Novel syntheses of murrayaquinone A and furostifoline through 4-oxygenated carbazoles by allene-mediated electrocyclic reactions starting from 2-chloroindole-3-carbaldehyde

Article abstract of DOI:10.1248/cpb.49.881

The formal total synthesis of murrayaquinone A (1) and the total synthesis of furostifoline (5) were completed by the construction of 4-oxygenated 3-methylcarbazoles 7 based on a new type of electrocyclic reaction through 2-alkenyl-3-allenylindole intermediates 8 derived from the 2-alkenyl-3-propargylindoles 9, starting from 2-chloroindole-3-carbaldehyde (11). The N, O-bisbenzyloxymethyl group of 16c and 22 underwent a Birch reduction followed by treatment with Triton B to produce the known 4-hydroxy-3-methylcarbazole (7a) and 4-hydroxy-3-methylfuro[3, 2-a]carbazole (7b) as precursors of murrayaquinone A (1) and furostifoline (5), respectively. The trifluoromethanesulfonyloxy-3-methylfuro[3, 2-a]carbazole (24), prepared from 7b, was subjected to reductive cleavage to provide furostifoline (5).

Full text of DOI:10.1248/cpb.49.881

July 2001
Chem. Pharm. Bull. 49(7) 881—886 (2001)
881
Novel Syntheses of Murrayaquinone A and Furostifoline through
4-Oxygenated Carbazoles by Allene-Mediated Electrocyclic Reactions
Starting from 2-Chloroindole-3-carbaldehyde
Hitomi HAGIWARA, Tominari CHOSHI, Junko NOBUHIRO, Hiroyuki FUJIMOTO, and Satoshi HIBINO*
Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences,
Fukuyama University, Fukuyama, Hiroshima 729–0292, Japan. Received February 19, 2001; accepted March 22, 2001
The formal total synthesis of murrayaquinone A (1) and the total synthesis of furostifoline (5) were com-
pleted by the construction of 4-oxygenated 3-methylcarbazoles 7 based on a new type of electrocyclic reaction
through 2-alkenyl-3-allenylindole intermediates 8 derived from the 2-alkenyl-3-propargylindoles 9, starting from
2-chloroindole-3-carbaldehyde (11). The N,O-bisbenzyloxymethyl group of 16c and 22 underwent a Birch reduc-
tion followed by treatment with Triton B to produce the known 4-hydroxy-3-methylcarbazole (7a) and 4-hydroxy-
3-methylfuro[3,2-a]carbazole (7b) as precursors of murrayaquinone A (1) and furostifoline (5), respectively. The
trifluoromethanesulfonyloxy-3-methylfuro[3,2-a]carbazole (24), prepared from 7b, was subjected to reductive
cleavage to provide furostifoline (5).
Key words murrayaquinone A; carbazole-1,4-quinone; furostifoline; furo[3,2-a]carbazole; allene; electrocyclic reaction
The carbazole-1,4-quinone, murrayaquinone A (1) was of Et3N and dimethylaminopyridine (DMAP) in CH2Cl2 gave
first isolated from the root bark of Murraya eucrestifolia the N-phenylsulfonylindole 12a in 20% yield. The cross-cou-
HAYATA (Rutaceae) collected in Taiwan together with three pling reaction between 12a and ethenyl tributylstannane in
closely related alkaloids [murrayaquinones B—D (2—4)] by the presence of bis(triphenylphosphine)palladium(II) chlo-
Furukawa and co-workers1,2) from 1983 to 1985. The new ride [Pd(PPh3)2Cl2] afforded the 2-ethenylindole 13a (90%).
tetracyclic furo[3,2-a]carbazole alkaloid, furostifoline (5), Treatment of 13a with ethynylmagnesium bromide followed
was isolated in 1990 by the same group3) along with by treatment of the resulting alcohol 14a with chloromethyl
furo[3,2-g]carbazole, eustifoline D (6) from the same origin. methyl ether (MOMCl) produced the 2-ethenyl-3-propar-
Extracts of the leaves and bark of this tree have been used as gylindole 15a (72% from 13a). An allene-mediated electro-
a folk medicine for analgesia and local anaesthesia and for cyclic reaction of 15a in the presence of potassium tert-bu-
the treatment of eczema, rheumatism and dropsy.2a) Among toxide (t-BuOK) in tert-butanol (t-BuOH) and THF (tetrahy-
these alkaloids, murrayaquinone A (1) has been found to ex- drofuran) was carried out at 90 °C according to the previous
hibit the cardiotonic activity on guinea pig papillary mus- reported method8) for the reverse type of allene generation to
cle.4)
give the N-deprotected 4-oxygenated 3-methylcarbazole 16a
A wide variety of syntheses of murrayaquinone A (1) have in 35% yield.
