An efficient synthesis of 4-(phenylsulfonyl)-4H-furo[3,4-b]indoles

Article abstract of DOI:10.1021/jo010938q

The fused heterocycle 4-(phenylsulfonyl)-4H-furo-[3,4-b]indole, which is an indole-2,3-quinodimethane synthetic analogue, is prepared in five steps from indole in 46% yield. A similar sequence is used to synthesize C-3 derivatives (3-methyl, 3-phenyl, and 3-heptyl). Thus, indole-3-carbaldehyde (1) is protected as the N-phenylsulfonyl derivative 2 and converted to the ethylene acetal 6. Lithiation at C-2 followed by treatment with an aldehyde affords the expected hydroxy acetals 7 and 8. Exposure to acid effects cyclization to the furoindoles 5 and 9. Furthermore, C-1 lithiation of furo[3,4-b]indole 9c followed by treatment with methyl iodide affords disubstituted furo[3,4-b]indole 10.

Full text of DOI:10.1021/jo010938q

J . Org. Chem. 2002, 67, 1001-1003
1001
Notes
Sch em e 1
An Efficien t Syn th esis of
4-(P h en ylsu lfon yl)-4H-fu r o[3,4-b]in d oles
Gordon W. Gribble,* J un J iang, and Yanbing Liu
Department of Chemistry, Dartmouth College,
Hanover, New Hampshire 03755-3564
grib@dartmouth.edu
Received September 21, 2001
Abstr a ct: The fused heterocycle 4-(phenylsulfonyl)-4H-furo-
[3,4-b]indole, which is an indole-2,3-quinodimethane syn-
thetic analogue, is prepared in five steps from indole in 46%
yield. A similar sequence is used to synthesize C-3 deriva-
tives (3-methyl, 3-phenyl, and 3-heptyl). Thus, indole-3-
carbaldehyde (1) is protected as the N-phenylsulfonyl de-
rivative 2 and converted to the ethylene acetal 6. Lithiation
at C-2 followed by treatment with an aldehyde affords the
expected hydroxy acetals 7 and 8. Exposure to acid effects
cyclization to the furoindoles 5 and 9. Furthermore, C-1
lithiation of furo[3,4-b]indole 9c followed by treatment with
methyl iodide affords disubstituted furo[3,4-b]indole 10.
Sch em e 2
The fused heterocycle 4H-furo[3,4-b]indole has served
admirably over the past 20 years as an indole-2,3-
quinodimethane synthetic analogue in Diels-Alder reac-
tions.1,2 We have employed this ring system in syntheses
of isomeric benzocarbazoles,1a,b,f bis(benzo[b]carbazoles),1c
and pyridocarbazoles, including the antitumor alkaloid
ellipticine.1d,e,2h
were unsuccessful. Although some improvement was
later found in the conversion of 3 to 4 by using methyl
formate in place of DMF (82 vs 72%),1e and the yields of
furan-ring substituted derivatives are invariably higher
than that of 5 (Thorpe-Ingold effect3), we now describe a
shorter and more efficient route to this fused heterocycle
and to C-3 alkyl- and aryl-substituted analogues of this
ring system.
Indole-3-carbaldehyde 14 was protected using a phase-
transfer method to give the N-phenylsulfonyl derivative
2 (Scheme 2). This method is higher-yielding than our
original method of N-protection (LDA/PhSO2Cl).1a Ac-
etalization under typical conditions gave acetal 6 (97%
yield). Lithiation of 6 at C-2 with sec-BuLi followed by
treatment with gaseous formaldehyde gave hydroxy
acetal 7 (not isolated). The reaction mixture was treated
with BF3‚Et2O and hydroquinone to afford furoindole 5
in 52% yield from acetal 6. This route to 5 represents a
significant improvement over our original synthesis1a (48
vs 28%).
