A concise synthesis of furostifoline by tetrabutylammonium fluoride-promoted indole ring formation.

Article abstract of DOI:10.1248/cpb.50.143

Furostifoline, a furo[3,2-a]carbazole alkaloid, was synthesized in 10% overall yield in four steps from 2-acetyl-3-bromofuran. The key step of this synthesis was the 2-substituted indole formation with tetrabutylammonium fluoride (TBAF) from 2-(2-propenyl

Full text of DOI:10.1248/cpb.50.143

January 2002
Notes
Chem. Pharm. Bull. 50(1) 143—145 (2002)
143
A Concise Synthesis of Furostifoline by Tetrabutylammonium
Fluoride-Promoted Indole Ring Formation
Akito YASUHARA,* Naoyuki SUZUKI, and Takao SAKAMOTO
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobaku, Sendai 980–8578, Japan.
Received September 18, 2001; accepted October 20, 2001
Furostifoline, a furo[3,2-a]carbazole alkaloid, was synthesized in 10% overall yield in four steps from 2-
acetyl-3-bromofuran. The key step of this synthesis was the 2-substituted indole formation with tetrabutylammo-
nium fluoride (TBAF) from 2-(2-propenyl)-3-((2-ethoxycarbonylamino)phenylethynyl)furan, which was easily
prepared from ethyl 2-ethynylphenylcarbamate with 3-bromo-2-(2-propenyl)furan by the Sonogashira reaction.
Key words total synthesis; furostifoline; indole; tetrabutylammonium fluoride
The furo[3,2-a]carbazole alkaloid, furostifoline (1), was rable by column chromatography. We surmised that the low
isolated in 1990 from Murrata euchrestitolia by Furukawa reactivity of 3 with TMSA for the Sonogashira reaction re-
and his group.1) Furostifoline was the first carbazole alkaloid quired high reaction temperature and extended reaction time,
exhibiting a furo[3,2-a]carbazole framework. Several syn- and the conditions caused self-condensation of TMSA and
thetic organic groups were interested in its unprecedented decomposition of 3 in the presence of the palladium catalyst.
framework and pharmacological potential.2,3a) The first total On the other hand, an ethyl ethynylphenylcarbamate–DMF
synthesis of 1 was reported by Knölker and Fröhner using (N,N-dimenylformamide) solution was dropped to the mix-
their convergent iron-mediated formation of carbazole,4) and ture of 3, DMF and the palladium catalyst at refluxing tem-
three other syntheses of 1 were achieved.3) Soós and co- perature for 1 h to give 5 in good yield. The reaction condi-
workers reported a five-step synthesis of 1 from bromocre- tions avoid the self-condensation of the terminal acetylene to
sole using the ring formation of carbazole through the nitrene obtain 5, but it was difficult to adopt these conditions for the
intermediate as a key reaction.3a) Hibino3b) and Beccalli3d) Sonogashira reaction of 3 with TMSA because of the low
developed an benzofuran ring formation by intramolecular boiling point of TMSA.
photocyclization and electrocyclization, leading to the prepa-
The TBAF-promoted cyclization reaction of 5 gave a mix-
ration of 1. Recently, Hibino and his group reported the syn- ture of 2-[(isopropenyl)furanyl]indole (7) and 3-(2-amino-
thesis of 1 by the allene-mediated electrocyclic reaction of 2- phenyl)ethynyl-(isopropenyl)furan (8), and the mixture was
furyl-3-propargylindole derivative.3c)
easily separated by silica gel column chromatography in 47%
We reported a cyclization reaction of 2-ethynylanilines and 33% yield, respectively. Compound 5 was reproduced by
with tetrabutylammonium fluoride (TBAF) gives the corre- the protection of 8 with ethyl chloroformate in 76% yield. Fi-
sponding 2-substituted indoles in good yields (Chart 2).5) nally, intramolecular photocyclization (high-pressure Hg
The method has wide usage for the synthesis of indoles hav- lamp) of 7 with a catalytic amount of I2 in toluene led di-
ing multi-functional groups, because the 2-ethynylanilines rectly to furostifoline (1) in 24% yield. Although 1 was ob-
are easily prepared by the Sonogashira reaction from 2-
haloanilines for which many synthetic methods have been re-
ported (i.e. by ortho-lithiation of N-protected anilines with
alkyllithium6)) and the cyclization reaction with TBAF pro-
ceeds without affecting many functional groups. Now we re-
port a concise synthesis of 1 using the cyclization with
TBAF from 2-ethynylanilines as a key reaction.
At the first step, isopropenyl-2-(3-bromo)furan (3) was
Chart 1
prepared by the Wittg reaction of 2-acetyl-3-bromofuran
with methyltriphenylphosphonium bromide and butyllithium
in 82% yield. Then, the Sonogashira reaction7) of 3 with
ethyl 2-ethynylphenylcarbamate gave 2-(isopropenyl)-3-[(2-
ethoxycarbonylamino)phenylethynyl]furan (5) in 79% yield,
as shown in Chart 3.
We also reported that a palladium-catalyzed cross-cou-
pling reaction of N-(2-iodophenyl)methanesulfonamide with
terminal alkynes gives the corresponding 2-substituted in-
doles instead of ethynylanilines8) (Chart 2). In order to use
this one-step palladium-catalyzed indole synthesis from 2-
haloanilines, we tried to prepare 3-trimethylsiliylethynyl-2-
(isopropenyl)furan (6) using the Sonogashira reaction of 3
with trimethylsilylacetylene (TMSA). However, the reaction
at 100 °C for 14 h gave a complex mixture that was not sepa-
Chart 2
To whom correspondence should be addressed. e-mail: yasuhara@mail.pharm.tohoku.ac.jp
© 2002 Pharmaceutical Society of Japan

