Metathesis reactions for the synthesis of ring-fused carbazoles

Article abstract of DOI:10.1021/jo051826s

The metathesis reaction is used as a key step for the synthesis of the indolo[2,3-α]carbazole core of rebeccamycin 13 and the sulfur analog of furostifoline 21. Using the same methodology for the attempted synthesis of furostifoline, we unexpectedly formed tert-butyl-2a-methyl-1,2,2a,10c- tetrahydro-6H-cyclobuta[c]furo[3,2-α]carbazole-6-carboxylate 26 from the unstable diene, tert-butyl 2-(2-isopropenyl-3-furyl)-3-vinyl-1H-indole-1- carboxylate 25, presumably via a spontaneous π₈ electrocyclization reaction.

Full text of DOI:10.1021/jo051826s

Metathesis Reactions for the Synthesis of Ring-Fused Carbazoles
†
‡
†
Stephen C. Pelly, Christopher J. Parkinson, Willem A. L. van Otterlo, and
Charles B. de Koning*,
†
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, P.O. Wits,
2
050 South Africa, and Biosciences, Council for Scientific and Industrial Research (CSIR),
Modderfontein, South Africa
dekoning@aurum.chem.wits.ac.za
Received August 30, 2005
The metathesis reaction is used as a key step for the synthesis of the indolo[2,3-a]carbazole core of
rebeccamycin 13 and the sulfur analog of furostifoline 21. Using the same methodology for the
attempted synthesis of furostifoline, we unexpectedly formed tert-butyl-2a-methyl-1,2,2a,10c-
tetrahydro-6H-cyclobuta[c]furo[3,2-a]carbazole-6-carboxylate 26 from the unstable diene, tert-butyl
2
-(2-isopropenyl-3-furyl)-3-vinyl-1H-indole-1-carboxylate 25, presumably via a spontaneous π
8
electrocyclization reaction.
Introduction
The development of methods for the synthesis of fused
carbazole nuclei is becoming increasingly important as
a result of the number of natural and nonnatural
carbazoles that display biological activity. For example,
the natural carbazoles, rebeccamycin (1a) and furostifo-
line (1b), are important natural products that fit into this
1
class (Figure 1). Rebeccamycin binds to DNA and has
anti-tumor properties,2 and in fact, a rebeccamycin
analog is presently undergoing clinical trials for the
treatment of patients with advanced liver and/or biliary
cancer and leukemia.7
-6
FIGURE 1. Naturally occurring [a]-fused carbazoles.
-9
Furostifoline, on the other hand, was isolated in 1990
from the root bark of Murraya euchrestifolia Hayata and
is used in Chinese folk medicine. Even though the
natural product is relatively simple, interest in this
product has resulted in at least six syntheses of this
[a]-fused carbazole.10 The synthesis of furostifoline has
been achieved using a variety of ways ranging from an
†
10
University of the Witwatersrand.
‡
CSIR.
(
1) Kn o¨ lker H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303 and
references therein.
(
(
2) Prudhomme, M. Curr. Med. Chem. 2000, 7, 1189.
3) Moreau, P.; Anizon, F.; Sancelme, M.; Prudhomme, M.; Bailly,
C.; Carrasco, C.; Ollier, M.; Sev e` re, D.; Riou, J.-F.; Fabbro, D.; Meyer,
T.; Aubertin, A.-M. J. Med. Chem. 1998, 41, 1631.
(
4) Moreau, P.; Anizon, F.; Sancelme, M.; Prudhomme, M.; Sev e` re,
(7) Long, B. H.; Rose, W. C.; Vyas, D. M.; Matson, J. A.; Forenza, S.
Curr. Med. Chem.: Anti-Cancer Agents 2002, 2, 255.
(8) Long, B. H.; Balasubramanian, B. N. Expert Opin. Ther. Pat.
2000, 10, 635.
(9) See ClinicalTrials.gov Web site. http://www.clinicaltrials.gov/ct/
gui/show/NCT00005997 or http://www.clinicaltrials.gov/ct/gui/show/
NCT00087204, accessed August 2005.
