Transition metal complexes in organic synthesis, part 63;1 convergent iron-mediated syntheses of the furo[3,2-a]carbazole alkaloid furostifoline

Article abstract of DOI:10.1055/s-2000-8714

Two highly efficient routes to the furo[3,2-a]carbazole alkaloid furostifoline are described. Both syntheses use the iron-mediated arylamine cyclization as the key-step and lead to the natural product in seven and five steps, respectively.

Full text of DOI:10.1055/s-2000-8714

SPECIAL TOPIC
2131
Transition Metal Complexes in Organic Synthesis, Part 63;1 Convergent Iron-
Mediated Syntheses of the Furo[3,2-a]carbazole Alkaloid Furostifoline
Hans-Joachim Knölker,* Wolfgang Fröhner
Institut für Organische Chemie, Universität Karlsruhe, Richard-Willstätter-Allee, D-76131 Karlsruhe, Germany
Fax +49(721)698529; E-mail: knoe@ochhades.chemie.uni-karlsruhe.de
Received 8 September 2000
moiety of the natural product is already completed at the
Abstract: Two highly efficient routes to the furo[3,2-a]carbazole
stage of the arylamine precursor and the two building
alkaloid furostifoline are described. Both syntheses use the iron-me-
blocks only have to be combined by the final iron-media-
diated arylamine cyclization as the key-step and lead to the natural
ted consecutive C-C and C-N bond formation furnishing
the carbazole framework. The iron complex salt 2 is readi-
ly prepared on a large scale using our 1-azabuta-1,3-diene
catalyzed complexation of cyclohexa-1,3-diene17 fol-
lowed by hydride abstraction with triphenylcarbenium
tetrafluoroborate.18 For the synthesis of 4-amino-7-meth-
ylbenzo[b]furan (3), we devised a straightforward route
(Scheme 2).
product in seven and five steps, respectively.
Key words: benzofurans, carbazole alkaloids, tricarbonyliron com-
plexes, electrophilic substitution, oxidative cyclization
Over the past decades many biologically active carbazole
alkaloids with challenging new structures were isolated
from different natural sources.2-5 The strong interest of
many research groups in these natural products led to the
development of novel methodologies for the synthesis of
carbazole alkaloids.6-10 We developed an efficient and
highly convergent iron-mediated construction of the car-
bazole framework which was applied to the total synthesis
of a broad range of carbazole alkaloids. The key-steps of
our approach are the consecutive C-C and C-N bond for-
mations, which are mediated by a tricarbonyliron frag-
ment between its coordinated cyclohexa-1,3-diene ligand
and a fully functionalized arylamine.10,11
Scheme 1
In 1990, Furukawa and his group at Nagoya reported the
isolation and structural elucidation of furostifoline 1.12
Furostifoline was obtained from the root bark of Murraya
euchrestifolia Hayata (Rutaceae), a shrub growing in Tai-
wan where extracts of the leaves and bark of this plant
have been used as a folk medicine. Furostifoline was the
first carbazole alkaloid exhibiting a furo[3,2-a]carbazole
framework. Because of its unprecedented framework and
pharmacological potential, furostifoline attracted the at-
tention of several synthetic organic groups. In 1996, we
described the first total synthesis of furostifoline by appli-
cation of our convergent iron-mediated formation of the
carbazole nucleus.13 Further total syntheses were reported
in 1998 by the groups of Beccalli and Hibino using differ-
ent electrocyclic ring closures as key-step.14,15 More re-
cently, Timári and co-workers elaborated an additional
synthesis of furostifoline using a palladium-catalyzed
cross-coupling followed by a regioselective nitrene inser-
tion.16 In this paper, we describe the full experimental de-
tails of our first furostifoline synthesis13 and an alternative
approach featuring a reversal of the sequence of the two
cyclization reactions.