144
Vol. 50, No. 1
Chart 3
Chart 4
tained as only one product in the reaction mixture of the pho- was washed with brine (100 mlϫ2). The residue obtained from the ethereal
extract was purified by silica gel column chromatography (hexane). The
tocyclization, some insoluble matter was founded. So we
supposed that the photocyclization caused the polymerization
of 7 and gave 1 in only 24% yield. The spectral data of our
product was purified by distillation. Colorless liquid (0.71 g, 82%). bp 70—
80 °C (90 mmHg). 1H-NMR (CDCl3) d: 2.16 (3H, s), 5.15 (1H, s), 5.73 (1H,
s), 6.43 (1H, d, Jϭ1.9 Hz), 7.28 (1H, d, Jϭ1.9 Hz). MS m/z 188, 186 (Mϩ).
HR-MS m/z: 185.9705 (Calcd for C7H779BrO: 185.968), 187.9657 (Calcd
for C7H781BrO: 187.9660).
synthetic furostifoline are in full agreement with those de-
1
scribed by Furukawa for the natural product (UV, IR, H-
3-[(2-Ethoxycarbonylamino)phenylethynyl]-2-isopropenylfuran (5)
After ethyl 2-ethnylphenylcarbamate10) (564 mg, 2.98 mmol) in DMF (5.0
ml) was added to a mixture of 3 (462 mg, 2.48 mmol), PdCl2(PPh3)2 (174
mg, 0.25 mmol), CuI (47 mg, 0.25 mmol), diisopropylamine (6 ml), and
DMF (15 ml) at refluxing temperature for 1 h, the mixture was refluxed for
1 h. Et2O (100 ml) was added to the mixture, and washed with brine (100
mlϫ2). The residue obtained from the extract was purified by silica gel col-
umn chromatography (hexane). Yellow viscous oil (580 mg, 79%). IR (neat)
NMR, MS).
In conclusion, our synthesis provides furostifoline in 4
steps and 10% overall yield based on 2-acetyl-3-bromfurane
using our synthetic method of 2-substituted indole with
TBAF as a key reaction.
Experimental
1
cmϪ1: 3404, 2210, 1740. H-NMR (CDCl3) d: 1.33 (3H, t, Jϭ7.1 Hz), 2.25
Melting point and boiling point are uncorrected. IR spectra were taken on
a Shimadzu FT-IR 8400 spectrophotometer. H-NMR spectra were recorded
1
(3H, s), 4.25 (2H, q, Jϭ7.1 Hz), 5.17 (1H, s), 5.84 (1H, s), 6.53 (1H, d,
Jϭ1.9 Hz), 7.01 (1H, dt, Jϭ1.1, 7.4 Hz), 7.03—7.36 (3H, m), 7.46 (1H, dd,
Jϭ1.6, 8.2 Hz), 8.16 (1H, d, Jϭ8.2 Hz). MS m/z 295 (Mϩ). HR-MS m/z:
295.1232 (Calcd for C18H17NO3: 295.1208).
Cyclization Reaction of 5 with TBAF A mixture of 5 (283 mg, 0.96
mmol), 1 M TBAF–THF solution (3 ml, 2.88 mmol), and THF (20 ml) was
refluxed for 12 h, and the mixture was concentrated under reduced pressure.
Water (50 ml) was added to the residue and extracted with AcOEt (50
mlϫ3). The AcOEt layer was washed with brine (50 mlϫ3). The residue ob-
tained from the extract was purified by silica gel column chromatography
(AcOEt : hexaneϭ1 : 20).
on Varian Gemini 200 (300 MHz) spectrometers. Chemical shifts are ex-
pressed in d (ppm) values with tetramethylsilane (TMS) as an internal refer-
ence. UV spectrum was recorded on Shimadzu UV-3100PC instrument. MS
and high-resolution (HR)-MS were recorded on JMS-DX303 and JMS-
AX500 instruments.
Isopropenyl-2-(3-bromo)furan (3) A mixture of methyltriphenylphos-
phonium bromide (2.49 g, 6.89 mmol), BuLi (1.43 M hexane solution, 5.0 ml,
6.98 mmol), and tetrahydrofuran (THF) (20 ml) was stirred for 1 h at room
temperature under Ar atmosphere. 2-Acetyl-3-bromofuran9) (0.86 g, 4.65
mmol) in THF (20 ml) was added to the mixture. The mixture was stirred for
14 h, filtrated and concentrated under reduced pressure. Water (50 ml) was
added to the residue and extracted with Et2O (50 mlϫ3). The ethereal layer
2-(2-Isopropenylfuran-3-yl)indole (7): Yellow viscous oil (101 mg, 47%).
1
IR (neat) cmϪ1: 3400. H-NMR (CDCl3) d: 2.10 (3H, s), 5.21 (1H, s), 5.49