(10) For a review, see: Fr o¨ hner, W.; Krahl, M. P.; Reddy, K. R.;
Kn o¨ lker, H.-J. Heterocycles 2004, 63, 2393.
D.; Riou, J.-F.; Goossens, J.-F.; H e´ nichart, J.-P.; Bailly, C.; Labourier,
E.; Tazzi, J.; Fabbro, D.; Meyer, T.; Aubertin, A. M. J. Med. Chem.
999, 42, 1816.
1
(
5) Bailly, C.; Riou, J.-F.; Colson, P.; Houssier, C.; Rodrigues-Periera,
E.; Prudhomme, M. Biochemistry 1997, 36, 3917.
(6) Rodrigues Pereira, E.; Belin, L.; Sancelme, M.; Prudhomme, M.;
Ollier, M.; Rapp, M.; Sev e` re, D.; Riou, J.-F.; Fabbro, D.; Meyer, T. J.
Med. Chem. 1996, 39, 4471.
10.1021/jo051826s CCC: $30.25 © 2005 American Chemical Society
10474
J. Org. Chem. 2005, 70, 10474-10481
Published on Web 11/08/2005

Reactions for the Synthesis of Ring-Fused Carbazoles
SCHEME 1a
FIGURE 2. Nonnatural [a]-fused carbazoles.
iron-mediated method11 to the use of thermal, reductive,
and photocyclization methodologies.1
2-15
As a result of the interest in these natural products,
the syntheses of many analogs that also have biological
activity have been described. Two unnatural products
that fit into this category are shown in Figure 2. Com-
pound 2a is a known organometallic inhibitor of glycogen
synthase kinase 3,16 while isogranulatimide (2b) is a G2
checkpoint inhibitor.17
Results and Discussion
a
t
Reagents and conditions: (i) ClCOCOCl, 99%; (ii) KOBu , 300
C, 80%; (iii) POCl3, DMF, 0 °C, 83%; (iv) Boc2O, DMAP, 25 °C,
Examination of these four examples shown in Figures
and 2 shows that they are all fused carbazoles contain-
°
1
89%; (v) MePPh2Br, n-BuLi, 0 °C; (vi) 8% Grubbs II, toluene, 25
C, 64% (over two steps).
°
ing at least one additional ring fused to the [a]-face of
the carbazole nucleus. As part of our ongoing program
on the synthesis of carbazoles,18 we wish to report in this
article on the synthesis of the core of rebeccamycin, the
unnatural sulfur analog of furostifoline, and our attempts
at using the same methodology to make the natural
product furostifoline.
article and in contrast to many syntheses, the construc-
tion of the bond between the two indole units at C-2 and
C-2′ of the rebeccamycin nucleus takes place at an early
stage of the synthesis. In addition, one of the key steps
is that an aromatic ring is formed using the metathesis
reaction19 (see, for example, transformation 5 f 6). This
is one of the first examples of the use of metathesis to
form an aromatic ring in one step.20
o-Toluidine (7) was treated as described in the litera-
ture21 with oxalyl chloride to give the diamide 8 in good
yield. Compound 8 was then subjected to potassium tert-
butoxide at 300 °C giving the desired bis-indole 9 in
excellent yield (Scheme 1).21 Normal Vilsmeier-Haack
reaction conditions on 9 provided the required dialdehyde
2
1
1
1
0, which was readily protected as the bis-carbamate
1.
To utilize the metathesis reaction to form the benzene
ring fused to both indole nuclei, the aldehydes first had
(
19) For reviews on metathesis, see: (a) Schmalz, H.-G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1833. (b) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (c) Grubbs, R.; Chang,
S. Tetrahedron 1998, 54, 4413. (d) F u¨ rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012. (e) Jørgensen, M.; Hadwiger, P.; Madsen, R.; St u¨ tz,
A. E.; Wrodnigg, T. M. Curr. Org. Chem. 2000, 4, 565. (f) Hoveyda, A.
H.; Schrock R. R. Chem.-Eur. J. 2001, 7, 945. (g) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18. (h) McReynolds, M. D.; Dougherty,
J. M.; Hanson, P. R. Chem. Rev. 2004, 104, 2239. (i) Deiters, A.; Martin,
S. F. Chem. Rev. 2004, 104, 2199.
In general, the synthesis of rebeccamycin (or analogs)
relies on the construction of the bond between the two
indole units at C-2 and C-2′ (see retrosynthesis) as one
1
of the last steps of the synthesis, viz. 3 f 4. In this
(
11) (a) Kn o¨ lker H.-J.; Fr o¨ hner, W. Tetrahedron Lett. 1996, 37, 9183.