Following a literature procedure, 2-methyl-5-nitrophenol
(4) is easily prepared by treatment of 2-methyl-5-nitro-
aniline with nitrous acid with heating.19 Compound 4 pre-
viously served as starting material for our molybdenum-
mediated total synthesis of the pyrano[3,2-a]carbazole al-
kaloid dihydroxygirinimbine.20 For the annulation of the
furan ring at the nitrophenol 4, we used bromoacetalde-
hyde diethyl acetal, which represents a well-established
C2-building block for the synthesis of benzofurans via
ether formation, and subsequent amberlyst 15 catalyzed
cyclization.21,22 The alkylation of the nitrophenol 4 with
2-bromo-1,1-diethoxyethane in N,N-dimethylformamide
at reflux in the presence of potassium carbonate provided
the 2-aryloxy-1,1-diethoxyethane 5. The reaction of the
nitroaryl ether 5 with catalytic amounts of amberlyst 15 in
chlorobenzene at 120 °C provided the desired 7-methyl-4-
nitrobenzo[b]furan in only 6% yield and led by cleavage
of the ether to the nitrophenol 4 as major product (see ex-
perimental section). Catalytic hydrogenation of the nitro
derivative 5 using palladium on activated carbon afforded
the arylamine 6. All attempts to achieve a cyclization of
the unprotected arylamine 6 with amberlyst 15, polyphos-
phoric acid, or boron trifluoride etherate resulted in com-
plete decomposition. Therefore, the amino group was
protected prior to the furan formation by conversion to the
The retrosynthetic analysis of furostifoline 1 leads to the
iron complex salt 2 and 4-amino-7-methylbenzofuran (3)
as precursors for a highly convergent iron-mediated syn-
thesis (Scheme 1). In this approach the whole benzofuran
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2132
H.-J. Knölker, W. Fröhner
SPECIAL TOPIC
ridine at 90 °C in the air and provided furostifoline 1 in
36% yield.
Scheme 3
In a novel approach to the furo[3,2-a]carbazole alkaloid
furostifoline we realized a reversal of the two cyclization
reactions by first forming the carbazole nucleus and then
fusing the furan ring (Scheme 4). This second synthesis is
shorter because an intermediate protection of the amino
function is not necessary. Electrophilic substitution at the
arylamine 6 by reaction with the iron complex salt 2 in ac-
etonitrile at room temperature provided in high yield the
iron complex 10. Although one equivalent of tetrafluo-
roboric acid was generated during this process, the acetal
protecting group in the side chain stayed intact. At this
stage, the carbazole heterocycle was first formed by an
iron-mediated arylamine cyclization of complex 10 with
iodine in pyridine, which afforded the carbazole 11 in
40% yield. Annulation of the furan ring by reaction of the
carbazole 11 with catalytic amounts of amberlyst 15 in
chlorobenzene at 120 °C led directly to furostifoline 1 in
66% yield.
Scheme 2
phthalimide 7. The subsequent annulation of the furan
ring by the amberlyst 15 catalyzed cyclization in chlo-
robenzene at 120 °C afforded the protected aminobenzo-
furan 8.21,22 Removal of the phthaloyl protecting group by
treatment of 8 with hydrazine hydrate in methanol at room
temperature provided 4-amino-7-methylbenzo[b]furan
(3). The present 5-step-sequence can be carried out easily
on a multigram scale and provides compound 3 in 52%
overall yield based on the nitrophenol 4.
The spectral data of our synthetic furostifoline are in full
agreement with those described by Furukawa for the na-
tural product (UV, IR, 1H NMR, and MS).12 We obtained
furostifoline as colorless crystals with a melting point of
174-175 °C, whereas the natural product was isolated as
a colorless oil.12
The C-C bond formation by electrophilic aromatic sub-
stitution at the aminobenzofuran 3 with the iron complex
salt 2 in acetonitrile at room temperature afforded quanti-
tatively the iron complex 9 (Scheme 3). The attempted ox-
idative cyclization of complex 9 with a range of reagents
(commercial manganese dioxide, very active manganese
dioxide, and ferricenium hexafluorophosphate) failed and
resulted exclusively in decomposition of the starting ma-
terial. An alternative reagent for the iron-mediated aryl-
amine cyclization is iodine in pyridine,23 although it was
demonstrated that this oxidant often leads to simple de-
metalation with only minor amounts of cyclization pro-
ducts.24,25 More recently, iodine in pyridine was success-
fully utilized for the first double iron-mediated arylamine
cyclization to indolo[2,3-b]carbazole.26 Oxidative cy-
clization of complex 9 with concomitant aromatization
was achieved by treatment with an excess of iodine in py-
In conclusion, our first synthesis provides furostifoline in
seven steps and 19% overall yield based on the nitrophe-
nol 4, while our second synthesis leads to the natural prod-
uct in only five steps and 21% overall yield based on the
same starting material.
