Transition metals in organic synthesis, part 104. Iron-mediated total synthesis of furoclausine-A

Article abstract of DOI:10.3987/COM-12-S(N)24

Using iron-mediated coupling reactions a convergent seven-step synthesis of the furo[3,2-a]carbazole alkaloid furoclausine-A is achieved.

Full text of DOI:10.3987/COM-12-S(N)24

HETEROCYCLES, Vol. 86, No. 1, 2012
357
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 357 - 370. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 31st May, 2012, Accepted, 13th July, 2012, Published online, 2nd August, 2012
DOI: 10.3987/COM-12-S(N)24
TRANSITION METALS IN ORGANIC SYNTHESIS, PART 104.1
IRON-MEDIATED TOTAL SYNTHESIS OF FUROCLAUSINE-A
Micha P. Krahl, Arndt W. Schmidt, and Hans-Joachim Knölker*
Department Chemie, Technische Universität Dresden, Bergstraße 66, 01069
Dresden, Germany; e-mail: hans-joachim.knoelker@tu-dresden.de
Abstract – Using iron-mediated coupling reactions a convergent seven-step
synthesis of the furo[3,2-a]carbazole alkaloid furoclausine-A is achieved.
INTRODUCTION
Over the past decades, many biologically active carbazole alkaloids with various structures have been
isolated from different natural sources and a range of methodologies for their synthesis has been
developed.2 Most of the carbazole alkaloids have been isolated from the taxonomically related higher
plants of the genera Murraya, Glycosmis and Clausena of the family Rutaceae. Furocarbazoles represent
a relatively young class of carbazole alkaloids.3 Till now, only four members of this class of carbazole
alkaloids have been isolated from natural sources. In 1990, Furukawa et al. isolated the first furocarbazole
alkaloids, furostifoline (1) and the isomeric eustifoline-D (2), from the acetone extract of the root bark of
Murraya euchrestifolia Hayata collected in December in the central and southern parts of Taiwan (Figure
1).4 Furoclausine-A (3) and furoclausine-B (4) were isolated by Wu and co-workers in 1997 from the
acetone extract of the root bark of Clausena excavata Burm. f., a shrub growing mainly in southern and
south eastern Asia.5 In Taiwan, this shrub is known by the name “Sun Soak Tree”. The roots and the root
bark of this tree are used in Chinese folk medicine for the treatment of several diseases such as cold and
malaria.
Me
O
Me
CHO
O
CHO
O
HO
HO
O
N
H
N
H
N
H
N
H
OH
furostifoline (1)
eustifoline-D (2)
furoclausine-A (3)
furoclausine-B (4)
Figure 1. Naturally occurring furocarbazole alkaloids.
Dedicated with respect to Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 1, 2012
Furostifoline (1), furoclausine-A (3) and furoclausine-B (4) feature a furo[3,2-a]carbazole skeleton,
whereas eustifoline-D (2) has a furo[2,3-c]carbazole skeleton. It is believed that the central intermediate
for the biosynthesis of carbazole alkaloids in higher plants is 3-methylcarbazole (5), which derives from
anthranilic acid and prenyl pyrophosphate.2a,2f Diverse oxidation and oxygenation steps as well as other
functionalisations like prenylation, geranylation and cyclisation reactions lead to the broad structural
variety of the known carbazole alkaloids. Furoclausine-A (3) is proposed to be formed via the naturally
occurring carbazole alkaloids clausine O (6), 7-hydroxyheptaphylline (7) and furoclausine-B (4), which
were all isolated from the same natural source: Clausena excavata (Scheme 1).5,6
O
Me
H
OH
oxidation of 3-Me
oxygenation
prenylation
HO
N
N
H
H
3-methylcarbazole (5)
6
clausine O ( )
O
O
H
H
epoxidation
HO
OH
HO
OH
a
N
H
N
H
O
b
7
8
7-hydroxyheptaphylline ( )
H2O
a
b
O
H
O
H
O
H
HO
HO
O
HO
OH
O
N
H
N
H
N
H
OH
OH
OH
OH
4
furoclausine-B ( )
9
10
)
clausine T ( )
clausine U (
O
H
oxidation
HO
O
O
–
N
H
furoclausine-A (3)
Scheme 1. Proposed biosynthesis of furoclausine-A (3)

HETEROCYCLES, Vol. 86, No. 1, 2012
359
Oxygenation of 3-methylcarbazole (5) at C-2 and C-7 and oxidation of the methyl group at C-3 leads to
clausine O (6). Prenylation at C-1 of clausine O (6) affords 7-hydroxyheptaphylline (7). Epoxidation of
the prenyl side chain followed by intramolecular attack of the C-2 hydroxy group at the secondary carbon
atom of the epoxide (path a) would provide furoclausine-B (4). Oxidation of the dihydrofuran ring with
concomitant extrusion of acetone would lead to furoclausine-A (3).7 Clausine T (9) and clausine U (10),
which were also isolated from Clausena excavata,5,6c probably derive from the same epoxide intermediate
8. Nucleophilic attack of the C-2 hydroxy group at the tertiary carbon atom of the epoxide (path b) would
afford clausine T (9), while epoxide opening by attack of water would generate clausine U (10).