(
b) Kn o¨ lker H.-J.; Fr o¨ hner, W. Synthesis 2000, 2131.
(
12) (a) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino,
(20) (a) For the synthesis of phenanthrenes using ring-closing
metathesis to form an aromatic ring, see: (i) Iuliano, A.; Piccioli, P.;
Fabbri, D. Org. Lett. 2004, 6, 3711 and (ii) Walker, E. R.; Leung, S.
Y.; Barrett, A. G. M. Tetrahedron Lett. 2005, 46, 6537. (b) Phenols,
naphthols, and naphthalenes, respectively, have been made using ring-
closing metathesis: (i) Yoshida, K.; Imamoto, T. J. Am. Chem. Soc.
2005, 127, 10470. (ii) van Otterlo, W. A. L.; Ngidi, E. M.; Coyanis, E.
M.; de Koning, C. B. Tetrahedron Lett. 2003, 44, 311. (iii) Huang, K.-
S.; Wang, E.-C. Tetrahedron Lett. 2001, 42, 6155. (c) For an example
of ring-closing metathesis followed by oxidative aromatization to form
a benzene ring, see: Kotha, S.; Mandal, K. Tetrahedron Lett. 2004,
45, 2585. (d) Some researchers have used the same initial retrosyn-
thetic approach as us by using the Suzuki-Miyaura coupling reaction
at an early stage to make the bis-indole 2 and 2′ linkage. See: Cai, C.;
Snieckus, V. Org. Lett. 2004, 6, 2293.
S. Chem. Pharm. Bull. 1998, 46, 1948. (b) Hagiwara, H.; Choshi, T.;
Nobuhiro, J.; Hibino, S. Chem. Pharm. Bull. 2001, 49, 881.
(
13) So o´ s, T.; Tim a´ ri, G.; Haj o´ s, G. Tetrahedron Lett. 1999, 40, 8607.
14) Beccalli, E.; Clerici, F.; Marchesini, A. Tetrahedron 1998, 54,
(
1
1675.
(
15) Yasuhara, A.; Suzuki, N.; Sakamoto, T. Chem. Pharm. Bull.
2
002, 50, 143.
(16) Bergman, H.; Williams, D. S.; Atilla, G. E.; Carroll P. J.;
Meggers, E. J. Am. Chem. Soc. 2004, 126, 13594.
17) Routier, S.; Peixoto, P.; M e´ rour, J.-Y.; Coudert, G.; Dias, N.;
Bailly, C.; Pierr e´ , A.; L e´ once S.; Caignard, D.-H. J. Med. Chem. 2005,
8, 1401.
(
4
(
18) (a) de Koning, C. B.; Michael, J. P.; Rousseau, A. L. J. Chem.
Soc., Perkin Trans. 1 2000, 1705. (b) de Koning, C. B.; Michael, J. P.;
Nhlapo, J. M.; Pathak, R.; van Otterlo, W. A. L. Synlett 2003, 705.
(21) Bergman, J.; Koch, E.; Pelcman, B. Tetrahedron 1995, 51, 5631.
J. Org. Chem, Vol. 70, No. 25, 2005 10475

Pelly et al.