Unfortunately, our original method1a of ring construc-
tion (Scheme 1) was plagued by a low-yielding and erratic
final cyclization step, particularly in the case of the
parent compound 5. Moreover, the lithiation of 3-(hy-
droxyalkyl)indoles such as 3 and quenching with formyl
(or acyl) equivalents were not conducive to a general
synthesis of C-3 substituted furo[3,4-b]indoles. Likewise,
our attempts to prepare 2-hydroxymethyl-1-(phenylsul-
fonyl)indole-3-carbaldehyde, which is isomeric with 4,
* To whom correspondence should be addressed. Phone: 603-646-
3118. Fax: 603-646-3946.
(1) (a) Saulnier, M. G.; Gribble, G. W. Tetrahedron Lett. 1983, 24,
5435-5438. (b) Gribble, G. W.; Saulnier, M. G.; Sibi, M. P.; Obaza-
Nutaitis, J . A. J . Org. Chem. 1984, 49, 4518-4523. (c) Gribble, G. W.;
Saulnier, M. G. J . Chem. Soc., Chem. Commun. 1984, 168-169. (d)
Davis, D. A.; Gribble, G. W. Tetrahedron Lett. 1990, 31, 1081-1084.
(e) Gribble, G. W.; Keavy, D. J .; Davis, D. A.; Saulnier, M. G.; Pelcman,
B.; Barden, T. C.; Sibi, M. P.; Olson, E. R.; BelBruno, J . J . J . Org.
Chem. 1992, 57, 5878-5891. (f) Gribble, G. W.; Silva, R. A.; Saulnier,
M. G. Synth. Commun. 1999, 29, 729-747.
(2) For other syntheses and/or uses of this ring system, see: (a)
Kuroda, T.; Takahashi, M.; Ogiku, T.; Ohmizu, H.; Kondo, K.; Iwasaki,
T. Chem. Commun. 1991, 1635-1636. (b) Miki, Y.; Hachiken, H.
Synlett 1993, 333-334. (c) Shiue, J .-S.; Fang, J .-M. J . Chem. Soc.,
Chem. Commun. 1993, 1277-1278. (d) Nagel, J .; Friedrichsen, W.;
Debaerdamaeker, T. Z. Naturforscher 1993, 48b, 213-223. (e) Kuroda,
T.; Takahashi, M.; Ogiku, T.; Ohmizu, H.; Nishitani, T.; Kondo, K.;
Iwasaki, T. J . Org. Chem. 1994, 59, 7353-7357. (f) Kappe, C. O.;
Padwa, A. J . Org. Chem. 1996, 61, 6166-6174. (g) Lin, S.-C.; Yang,
F.-D.; Shiue, J .-S.; Yang, S.-M.; Fang, J .-M. J . Org. Chem. 1998, 63,
2909-2917. (h) D´ıaz, M. T.; Cobas, A.; Guitia´n, E.; Castedo, L. Synlett
1998, 157-158.
Given the facility with which aldehydes serve as
electrophiles in lithiation reactions, this furoindole syn-
(3) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J . F. J . Chem. Soc. 1915,
107, 1080-1106. For early discussions of this phenomenon, see: (b)
Hammond, G. S. In Steric Effects in Organic Chemistry; Newman, M.
S., Ed.; J ohn Wiley: New York, 1956; pp 460-470. (c) Eliel, E. L.
Stereochemistry of Carbon Compounds; McGraw-Hill: New York, 1962;
pp 197-202. (d) Eliel, E. L.; Allinger, N. L.; Angyal, S. J .; Morrison,
G. A. Conformational Analysis; Interscience: New York, 1965; pp 191-
192. (e) Allinger, N. L.; Zalkow, V. J . Org. Chem. 1960, 25, 701. (f) For
a recent example, see: Fujita, M.; Matsushima, H.; Sugimura, T.; Tai,
A.; Okuyama, T. J . Am. Chem. Soc. 2001, 123, 2946-2957. (g) See
also: J ung, M. E. Synlett 1999, 843-846.
(4) J ames, P. N.; Snyder, H. R. Org. Synth. Coll. Vol. IV 1963, 539-
542.