been reported by twelve groups including our ap-
Although all of the reactions proceeded, the yields of the
proach.2c,4a,5,6) In addition, the syntheses of furostifoline (5) two steps were poor; to improve them, two other protecting
have been completed by three groups7) as well as ourselves.6) groups were examined. Treatment of 11 with chloromethyl
Among these works, total syntheses of both alkaloids have methyl ether (MOMCl) [or benzyl chloromethyl ether
been achieved by the Knölker group using a convergent iron- (BOMCl)] in the presence of potassium carbonate in DMF
mediated construction of the carbazole nucleus.5g,7a) We have (dimethylformamide) afforded the N-MOM-indole 12b
also been interested in the syntheses of both alkaloids in the (93%) and the N-BOM-indole 12c (99%). The cross-cou-
course of our studies and have recently reported total synthe- pling reaction between 12b (or 12c) and ethenyl tributylstan-
ses of 3-oxygenated and 3,4-dioxygenated carbazole alka- nane in the presence of Pd(PPh3)2Cl2 gave the 2-ethenylin-
loids based on the thermal electrocyclic reaction of the 3- doles 13b (97%) and 13c (78%). The Grignard reaction of
alkenyl-2-allenylindole intermediate derived from 3-alkenyl- 13b (or 13c) with ethynylmagnesium bromide followed by
2-propargylindole.8) We describe here the details of our pre-
liminary report6) describing the formal synthesis of mur-
rayaquinone A (1) and the total synthesis of furostifoline (5).
We envisaged that 4-oxygenated 3-methylcarbazoles 7a and
7b might be obtained by electrocyclic reactions through re-
verse 3-allenylindole intermediates 8a and 8b, which would
be derived from 3-propargylindoles 9a and 9b, respectively.
These precursors 9a and 9b would be provided from 2-
chloroindole-3-carbaldehyde (11)9) as a common starting ma-
terial depicted in the retro-synthetic analysis (Chart 2).
For the synthesis of known 4-hydroxy-3-methylcarbazole
(7a),5d—f ) we initially used phenylsulfonyl group as the N-
protecting group of 2-chloroindole-3-carbaldehyde (11).
Treatment of 11 with phenylsulfonyl chloride in the presence
Chart 1
To whom correspondence should be addressed. e-mail: hibino@fupharm.fukuyama-u.ac.jp
© 2001 Pharmaceutical Society of Japan

882
Vol. 49, No. 7
Chart 2
treatment of the resulting alcohol 14b (or 14c) with MOMCl furo[3,2-a]carbazole 7b as a precursor of furostifoline (5).
(or BOMCl) produced the 2-alkenyl-3-propargylindoles 15b The cross-coupling reaction of 11 with furan-3-boronic acid
(90% from 13b) and 15c (56% from 13c). The 3-propar- (18)11) was carried out in the presence of palladium(II) ac-
gylindole 15b (or 15c) was subjected to an electrocyclic re- etate and triphenylphosphine in DMF to obtain the 2-(3-
action under similar conditions to yield the expected car- furyl)indole 10b (84%). After protection of the indole nitro-
bazoles 16b (58%) and 16c (81%). Two types of 4-oxy- gen atom of 10b with BOMCl in the presence of potassium
genated 3-methylcarbazole 16b and 16c were obtained in carbonate in DMF, the subsequent Grignard reaction of 19
47% and 34% yields from 11, respectively. Next, the depro- with ethynylmagnesium bromide gave alcohol 20 (97%). Al-
tection of N-MOM-4-MOMoxy-3-methylcarbazole (16b) cohol 20 was treated with BOMCl and sodium hydride in
was examined under several acidic conditions or with sodium THF to yield the 2-(3-furyl)-3-propargylindole 21, which
iodide and TMSCl (chlorotrimethylsilane). However, the ex- was subjected to a thermal electrocyclic reaction in the pres-
pected 4-hydroxy-3-methylcarbazole (7a) was not obtained. ence of t-BuOK in t-BuOH at 90 °C to produce the 4-oxy-
In particular, it was difficult to remove the N-MOM group of genated tetracyclic furocarbazole 22 (61% yield from 20).
16b. In contrast, deprotection of N,O-bis-BOM group of 16c Birch reduction of 22 for the deprotection of N,O-bis-BOM
was investigated by hydrogenolysis or under Birch conditions groups gave a separable mixture of the desired 4-hydroxy-3-
to give a separable mixture of 4-hydroxy-3-methylcarbazole methylfuro[3,2-a]carbazole 7b (51%) and 4-hydroxy-N-(hy-
(7a) (22%) and N- or O-hydroxymethyl-4-hydroxy-3-methyl- droxymethyl)-3-methylfuro[3,2-a]carbazole 23 (41%). Com-
carbazole (17a) (75%) under Birch conditions, respectively. pound 23 was similarly converted to 7b by treatment with
It is unclear at this time whether the structure of 17a is N-hy- Triton B10) (93%). Finally, treatment of the phenol 7b with
droxymethylcarbazole (17a) or O-hydroxymethylcarbazole trifluoromethanesulfonic anhydride (Tf2O) and pyridine af-
(16a). When the carbazole 17a was treated with 0.5 M HCl in forded the triflate 24, which was subjected to a reductive
methanol to remove the N- or O-hydroxymethyl group of cleavage of the 4-trifluoromethanesulfonyloxy group of 24
17a, 17a was converted into the N- or O-MOM-carbazole with palladium(II) acetate and triphenylphosphine in the
17b. This carbazole 17b was not identical to the formerly presence of formic acid and triethylamine in DMF at 60 °C
synthesized 4-MOMoxy-3-methylcarbazole (16a) based on a according to Ortar’s procedure12) to produce furostifoline (5)
1
comparison of H-NMR spectra. Accordingly, the structure (99%) (Chart 4). The synthetic 3-methylfuro[3,2-a]carbazole
of 17a was determined to be N-hydroxymethyl-4-hydroxy-3- (5) was identical in all respects to natural1b) and synthetic
methylcarbazole. The removal of the N-hydroxymethyl group products.7)
of 17a successfully proceeded by heating with Triton B in an
Thus, new synthetic routes to the carbazole-1,4-quinone,
aqueous THF according to the Anderson procedure10) to murrayaquinone A (1) and the tetracyclic furo[3,2-a]car-
yield 7a (71%) (Chart 3). The synthetic 4-hydroxy-3-methyl- bazole, furostifoline (5) have been established by the con-
carbazole (7a) was identical in all respects to the precursor of struction of the 4-oxygenated-3-methylcarbazole nucleus 7
murrayaquinone A (1), as reported previously.5d—f ) This con- based on a new type of allene-mediated electrocyclic reac-
stitutes the formal total synthesis of murrayaquinone A (1).