SCHEME 2a
SCHEME 3a
a
Reagents and conditions: (i) 10% Pd(PPh3)4, DME, aqueous
Na2CO3, 100 °C, 78%; (ii) AlCl3, CH2Cl2, 0 °C, 87% or SiO2,
microwave, 99%; (iii) (a) POCl3, DMF, 0 °C; (b) Boc2O, DMAP, 25
a
Reagents and conditions: (i) 10% Pd(PPh3)4, DME, aqueous
Na2CO3, 100 °C, 78%; (ii) (a) AlCl3, CH2Cl2, 0 °C, 84%; or (b) silica
gel, microwave, 83%; (iii) (a) POCl3, DMF, 0 °C; (b) Boc2O, DMAP,
°
C, 50% (over two steps); (iv) MePPh2Br, n-BuLi, 0 °C; (v) 11%
Grubbs II, toluene, 25 °C, 40% (over two steps); (vi) TFA, CH2Cl2,
reflux, 72%.
2
5 °C, 79%; (iv) MePPh2Br, n-BuLi, 0 °C, 28% (24 f 26).
1
8, which was then subjected to Wittig conditions to
to be converted into alkenes. This was readily achieved
using the Wittig reaction to give 12. Exposure of 12 to
the Grubbs second-generation catalyst then gave the
desired indole-fused carbazole 13 in 64% yield.
afford 19. It was noted that diene 19 was substantially
more unstable than diene 12, and it could not be
concentrated down without significant decomposition
taking place. To circumvent this problem, an excess of
toluene was utilized to drive off the lower boiling solvents
from 19, and then without delay Grubbs catalyst was
added, and the reaction was left to stir at room temper-
ature for 21 h. After purification, the desired carbazole
Since the previous synthesis was successful, the syn-
thesis of a product containing a thiophene fused to the
carbazole nucleus rather than an indole was attempted.
This would constitute the synthesis of a sulfur analog of
furostifoline (1b). To this end, the synthesis of the desired
2
0 was obtained in 40% yield over the two steps. The
indole boronic acid 14 was accomplished using known
methodology (Scheme 2).18 In addition, the halogenated
Boc-protecting group was then easily removed by expo-
sure of 20 to TFA to furnish the sulfur analog of
furostifoline 21 in 72% yield.
thiophene 15 required for the Suzuki coupling was
prepared by Friedel-Crafts acylation of 3-bromothiophene
to afford exclusively 2-acetyl-3-bromothiophene (15) using
methodology similar to that used by Tanaka and co-
At the same time, the attempted synthesis of furosti-
foline (1b) was carried out as shown in Scheme 3.
Conversion of 14 to 24 in three steps proved to be
uneventful and provided the same types of intermediates
as those described for the sulfur series. However, treat-
ment of 24 using traditional Wittig reaction conditions
did not afford diene 25 but gave cyclobutane 26 as the
only product. It is believed that diene 25 undergoes a
2
2
workers.
Treatment of indole boronic acid 14 with 2-acetyl-3-
bromothiophene (15)2 under palladium-catalyzed condi-
tions resulted in the formation of the required carbon-
carbon bond, to yield 16 together with a 2-5% of 17
depending on the amount of solvent used. Since a small
amount of 15 remained unreacted and because 17 and
2b
8 6
spontaneous π electrocyclization followed by a π elec-
1
f
5 had very similar R values, the crude material was
trocyclization reaction to afford 26. All attempts to trap
the intermediate diene 25 in situ and to react this with
the Grubbs second-generation catalyst failed to yield the
desired carbazole 27. Attempts to coerce the cyclobutane
treated with an excess of Boc anhydride, thus converting
all 17 to 16 and enabling proper separation from unre-
acted 15. Then subsequent removal of the Boc-protecting
group of 16 with AlCl
3
gave the unprotected indole 17.
under Vils-
2
6 to undergo aromatization with the loss of ethylene to
Treatment of 17 with DMF and POCl
3
afford 27 under a range of reaction conditions were also
meier-Haack reaction conditions resulted in the intro-
duction of a formyl group at the 3-position of the indole
unsuccessful.
In conclusion, we have demonstrated for the first time
that the metathesis reaction can be used for the con-
struction of the central aromatic ring of both the indolo-
2
nucleus. Reaction of this intermediate with Boc O gave
(
22) (a) Koyanagi, J.; Yamamoto, K.; Nakayama, K.; Tanaka, A. J.
[
2,3-a]carbazole and the thieno[3,2-a]carbazole nucleus.
