, C-8b); 121.1 (CH, C-8); 123.9 (C, C-3a);
124.7 (CH, C-6); 126.4 (CH, C-7); 127.9 (C, C-10); 128.5 (C, C-8a);
129.3 (CH, C-20, C-60); 137.4 (C, C-4a); 138.2 (C, C-3); 145.3 (C, C-1);
163.5 (C, C-40). C22H23NO4S (397.13): calcd C 66.48, H 5.83, N 3.52;
found C 66.78, H 5.98, N 3.67.
4.3.6. Preparation of N-benzenesulfonyl-1,3-dialkyl-3-hydroxyfuro[3,4-
b]indoles and 1,3-dialkyl-3-hydroxy-N-(4-methoxybenzenesulfonyl)
furo[3,4-b]indoles. The compound (0.40 mmol) dissolved in THF
(5 mL) was transferred to a three-necked anhydrous flask equipped
with stirrer and cooled to ꢀ78 ꢁC by a bath of solid carbon dioxi-
deeacetone. Then, 2.5 equiv of alkyllithium (1.00 mmol) were added.
The mixture was stirred at fixed temperature for 2 h. Then, the crude
product was treated with NH4Cl and extracted with purified water/
mixture of ethyl ether and drops of ethyl acetate (3ꢂ10 mL). The
organic layer was dried over Na2SO4 and the solvent was removed
under reduced pressure, obtaining the crude compound as yellow oil.
4.4. Preparation of 1,3-disubstituted furo[3,4-b]indoles.
Route C
4.4.1. Preparation of 1,3-disubstituted furo[3,4-b]indoles. Route C.
Preparation of 3-acylindoles (17aec). For the preparation of 3-
acylindoles, we followed the method described by Stalick.13 Using
butyryl chloride and valeroyl chloride as reagents, we obtained the
3-acyl derivatives in good yields (86e95%). Note that 3-acetylindole
was purchased from SigmaeAldrich.
4.3.7. Preparation of N-benzenesulfonyl-1,3-dialkylfuro[3,4-b]indoles
(12, 14) and 3-alkyl-N-(4-methoxybenzenesulfonyl)-1-methylfuro
[3,4-b]indoles (13, 15). The starting material (0.27 mmol) was dis-
solved in anhydrous CH2Cl2 (15 mL) and some drops of CF3COOH
(0.1 mL, 1.35 mmol), dried over Na2SO4, and stirred at room tem-
perature for 4 h. The crude product was filtered and washed with
NaHCO3/CH2Cl2 (3ꢂ10 mL), the organic layer was dried over
Na2SO4, and the solvent was removed under reduced pressure.
Purification by silica gel column chromatography, using hexane/
ethyl acetate as eluent, allowed us to obtain the desired dienes as
yellow oil in 80e88% of average yield (24e40% global yields from
4.4.2. Preparation of 1-[N-(4-methoxybenzenesulfonyl)indol-3-yl]al-
kanones (18aec). Indol-3-yl-alkanone (12.6 mmol) was dissolved
in dry DMF. NaH (0.67 g, 16.4 mmol) was slowly added and stirred
at room temperature for 30 min. Then, the flask was cooled down
on a bath of ice and MeOPhSO2Cl (3.38 g, 16.4 mmol) dissolved in
DMF was slowly added to the flask. The mixture was stirred at room
temperature overnight. Then, the crude product was extracted with
AcOEt/water (20:20 mL), the organic layers were dried over
Na2SO4, and the solvent was removed under reduced pressure to

J. Basset et al. / Tetrahedron 68 (2012) 356e362
361
give the desired compound as a white solid in quantitative yield
1.28e1.32 (m, 2H, CH3CH2CH2CH2eAr); 1.65e1.69 (m, 2H,
CH3CH2CH2CH2eAr); 2.68 (s, 3H, CH3eAr); 2.77 (t, J¼7.5 Hz, 2H,
CH3CH2CH2CH2eAr); 3.74 (s, 3H, CH3eO); 6.75 (d, J¼9.0 Hz, 2H, H-
30, H-50); 7.18 (t, J¼7.5 Hz, 1H, H-7); 7.28 (t, J¼7.5 Hz, 1H, H-6); 7.40
(d, J¼7.5 Hz, 1H, H-5); 7.55 (d, J¼9.0 Hz, 2H, H-20, H-60); 8.03
(99%). Compounds (18a),20 (18b), and (18c).