January 2002
145
(Mϩ). HR-MS m/z: 221.0851 (Calcd for C15H11NO: 221.0841).
(1H, s), 6.58 (1H, d, Jϭ1.6 Hz), 6.59—6.60 (1H, m), 7.07—7.20 (2H, m),
7.33 (1H, d, Jϭ7.4 Hz), 7.39 (1H, d, Jϭ1.6 Hz), 7.59 (1H, d, Jϭ7.4 Hz),
8.32 (1H, br). MS m/z 223 (Mϩ). HR-MS m/z: 223.0977 (Calcd for
C15H13NO: 223.0997).
References
1) Ito C., Furukawa H., Chem. Pharm. Bull., 38, 1548—1550 (1990).
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Med. Chem. Lett., 6, 2831—2836 (1996).
3-(2-Aminophenylethynyl)-2-isopropenylfuran (8): Pale yellow viscous
1
oil (70 mg, 33%). IR (neat) cmϪ1: 3445, 3381, 2206. H-NMR (CDCl3) d:
3) a) Soós T., Timári G., Hajós G., Tetrahedron Lett., 40, 8607—8609
(1999); b) Hagiwara H., Choshi T., Fujimoto H., Sugino E., Hibino S.,
Chem. Pharm. Bull., 46, 1948—1949 (1998); c) Hagiwara H., Choshi
T., Nobuhiro J., Fujimoto H., Hibino S., ibid., 49, 881—886 (2001); d)
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11682 (1998).
4) a) Knölker H. J., Fröhner W., Tetrahedron Lett., 37, 9183—9186
(1996); b) Idem, Synthesis, 2000, 2131—2136.
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Sakamoto T., J. Chem. Soc., Perkin Trans. 1, 1999, 529—534.
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4467—4470.
8) Sakamoto T., Kondo Y., Iwashita S., Nagano T., Yamanaka H., Chem.
Pharm. Bull., 36, 1305—1308 (1988).
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2.23 (3H, s), 4.22 (2H, br), 5.13 (1H,s), 5.88 (1H, s), 6.49 (1H, d, Jϭ1.9 Hz),
6.68—6.73 (2H, m), 7.13 (1H, dt, Jϭ1.6, 6.6 Hz), 7.30—7.33 (2H, m). MS
m/z 223 (Mϩ). HR-MS m/z: 223.1012 (Calcd for C15H13NO: 223.0997).
The Protection of 8 with Ethyl Chloroformate A mixture of 8 (28 mg,
1.26 mmol), ethyl chloroformate (164 mg, 1.51 mmol), and pyridine (5 ml)
was stirred for 3 h at room temperature, and concentrated. Water (50 ml) was
added to the residue, and extracted with Et2O (50 mlϫ3). The ethereal layer
was washed with CuSO4·5H2O (50 mlϫ2) and water (100 mlϫ2). The
residue obtained from the extract was purified by silica gel column chro-
matography (hexane) to give 5 as a yellow viscous oil (283 mg, 76%).
Furostifoline (1)1) A mixture of 7 (23 mg, 0.10 mmol), a catalytic
amount of I2, and toluene (10 ml) was irradiated for 30 min. The residue ob-
tained from the mixture was purified by silica gel column chromatography
(AcOEt : hexaneϭ1 : 20). Colorless prisms from hexane (5.6 mg, 24%). mp
175—176 °C (lit.4b) 174—175 °C). IR (KBr) cmϪ1: 3406, 1457, 1442, 1360,
1
1308, 1159, 1043, 878, 746, 735. H-NMR (CDCl3) d: 2.68 (3H, s), 7.00
(1H, d, Jϭ2.2 Hz), 7.23—7.28 (1H, m), 7.38 (1H, t, Jϭ8.2 Hz), 7.49 (1H, d,
Jϭ8.2 Hz), 7.73 (1H, d, Jϭ2.2 Hz), 7.77 (1H, s), 8.06 (1H, d, Jϭ8.2 Hz),
8.28 (1H, br). UV l (MeOH) nm: 260, 278, 295, 322, 334. MS m/z 221