All reactions were carried out in dry solvents under an inert gas at-
mosphere unless otherwise stated. Flash chromatography: Merck
silica gel (0.03-0.06 mm). Amberlyst 15 was obtained from Flu-
ka.22 Mps: Büchi 535. UV spectra: Perkin-Elmer Lambda 2 (UV/
VIS spectrometer). IR spectra: Bruker IFS 88 (FT-IR). 1H NMR and
13C NMR spectra: Bruker AM-400 and Bruker DRX 500; internal
standard: TMS or the signal of the deuterated solvent; d in ppm;
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SPECIAL TOPIC
Transition Metal Complexes in Organic Synthesis, Part 63
2133
was the nitrophenol 4. After cooling to r.t., the reaction mixture was
filtered and the filter washed with Et2O (50 mL). The combined fil-
trates were washed with NaOH (5%, 3 x 30 mL) to remove the ni-
trophenol 4, then with H2O (50 mL), and dried (Na2SO4).
Evaporation of the solvent and flash chromatography (CH2Cl2) of
the residue on silica gel provides 7-methyl-4-nitrobenzofuran as
light yellow crystals, yield: 166 mg (6%), mp: 110-111 °C (ace-
tone).
UV (MeOH): l = 193, 224, 307 nm.
IR (drift): n = 3173, 3137, 1511, 1324, 1127, 815, 784, 733 cm-1.
1H NMR (400 MHz, CDCl3): d = 2.61 (s, 3H), 7.18 (d, 1H, J = 8.3
Hz), 7.47 (d, 1H, J = 2.2 Hz), 7.82 (d, 1H, J = 2.2 Hz), 8.09 (d, 1H,
J = 8.3 Hz).
13C NMR and DEPT (100 MHz, CDCl3): d = 15.47 (CH3), 107.33
(CH), 119.85 (CH), 122.56 (C), 124.57 (CH), 129.82 (C), 139.05
(C), 148.13 (CH), 154.61 (C).
MS (20 °C): m/z (%) = 177 (M+, 100), 147 (35), 131 (45), 102 (11),
91 (12), 77 (35).
HRMS: m/z calcd for C9H7NO3 (M+): 177.0426. Found: 177.0436.
Anal. calcd for C9H7NO3: C, 61.01; H, 3.98; N, 7.91. Found: C,
60.76; H, 4.01; N, 7.70.
3-(2,2-Diethoxyethoxy)-4-methylaniline (6)
Palladium on activated carbon (10%, 970 mg) was added to a solu-
tion of the nitrobenzene 5 (9.69 g, 36.0 mmol) in MeOH (100 mL).
The solution was stirred vigorously under a H2 atm until no further
uptake of H2 was detected. The reaction mixture was filtered over a
short path of Celite (which was subsequently washed with MeOH)
and the solvent was removed. The residue was subjected to flash
chromatography (Et2O) on silica gel to afford the arylamine 6 as a
light red oil, yield: 8.48 g (99%).
Scheme 4
coupling constants (J) in Hz. MS: Finnigan MAT-90; ionization po-
tential: 70 eV. Elemental analyses: Heraeus CHN-Rapid.
UV (MeOH): l = 204, 237, 288 nm.
IR (film): n = 3450, 3365, 2976, 2932, 1622, 1514, 1183, 1130,
3-(2,2-Diethoxyethoxy)-4-methylnitrobenzene (5)
1072, 827 cm-1.
Bromoacetaldehyde diethyl acetal (14.2 g, 71.8 mmol) was added to
a refluxing mixture of 2-methyl-5-nitrophenol (4) (10.0 g,
65.3 mmol) and potassium carbonate (10.9 g, 79.0 mmol) in N,N-
dimethyl formamide (40 mL) over 45 min. The reaction mixture
was stirred for an additional 3.5 h at reflux and cooled to r.t. The
mixture was poured into NaOH (1%, 180 mL) and the aqueous layer
was extracted with Et2O (2 x 80 mL). The combined organic layers
were washed with H2O and dried (Na2SO4). After removal of the
solvent, the residue was distilled in vacuo to provide the acetal 5 as
a pale yellow oil, yield: 14.3 g (81%), bp: 122 °C/0.3 Torr.
1H NMR (400 MHz, CDCl3): d = 1.24 (t, 6H, J = 7.1 Hz), 2.11 (s,
3H), 3.54 (br s, 2H), 3.64 (dq, 2H, J = 9.4, 7.1 Hz), 3.77 (dq, 2H,
J = 9.4, 7.1 Hz), 3.93 (d, 2H, J = 5.3 Hz), 4.83 (t, 1H, J = 5.3 Hz),
6.17-6.21 (m, 2H), 6.87 (d, 1H, J = 7.8 Hz).
13C NMR and DEPT (100 MHz, CDCl3): d = 15.37 (3 CH3), 62.80
(2 CH2), 68.79 (CH2), 99.54 (CH), 100.81 (CH), 107.21 (CH),
116.55 (C), 131.01 (CH), 145.61 (C), 157.35 (C).