tion involving the indole 2,3-bond.
We then turned to the synthesis of 4-oxygenated-3-methyl-

July 2001
883
Chart 3
Chart 4

884
Vol. 49, No. 7
Experimental
A solution of ethynylmagnesium bromide (0.5 in THF, 4 ml, 2.09 mmol) was
All air-sensitive reactions were conducted in flame-dried glassware under added to a stirred solution of 2-ethenylindole 13a (100 mg, 0.32 mmol) in
an nitrogen atmosphere unless otherwise stated. THF was freshly distilled dried THF (5 ml) under cooling with ice. After stirring at the same tempera-
from benzophenone ketyl. DMF, triethylamine and ethyl diisopropylamine ture for 2 h, the reaction mixture was quenched with an aqueous NH4Cl (sat-
were freshly distilled after drying over CaH2. Dichloromethane was freshly urated) solution, then extracted with EtOAc. The EtOAc layer was washed
distilled after drying over P2O5. Silica gel (70—230 mesh, Merck Art. 7734) with brine, dried over Na2SO4 and concentrated. The residue was purified by
was used for column chromatography. Melting points were measured by a column chromatography (silica gel, 20 g) using EtOAc–hexane (3 : 7) as an
Yanagimoto MP-500D micro melting points apparatus and are uncorrected. eluent to give the oily propargyl alcohol 14a (109 mg, 99%). IR (neat) cmϪ1
:
IR spectra were recorded on a Shimadzu FTIR-8500 spectrophotometer. 1H- 3294, 2117. 1H-NMR (CDCl3) d: 2.27 (1H, br s), 2.53 (1H, d, Jϭ2 Hz),
and 13C-NMR spectra were taken with a JEOL-AL 300 using tetramethylsi- 5.12—6.89 (4H, m), 6.66—8.33 (9H, m). MS m/z: 337 (Mϩ). HR-MS m/z:
lane as an internal standard. All mass spectra were obtained using Shimadzu 337.0773 (Calcd for C19H15NO3S: 337.0765).
9020DF and QP5050 spectrometers equipped with an electrospray ioniza-
tion source at 70 eV.
2-Chloro-N-(phenylsulfonyl)indole-3-carbaldehyde (12a) Phenylsul-
fonyl chloride (818 ml, 3.35 mmol) was added to the stirred mixture of 2-
2-Ethenyl-3-(1-hydroxyprop-2-yn-1-yl)-N-(methoxymethyl)indole
(14b) The same procedure as above was carried out using 13b (372 mg,
1.42 mmol) to give the oily propargyl alcohol 14b (337 mg, 98%). IR (neat)
1
cmϪ1: 3296, 2094. H-NMR (CDCl3) d: 2.24 (1H, d, Jϭ5 Hz), 2.65 (1H, d,
chloroindole 11 (500 mg, 2.79 mmol), Et3N (482 ml, 3.07 mmol) and DMAP Jϭ2.5 Hz), 3.30 (3H, s), 5.44 (2H, s), 5.71 (1H, dd, Jϭ1.5, 11 Hz), 5.78 (1H,
(340 mg, 2.79 mmol) in CH2Cl2 (5 ml) under cooling with ice. The mixture dd, Jϭ1.5, 17 Hz), 5.81—5.82 (1H, m), 6.87 (1H, dd, Jϭ11, 17 Hz), 7.02
was stirred at room temperature for 12 h, which was quenched with water, (1H, d, Jϭ9 Hz), 7.26 (1H, t, Jϭ9 Hz), 7.45 (1H, d, Jϭ8 Hz), 8.09 (1H, t,
then extracted with EtOAc. The EtOAc layer was washed with brine, dried
over Na2SO4 and concentrated. The residue was purified by column chro- 241.1098).
Jϭ8 Hz). MS m/z: 241 (Mϩ). HR-MS m/z: 241.1103 (Calcd for C15H15NO2:
matography (silica gel, 30 g) using EtOAc–hexane (1 : 9) as an eluent to give
N-(Benzyloxymethyl)-2-ethenyl-3-(1-hydroxyprop-2-yn-1-yl)indole
the N-(phenylsulfonyl)indole 12a (174 mg, 20%). mp 166—167 °C (EtOAc). (14c) The same procedure as above was carried out using 13c (480 mg,
IR (KBr) cmϪ1: 1677, 1388. 1H-NMR (CDCl3) d: 7.43—8.53 (9H, m), 1.65 mmol) to give the oily propargyl alcohol 14c (439 mg, 84%). IR (neat)
1
10.30 (1H, s). MS m/z: 321 (Mϩϩ2), 319 (Mϩ). Anal. Calcd for cmϪ1: 3294, 2114. H-NMR (CDCl3) d: 2.28 (1H, d, Jϭ5 Hz), 2.65 (1H, d,
C15H10ClNO3S: C, 56.34; H, 3.15; N, 4.38. Found: C, 56.46; H, 3.34; N,
4.28.