Many coumarins and carbazoles isolated from plants of the Rutaceae family show antiplatelet,
antiplasmodial, antimicrobial, antitumour and anti-HIV activities.2 Recently, we described the anti-TB
activity of several carbazole derivatives.8 Because of their unprecedented furan framework and the
pharmacological potential, furocarbazoles have attracted a lot of interest from synthetic chemists over the
last 15 years. Therefore, several strategies for the synthesis of the furocarbazole framework have been
developed.3 Prior to the total synthesis of naturally occurring furocarbazole alkaloids, synthetic
furocarbazoles were prepared using the Fischer indole synthesis, nitrene insertions, benzotriazole-based
approaches and photocyclisation reactions.9
After the first total synthesis of furostifoline (1) reported by us in 1996,10a several alternative routes have
been published.10 Using an approach which is analogous to our improved route to furostifoline (1),10b we
have achieved the first total synthesis of furoclausine-A (3).11 Herein, we describe full experimental
details of our approach.
RESULTS AND DISCUSSION
+
–
CHO
O
(OC)3Fe
BF4
Me
O
+
HO
OEt
OEt
N
MeO
H2N
H
furoclausine-A (3)
11
12
Scheme 2. Retrosynthetic analysis of furoclausine-A (3)
The retrosynthetic analysis of furoclausine-A (3) leads to the iron complex salt 11 and the arylamine 12 as
precursors for an iron-mediated synthesis of this alkaloid (Scheme 2).

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HETEROCYCLES, Vol. 86, No. 1, 2012
OMe
OMe
MeO
a
b
(OC)3Fe
+
Fe(CO5) +
(OC)3Fe
Ar
N
Ph
14
13
15a
15b
(Ar = 4-MeOC6H4)
OMe
OMe
OMe
O
c
(OC)3Fe
+ (OC)3Fe
(OC)3Fe
+ (OC)3Fe
–
–
–
BF4
BF4
BF4
11
16
11
17
Scheme 3. Synthesis of the iron complex salt 11. Reagents and conditions: (a) 1.8 equiv. 13, 0.14 equiv.
4-methoxy-N-(3-phenylallylidene)aniline (14), dioxane, reflux, 5 d, 78% (15a/15b, 1:1); (b) 1.3 equiv.
–
Ph3C+BF4 , CH2Cl2, rt, 90 min, 100% (11 and 16); (c) H2O, reflux, 2 h, 82% (11: 37%, 17: 45%).
The iron complex salt 11 was prepared via an azadiene-catalysed complexation of 1-methoxycyclohexa-
1,4-diene (13) with pentacarbonyliron (Scheme 3).12 Heating of 1-methoxycyclohexadiene (13) (technical
grade) and pentacarbonyliron in the presence of catalytic amounts of the 1-azabuta-1,3-diene 14 afforded
on a multigram scale a 1:1 mixture of the iron complexes 15a and 15b in 78% yield. Hydride abstraction
with triphenylcarbenium tetrafluoroborate and subsequent hydrolytic separation of the iron complex salts
11 and 16 provided the desired iron complex salt 11.13
Me
Me
OEt
OEt
Me
OEt
OEt
OH
O
O
a
b
NO2
NO2
NH2
18
19
12
Scheme 4. Synthesis of the arylamine 12. Reagents and conditions: (a) 1.1 equiv. 2-bromo-1,1-diethoxy-
ethane, 1.2 equiv. K2CO3, DMF, reflux, 3.5 h, 81%; (b) cat. 10% Pd/C, H2, MeOH, rt, 17.5 h, 99%.
The arylamine 12 was already used as building block in our iron-mediated synthesis of furostifoline (1)
and was prepared as described previously (Scheme 4).10b Bromoacetaldehyde diethyl acetal is a
well-established C2-building block for the synthesis of benzofurans.14 Treatment of the commercially
available nitrophenol 18 with 2-bromo-1,1-diethoxyethane in the presence of potassium carbonate in
N,N-dimethylformamide at reflux provided the nitrobenzene 19 in 81% yield. Subsequent hydrogenation

HETEROCYCLES, Vol. 86, No. 1, 2012
361
of the nitrobenzene 19 using palladium on activated carbon as catalyst at room temperature afforded the
arylamine 12 almost quantitatively. Following this route, the arylamine 12 is accessible on a multigram
scale.