MS (20 °C): m/z (%) = 239 (M+, 66), 148 (16), 123 (14), 122 (14),
106 (15), 103 (100), 75 (46), 47 (27).
HRMS: m/z calcd for C13H21NO3 (M+): 239.1521. Found: 239.1530.
UV (MeOH): l = 210, 229, 279, 323 nm.
IR (film): n = 2977, 2931, 2884, 1522, 1346, 1253, 1133, 1071, 866,
815, 740 cm-1.
3-(2,2-Diethoxyethoxy)-4-methylphthaloylimidobenzene (7)
A mixture of the arylamine 6 (2.34 g, 9.78 mmol) and phthalic an-
hydride (1.63 g, 11.0 mmol) was stirred in CHCl3 (30 mL) at reflux
for 27 h. Additional phthalic anhydride (250 mg, 1.69 mmol) was
added to the reaction mixture, which was stirred further at reflux for
19 h. The solvent was evaporated and the residue was subjected to
flash chromatography (hexane/EtOAc, 2:1) on silica gel to afford
the phthalimide 7 as a colorless solid, yield: 3.18 g (88%), mp: 110-
111 °C.
1H NMR (400 MHz, CDCl3): d = 1.27 (t, 6H, J = 7.1 Hz), 2.32 (s,
3H), 3.68 (dq, 2H, J = 9.3, 7.1 Hz), 3.81 (dq, 2H, J = 9.3, 7.1 Hz),
4.09 (d, 2H, J = 5.2 Hz), 4.90 (t, 1H, J = 5.2 Hz), 7.26 (d, 1H,
J = 8.1 Hz), 7.67 (d, 1H, J = 2.1 Hz), 7.76 (dd, 1H, J = 8.1, 2.1 Hz).
13C NMR and DEPT (100 MHz, CDCl3): d = 15.37 (2 CH3), 16.64
(CH3), 63.00 (2 CH2), 69.19 (CH2), 100.38 (CH), 105.82 (CH),
115.99 (CH), 130.60 (CH), 135.21 (C), 147.10 (C), 156.86 (C).
MS (35 °C): m/z (%) = 269 (M+, 1), 178 (12), 103 (100), 75 (42), 47
(32).
UV (MeOH): l = 197, 218, 279 nm.
IR (drift): n = 2977, 2930, 2892, 1720, 1515, 1393, 1260, 1133,
HRMS: m/z calcd for C13H19NO5 (M+): 269.1263. Found: 269.1253.
1109, 1082, 712 cm-1.
1H NMR (400 MHz, CDCl3): d = 1.25 (t, 6H, J = 7.1 Hz), 2.28 (s,
3H), 3.65 (dq, 2H, J = 9.3, 7.1 Hz), 3.78 (dq, 2H, J = 9.3, 7.1 Hz),
4.03 (d, 2H, J = 5.2 Hz), 4.88 (t, 1H, J = 5.2 Hz), 6.89 (d, 1H,
7-Methyl-4-nitrobenzo[b]furan
A mixture of the nitroaryl ether 5 (3.96 g, 14.7 mmol) and amberlyst
15 (400 mg) in dry chlorobenzene (10 mL) was stirred at 120 °C for
2 days. TLC analysis, at this stage, indicated that the major product
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2134
H.-J. Knölker, W. Fröhner
SPECIAL TOPIC
J = 1.8 Hz), 6.94 (dd, 1H, J = 7.9, 1.8 Hz), 7.25 (d, 1H, J = 7.9 Hz),
7.75-7.79 (m, 2H), 7.90-7.93 (m, 2H).
13C NMR and DEPT (100 MHz, CDCl3): d = 15.25 (2 CH3), 16.00
(CH3), 62.66 (2 CH2), 68.81 (CH2), 100.45 (CH), 109.75 (CH),
118.75 (CH), 123.55 (2 CH), 127.11 (C), 129.98 (C), 130.64 (CH),
131.63 (2 C), 134.25 (2 CH), 156.75 (C), 167.24 (2 C=O).
h at r.t. The solvent was evaporated and the residue was subjected
to flash chromatography (hexane/EtOAc, 2:1) on silica gel to pro-
vide the iron complex 9 as yellow crystals, yield: 139 mg (100%),
mp: 116 °C.
UV (MeOH): l = 210 (sh), 225, 301 nm.
IR (drift): n = 3445, 3365, 3005, 2938, 2846, 2039, 1949, 1631,
MS (100 °C): m/z (%) = 369 (M+, 10), 278 (14), 103 (100), 75 (26),
1480, 1155, 745, 625 cm-1.