Jϭ2.5 Hz), 4.49 (2H, s), 5.54 (2H, s), 5.68 (1H, dd, Jϭ2, 11 Hz), 5.77 (1H,
dd, Jϭ2, 17 Hz), 5.80 (1H, dd, Jϭ2.5, 5 Hz), 6.87 (1H, dd, Jϭ11, 17 Hz),
2-Chloro-N-(methoxymethyl)indole-3-carbaldehyde (12b) MOMCl 7.24—7.36 (8H, m), 8.07 (1H, d, Jϭ7 Hz). MS m/z: 317 (Mϩ). HR-MS m/z:
(0.21 ml, 2.79 mmol) was added to a stirred mixture of 2-chloroindole 11
317.1416 (Calcd for C21H19NO2: 317.1426).
(100 mg, 0.56 mmol) and K2CO3 (385 mg, 2.79 mmol) in DMF (5 ml) under
2-Ethenyl-3-[1-(methoxymethyloxy)prop-2-yn-1-yl]-N-(phenylsul-
cooling with ice. The mixture was stirred at room temperature for 12 h, fonyl)indole (15a)
A stirred solution of the propargyl alcohol 14a
which was quenched with water, then extracted with EtOAc. The EtOAc (100 mg, 0.30 mmol), MOMCl (0.14 ml, 1.77 mmol), and iso-Pr2NEt
layer was washed with water and brine, dried over Na2SO4 and concentrated. (0.41 ml, 2.36 mmol) in CH2Cl2 (5 ml) was heated at 45 °C for 12 h. The so-
The residue was purified by column chromatography (silica gel, 30 g) using lution was treated with water, and the mixture was extracted with CH2Cl2.
EtOAc–hexane (1 : 9) as an eluent to give the N-(methoxymethyl)indole 12b The CH2Cl2 layer was washed with brine, dried over Na2SO4 and concen-
(116 mg, 93%). mp 232—233.5 °C (CHCl3). IR (KBr) cmϪ1: 1639. 1H-NMR trated. The residue was purified by column chromatography (silica gel, 20 g)
(CDCl3) d: 3.43 (3H, s), 5.63 (2H, s), 7.23—7.57 (4H, m), 10.18 (1H, s). using EtOAc–hexane (3 : 7) as an eluent to give the oily O-MOM-ether 15a
MS m/z: 225 (Mϩϩ2), 223 (Mϩ). Anal. Calcd for C11H10ClNO2: C, 59.07;
(81 mg, 72%). 1H-NMR (CDCl3) d: 2.68 (1H, d, Jϭ2 Hz), 3.84 (3H, s), 4.58
(1H, d, Jϭ7 Hz), 5.03 (1H, d, Jϭ7 Hz), 5.33—6.00 (4H, m), 6.66—8.33
H, 4.51; N, 6.26. Found: C, 60.11; H, 4.58; N, 6.06.
N-(Benzyloxymethyl)-2-chloroindole-3-carbaldehyde (12c) The same (9H, m). MS m/z: 381 (Mϩ). HR-MS m/z: 381.1035 (Calcd for C21H19NO4S:
procedure as above was carried out using 11 with BOMCl to give the oily N- 381.1052).
(benzyloxymethyl)indole 12c (99%). IR (neat) cmϪ1: 1653. 1H-NMR
2-Ethenyl-N-(methoxymethyl)-3-[1-(methoxymethyloxy)prop-2-yn-1-
(CDCl3) d: 4.51 (2H, s), 5.38 (2H, s), 7.24—7.37 (9H, m), 10.16 (1H, s). yl]indole (15b) The same procedure as above was carried out using 14b
MS m/z: 301 (Mϩϩ2), 299 (Mϩ). HR-MS m/z: 299.0713 (Calcd for (215 mg, 0.89 mmol) to give the oily O-MOM-ether 15b (229 mg, 90%). 1H-
C17H14ClNO2: 299.0722).
2-Ethenyl-N-(phenylsulfonyl)indole-3-carbaldehyde (13a) Tributyl- d, Jϭ7 Hz), 4.59 (1H, d, Jϭ7 Hz), 5.41 (2H, s), 5.50—6.00 (3H, m), 6.77
(vinyl)tin (59 ml, 0.203 mmol) was added to a stirred mixture of the 2- (1H, dd, Jϭ11, 17 Hz), 6.59—7.59 (3H, m), 7.74—8.17 (1H, m). MS m/z:
chloroindole 12a (30 mg, 0.135 mmol), Et4NCl (22 mg, 0.135 mmol) and 285 (Mϩ). HR-MS m/z: 285.1365 (Calcd for C17H19NO3: 285.1344).