OMe
Me
OEt
OEt
Me
O
(OC)3Fe
MeO
+
a
b
(OC)3Fe
O
OEt
OEt
+
–
BF4
H2N
NH2
11
12
20
Me
Me
Me
c
d
O
MeO
MeO
HO
O
O
N
H
N
H
N
H
EtO
OEt
21
22
23
e
CHO
O
CHO
O
f
MeO
HO
N
H
N
H
24
furoclausine-A (3)
Scheme 5. Synthesis of furoclausine-A (3). Reagents and conditions: (a) 2.0 equiv. 12, MeCN, rt, 23 h,
87%; (b) 3.2 equiv. I2, pyridine, air, 90 °C, 6 h, 71%; (c) amberlyst 15, PhCl, 120 °C, 20 h, 81%; (d) 2.0
equiv. BBr3, CH2Cl2, –78 °C to rt, 6 h, 37%; (e) 2.3 equiv. DDQ, MeOH–H2O (4:1), rt, 55 min, 42%; (f)
2.2 equiv. BBr3, CH2Cl2, –78 °C to –20 °C, 3.5 d, 41%.
Electrophilic substitution of the arylamine 12 by reaction with the iron complex salt 11 in acetonitrile at
room temperature led to the iron complex 20 in 87% yield. Treatment of complex 20 with an excess of
iodine in pyridine at 90 °C under air induced the oxidative cyclisation with concomitant aromatisation to
afford the carbazole 21 in 71% yield. The oxidative cyclisation of an analogous iron complex lacking the
methoxy group at the cyclohexadiene fragment has already been described in our improved total synthesis
of furostifoline (1).10b In the present case, the yields are much better (71% versus 40%) which is ascribed
to the more electron-rich iron–diene fragment of complex 20.15 The oxidative cyclisation of complex 20
using ferrocenium hexafluorophosphate failed and led exclusively to decomposition of starting material.

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HETEROCYCLES, Vol. 86, No. 1, 2012
Annulation of the furan ring was achieved by heating of compound 21 in chlorobenzene at 120 °C in the
presence of catalytic amounts of amberlyst 15 to afford 7-methoxyfurostifoline (22) in 81% yield. The
completion of the synthesis of furoclausine-A (3) required two final steps: Cleavage of the methyl ether
and oxidation of the methyl group to a formyl group. Cleavage of the methyl ether of
7-methoxyfurostifoline (22) using boron tribromide in dichloromethane afforded the hydroxycarbazole 23
in 37% yield. However, all attempts to oxidise the methyl group using either selenium(IV) oxide,
2-iodoxybenzoic acid (IBX), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or manganese(IV) oxide
failed and resulted exclusively in decomposition of the starting material. Presumably, the electron-rich
8-hydroxyfuro[3,2-a]carbazole framework is incompatible with oxidising agents and decomposition via
quinone imine methide intermediates is faster than the desired benzylic oxidation. Therefore, we tried to
conduct the two final steps in reverse order. First, the methyl group at C-4 was oxidised to a formyl group
using DDQ in a mixture of methanol and water (4:1) to afford O-methylfuroclausine-A (24) in moderate
yield. Subsequent cleavage of the methyl ether with boron tribromide under carefully controlled reaction
conditions provided furoclausine-A (3) in seven steps and 7% overall yield based on the nitrophenol 18.
1
13
The spectroscopic data of our synthetic furoclausine-A (3) (UV, IR, H NMR, C NMR and MS) are in
good agreement with those reported by Wu et al. for the natural product.5 However, we obtained
furoclausine-A (3) as light yellow crystals (decomposition at 110 °C), whereas the natural product was
described as yellow oil.
MeO
Me
CHO
O
OMe
a
b
MeO
MeO
MeO
O
O
N
H
N
H
N
H
24
22
25
Scheme 6. Alternative route to furoclausine-A (3). Reagents and conditions: (a) 2.25 equiv. DDQ, dry
MeOH, –5 °C, 60 min, 39%; (b) 3.2 equiv. BBr3, CH2Cl2, –78 °C to 0 °C, 3 h, 98%.
Alternatively, the methyl group of 22 was oxidised with DDQ at –5 °C using water-free, degassed
methanol as solvent (Scheme 6). These reaction conditions afforded the dimethyl acetal 25 in 39% yield.