4.4.3. Preparation of 3-(2-alkyl-1,3-dioxolan-2-yl)-N-(4-methoxybe-
nzene
sulfonyl)-1H-indoles (19e21). The 3-indolylalkanone
(4.5 mmol), ethylene glycol (1.7 mL; 30.5 mmol) and a catalytic
amount of PTSA were added in a flask containing toluene as a sol-
vent. The mixture was heated at reflux temperature and stirred for
3e4 h. At the end of the reaction, the mixture was diluted with
ethyl acetate (20 mL) and washed with NaHCO3 0.5 N aqueous so-
lution (20 mL). The organic layer was dried over Na2SO4 and the
solvent was removed under reduced pressure to give the crude
ketal in quantitative yield (99%). Ketals are not purified due to its
lack of stability. The reaction was monitored by TLC and 1H NMR.
(d, J¼8.3 Hz, 1H, H-8). NMR 13C (CDCl3, 75.5 MHz)
d (ppm):
13.2 (CH3, CH3eAr); 13.9 (CH3, CH3CH2CH2CH2eAr); 22.4 (CH2,
CH3CH2CH2CH2eAr); 28.0 (CH2, CH3CH2CH2CH2eAr); 30.5 (CH2,
CH3CH2CH2CH2eAr); 55.6 (CH3, CH3eO); 114.1 (CH, C-30, C-50);
116.9 (CH, C-5); 118.4 (C, C-8b); 121.4 (CH, C-8); 124.0 (C, C-3a);
124.7 (CH, C-6); 126.4 (CH, C-7); 128.2 (C, C-10); 128.3 (C, C-8a);
129.3 (CH, C-20, C-60); 132.6 (C, C-4a); 142.7 (C, C-3); 145.3 (C, C-1);
163.5 (C, C-40). C22H23NO4S (397.13): calcd C 66.48, H 5.83, N 3.52;
found C 66.76, H 6.03, N 3.43.
4.4.4. Preparation of 3-(2-alkyl-1,3-dioxolan-2-yl)-2-(1-hydroxyalkyl)-
N-(4-methoxybenzenesulfonyl)-1H-indoles (22e27). The crude ketal
(1.14 mmol) was dissolved in distilled THF in an anhydrous flask
under argon atmosphere and was transferred to a three-necked an-
hydrous flask equipped with stirrer, cooled and maintained at ꢀ78 ꢁC
by a solid carbon dioxideeacetone bath. Then 3.5 equiv of LDA
(2.2 mL; 3.96 mmol) were added. The mixture was stirred at con-
trolled temperature for 3 h. After that, an excess of acetaldehyde
(0.5 mL, 8.96 mmol) were added. The mixture was stirred at room
temperature overnight. The crude product was treated with a satu-
rated aqueous solution of NH4Cl and then extracted with ethyl ace-
tate (3ꢂ25 mL). The organic layer was dried over Na2SO4, the solvent
was removed in vacuum to give the crude product (62e80%), which
is not purified due to its lack of stability. The quality control of the
reaction was monitored by TLC and 1H NMR. Hydroxyketals are not
purified due to its lack of stability.