47 (20).
1H NMR (400 MHz, CDCl3): d = 1.65 (br d, 1H, J = 15.3 Hz), 2.40
(ddd, 1H, J = 15.3, 11.1, 4.0 Hz), 2.40 (d, 3H, J = 0.7 Hz), 3.15-
3.22 (m, 2H), 3.49 (dt, 1H, J = 11.1, 3.7 Hz), 3.71 (br s, 2H), 5.49-
5.55 (m, 2H), 6.62 (d, 1H, J = 2.3 Hz), 6.81 (s, 1H), 7.51 (d, 1H,
J = 2.3 Hz).
HRMS: m/z calcd for C21H23NO5 (M+): 369.1576. Found: 369.1566.
Anal. calcd for C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C,
68.32; H, 6.06; N, 3.91.
13C NMR and DEPT (100 MHz, CDCl3): d = 14.66 (CH3), 31.62
(CH2), 38.54 (CH), 60.34 (CH), 65.71 (CH), 84.93 (CH), 85.64
(CH), 103.42 (CH), 112.05 (C), 116.26 (C), 122.84 (C), 124.28
(CH), 134.17 (C), 143.51 (CH), 153.18 (C), 212.05 (3 CO).
MS (75 °C): m/z (%) = 365 (M+, 20), 337 (6), 309 (37), 281 (70),
279 (100), 223 (41), 203 (81), 147 (42).
7-Methyl-4-phthaloylimidobenzo[b]furan (8)
A mixture of the phthalimide 7 (665 mg, 1.80 mmol) and amberlyst
15 (70 mg) in chlorobenzene (1 mL) was stirred at 120 °C for 20 h.
After cooling to r.t., the reaction mixture was diluted with CH2Cl2
and filtered. The solvent was evaporated and the residue was recrys-
tallized from tetrachloromethane to give the benzofuran 8 as pale
yellow crystals, yield: 465 mg (93%), mp: 183 °C.
HRMS: m/z calcd for C18H15FeNO4 (M+): 365.0350. Found:
365.0334.
UV (MeOH): l = 215, 237, 255 nm.
IR (drift): n = 1724, 1505, 1383, 882, 806, 717 cm-1.
1H NMR (400 MHz, CDCl3): d = 2.58 (s, 3H), 6.61 (d, 1H, J = 2.2
Hz), 7.18 (d, 1H, J = 7.8 Hz), 7.23 (d, 1H, J = 7.8 Hz), 7.66 (d, 1H,
J = 2.2 Hz), 7.79-7.82 (m, 2H), 7.96-7.99 (m, 2H).
Anal. calcd for C18H15FeNO4: C, 59.20; H, 4.14; N, 3.84. Found: C,
59.27; H, 4.26; N, 3.98.
Furostifoline (4-Methyl-10H-furo[3,2-a]carbazole) (1)
Iodine (2.08 g, 8.20 mmol) was added to a solution of the iron com-
plex 9 (1.00 g, 2.74 mmol) in pyridine (30 mL) at 90 °C. After stir-
ring for 4 h at 90 °C in the air, additional iodine (340 mg,
1.34 mmol) was added to the dark brown solution. The reaction
mixture was stirred further for 2 h at 90 °C and was cooled to r.t. A
solution of sodium thiosulfate (10 g) and citric acid (5 g) in H2O (60
mL) was added and the mixture was extracted with Et2O (2 x 80
mL). The combined organic layers were washed with H2O and dried
(Na2SO4). After evaporation of the solvent, the residue was subject-
ed to flash chromatography (hexane/EtOAc/Et3N, 6:3:1) on silica
gel to afford furostifoline 1 as colorless crystals, yield: 215 mg
(36%), mp: 174-175 °C (cyclohexane).
13C NMR and DEPT (100 MHz, CDCl3): d = 15.03 (CH3), 105.40
(CH), 121.85 (C), 121.90 (CH), 122.59 (C), 123.82 (2 CH), 124.49
(C), 125.23 (CH), 131.95 (2 C), 134.41 (2 CH), 145.24 (CH),
154.56 (C), 167.17 (2 C=O).
MS (65 °C): m/z (%) = 277 (M+, 100), 233 (5), 204 (6), 130 (4), 104
(4), 76 (9).
HRMS: m/z calcd for C17H11NO3 (M+): 277.0739. Found: 277.0753.
Anal. calcd for C17H11NO3: C, 73.64; H, 4.00; N, 5.05. Found: C,
73.45; H, 4.04; N, 5.01.