Subsequent selective cleavage of the acetal using boron tribromide in dichloromethane at 0 °C afforded
O-methylfuroclausine-A (24) in 98% yield. However, this approach is not superior compared to the direct
route described above (cf. Scheme 5).

HETEROCYCLES, Vol. 86, No. 1, 2012
363
CONCLUSION
We have achieved the total synthesis of the furo[3,2-a]carbazole alkaloid furoclausine-A (3) in seven
steps and 7% overall yield based on the commercially available nitrophenol 18. The natural product has
been obtained as light yellow crystals and full spectroscopic characterisation has confirmed the structural
assignment. The iron-mediated route to the synthetically challenging oxygen-substituted
furo[3,2-a]carbazole framework emphasises the utility of this method.
EXPERIMENTAL
General: All reactions were carried out in dry solvents under an inert gas atmosphere (argon), unless
stated otherwise. All solvents were dried and degassed using an MBraun solvent purification system.
Chemicals were used as received from commercial sources. Flash chromatography: Merck silica gel
(0.040–0.063 mm). Melting points: Electrothermal IA9100. UV spectra: Varian CARY 3. IR spectra:
Thermo Nicolet Avatar 360 FT-IR;  in cm–1. NMR spectra: Bruker DRX 500 and AC 300 P;  in ppm, J
in Hz. Mass spectra: Finnigan MAT-95, ionisation potential: 70 eV. Elemental analyses: EuroVector
EuroEA3000.
Tricarbonyl[(1–4-η)-1-methoxycyclohexa-1,3-diene]iron (15a) and tricarbonyl[(1–4-η)-2-methoxy-
cyclohexa-1,3-diene]iron (15b)
A dried two-neck flask with argon inlet and condenser with gas bubbler was charged under argon
atmosphere with 4-methoxy-N-(3-phenylallylidene)aniline (14) (4.66 g, 19.6 mmol) and 1,4-dioxane (200
mL). Pentacarbonyliron (28.3 g, 18.8 mL, 144 mmol) was added and the solution was stirred for 30 min
at room temperature. 1-Methoxycyclohexa-1,4-diene (13) (22.6 g, 205 mmol; technical grade) and
1,4-dioxane (300 mL) were added and the mixture was heated at reflux for 5 days. During the reaction a
light flow of argon was directed through the apparatus. After cooling, the mixture was filtered through
Celite. The Celite was then washed with hexane and the combined filtrates were evaporated to afford the
1
iron complexes 15a and 15b (28.0 g, 78%; ratio 15a:15b = 1:1, assigned by H NMR spectrum); yellow
oil. The mixture of 15a and 15b was used for the next step without further purification. For spectral data,
see ref.12e,13
Tricarbonyl[(1–5-η)-2-methoxycyclohexadienylium]iron tetrafluoroborate (11) and tricarbonyl-
[(1–5-η)-1-methoxycyclohexadienylium]iron tetrafluoroborate (16)
A solution of a 1:1 mixture of the iron complexes 15a and 15b (28.0 g, 112 mmol) in dichloromethane
(140 mL) was added at room temperature to a suspension of triphenylcarbenium tetrafluoroborate (46.9 g,
142 mmol) in dichloromethane (140 mL) and the reaction mixture was stirred at room temperature for 90

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min. The mixture was poured into diethyl ether (1.40 L) and the precipitate was collected. The filtrate was
concentrated and additional precipitate was collected. The combined precipitates were dried in vacuum to
give a mixture of regioisomeric iron complex salts 11 and 16 (37.6 g, 100%; ratio of 11:16 was not
determined); yellow crystals. The mixture of 11 and 16 was used for the next step without further
purification.