4.4.8. 3-Hexyl-N-(4-methoxybenzenesulfonyl)-1-methylfuro[3,4-b]
indole (30). Mp: 92e94 ꢁC (hexane/AcOEt). IR (ATR)
n
cmꢀ1: 1593
(C]C); 1256 (AreO); 1183 (AreS); 1169 (CeO). NMR 1H (CDCl3,
300 MHz)
(ppm): 0.90 (t, J¼6.9 Hz, 3H, CH3CH2CH2CH2CH2CH2eAr);
d
1.21e1.45 (m, 6H, CH3CH2(CH2)4eAr, CH3CH2CH2(CH2)3eAr,
CH3CH2CH2CH2CH2CH2eAr); 1.76 (q, J¼7.6 Hz, 2H, CH3CH2CH2CH2-
CH2CH2eAr); 2.42 (s, 3H, CH3eAr); 3.10 (t, J¼7.5 Hz, 2H,
CH3CH2CH2CH2CH2CH2eAr); 3.68 (s, 3H, CH3eO); 6.70 (d, J¼9.0 Hz,
2H, H-30, H-50); 7.15 (td, J1¼1.1 Hz, J2¼7.5 Hz, 1H, H-7); 7.25 (td,
J1¼1.4 Hz, J2¼7.5 Hz,1H, H-6); 7.37 (dd, J1¼1.0 Hz, J2¼7.5 Hz,1H, H-5);
7.55 (d, J¼9.0 Hz, 2H, H-20, H-60); 8.02 (d, J¼8.2 Hz, 1H, H-8). NMR 13C
(CDCl3, 75.5 MHz)
d (ppm): 13.5 (CH3, CH3CH2CH2CH2CH2CH2eAr);
14.2 (CH3, CH3eAr); 22.7 (CH2, CH3CH2CH2CH2CH2CH2eAr); 27.0
(CH2, CH3CH2CH2CH2CH2CH2eAr); 28.9 (CH2, CH3CH2CH2CH2CH2-
CH2eAr); 29.2 (CH2, CH3CH2CH2CH2CH2CH2eAr); 31.8 (CH2,
CH3CH2CH2CH2CH2CH2eAr); 55.5 (CH3, CH3eO); 113.9 (CH, C-30, C-
50); 116.8 (CH, C-5); 118.5 (C, C-8b); 121.0 (CH, C-8); 123.8 (C, C-3a);
124.6; 126.3 (CH, C-7); 127.8 (C, C-10); 128.4 (C, C-8a); 129.2 (CH, C-20,
C-60); 137.3 (C, C-4a); 138.1 (C, C-3); 145.2 (C, C-1); 163.5 (C, C-40).
C24H27NO4S (425.17): calcd C 67.74, H 6.40, N 3.29; found C 67.84, H
6.13, N 3.06.
4.4.5. Preparation of N-(4-methoxybenzenesulfonyl)-1,3-dialkylfuro
[3,4-b]indole (28e31). 1.0 g of acid resin (Amberlyst-15) was
added to the crude hydroxyketal compound (1.80 mmol) dissolved
with a mixture of 1% purified water in i-PrOH and the solution was
stirred at room temperature for 2 h. The mixture was filtered and the
solvent was removed in vacuum to give the crude product. The ob-
tained residue was purified by silica gel column chromatography
using hexane/ethyl acetate as eluent to obtain the desired diene as
a white solid in 87e92% yield (65e70% global yields from the N-
protected alkanones).
4.4.9. N-(4-Methoxybenzenesulfonyl)-3-methyl-1-pentylfuro[3,4-b]
indole (31). Yellow oil. IR (ATR)
n
cmꢀ1: 1594 (C]C); 1261 (AreO);
1181 (AreS); 1165 (CeO). NMR 1H (CDCl3, 300 MHz)
d
(ppm): 0.85
(t, J¼7.0 Hz, 3H, CH3CH2CH2CH2CH2eAr); 1.25e1.31 (m, 4H,
CH3CH2CH2CH2CH2eAr, CH3CH2CH2CH2CH2eAr); 1.66e1.69 (m,
2H, CH3CH2CH2CH2CH2eAr); 2.69 (s, 3H, CH3eAr); 2.76 (t, J¼7.4 Hz,
2H, CH3CH2CH2CH2CH2eAr); 3.71 (s, 3H, CH3eO); 6.73 (d, J¼9.1 Hz,
2H, H-30, H-50); 7.17 (td, J1¼1.1 Hz, J2¼7.5 Hz, 1H, H-7); 7.28 (td,
J1¼1.4 Hz, J2¼7.5 Hz, 1H, H-6); 7.40 (dd, J1¼0.9 Hz, J2¼7.5 Hz, 1H, H-
5); 7.48 (d, J¼9.0 Hz, 2H, H-20, H-60); 8.03 (d, J¼8.3 Hz, 1H, H-8).