Heterocycl. Chem. 1995, 32, 1289. (b) Lutz, G.-B.; Otto, H.-H. Arch.
Pharm. 1991, 324, 563
Unfortunately, using the same methodology for the
10476 J. Org. Chem., Vol. 70, No. 25, 2005

Reactions for the Synthesis of Ring-Fused Carbazoles
synthesis of the natural product furostifoline was frus-
tratingly unsuccessful.
AlCl
freshly distilled acetyl chloride (1.34 mL, 1.48 g, 19.6 mmol)
in CH Cl (15 mL), and this was added over a 10-min period
to the AlCl suspension. After about 30 min of being stirred
at 0 °C most of the AlCl had dissolved. A second dropping
funnel was charged with 3-bromothiophene (0.574 mL, 1.00
g, 6.13 mmol) in CH Cl (15 mL), and this was added to the
reaction mixture over a 10-min period. The reaction was left
to proceed at 0 °C for 30 min and then warmed slowly to room
temperature for another hour. Then the reaction mixture was
cooled to 0 °C once again, and water (40 mL) was added
carefully. After being transferred to a separating funnel, the
3
was observed. A dropping funnel was charged with
2
2
3
Experimental Section
3
N,N′-Di-tert-butyldicarboxylate-2,2′-biindolyl-3,3′-di-
carboxaldehyde 11. Into a 50-mL flame-dried round-bottom
flask was placed the bis-indole 10 (200 mg, 0.694 mmol)
followed by dry THF (20 mL), thus forming an insoluble
2
2
2
suspension. Boc O (0.500 mL, 475 mg, 2.18 mmol) was then
added in one portion followed by DMAP (21 mg, 0.17 mmol).
The reaction was left to proceed under Ar for 10 min, during
which time the solution became homogeneous. TLC of the
reaction mixture indicated that the reaction was complete. The
solvent was evaporated, and the crude material was purified
by column chromatography (20% EtOAc/hexane), affording
N,N′-di-tert-butyldicarboxylate-2,2′-biindolyl-3,3′-dicarboxalde-
hyde 11 as a white crystalline material (300 mg, 89%). mp >
2 2
reaction mixture was diluted with more CH Cl (150 mL) and
another portion of water (150 mL) was added. After being
thoroughly mixed, the water layer was extracted twice with
CH
saturated NaHCO
dried over anhydrous MgSO
2
Cl
2
, and the combined organic extracts were washed with
(100 mL), then brine (100 mL) and finally
. Evaporation of the solvent and
3
4
purification by column chromatography (5% EtOAc/hexane)
1
70 °C dec; δ
H
/ppm (300 MHz): 9.83 (2H, s), 8.44 (2H, d, J )
followed by bulb-bulb distillation (130 °C at 10 mbar) afforded
the desired compound as a white waxy solid (1.23 g, 98%). δ /
H
7
.4 Hz), 8.33 (2H, d, J ) 8.2 Hz), 7.55-7.44 (4H, m), 1.26 (18H,
C
s); δ /ppm (75 MHz): 186.1, 148.6, 136.7, 136.2, 127.3, 125.3,
-
1
ppm (300 MHz): 7.52 (1H, d, J ) 5.2 Hz), 7.11 (1H, d, J ) 5.2
Hz), 2.70 (3H, s); δ /ppm (75 MHz): 190.1, 139.1, 133.6, 132.2,
1
25.1, 123.4, 122.3, 115.6, 86.1, 27.6; νmax/cm (film): 2982,
C
1
746, 1677, 1607, 1521, 1481, 1346, 1316; HRMS calcd for
-
1
+
114.3, 29.6; νmax/cm : 1658, 1492, 1405, 1359, 1254; HRMS
calcd for C BrOS: 203.9244, found: 203.92506; MS: m/z 204
M , 57%), 189 (99), 82 (22).
tert-Butyl 2-(2-Acetyl-3-thienyl)-1H-indole-1-carboxy-
late 16. Into 50-mL two-necked round-bottom flask fitted with
a dropping funnel and a condenser was placed Pd(PPh (1.12
g, 0.969 mmol) followed by 1-(tert-butoxycarbonyl)-1H-indol-
-yl-2-boronic acid 14 (1.90 g, 7.28 mmol), and the flask was
C
4
28
H
28
N
2
O
6
: 488.1947, found: 488.1916; MS: m/z 488 (M ,
6 5
H
0%), 359 (27), 303 (85), 288 (78), 259 (100), 232 (24), 57 (99).