4-Amino-7-methylbenzo[b]furan (3)
UV (MeOH): l = 211, 226, 237, 260, 274, 296, 319, 333 nm.
Hydrazine hydrate (85%, 2.7 mL) was added dropwise to a stirred
suspension of the benzofuran 8 (1.67 g, 6.02 mmol) in MeOH
(50 mL) and the resulting orange colored solution was stirred for 1
h at r.t. After removal of the solvent, the residue was extracted with
Et2O (3 x 50 mL). The combined organic layers were evaporated
and the residue was distilled in vacuo to afford the aminobenzofu-
ran 3 as a light yellow oil, yield: 719 mg (81%), bp: 60-62 °C/0.06
Torr.
IR (drift): n = 3415, 1457, 1445, 1361, 1308, 1159, 1044, 878, 747,
735, 679 cm-1.
1H NMR (500 MHz, CDCl3): d = 2.67 (d, 3H, J = 0.8 Hz), 6.97 (d,
1H, J = 2.2 Hz), 7.25 (dt, 1H, J = 0.9, 7.5 Hz), 7.37 (ddd, 1H,
J = 7.5, 7.2, 1.1 Hz), 7.47 (br d, 1H, J = 8.0 Hz), 7.71 (d, 1H, J = 2.2
Hz), 7.77 (br s, 1H), 8.05 (br d, 1H, J = 7.7 Hz), 8.21 (br s, 1H).
13C NMR and DEPT (125 MHz, CDCl3): d = 15.45 (CH3), 103.72
(CH), 110.74 (CH), 111.37 (C), 114.29 (C), 116.68 (CH), 117.85
(C), 119.58 (CH), 119.63 (CH), 124.01 (C), 124.30 (CH), 131.00
(C), 138.87 (C), 143.76 (CH), 154.05 (C).
UV (MeOH): l = 219, 259, 297 nm.
IR (film): n = 3354 (br), 2922, 1635, 1505, 1359, 1299, 1177, 1144,
1041, 878, 809, 770, 732, 622 cm-1.
1H NMR (400 MHz, CDCl3): d = 2.40 (s, 3H), 3.60 (br s, 2H), 6.40
(d, 1H, J = 7.7 Hz), 6.64 (d, 1H, J = 2.2 Hz), 6.87 (d, 1H, J = 7.7
Hz), 7.50 (d, 1H, J = 2.2 Hz).
13C NMR and DEPT (100 MHz, CDCl3): d = 14.46 (CH3), 103.46
(CH), 107.62 (CH), 112.09 (C), 115.77 (C), 125.68 (CH), 137.78
(C), 143.07 (CH), 154.77 (C).
MS (20 °C): m/z (%) = 147 (M+, 100), 146 (99), 91 (6), 74 (5).
HRMS: m/z calcd for C9H9NO (M+): 147.0684. Found: 147.0674.
MS (45 °C): m/z (%) = 221 (M+, 100), 220 (56), 191 (11).
HRMS: m/z calcd for C15H11NO (M+): 221.0841. Found: 221.0830.
Anal. calcd for C15H11NO: C, 81.43; H, 5.01; N, 6.33. Found: C,
81.62; H, 5.35; N, 6.41.
[(1-4-h)-5-{2-Amino-4-(2,2-diethoxyethoxy)-5-methylphe-
nyl}cyclohexa-1,3-diene]tricarbonyliron (10)
A solution of the arylamine 6 (1.00 g, 4.19 mmol) and tricarbon-
yl(h5-cyclohexadienylium)iron tetrafluoroborate (2) (640 mg,
2.09 mmol) in degassed MeCN (20 mL) was stirred for 3 h at r.t.
The solvent was evaporated and the residue was subjected to flash
chromatography (hexane/EtOAc, 2:1) on silica gel to provide the
iron complex 10 as light yellow crystals, yield: 930 mg (97%), mp:
91-92 °C.
[(1-4-h)-5-(4-Amino-7-methylbenzo[b]furan-5-yl)cyclohexa-
1,3-diene]tricarbonyliron (9)
A solution of the aminobenzofuran 3 (112 mg, 0.761 mmol) and tri-
carbonyl(h5-cyclohexadienylium)iron
tetrafluoroborate
(116 mg, 0.379 mmol) in degassed MeCN (2 mL) was stirred for 3.5
(2)
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SPECIAL TOPIC
Transition Metal Complexes in Organic Synthesis, Part 63
2135
UV (MeOH): l = 205, 296 nm.
Acknowledgement
IR (drift): n = 3451, 3370, 2983, 2940, 2889, 2042, 1967, 1949,
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We are grateful to the
BASF AG, Ludwigshafen, for a supply of pentacarbonyliron.