10.1021/jo010938q CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/15/2002

1002 J . Org. Chem., Vol. 67, No. 3, 2002
Notes
afforded an additional 4.8 g for a total yield of 8.9 g (97%), mp
87-90 °C. The analytical sample was prepared by recrystalli-
zation from ether/hexane: mp 95-97 °C; 1H NMR (CDCl3) δ
7.94-7.83 (m, 3H), 7.63-7.17 (m, 7H), 6.03 (s, 1H), 4.11-3.98
(m, 4H). Anal. Calcd for C17H15NO4S: C, 61.99; H, 4.59; N, 4.25;
S, 9.74. Found: C, 61.75; H, 4.63; N, 4.36; S, 9.85.
Sch em e 3
4-(P h en ylsu lfon yl)-4H-fu r o[3,4-b]in d ole (5). To a -70 °C
stirred solution of 1-(phenylsulfonyl)indole-3-carbaldehyde eth-
ylene acetal (6) (0.66 g, 2.0 mmol) dissolved in dry THF (50 mL)
under nitrogen was added a solution of sec-butyllithium (1.3 M
in cyclohexane, 2.4 mmol) dropwise via syringe. The reaction
mixture was stirred at -70 °C for 2 h and allowed to warm to
room temperature for 2 h. The dark brown reaction mixture was
recooled to 0 °C; then, gaseous formaldehyde generated by
cracking paraformaldehyde (0.12 g, 4.0 mmol) was bubbled in,
and the mixture was stirred at room temperature for 2 h. The
resulting mixture was diluted with THF (100 mL), and hydro-
quinone (0.1 g) and boron trifluoride etherate (2.6 mL, 20 mmol)
were added successively; the mixture was stirred at room
temperature for 15 min. The mixture was basified by triethyl-
amine (4 mL) and quenched with saturated aqueous sodium
bicarbonate (100 mL). The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate (3 × 50 mL).
The combined organic layers were washed with brine, dried (Na2-
SO4), and concentrated in vacuo. The resulting oil was purified
by flash chromatography (10% ethyl acetate in hexanes) to give
0.31 g (52%) of 5 as white crystals, mp 146-147 °C (lit.1e 145
thesis is readily applicable to C-3 substituted derivatives
(Scheme 3). Thus, lithiation of acetal 6 followed by
reactions with aldehydes gave hydroxy acetals 8. Flash
chromatography of 8 and exposure to trifluoroacetic acid
and hydroquinone in dichloromethane at room temper-
ature afforded furoindoles 9 in 52-70% yields from acetal
6. By comparison, our previous syntheses of 9a and 9b
involved six steps from 3-methyl-1-(phenylsulfonyl)indole
(24-30% overall yields).
1
°C). The H and 13C NMR spectra matched literature reports.1e
Finally, lithiation of these C-3 substituted furoindoles
affords a route to C-1,C-3 disubstituted furoindoles. Thus,
treatment of 9c with sec-BuLi followed by the addition
of methyl iodide gave furoindole 10 (80% yield). This
complements our earlier selective C-3 lithiation of the
parent furoindole 5.1e
In summary, we have improved the synthesis of
furoindoles 5 and 9 from indole-3-carbaldehyde. The
parent furoindole 5 is now available from 1 in three
operations and in an overall yield of 48%. The overall
yields of 5 and 9 from indole are 46-63%.
Gen er a l P r oced u r e for 3-Su b st it u t ed -4-(p h en ylsu l-
fon yl)-4H-fu r o[3,4-b]in doles 9. 3-Heptyl-4-(ph en ylsu lfon yl)-
4H-fu r o[3,4-b]in d ole (9c). To a -70 °C stirred solution of
1-(phenylsulfonyl)indole-3-carbaldehyde ethylene acetal (6) (0.66
g, 2.0 mmol) in dry THF (50 mL) under nitrogen was added a
solution of sec-butyllithium (1.3 M in cyclohexane, 2.4 mmol)
dropwise via syringe. The reaction mixture was stirred at -70
°C for 2 h and allowed to warm to room temperature for 2 h.