4.4.6. N-(4-Methoxybenzenesulfonyl)-1-methyl-3-pentylfuro[3,4-b]
indole (28). Yellow oil. IR (ATR)
n
cmꢀ1: 1594 (C]C); 1262 (AreO);
1180 (AreS); 1166 (CeO). NMR 1H (CDCl3, 300 MHz)
d
(ppm):
0.89e0.92 (m, 3H, CH3CH2CH2CH2CH2eAr); 1.27e1.32 (m, 2H,
CH3CH2CH2CH2CH2eAr); 1.40e1.42 (m, 2H, CH3CH2CH2CH2CH2eAr);
1.74e1.78 (m, 2H, CH3CH2CH2CH2CH2eAr); 2.39 (s, 3H, CH3eAr); 3.10
(t, J¼7.3 Hz, 2H, CH3CH2CH2CH2CH2eAr);3.60(s, 3H, CH3eO);6.64(d,
J¼9.0 Hz, 2H, H-30, H-50); 7.12 (t, J¼7.5 Hz, 1H, H-7); 7.23 (t, J¼8.3 Hz,
1H, H-6); 7.34 (d, J¼7.6 Hz,1H, H-5); 7.53 (d, J¼8.6 Hz, 2H, H-20, H-60);
NMR 13C (CDCl3, 75.5 MHz)
d (ppm): 13.1 (CH3, CH3eAr); 14.1 (CH3,
CH3CH2CH2CH2CH2eAr); 22.5 (CH2, CH3CH2CH2CH2CH2eAr); 28.1
(CH2, CH3CH2CH2CH2CH2eAr); 28.2 (CH2, CH3CH2CH2CH2CH2eAr);
31.4 (CH2, CH3CH2CH2CH2CH2eAr); 55.6 (CH3, CH3eO); 114.0 (CH,
C-30, C-50); 116.8 (CH, C-5); 118.4 (C, C-8b); 121.4 (CH, C-8); 123.9 (C,
C-3a); 124.7 (CH, C-6); 126.4 (CH, C-7); 128.1 (C, C-10); 128.3 (C, C-
8a); 129.3 (CH, C-20, C-60); 132.5 (C, C-4a); 142.8 (C, C-3); 145.2 (C,
C-1); 163.5 (C, C-40); (CH, C-6); 126.3 (CH, C-7); 127.8 (C, C-10);
128.4 (C, C-8a); 129.2 (CH, C-20, C-60); 137.3 (C, C-4a); 138.1 (C, C-3);
145.2 (C, C-1); 163.5 (C, C-40). C22H25NO4S (411.15): calcd C 67.13, H
6.12, N 3.40; found C 67.34, H 6.32, N 3.76.
8.01 (d, J¼8.3 Hz, 1H, H-8). NMR 13C (CDCl3, 75.5 MHz)
d (ppm): 13.4
(CH3, CH3CH2CH2CH2CH2eAr); 14.1 (CH3, CH3eAr); 22.5 (CH2,
CH3CH2CH2CH2CH2eAr); 26.9 (CH2, CH3CH2CH2CH2CH2eAr); 28.6
CH2, (CH3CH2CH2CH2CH2eAr); 31.7 (CH2, CH3CH2CH2CH2CH2eAr);
55.3 (CH3, CH3eO); 113.8 (CH, C-30, C-50); 116.7 (CH, C-5); 118.4 (C, C-
8b); 120.9 (CH, C-8); 123.7 (C, C-3a); 124.5 (CH, C-6); 126.2 (CH, C-7);
127.7 (C, C-10); 128.2 (C, C-8a); 129.1 (CH, C-20, C-60); 137.2 (C, C-4a);
138.1 (C, C-3); 145.1 (C, C-1); 163.4 (C, C-40). C22H25NO4S (411.15):
calcd C 67.13, H 6.12, N 3.40; found C 67.38, H 5.99, N 3.59.
Acknowledgements
4.4.7. 1-Butyl-N-(4-methoxybenzenesulfonyl)-3-methylfuro[3,4-b]
The authors express their sincere gratitude to the Ministerio de
Ciencia y Tecnología (CTQ2007-60614/BQU). One of us (J.B.) ac-
knowledges the Generalitat de Catalunya (AGAUR) for predoctoral
fellowship.
indole (29). Mp: 87e89 ꢁC (hexane/AcOEt). IR (ATR)
n
cmꢀ1: 1594
(C]C); 1261 (AreO); 1184 (AreS); 1163 (CeO). NMR 1H (CDCl3,
300 MHz)
(ppm): 0.90 (t, J¼7.4 Hz, 3H, CH3CH2CH2CH2eAr);
d

362
J. Basset et al. / Tetrahedron 68 (2012) 356e362
M. D. J. Med. Chem. 2007, 50, 294e307; (e) Romero, M.; Caignard, D.-H.; Renard,
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