Tricarbonyl[(1–5-η)-2-methoxycyclohexadienylium]iron tetrafluoroborate (11) and tricarbonyl-
[(2–5-η)-cyclohexa-2,4-dienone]iron (17)
A mixture of the iron complex salts 11 and 16 (5.00 g, 14.9 mmol) was added to degassed water (100
mL) and the mixture was heated at reflux for 2 h. The aqueous layer was extracted several times with
Et2O until the organic layer remained almost colourless. The organic layer was dried over magnesium
sulfate and the solvent was evaporated to provide the iron complex 17 (1.57 g, 45%); yellow solid. For
spectral data, see ref.13 The aqueous layer was concentrated to dryness and the resulting solid was
dissolved in a mixture of MeCN (50 mL) and water (10 mL). Et2O (700 mL) was added and the
precipitate was collected. The resulting crystals were dried in vacuum to give the iron complex salt 11
(1.84 g, 37%); yellow solid. For spectral data, see ref.13
Tricarbonyl[(1–4-η)-5-(2-amino-4-(2,2-diethoxyethoxy)-5-methylphenyl)-2-methoxycyclohexa-1,3-
diene]iron (20)
A solution of the arylamine 12 (287 mg, 1.20 mmol) and the iron complex salt 11 (200 mg, 0.596 mmol)
in MeCN (20 mL) was stirred at room temperature for 23 h. The solvent was removed and the residue
was purified by flash chromatography (hexane–EtOAc, 2:1) on silica gel to afford the iron complex 20
(254 mg, 87%); light yellow crystals; mp 73–74 °C; UV (MeOH): λ = 205, 298 nm. IR (ATR): υ = 3364,
2976, 2932, 2038, 1953, 1622, 1510, 1484, 1458, 1423, 1375, 1309, 1226, 1113, 1065, 1020, 885, 825,
1
754, 680, 620, 608, 572 cm–1. H NMR (500 MHz, CDCl3): δ = 1.229 (t, J = 7.1 Hz, 3 H), 1.232 (t, J =
7.0 Hz, 3 H), 1.67 (ddd, J = 14.7, 3.4, 2.3 Hz, 1 H), 2.11 (s, 3 H), 2.36 (ddd, J = 14.7, 11.1, 3.7 Hz, 1 H),
2.73 (dd, J = 6.5, 3.4 Hz, 1 H), 3.12 (dt, J = 11.1, 3.4 Hz, 1 H), 3.42 (m, 3 H), 3.59–3.66 (m, 2 H), 3.68 (s,
3 H), 3.72–3.78 (m, 2 H), 3.90 (d, J = 5.2 Hz, 2 H), 4.80 (t, J = 5.2 Hz, 1 H), 5.24 (dd, J = 6.5, 2.2 Hz, 1
H), 6.12 (s, 1 H), 6.78 (s, 1 H). 13C NMR and DEPT (125 MHz, CDCl3): δ = 15.34 (2 CH3), 15.57 (CH3),
32.62 (CH2), 37.58 (CH), 53.10 (CH), 54.01 (CH), 54.39 (CH3), 62.70 (CH2), 62.73 (CH2), 66.98 (CH),
68.99 (CH2), 100.14 (CH), 100.73 (CH), 116.93 (C), 122.74 (C), 128.50 (CH), 139.93 (C), 142.10 (C),
155.53 (C), 211.25 (3 CO). MS (EI): m/z (%) = 487 (5) [M+], 431 (62), 403 (100), 347 (36), 345 (26), 329
(58), 315 (35), 299 (16), 287 (88), 285 (74), 223 (70), 179 (70), 103 (70). HRMS: m/z calcd for

HETEROCYCLES, Vol. 86, No. 1, 2012
365
C23H29FeNO7 [M+]: 487.1293; found: 487.1258. Anal. Calcd for C23H29FeNO7: C, 56.69; H, 6.00; N, 2.87.
Found: C, 56.77; H, 6.12; N, 2.91.
2-(2,2-Diethoxyethoxy)-7-methoxy-3-methyl-9H-carbazole (21)
Iodine (1.18 g, 4.65 mmol) was added to a solution of the iron complex 20 (713 mg, 1.46 mmol) in
anhydrous pyridine (20 mL) at 90 °C and the mixture was stirred at the same temperature for 6 h under air.
The reaction mixture was cooled to room temperature, a solution of sodium thiosulfate (2.37 g) and citric
acid (1.25 g) in water (24 mL) was added, and the resulting mixture was extracted with Et2O several
times until the organic layer remained almost colourless. The combined organic layers were washed with
water three times and dried over magnesium sulfate. The solvent was evaporated and the residue was
purified by flash chromatography (hexane–EtOAc, 1:1) on silica gel to provide the carbazole 21 (356 mg,
71%); colourless crystals; mp 195–196 °C; UV (MeOH): λ = 210, 236, 262, 310, 318 nm. IR (ATR): υ =
3385, 2974, 2930, 2872, 1618, 1578, 1459, 1371, 1346, 1308, 1270, 1233, 1189, 1133, 1069, 1025, 942,
886, 857, 822, 807, 745, 726, 672, 632 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 6 H),
2.36 (s, 3 H), 3.66–3.72 (m, 2 H), 3.78–3.84 (m, 2 H), 3.87 (s, 3 H), 4.06 (d, J = 5.2 Hz, 2 H), 4.91 (t, J =
5.2 Hz, 1 H), 6.80 (dd, J = 8.4, 2.2 Hz, 1 H), 6.81 (s, 1 H), 6.85 (d, J = 2.2 Hz, 1 H), 7.68 (s, 1 H), 7.79 (d,
13
J = 8.4 Hz, 1 H), 7.80 (br s, 1 H). C NMR and DEPT (125 MHz, CDCl3): δ = 15.39 (2 CH3), 16.68
(CH3), 55.62 (CH3), 62.92 (2 CH2), 69.34 (CH2), 93.80 (CH), 94.88 (CH), 100.90 (CH), 107.67 (CH),
116.73 (C), 117.38 (C), 119.34 (C), 119.97 (CH), 120.81 (CH), 138.88 (C), 140.55 (C), 155.32 (C),
157.93 (C). MS (EI): m/z (%) = 343 (100) [M+], 297 (30), 251 (15), 227 (60), 178 (69), 161 (34). HRMS:
m/z calcd for C20H25NO4 [M+]: 343.1784; found: 343.1780. Anal. Calcd for C20H25NO4: C, 69.95; H,
7.34; N, 4.08. Found: C, 70.03; H, 7.48; N, 4.15.