PdCl2(PPh3)2 (2.8 mg, 4.05 mmol) in DMF (1 ml) under argon. The mixture N-(Benzyloxymethyl)-3-[1-(benzyloxymethyloxy)prop-2-yn-1-yl]-2-
was heated at 80 °C for 2 h, then cooled to an ambient temperature and ethenylindole (15c) A solution of the propargyl alcohol 14c (100 mg,
quenched with an aqueous 30% KF solution (50 ml). The mixture was 0.315 mmol) in dried THF (3 ml) was added to a stirred suspension of 60%
NMR (CDCl3) d: 2.54 (1H, d, Jϭ2 Hz), 3.28 (3H, s), 3.38 (3H, s), 4.56 (1H,
stirred at room temperature for 30 min and filtered through a Celite pad. The NaH (15 mg, 0.379 mmol) in dried THF (2 ml) under cooling with ice. After
filtrate was extracted with EtOAc. The EtOAc layer was washed with water stirring at the same temperature for 30 min, BOMCl (53 ml, 0.379 mmol)
and brine, dried over Na2SO4 and concentrated. The residue was purified by was added to the reaction mixture. The mixture was stirred at the same tem-
column chromatography (silica gel, 10 g) using EtOAc–hexane (3 : 17) as an perature for 1 h, then quenched with water and extracted with EtOAc. The
eluent to give the 2-ethenylindole 13a (38 mg, 90%). mp 133—134 °C EtOAc layer was washed with brine, dried over Na2SO4 and concentrated.
(EtOAc). IR (KBr) cmϪ1: 1643, 1383. 1H-NMR (CDCl3) d: 5.59 (1H, dd,
The residue was purified by column chromatography (silica gel, 10 g) using
Jϭ1.5, 17 Hz), 5.94 (1H, dd, Jϭ1.5, 11 Hz), 7.26—8.31 (10H, m), 9.99 (1H, EtOAc–hexane (3 : 7) as an eluent to give the oily O-BOM–ether 15c
s). MS m/z: 311 (Mϩ). Anal. Calcd for C17H13NO3S: C, 65.58; H, 4.21; N,
4.50. Found: C, 65.71; H, 4.36; N, 4.44.
(75 mg, 56%). IR (neat) cmϪ1: 2115. 1H-NMR (CDCl3) d: 2.59 (1H, d,
Jϭ2.5 Hz), 4.51 (2H, s), 4.64 (2H, s), 4.77 (1H, d, Jϭ7 Hz), 5.08 (1H, d,
2-Ethenyl-N-(methoxymethyl)indole-3-carbaldehyde (13b) The same Jϭ7 Hz), 5.55 (2H, s), 5.63 (1H, dd, Jϭ1.5, 11 Hz), 5.80 (1H, dd, Jϭ1.5,
procedure as above was carried out using 12b to give the oily 2-ethenylin- 17 Hz), 5.80 (1H, dd, Jϭ2.5 Hz), 6.87 (1H, dd, Jϭ11, 17 Hz), 7.17—7.39
1
dole 13b (97%). IR (neat) cmϪ1: 1697. H-NMR (CDCl3) d: 3.33 (3H, s),
5.49 (2H, s), 5.90 (1H, dd, Jϭ1.5, 17 Hz), 5.93 (1H, dd, Jϭ1.5, 12 Hz), 7.02
(1H, dd, Jϭ12, 17 Hz), 7.26—7.38 (2H, m), 7.48 (1H, d, Jϭ7 Hz), 8.39 (1H,
d, Jϭ7 Hz), 10.13 (1H, s). MS m/z: 215 (Mϩ). HR-MS m/z: 215.0946 (Calcd
for C13H13NO2: 215.0958).
(13H, m), 7.99 (1H, d, Jϭ7 Hz). MS m/z: 437 (Mϩ). HR-MS m/z: 437.1991
(Calcd for C29H27NO3: 437.1987).
4-(Methoxymethyloxy)-3-methylcarbazole (16a)
A solution of the
MOM-ether 15a (80 mg, 0.21 mmol) in THF (1.5 ml) was added to a stirred
solution of t-BuOK (71 mg, 0.63 mmol) in t-BuOH (3.5 ml) at an ambient
temperature. The mixture was refluxed at 90 °C for 2 h and cooled to room
N-(Benzyloxymethyl)-2-ethenylindole-3-carbaldehyde (13c) The
same procedure as above was carried out using 12c (650 mg, 2.17 mmol) to temperature, then quenched with an aqueous NH4Cl (saturated) solution, and
1
give the oily 2-ethenylindole 13c (494 mg, 78%). IR (neat) cmϪ1: 1693. H- then the mixture was extracted with EtOAc. The EtOAc layer was washed
NMR (CDCl3) d: 4.52 (2H, s), 5.59 (2H, s), 5.90 (1H, dd, Jϭ1.5, 12 Hz), with brine, dried over Na2SO4 and concentrated. The residue was purified by
5.91 (1H, dd, Jϭ1.5, 17 Hz), 6.79 (1H, dd, Jϭ12, 17 Hz), 7.24—7.40 (9H, column chromatography (silica gel, 20 g) using EtOAc–hexane (1 : 9) as an
m), 10.12 (1H, s). MS m/z: 291 (Mϩ). HR-MS m/z: 291.1259 (Calcd for eluent to give the oily carbazole 16a (20 mg, 35%). IR (neat) cmϪ1: 3410.
C19H17NO2: 291.1266).