+
(
N,N′-Di-tert-butyldicarboxylate-2,2′-biindolyl-3,3′-divi-
nyl 12. Into a 50-mL two-necked oven-dried flask, fitted with
a dropping funnel, was placed MePPh
and the contents of the flask were blanketed with Ar. THF
10 mL) was added, forming a white suspension, and after
3
Br (533 mg, 1.49 mmol),
3 4
)
(
2
cooling to -50 °C, nBuLi (1.2 M, 1.2 mL, 1.4 mmol) was added,
resulting in a yellow solution with a white suspension. The
reaction was allowed to proceed under Ar for 30 min at -50
degassed and refilled with Ar five times. The dropping funnel
was then fitted with a pasteur pipet attached to an Ar line to
act as a bubbler for the purposes of degassing the subsequent
solvents. DME (12 mL) was added to the dropping funnel
followed by 3-bromo-2-acetylthiophene 15 (1.00 g, 4.88 mmol),
and the mixture was degassed for 10 min by gently bubbling
Ar through the solution. This solution was then added to the
flask in one portion, and the dropping funnel was charged with
°
C and was then warmed to 0 °C for 10 min. The reaction was
again cooled to -30 °C, and the bis-indole 11 (300 mg, 0.614
mmol) in THF (15 mL) was added dropwise over 5 min. The
reaction was left to proceed for 18 h at 0 °C before the reaction
mixture was poured onto water/crushed ice. The crude diene
1
2 was extracted into EtOAc and rapidly purified by column
chromatography (5% EtOAc/hexane), affording the slightly
2 3
an aqueous Na CO solution (2.00 M, 2.59 g, 24.5 mmol). This
impure diene 12 (as shown by NMR) as a yellow oil. δ
H
/ppm
solution was similarly degassed before being added to the flask
in one portion. The reaction mixture was then heated to reflux,
and after about 1 h the solution became homogeneous and was
pale orange in color. The mixture was heated at reflux for 3 d
during which time a color change was observed from pale
orange to light brown. Analysis of the reaction mixture
indicated that the reaction had consumed nearly all of the
thiophene 15 and that the desired compound 16 had formed
as well as some of the deprotected analog 17. After cooling,
the reaction mixture was diluted with EtOAc (50 mL), water
was added (50 mL), and the two phases were thoroughly
mixed. The organic layer was separated, and the aqueous layer
was extracted twice with EtOAc (2 × 50 mL). The combined
organic fractions were washed with brine (100 mL) and dried
(
300 MHz): 8.40 (2H, d, J ) 8.3 Hz), 7.92 (2H, d, J ) 7.6 Hz),
7
.43-7.31 (4H, m), 6.46 (2H, dd, J ) 18.0 and 11.6 Hz), 5.75
(
2H, dd, J ) 18.0 and 1.1 Hz), 5.26 (2H, dd, J ) 11.6 and 1.1
Hz), 1.14 (18H, s).