8-Methoxy-4-methyl-10H-furo[3,2-a]carbazole (7-methoxyfurostifoline) (22)
A mixture of carbazole 21 (1.00 g, 2.92 mmol) and amberlyst 15 (411 mg, 41 wt%) in chlorobenzene (90
mL) was stirred at 120 °C for 20 h. After cooling to room temperature the solvent was evaporated and the
residue was purified by flash chromatography (hexane–EtOAc, 3:1) on silica gel to provide
8-methoxy-4-methyl-10H-furo[3,2-a]carbazole (22) (592 mg, 81%); colourless crystals; mp 200–201 °C;
UV (MeOH): λ = 214 (sh), 229 (sh), 239, 244, 271, 277 (sh), 306, 329 nm. IR (ATR): υ = 3429, 3151,
3122, 2967, 2928, 2828, 1721, 1619, 1579, 1486, 1446, 1354, 1316, 1272, 1252, 1192, 1153, 1042, 1017,
989, 946, 878, 824, 805, 771, 749, 734, 676 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.65 (s, 3 H), 3.90 (s,
3 H), 6.87 (dd, J = 8.5, 2.2 Hz, 1 H), 6.94 (d, J = 2.2 Hz, 1 H), 6.96 (d, J = 2.2 Hz, 1 H), 7.68 (s, 1 H),
13
7.70 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1 H), 8.13 (br s, 1 H). C NMR and DEPT (125 MHz,
CDCl3): δ = 15.42 (CH3), 55.67 (CH3), 95.18 (CH), 103.54 (CH), 108.12 (CH), 111.37 (C), 114.11 (C),

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116.06 (CH), 117.94 (C), 118.00 (C), 120.16 (CH), 130.69 (C), 140.01 (C), 143.72 (CH), 153.35 (C),
157.96 (C). MS (EI): m/z (%) = 251 (100) [M+], 236 (63), 208 (22), 178 (38), 161 (15). HRMS: m/z calcd
for C16H13NO2 [M+]: 251.0946; found: 251.0962. Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57.
Found: C, 76.27; H, 5.31; N, 5.74.
4-Methyl-10H-furo[3,2-a]carbazol-8-ol (23)
A 1 M solution of boron tribromide in CH2Cl2 (400 µL, 0.400 mmol) was added at –78 °C to a solution of
the carbazole 22 (51.0 mg, 0.203 mmol) in CH2Cl2 (10 mL). The solution was stirred for 2 h at –78 °C,
for 1 h at –10 °C and for 3 h at room temperature. Methanol (4 mL) was added and the mixture was
washed with brine. The aqueous layer was extracted with CH2Cl2 three times and the combined organic
layers were dried over magnesium sulfate. The solvent was removed in vacuum and the residue was
purified by flash chromatography (hexane–EtOAc, 1:1) on silica gel to afford the furo[3,2-a]carbazole 23
(17.9 mg, 37%); light yellow crystals; mp 210 °C (decomp.); UV (MeOH): λ = 212 (sh), 228 (sh), 238,
242 (sh), 271, 287 (sh), 308, 316 (sh), 333 nm. IR (ATR): υ = 3408, 2920, 1621, 1487, 1441, 1353, 1318,
1282, 1208, 1154, 1043, 955, 730 cm–1. 1H NMR (300 MHz, acetone-d6): δ = 2.63 (s, 3 H), 6.79 (dd, J =
8.4, 2.1 Hz, 1 H), 7.00 (d, J = 2.1 Hz, 1 H), 7.18 (d, J = 2.1 Hz, 1 H), 7.74 (s, 1 H), 7.89 (m, 2 H), 8.21 (s,
1 H), 10.45 (br s, 1 H). 13C NMR and DEPT (75 MHz, acetone-d6): δ = 15.46 (CH3), 97.82 (CH), 105.05
(CH), 109.50 (CH), 112.64 (C), 113.61 (C), 116.69 (CH), 118.04 (C), 119.02 (C), 120.76 (CH), 132.22
(C), 141.94 (C), 144.67 (CH), 154.02 (C), 156.45 (C). MS (EI): m/z (%) = 237 (100) [M+], 208 (7), 178
(4), 152 (4), 118 (6).