1920, 1626, 1511, 1058, 618 cm-1.
1H NMR (400 MHz, CDCl3): d = 1.24 (t, 6H, J = 7.1 Hz), 1.57 (br
d, 1H, J = 15.1 Hz), 2.11 (s, 3H), 2.33 (ddd, 1H, J = 15.1, 11.1, 3.9
Hz), 3.12 (m, 1H), 3.17 (m, 1H), 3.31 (dt, 1H, J = 11.1, 3.5 Hz),
3.47 (br s, 2H), 3.63 (dq, 2H, J = 9.2, 7.1 Hz), 3.76 (dq, 2H, J = 9.2,
7.1 Hz), 3.90 (d, 2H, J = 5.2 Hz), 4.80 (t, 1H, J = 5.2 Hz), 5.49 (m,
2H), 6.11 (s, 1H), 6.81 (s, 1H).
13C NMR and DEPT (100 MHz, CDCl3): d = 15.38 (2 CH3), 15.56
(CH3), 31.35 (CH2), 38.33 (CH), 60.29 (CH), 62.77 (2 CH2), 65.34
(CH), 68.99 (CH2), 84.94 (CH), 85.66 (CH), 100.20 (CH), 100.77
(CH), 116.92 (C), 122.47 (C), 129.00 (CH), 142.16 (C), 155.62 (C),
212.07 (3 CO).
MS (90 °C): m/z (%) = 457 (M+, 20), 429 (1), 412 (5), 401 (14), 373
(100), 371 (12), 317 (18), 315 (17), 301 (21), 299 (16), 257 (22),
255 (32), 253 (20), 223 (21), 103 (31).
HRMS: m/z calcd for C22H27FeNO6 (M+): 457.1188. Found:
457.1179.
References
(1) Part 62: Knölker, H.-J.; Cämmerer, S. Tetrahedron Lett. 2000,
41, 5035.
(2) Chakraborty, D. P. In Prog. Chem. Org. Nat. Prod., Vol. 34;
Herz, W., Grisebach, H., Kirby, G. W., Eds.; Springer: Wien,
1977; p 299.
(3) Bhattacharyya, P.; Chakraborty, D. P. In Prog. Chem. Org.
Nat. Prod., Vol. 52; Herz, W., Grisebach, H., Kirby, G. W.,
Eds.; Springer: Wien, 1987; p 159.
(4) Chakraborty, D. P.; Roy, S. In Prog. Chem. Org. Nat. Prod.,
Vol. 57; Herz, W., Grisebach, H., Kirby, G. W., Tamm, C.,
Eds.; Springer: Wien, 1991; p 71.
(5) Chakraborty, D. P. In The Alkaloids, Vol. 44; Cordell, G. A.,
Ed.; Academic Press: New York, 1993; p 257.
(6) Pindur, U. Heterocycles 1988, 27, 1253.
Pindur, U. Chimia 1990, 44, 406.
Anal. calcd for C22H27FeNO6: C, 57.78; H, 5.95; N, 3.06. Found: C,
57.89; H, 5.94; N, 3.16.
Pindur, U.; Rogge, M. Chimia 1992, 46, 441.
Pindur, U. In Advances in Nitrogen Heterocycles; Moody, C.
J., Ed.; JAI Press: Greenwich (CT), 1995; p 121.
(7) Bergman, J.; Pelcman, B. Pure Appl. Chem. 1990, 62, 1967.
(8) Moody, C. J. Synlett 1994, 681.
2-(2,2-Diethoxyethoxy)-3-methylcarbazole (11)
Iodine (2.60 g, 10.2 mmol) was added to a solution of the iron com-
plex 10 (1.34 g, 2.93 mmol) in pyridine (35 mL) at 90 °C. After stir-
ring for 6 h at 90 °C in the air, the dark brown solution was cooled
to r.t. A solution of sodium thiosulfate (13 g) and citric acid (7 g) in
H2O (60 mL) was added and the mixture was extracted with Et2O
(2 x 80 mL). The combined organic layers were washed with H2O
(4 x 80 mL) and dried (Na2SO4). After removal of the solvent, the
residue was purified by flash chromatography (hexane/EtOAc, 2:1)
on silica gel to afford the carbazole 11 as colorless crystals, yield:
364 mg (40%), mp: 110-111 °C (hexane).
(9) Kawasaki, T.; Sakamoto, M. J. Indian Chem. Soc. 1994, 71,
443.