The dark brown reaction mixture was recooled to -70 °C; then,
octyl aldehyde (0.48 mL, 3.0 mmol) was added, and the mixture
was stirred for 16 h. The mixture was quenched by aqueous
ammonium chloride (100 mL). The organic layer was separated;
the aqueous layer was extracted with ethyl acetate (3 × 50 mL),
and the combined organic layers were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The resulting oil was
purified by flash chromatography (30% ethyl acetate in hexanes)
to give crude hydroxy acetal 8 as a syrup, which was dissolved
in CH2Cl2 (125 mL). Hydroquinone (0.1 g) and TFA (0.1 mL)
were added, and the mixture was stirred at room temperature
for 2 h. The mixture was basified with triethylamine (0.5 mL),
and the solvent was removed in vacuo. The resulting oil was
purified by flash chromatography (10% ethyl acetate in hexanes)
over basic alumina to give 0.48 g (61%) of 9c as white crystals.
Recrystallization from ether/hexane gave the analytical sam-
ple: mp 66-68 °C; 1H NMR (CDCl3) δ 8.05-8.10 (d, 1H, 8.7),
7.59-7.65 (d, 2H, 8.7), 7.45-7.50 (m, 3H), 7.18-7.39 (m, 4H),
3.17 (t, 2H, 7.5), 1.73-1.85 (m, 2H); 1.23-1.47 (m, 8H), 0.86-
0.93 (t, 3H, 6.9); 13C NMR (CDCl3) δ 146.3, 140.8, 137.4, 134.3,
129.7, 129.4, 128.4, 128.2, 127.9, 125.8, 124.1, 123.7, 123.1, 117.9,
32.8, 30.4, 30.1, 29.5, 28.0, 23.6, 15.1; IR (KBr) νmax 2926, 2856,
1451, 1370, 1176, 751, 724 cm-1; MS m/z 395 (M+, 100%), 310,
254, 226, 170, 128, 77; HRMS calcd for M+ m/z 395.1555, found
395.1546. Anal. Calcd for C23H25NO3S: C, 69.84; H, 6.37; N, 3.54;
S, 8.11. Found: C, 69.60; H, 6.19; N, 3.60; S, 8.08.
3-Meth yl-4-(p h en ylsu lfon yl)-4H-fu r o[3,4-b]in d ole (9a ).
This was prepared from 6 and acetaldehyde in 52% yield by the
general method. The product is a white solid, mp 145-146 °C
(lit.1e 146-148 °C). The 1H and 13C NMR spectra matched
literature reports.1e
3-P h en yl-4-(p h en ylsu lfon yl)-4H-fu r o[3,4-b]in d ole (9b).
This was prepared from 6 and benzaldehyde in 70% yield by
the general method. The product is a white solid, mp 148-149
°C (lit.1e 148.5-149.5 °C). The 1H and 13C NMR spectra matched
literature reports.1e
1-Met h yl-3-h ep t yl-4-(p h en ylsu lfon yl)-4H -fu r o[3,4-b]in -
d ole (10). To a -70 °C stirred solution of 3-heptyl-4-(phenyl-
sulfonyl)-4H-furo[3,4-b]indole (9c) (198 mg, 0.50 mmol) dissolved
in dry THF (5 mL) under nitrogen was added a solution of sec-
butyllithium (1.3 M in cyclohexane, 0.60 mmol) dropwise via
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected. El-
emental analyses were done by Atlantic Microlab, Inc. High-
resolution mass spectrometry (HRMS) was carried out at the
Mass Spectrometry Laboratory, School of Chemical Sciences,
University of Illinois at Urbana Champaign. Tetrahydrofuran
(THF) was distilled from sodium/benzophenone.
In d ole-3-ca r ba ld eh yd e (1). This was prepared from indole
in 96% yield according to a known procedure:4 mp 190-192 °C
(lit.4 196-197 °C).