8-Methoxy-10H-furo[3,2-a]carbazole-4-carbaldehyde (24)
Method A: DDQ (211 mg, 0.929 mmol) was added at room temperature to a solution of the carbazole 22
(101 mg, 0.402 mmol) in a mixture of MeOH (40 mL) and water (10 mL) and the solution was stirred for
55 min. Et2O was added and the organic layer was washed with 2 N aqueous sodium hydroxide and brine.
Then, most of the solvent was evaporated (not to dryness). Purification of the residue by flash
chromatography (hexane–EtOAc, 3:4; 1% triethylamine) on silica gel afforded the aldehyde 24 (45.0 mg,
42%); light yellow crystals; mp 204–205 °C; UV (MeOH): λ = 221, 236, 284 (sh), 299, 342 nm. IR
(ATR): υ = 3298, 3121, 2926, 2833, 2728, 2458, 1669, 1627, 1581, 1532, 1468, 1398, 1347, 1272, 1228,
1205, 1178, 1156, 1092, 1033, 995, 848, 774, 708, 689 cm–1. 1H NMR (500 MHz, acetone-d6): δ = 3.93 (s,
3 H), 6.98 (dd, J = 8.6, 2.2 Hz, 1 H), 7.18 (d, J = 2.2 Hz, 1 H), 7.33 (d, J = 2.2 Hz, 1 H), 8.05 (d, J = 2.2
Hz, 1 H), 8.16 (d, J = 8.6 Hz, 1 H), 8.53 (s, 1 H), 10.47 (s, 1 H), 11.28 (br s, 1 H). 13C NMR and DEPT
(125 MHz, acetone-d6): δ = 55.82 (CH3), 96.40 (CH), 104.73 (CH), 110.14 (CH), 113.56 (C), 116.30 (C),
118.31 (C), 119.11 (C), 120.11 (CH), 121.58 (CH), 137.80 (C), 142.31 (C), 146.06 (CH), 154.11 (C),

HETEROCYCLES, Vol. 86, No. 1, 2012
367
159.99 (C), 187.79 (CHO). MS (EI): m/z (%) = 265 (100) [M+], 251 (38), 250 (72), 222 (42), 193 (10).
HRMS: m/z calcd for C16H11NO3 [M+]: 265.0739; found: 265.0706. Anal. Calcd for C16H11NO3: C, 72.45;
H, 4.18; N, 5.28. Found: C, 72.31; H, 4.20; N, 5.49.
8-Hydroxy-10H-furo[3,2-a]carbazole-4-carbaldehyde (furoclausine-A) (3)
A 1 M solution of boron tribromide in CH2Cl2 (0.75 mL, 0.75 mmol) was added dropwise to a stirred
solution of the aldehyde 24 (90 mg, 0.34 mmol) in CH2Cl2 (25 mL) at –78 °C and the mixture was stirred
for 3.5 d at –20 °C. MeOH (25 mL) and degassed brine were added and the layers were separated. The
aqueous layer was extracted with CH2Cl2, the organic layers were combined and the solvent was
evaporated. Purification of the residue by flash chromatography (hexane–EtOAc, 3:4) on silica gel
provided 8-hydroxy-10H-furo[3,2-a]carbazole-4-carbaldehyde (furoclausine-A) (3) (35 mg, 41%); light
yellow crystals; mp 110 °C (decomp.); UV (MeOH): λ = 220, 235, 287 (sh), 300, 345 nm. IR (ATR): υ =
3302, 1703, 1670, 1619, 1590, 1444, 1350, 1325, 1302, 1276, 1258, 1228, 1165, 1149, 1114, 1070, 1040,
993, 956, 856, 830, 810, 799, 775, 750, 730, 686, 629, 591, 549 cm–1. 1H NMR (500 MHz, acetone-d6): δ
= 6.92 (dd, J = 8.4, 2.1 Hz, 1 H), 7.09 (d, J = 2.1 Hz, 1 H), 7.32 (d, J = 2.2 Hz, 1 H), 8.05 (d, J = 2.2 Hz, 1
H), 8.10 (d, J = 8.4 Hz, 1 H), 8.51 (s, 1 H), 8.54 (s, 1 H), 10.47 (s, 1 H), 11.16 (br s, 1 H). 13C NMR and
DEPT (125 MHz, acetone-d6): δ = 98.22 (CH), 104.67 (CH), 110.73 (CH), 113.43 (C), 116.16 (C),
117.64 (C), 119.36 (C), 119.85 (CH), 121.62 (CH), 137.75 (C), 142.57 (C), 146.02 (CH), 154.09 (C),
157.49 (C), 187.75 (CHO). MS (EI): m/z (%) = 251 (100) [M+], 250 (74), 222 (26), 194 (11), 139 (3).