Di(tert-butyl)indolo[2,3-a]carbazole-11,12-dicarboxy-
late 13. Into a two-necked round-bottom flask fitted with a
condenser (oven-dried and under Ar) was placed the diene 12
(
assume 0.614 mmol) dissolved in toluene (60 mL). To the
solution was added Grubbs II catalyst (26 mg, 0.031 mmol),
and the solution was vacuum degassed before being covered
by an Ar atmosphere. The solution was heated to 80 °C for 20
h, and then analysis of the reaction mixture by TLC indicated
that not all the diene had reacted. More Grubbs II catalyst
was added (14 mg, 0.016 mmol), and the reaction was left to
proceed at 80 °C for another 4 h. The solvent was then
evaporated in vacuo, and the crude material was purified by
column chromatography (5-10% EtOAc/hexane). Recrystalli-
zation from an EtOAc/hexane mixture afforded the desired
compound 13 as white crystals (178 mg, 64% or 74% if the
recovered starting material is taken into account). mp > 230
over anhydrous MgSO
4
. After removal of the solvent in vacuo,
the crude mixture was taken up in THF (50 mL) and treated
2
with Boc O (2.20 mL, 2.09 g, 9.58 mmol) and DMAP (90 mg,
0.74 mmol) for 2 h, thus converting trace amounts of the
deprotected indole 17 back to the desired 16 (17 and 15 have
f
almost identical R values and so for purification purposes it
is desirable to convert all 17 back to 16). The reaction mixture
was then diluted with EtOAc (50 mL) and water (50 mL). The
organic layer was separated, and the aqueous layer was
extracted with EtOAc (2 × 50 mL). The combined organic
fractions were washed with brine (100 mL) and dried over
°
7
H
C dec; δ /ppm (300 MHz): 8.26 (2H, brd, J ) 7.9 Hz), 8.03-
.99 (4H, m), 7.50-7.45 (2H, m), 7.40-7.35 (2H, m), 1.61 (18H,
s); δ
C
/ppm (75 MHz): 151.4, 139.8, 128.1, 127.3, 126.9, 126.7,
-
1
1
23.2, 119.5, 116.3, 115.4, 84.2, 28.3; νmax/cm (film): 2980,
1
728, 1454, 1432, 1334, 1295, 1152; HRMS calcd for C28
H
28
-
4
anhydrous MgSO . Evaporation of the solvent in vacuo and
+
N
2
O
4
: 456.2049, found: 456.2011; MS: m/z 456 (M , 28%),
00 (64), 256 (100), 237 (6), 57 (41).
-Acetyl-3-bromothiophene 15.22b Into a 100-mL three-
Cl
purification by column chromatography (5-10% EtOAc/hex-
ane) afforded the desired tert-butyl 2-(2-acetylthiophen-3-yl)-
1H-indole-1-carboxylate 16 (1.299 g, 78%) as a pale yellow
3
2
neck round-bottom flask (dry, under Ar) was placed CH
2
2
H
solid. mp 92-94 °C; δ /ppm (300 MHz): 8.29 (1H, d, J ) 8.3
Hz), 7.57-7.53 (2H, m), 7.39-7.36 (1H, m), 7.34-7.24 (1H,
m), 7.07 (1H, d, J ) 5.0 Hz), 6.58 (1H, s), 2.19 (3H, s), 1.34
(
15 mL), and the solvent was cooled using an ice bath before
AlCl
3
(2.45 g, 18.4 mmol) was added. Partial dissolution of the
J. Org. Chem, Vol. 70, No. 25, 2005 10477

Pelly et al.
(
9H, s); δ
C
/ppm (75 MHz): 191.0, 149.5, 141.3, 138.3, 136.7,
by the careful addition of cold water (50 mL) and transferred
1
8
1
32.4, 132.0, 130.4, 128.7, 124.8, 123.0, 120.5, 115.6, 111.0,
2 2
to a 500-mL beaker. CH Cl was added to dilute the mixture
-1
3.5, 28.0, 27.5; νmax/cm (film): 2980, 1733, 1655, 1453, 1369,
333, 1221, 1161; HRMS calcd for C19 S: 341.1086,
(100 mL), followed by water (100 mL), and the mixture was
stirred vigorously. By means of gentle heating, the two-phase
mixture was warmed to the boiling point of the CH Cl , and
2 2
then an aqueous 1 M NaOH solution was slowly added until
the pH of the solution remained slightly basic. The organic
phase was separated, and the aqueous phase was extracted
H
19NO
3
+
found: 341.1057; MS: m/z 341 (M , 27%), 241 (100), 226 (16),
7 (48).
-(2-Acetyl-3-thienyl)-1H-indole 17. Method 1: Using
AlCl . Into a dry 100-mL round-bottom flask under Ar was
placed tert-butyl 2-(2-acetylthiophen-3-yl)-1H-indole-1-carboxy-
late 16 (1.00 g, 2.93 mmol) followed by dry CH Cl (50 mL).