2-Ethenyl-3-(1-hydroxyprop-2-yn-1-yl)-N-(phenylsulfonyl)indole (14a) Jϭ8 Hz), 7.13—7.36 (4H, m), 7.96 (1H, br s), 8.13 (1H, d, Jϭ7.7 Hz). MS
1H-NMR (CDCl3) d: 2.39 (3H, s), 3.59 (3H, s), 5.24 (2H, s), 7.03 (1H, d,

July 2001
885
m/z: 241 (Mϩ). HR-MS m/z: 241.1103 (Calcd for C15H15NO2: 241.1088).
N-(Methoxymethyl)-4-(methoxymethyloxy)-3-methylcarbazole (16b)
The same procedure as above was carried out using 15b (150 mg,
dd, Jϭ0.7, 1.8 Hz), 7.26—7.48 (8H, m), 7.62 (1H, t, Jϭ1.8 Hz), 7.84 (1H, d,
Jϭ0.7 Hz), 8.41—8.44 (1H, m), 9.98 (1H, s). MS m/z: 331 (Mϩ). HR-MS
m/z: 331.1208 (Calcd for C21H17NO3: 331.1219).
1
0.53 mmol) to give the oily carbazole 16b (87 mg, 58%). H-NMR (CDCl3)
N-(Benzyloxymethyl)-2-(3-furyl)-3-(1-hydroxyprop-2-yn-1-yl)indole
(20) The same procedure as the synthesis of 13c from 12c was carried out
using 19 (276 mg, 0.83 mmol) to give the oily alcohol 20 (295 mg, 99%). IR
(neat) cmϪ1: 3288, 2106. 1H-NMR (CDCl3) d: 2.20 (1H, d, Jϭ4.8 Hz), 2.65
(1H, d, Jϭ2.6 Hz), 4.52 (2H, s), 5.50 (2H, s), 5.65 (1H, dd, Jϭ2.6, 4.8 Hz),
6.72 (1H, dd, Jϭ0.7, 1.8 Hz), 7.22—7.45 (8H, m), 7.57 (1H, t, Jϭ1.8 Hz),
7.77 (1H, d, Jϭ0.7 Hz), 8.10—8.13 (1H, m). MS m/z: 357 (Mϩ). HR-MS
m/z: 357.1365 (Calcd for C23H19NO3: 357.1384).
d: 2.39 (3H, s), 3.27 (3H, s), 3.60 (3H, s), 5.24 (2H, s), 5.52 (2H, s), 7.02—
7.36 (5H, m), 8.13 (1H, d, Jϭ8 Hz). MS m/z: 285 (Mϩ). HR-MS m/z:
285.1365 (Calcd for C17H19NO3: 285.1379).
N-(Benzyloxymethyl)-4-(benzyloxymethyloxy)-3-methylcarbazole
(16c) The same procedure as above was carried out using 15c (2.1 g,
4.80 mmol) to give the carbazole 16c (1.7 g, 81%). mp 70—71 °C (Et2O–
1
hexane). H-NMR (CDCl3) d: 2.52 (3H, s), 4.47 (2H, s), 4.93 (2H, s), 5.44
(2H, s), 5.75 (2H, s), 7.19—7.50 (15H, m), 8.26 (1H, d, Jϭ8 Hz). MS m/z:
437 (Mϩ). Anal. Calcd for C29H27NO3: C, 79.61; H, 6.22; N, 3.20. Found: C,
79.76; H, 6.38; N, 3.05.
N-(Benzyloxymethyl)-3-[1-(benzyloxymethyloxy)prop-2-yn-1-yl]-2-(3-
furyl)indole (21) The same procedure as the synthesis of 15c from 14c
was carried out using 20 (431 mg, 1.20 mmol) to give the O-BOM ether 21.
Compound 21 was used in the next step without further purification.
N-(Benzyloxymethyl)-4-(benzyloxymethyloxy)-3-methylfuro[3,2-a]car-
bazole (22) The same procedure as the synthesis of 16c from 15c was car-
ried out using 21 to give the carbazole 22 (350 mg, 61% from 20). mp 79—
4-Hydroxy-N-(hydroxymethyl)-3-methylcarbazole (17a) and 4-Hy-
droxy-3-methylcarbazole (7a) A solution of the carbazole 16c (100 mg,
0.23 mmol) in THF (3 ml) was added to a liquid NH3 at Ϫ78 °C. A piece of
Na (54 mg, 2.33 mmol) was added to the mixture. After stirring at the same
temperature for 30 min, the mixture was quenched with NH4Cl and then the
temperature was raised to room temperature. The resultant mixture was ex-
tracted with EtOAc. The EtOAc layer was washed with brine, dried over
Na2SO4 and concentrated. The residue was purified by column chromatogra-
phy (silica gel, 10 g) using EtOAc–hexane (3 : 17) as an eluent to give the N-
hydroxymethylcarbazole 17a (39 mg, 75%) and the carbazole 7a (10 mg,
22%). 17a: mp 122—125 °C (EtOAc–hexane). IR (KBr) cmϪ1: 3368. 1H-
NMR (CDCl3) d: 2.41 (3H, s), 2.87 (1H, t, Jϭ6.6 Hz, exchangeable with
D2O), 5.26 (1H, br s), 5.82 (2H, d, Jϭ6.6 Hz), 7.03 (1H, d, Jϭ8 Hz), 7.20—
7.34 (2H, m), 7.41—7.50 (2H, m), 8.28 (1H, d, Jϭ8 Hz). MS m/z: 227 (Mϩ).
Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 74.13; H,
5.84; N, 6.01. 7a: mp 160—163 °C (EtOAc–hexane) (lit.,5f) mp 161—
163 °C). IR (KBr) cmϪ1: 3380, 1611. 1H-NMR (CDCl3) d: 2.40 (3H, s), 5.21
(1H, br s), 6.93 (1H, d, Jϭ8 Hz), 7.16 (1H, d, Jϭ8 Hz), 7.20—7.26 (1H, m),
7.37—7.39 (2H, m), 7.94 (1H, br s), 8.26 (1H, d, Jϭ8 Hz). 13C-NMR
(CDCl3) d: 149.7, 140.0, 139.2, 128.5, 125.0, 122.6, 122.3, 119.5, 112.0,
111.9, 110.0, 102.8, 14.8. MS m/z: 197 (Mϩ). Anal. Calcd for C13H11NO: C,
79.16; H, 5.62; N, 7.10. Found: C, 79.31; H, 5.78; N, 6.94.
4-Hydroxy-3-methylcarbazole (7a) from 4-Hydroxy-N-(hydroxy-
methyl)-3-methylcarbazole (17a) Triton B (40% in water, 1 drop with a
pipet) was added to a stirred solution of N-hydroxymethylcarbazole 17a
(12 mg, 0.0528 mmol) in THF (2 ml) and H2O (1 ml). The mixture was
heated at 100 °C for 20 min, cooled to an ambient temperature, diluted with
water, and then the mixture was extracted with EtOAc. The EtOAc layer was
washed with brine, dried over Na2SO4 and concentrated. The residue was
purified by column chromatography (silica gel, 10 g) using EtOAc–hexane
(1 : 4) as an eluent to give the carbazole 7a (8 mg, 71%).
1
81 °C (Et2O–hexane). H-NMR (CDCl3) d: 2.63 (3H, s), 4.53 (2H, s), 4.96
(2H, s), 5.45 (2H, s), 5.95 (2H, s), 7.14 (1H, d, Jϭ2.2 Hz), 7.23—7.48 (13H,
m), 7.72 (1H, d, Jϭ2.2 Hz), 8.29 (1H, d, Jϭ7 Hz). MS m/z: 477 (Mϩ). Anal.
Calcd for C31H27NO4: C, 77.97; H, 5.70; N, 2.93. Found: C, 78.11; H, 5.91;
N, 2.75.
4-Hydroxy-N-hydroxymethyl-3-methylfuro[3,2-a]carbazole (23) and
4-Hydroxy-3-methylfuro[3,2-a]carbazole (7b) The same procedure as
the synthesis of 17a and 7a from 16c was carried out using 22 (114 mg,
0.24 mmol) to give the N-hydroxymethylcarbazole 23 (26 mg, 41%) and the
carbazole 7b (29 mg, 51%). 23: mp 142—145 °C (Et2O–hexane). IR (KBr)
1
cmϪ1: 3309. H-NMR (CDCl3) d: 2.54 (3H, s), 2.46 (1H, t, Jϭ7 Hz), 5.26
(1H, s), 6.02 (2H, d, Jϭ7 Hz), 7.14 (1H, d, Jϭ1.8 Hz), 7.31 (1H, t, Jϭ8 Hz),
7.43 (1H, t, Jϭ8 Hz), 7.54 (1H, d, Jϭ8 Hz), 7.69 (1H, d, Jϭ1.8 Hz), 8.34
(1H, d, Jϭ8 Hz). MS m/z: 267 (Mϩ). Anal. Calcd for C16H13NO3: C, 71.90;
H, 4.90; N, 5.24. Found: C, 71.93; H, 4.86; N, 5.28. 7b: mp 170—173 °C
(Et2O–hexane). IR (KBr) cmϪ1: 3421. 1H-NMR (CDCl3) d: 2.53 (3H, s),
5.28 (1H, br s), 6.92 (1H, d, Jϭ2.2 Hz), 7.27 (1H, t, Jϭ8 Hz), 7.37 (1H, t,
Jϭ8 Hz), 7.47 (1H, d, Jϭ8 Hz), 7.63 (1H, d, Jϭ2.2 Hz), 8.29 (1H, br s), 8.30
(1H, d, Jϭ8 Hz). MS m/z: 237 (Mϩ). Anal. Calcd for C15H11NO2: C, 75.94;
H, 4.67; N, 5.90. Found: C, 76.16; H, 4.90; N, 5.71.
4-Hydroxy-3-methylfuro[3,2-a]carbazole (7b) from 23 The same pro-
cedure as the synthesis of 7a from 17a was carried out using 23 (6 mg,
0.024 mmol) to give the carbazole 7b (5 mg, 93%).