Hibino, S.; Sugino, E. In Advances in Nitrogen Heterocycles;
Moody, C. J., Ed.; JAI Press: Greenwich (CT), 1995; p 205.
(10) Knölker, H.-J. In 40 Jahre Fonds der Chemischen Industrie
1950-1990; Verband der Chemischen Industrie, Ed.;
Frankfurt, 1990; p 219.
Knölker, H.-J. In Organic Synthesis via Organometallics;
Dötz, K. H., Hoffmann, R. W., Eds.; Vieweg: Braunschweig,
1991; p 119.
UV (MeOH): l = 211, 229 (sh), 235, 250 (sh), 256, 301, 331 nm.
IR (drift): n = 3402, 2976, 2930, 1633, 1610, 1473, 1458, 1348,
1306, 1231, 1185, 1142, 1072, 751, 724 cm-1.
Knölker, H.-J. Synlett 1992, 371.
Knölker, H.-J. In Advances in Nitrogen Heterocycles; Moody,
C. J., Ed.; JAI Press: Greenwich (CT), 1995; p 173.
Knölker, H.-J. In Transition Metals for Organic Synthesis,
Vol. 1; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
1998; p 534.
1H NMR (500 MHz, CDCl3): d = 1.27 (t, 6H, J = 7.2 Hz), 2.37 (s,
3H), 3.69 (dq, 2H, J = 9.7, 7.2 Hz), 3.81 (dq, 2H, J = 9.7, 7.2 Hz),
4.06 (d, 2H, J = 5.6 Hz), 4.91 (t, 1H, J = 5.6 Hz), 6.76 (s, 1H), 7.17
(m, 1H), 7.31 (m, 2H), 7.77 (s, 1H), 7.87 (br s, 1H), 7.93 (d, 1H,
J = 8.2 Hz).
13C NMR and DEPT (125 MHz, CDCl3): d = 15.44 (2 CH3), 16.74
(CH3), 63.03 (2 CH2), 69.37 (CH2), 93.69 (CH), 101.00 (CH),
110.36 (CH), 116.60 (C), 119.31 (CH), 119.37 (CH), 119.49 (C),
121.57 (CH), 123.46 (C), 124.26 (CH), 139.09 (C), 139.43 (C),
156.33 (C).
Knölker, H.-J. Chem. Soc. Rev. 1999, 28, 151.
(11) Fore more recent applications, see: Knölker, H.-J.; Baum, E.;
Hopfmann, T. Tetrahedron 1999, 55, 10391.
Knölker, H.-J.; Fröhner, W. Tetrahedron Lett. 1999, 40, 6915.
Knölker, H.-J.; Baum, E.; Reddy, K. R. Tetrahedron Lett.
2000, 41, 1171.
MS (95 °C): m/z (%) = 313 (M+, 93), 268 (8), 197 (38), 196 (41),
180 (15), 168 (13), 167 (22), 103 (100), 75 (37), 47 (24).
Knölker, H.-J.; Baum, E.; Reddy, K. R. Chirality 2000, 12,
526.
(12) Ito, C.; Furukawa, H. Chem. Pharm. Bull. 1990, 38, 1548.
(13) For a preliminary communication, see: Knölker, H.-J.;
Fröhner, W. Tetrahedron Lett. 1996, 37, 9183.
(14) Beccalli, E. M.; Clerici, F.; Marchesini, A. Tetrahedron 1998,
54, 11675.
HRMS: m/z calcd for C19H23NO3 (M+): 313.1678. Found: 313.1662.
Anal. calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C,
72.61; H, 7.36; N, 4.59.
(15) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S.
Chem. Pharm. Bull. 1998, 46, 1948.
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Organometallics 1998, 17, 3916.
Knölker, H.-J. Chem. Rev. 2000, 100, 2941.
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3787.
Furostifoline (4-Methyl-10H-furo[3,2-a]carbazole) (1)
A mixture of the carbazole 11 (32 mg, 0.102 mmol) and a catalytic
amount of amberlyst 15 in chlorobenzene (1 mL) was stirred at
120 °C for 7 h. The solvent was evaporated and the residue was sub-
jected to flash chromatography (hexane/EtOAc, 2:1) on silica gel to
provide furostifoline 1 as colorless crystals, yield: 15 mg (66%).
Spectral data, see above.
Synthesis 2000, No. 14, 2131–2136 ISSN 0039-7881 © Thieme Stuttgart · New York

2136
H.-J. Knölker, W. Fröhner
SPECIAL TOPIC
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1992, 125, 2783.
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Synthesis 2000, No. 14, 2131–2136 ISSN 0039-7881 © Thieme Stuttgart · New York