1-(P h en ylsu lfon yl)in d ole-3-ca r ba ld eh yd e (2). To an ice-
cooled, stirred mixture of indole-3-carbaldehyde (1) (11.95 g,
0.0823 mol), crushed sodium hydroxide pellets (9.65 g, 0.241
mol), and tetra-n-butylammonium hydrogen sulfate (1.09 g, 3.21
mmol) in dichloromethane (100 mL) was added dropwise via an
addition funnel over 10 min benzenesulfonyl chloride (17.16 g,
0.0972 mol). The mixture was stirred at room temperature for
2 h. Water was added, and the organic layer was separated,
washed with water, and dried (MgSO4). Rotary evaporation of
the organic layer gave 22.6 g (96%) of 2 as a colorless solid: mp
156-157 °C (lit.5 158-158.8 °C); 1H NMR (CDCl3) δ 10.06 (s,
1H), 8.22-8.17 (m, 2H), 7.94-7.89 (m, 3H), 7.58-7.32 (m, 5H).
1-(P h en ylsu lfon yl)in d ole-3-ca r b a ld eh yd e
E t h ylen e
Acet a l (6). A suspension of 1-(phenylsulfonyl)indole-3-carb-
aldehyde (2) (8.0 g, 28 mmol), ethylene glycol (40 mL, 0.7 mol),
and p-toluenesulfonic acid (0.30 g, 1.6 mmol) in benzene (100
mL) was heated at reflux with a Dean-Stark trap for 16 h. The
mixture was allowed to cool to room temperature, and the
benzene layer was separated and evaporated in vacuo to give
an oil. Trituration with cold ethyl acetate/hexane (3:7) gave 4.1
g of 6 as colorless needles. Concentration of the mother liquor
(5) Saulnier, M. G.; Gribble, G. W. J . Org. Chem. 1982, 47, 757-
761.

Notes
J . Org. Chem., Vol. 67, No. 3, 2002 1003
syringe. The reaction mixture was stirred at -70 °C for 2 h and
allowed to warm to room temperature for 2 h. The yellow
reaction mixture was recooled to -70 °C; then, iodomethane
(0.05 mL, 0.7 mmol) was added, and the mixture was stirred
overnight. The reaction was quenched with saturated aqueous
ammonium chloride (20 mL). The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate (3 × 20
mL). The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The resulting oil was
purified by flash chromatography (5% ethyl acetate in hexanes)
to give 164 mg (80%) of 10. Recrystallization from ether/hexane
gave the analytical sample as white crystals: mp 78-79 °C; 1H
NMR (CDCl3) δ 8.03-8.07 (m, 1H), 7.63-7.69 (m, 2H), 7.38-
7.47 (m, 2H), 7.25-7.34 (m, 3H), 7.16-7.22 (m, 1H), 3.12 (t, 2H,
7.5), 2.45 (s, 3H), 1.72-1.83 (m, 2H), 1.25-1.49 (m, 8H), 0.91 (t,
3H, 6.9); 13C NMR (CDCl2) δ 146.0, 139.2, 138.3, 137.7, 134.4,
129.7, 128.5, 128.0, 127.3, 125.7, 124.7, 122.0, 119.6, 117.7, 32.8,
30.4, 30.1, 29.8, 27.9, 23.7, 15.1, 14.5; IR (KBr) νmax 2921, 2849,
1675, 1449, 1363, 1173, 1091, 964, 751, 684 cm-1; MS m/z 410
(M+ + 1), 408, 286, 270 (100%), 268, 228, 184, 137; HRMS calcd
for M+ + 1 m/z 410.1791, found 410.1774. Anal. Calcd for C24H27
-
NO3S: C, 70.39; H, 6.64; N, 3.42; S, 7.83. Found: C, 70.24; H,
6.50; N, 3.48; S, 7.80.
Ack n ow led gm en t . This investigation was sup-
ported by the National Institutes of Health (GM58601),
for which support we are grateful.
J O010938Q