3-Methyl-4-(trifluoromethanesulfonyloxy)furo[3,2-a]carbazole
(24)
Tf2O (7.4 ml, 0.0443 mmol) was added to a stirred solution of the 4-hydroxy-
carbazole 7b (7 mg, 0.0295 mmol) and pyridine (7.2 ml, 0.0885 mmol) in
CH2Cl2 (1 ml) under cooling with ice. After stirring at room temperature for
10 min, the solution was treated with water, and the mixture was extracted
with CH2Cl2. The CH2Cl2 layer was washed with brine, dried over Na2SO4
and concentrated. The residue was purified by column chromatography (sil-
ica gel, 10 g) using EtOAc–hexane (3 : 17) as an eluent to give the triflate 24
(10 mg, 92%). mp 138—140 °C (Et2O–hexane). IR (KBr) cmϪ1: 3446, 1383,
1134. 1H-NMR (CDCl3) d: 2.67 (3H, s), 7.01 (1H, d, Jϭ2.2 Hz), 7.26—7.47
(3H, m), 7.80 (1H, d, Jϭ2.2 Hz), 8.32 (1H, d, Jϭ8 Hz), 8.47 (1H, br s). MS
m/z: 369 (Mϩ). Anal. Calcd for C16H10F3NO4S: C, 52.03; H, 2.73; N, 3.79.
Found: C, 52.32; H, 2.98; N, 3.71.
4-Hydroxy-N-(methoxymethyl)-3-methylcarbazole (17b) A solution
of N-hydroxymethylcarbazole 17a (12 mg, 0.0528 mmol), ethylene glycol
(0.5 ml), and 0.5 M HCl (2 ml) in THF (2 ml) was stirred at room temperature
for 30 min. The mixture was basified with an aqueous Na2CO3 (saturated)
solution, and then the resulting mixture was extracted with EtOAc. The
EtOAc layer was washed with brine, dried over Na2SO4 and concentrated.
The residue was purified by preparative TLC using EtOAc–hexane (1 : 4) as
an eluent to give the oily N-MOM-carbazole 17b (13 mg, 75%). 1H-NMR
(CDCl3) d: 2.39 (3H, s), 3.59 (3H, s), 5.24 (2H, s), 7.03 (1H, d, Jϭ8 Hz),
7.13—7.36 (4H, m), 8.13 (1H, d, Jϭ7.7 Hz). MS m/z: 241 (Mϩ). HR-MS
m/z: 241.1103 (Calcd for C15H15NO2: 331.1123).
Furostifoline (5) HCOOH (22 ml, 0.54 mmol) was added to the mixture
of the triflate 24 (10 mg, 0.027 mmol), Et3N (34 ml, 0.234 mmol), PPh3
(0.28 mg, 0.0011 mmol) and Pd(OAc)2 (0.12 mg, 0.00054 mmol) in DMF
(3 ml) under argon. The mixture was heated at 60 °C for 12 h. After cooling
to an ambient temperature, the solution was treated with water, and then the
mixture was extracted with EtOAc. The EtOAc layer was washed with water
and brine, dried over Na2SO4 and concentrated. The residue was purified by
column chromatography (silica gel, 10 g) using EtOAc–hexane (1 : 9) as an
eluent to give furostifoline (5) (6 mg, 99%). mp 173—175 °C (Et2O–hexane)
2-(3-Furyl)indole-3-carbaldehyde (10b)
A stirred mixture of 2-
chloroindole 11 (995 mg, 5.56 mmol), furan-3-boronic acid (18) (1.12 g,
10 mmol), Et3N (2.3 ml, 16.7 mmol), PPh3 (mg, 0.34 mmol), and Pd(OAc)2
(38 mg, 0.17 mmol) in DMF (10 ml) was heated at 100 °C for 5 h. After
cooling to an ambient temperature, the mixture was quenched with water,
and then the mixture was extracted with EtOAc. The EtOAc layer was
washed with brine, dried over Na2SO4 and concentrated. The residue was
purified by column chromatography (silica gel, 30 g) using EtOAc–hexane
(3 : 7) as an eluent to give the 2-furylindole 10b (982 mg, 84%). mp 255—
1
(lit.,3) mp 174—175 °C). IR (KBr) cmϪ1: 3408, 1456. H-NMR (CDCl3) d:
2.68 (3H, s), 7.00 (1H, d, Jϭ2.2 Hz), 7.26 (1H, dt, Jϭ1.1, 8.1 Hz), 7.38 (1H,
dt, Jϭ1.1, 8.1 Hz), 7.49 (1H, br d, Jϭ8.1 Hz), 7.73 (1H, d, Jϭ2.2 Hz), 7.78
(1H, br s), 8.06 (1H, br d, Jϭ8.1 Hz), 8.26 (1H, br s). MS m/z: 221 (Mϩ).
Anal. Calcd for C15H11NO: C, 81.43; H, 5.01; N, 6.33. Found: C, 81.59; H,
5.32; N, 6.11.
1
258 °C (CHCl3). IR (KBr) cmϪ1: 3157, 1632. H-NMR (acetone-d6) d: 6.77
(1H, dd, Jϭ0.7, 1.8 Hz), 7.26—7.50 (3H, m), 7.62 (1H, t, Jϭ1.8 Hz), 8.02
(1H, d, Jϭ0.7 Hz), 8.34 (1H, m), 8.66 (1H, br s), 10.22 (1H, s). MS m/z: 211
(Mϩ). Anal. Calcd for C13H9NO2: C, 73.92; H, 4.29; N, 6.63. Found: C,
74.25; H, 4.40; N, 6.49.
N-(Benzyloxymethyl)-2-(3-furyl)indole-3-carbaldehyde
(19) The
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