HRMS: m/z calcd for C15H9NO3 [M+]: 251.0582; found: 251.0568.
4-(Dimethoxymethyl)-8-methoxy-10H-furo[3,2-a]carbazole (25)
DDQ (102 mg, 0.45 mmol) was added portionwise to a solution of carbazole 22 (50.3 mg, 0.200 mmol)
in dry MeOH (25 mL) at –5 °C and the mixture was stirred at the same temperature for 1 h. After
consumption of the starting material, Et2O (25 mL) was added. The solution was washed twice with
aqueous 2 N sodium hydroxide and with brine. The combined organic layers were dried over magnesium
sulfate and the solvent was removed in vacuo. Purification by flash chromatography (hexane–EtOAc, 1:1;
1% triethylamine) on silica gel afforded 4-(dimethoxymethyl)-8-methoxy-10H-furo[3,2-a]carbazole (25)
(24.1 mg, 39%); colourless crystals; mp 124–125 °C; UV (MeOH): λ = 212 (sh), 230 (sh), 238, 243, 264
(sh), 278, 305, 314 (sh), 327 nm. IR (ATR): υ = 3416, 3134, 3112, 2926, 2542, 2216, 2068, 1734, 1617,
1
1530, 1486, 1445, 1342, 1274, 1250, 1203, 1159, 1122, 1031, 808, 751, 732 cm–1. H NMR (500 MHz,
acetone-d6): δ = 3.416 (s, 3 H), 3.418 (s, 3 H), 3.91 (s, 3 H), 6.01 (s, 1 H), 6.90 (dd, J = 8.5, 2.2 Hz, 1 H),
7.13 (d, J = 2.2 Hz, 1 H), 7.23 (d, J = 2.1 Hz, 1 H), 7.92 (d, J = 2.1 Hz, 1 H), 8.06 (d, J = 8.5 Hz, 1 H),
13
8.11 (s, 1 H), 10.79 (br s, 1 H). C NMR and DEPT (125 MHz, acetone-d6): δ = 53.12 (CH3), 55.73 (2

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HETEROCYCLES, Vol. 86, No. 1, 2012
CH3), 95.83 (CH), 100.97 (CH), 104.78 (CH), 109.09 (CH), 112.93 (C), 114.76 (CH), 115.53 (C), 118.00
(C), 118.64 (C), 120.98 (CH), 133.66 (C), 141.73 (C), 144.96 (CH), 152.51 (C), 159.25 (C). MS (EI): m/z
(%) = 311 (51) [M+], 281 (60), 280 (100), 265 (52), 250 (46), 236 (11), 222 (14), 140 (17). HRMS: m/z
calcd for C18H17NO4 [M+]: 311.1158; found: 311.1134. Anal. Calcd for C18H17NO4: C, 69.44; H, 5.50; N,
4.50. Found: C, 69.31; H, 5.52; N, 4.53.
8-Methoxy-10H-furo[3,2-a]carbazole-4-carbaldehyde (24)
Method B: A 1 M solution of boron tribromide in CH2Cl2 (192 μL, 0.192 mmol) was added dropwise to a
solution of carbazole 25 (20.0 mg, 0.064 mmol) in CH2Cl2 (6 mL) at –78 °C. After stirring for 2 h at the
same temperature, the mixture was warmed to 0 °C and stirred for additional 60 min. MeOH (6 mL) and
brine (15 mL) were added and the mixture was extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were dried over magnesium sulfate and the solvent was evaporated. Purification of the
residue by flash chromatography (hexane–EtOAc, 1:1; 1% triethylamine) on silica gel provided
8-methoxy-10H-furo[3,2-a]carbazole-4-carbaldehyde (24) (16.6 mg, 98%). For spectral data, see above.
ACKNOWLEDGEMENTS
We thank the BASF SE, Ludwigshafen, for a gift of pentacarbonyliron.
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