The solution was cooled by means of an ice bath, and then
AlCl (508 mg, 3.81 mmol) was added in one portion. A color
5
2
3
with CH
washed with brine (100 mL), separated, and dried over
anhydrous MgSO . Filtration and evaporation of the solvent
Cl
2 2
(3 × 80 mL). The combined organic fractions were
2
2
4
in vacuo afforded the crude intermediate, 2-(2-acetylthiophen-
3-yl)-1H-indole-3-carbaldehyde, as a dark red solid. This crude
material was taken up in dry THF (200 mL) and transferred
to a dry 250-mL round-bottom flask under Ar. To the flask at
3
change from pale yellow to bright red occurred over a period
of 15 min. The reaction was left to proceed at 0 °C for 1 h and
then was quenched by the careful addition of water (50 mL).
The reaction mixture was then diluted with CH
2
Cl
2
(100 mL)
2
room temperature was added Boc O (3.30 mL, 3.14 g, 14.4
and water (100 mL), and the phases were thoroughly mixed.
The organic phase was separated, and the aqueous phase was
mmol) followed by DMAP (0.122 g, 0.998 mmol), and the
reaction was left to proceed for 18 h under Ar before being
transferred to a separating funnel. Water (200 mL) was added,
followed by EtOAc (200 mL), and after vigorous shaking the
organic phase was separated. The aqueous phase was ex-
tracted with EtOAc (3 × 100 mL), and the combined organic
fractions were washed with brine, separated, and dried over
extracted three times with CH
organic fractions were washed with brine (100 mL) and, after
separation, dried over anhydrous MgSO . Evaporation of the
solvent in vacuo and purification by column chromatography
2
Cl
2
(3 × 50 mL). The combined
4
(
5-10% EtOAc/hexane) afforded the desired product 17 as a
bright yellow solid (612 mg, 87%).
4
anhydrous MgSO . After filtration and evaporation of the
solvent in vacuo, the crude product was obtained as a brown
solid. Column chromatography (20-40% EtOAc/hexane) fol-
lowed by recrystallization from EtOAc/hexane afforded the
desired product 18 as an off-white solid (1.64 g, 50% over two
2
Method 2: Using Microwave and SiO . Into a 250-mL
round-bottom flask was placed tert-butyl 2-(2-acetylthiophen-
3
-yl)-1H-indole-1-carboxylate 16 (3.329 g, 9.750 mmol) followed
by EtOAc (150 mL) and silica gel (150 g). The solvent was
removed in vacuo, thus adsorbing the compound onto the silica
gel, and trace amounts of solvent were removed under vacuum
for 1 h. The adsorbate was then placed into a conventional
microwave (500 W) for 30-s bursts with 2 min of cooling
between each burst. After each burst, the adsorbate was mixed
to ensure that the reaction progressed evenly through the
adsorbate, and a small sample was removed for analysis by
TLC (a small amount of the silica was placed into EtOAc to
dissolve the adsorbed material, and this was analyzed by TLC).
As the reaction progressed, the silica gel changed color from
off-white to bright yellow. In this particular case, 7 × 45 s
bursts were required to complete the reaction. Once the
reaction was complete, the adsorbed product was loaded onto
a column and purified by column chromatography (5-10%
EtOAc/hexane). Evaporation of volatiles in vacuo afforded 17
steps). mp 139-140 °C (EtOAc/hexane); δ
H
/ppm (300 MHz):
.65 (1H, s), 8.36 (1H, d, J ) 7.2 Hz), 8.25 (1H, d, J ) 8.3 Hz),
.68 (1H, d, J ) 5.0 Hz), 7.48-7.38 (2H, m), 7.20 (1H, d, J )
.0 Hz), 2.31 (3H, s), 1.37 (9H, s); δ /ppm (75 MHz): 189.4,
86.6, 148.8, 143.0, 141.7, 136.3, 134.1, 132.3, 130.6, 126.2,
9
7
5
1
1
C
-
1
25.3, 124.8, 121.9, 120.4, 115.3, 85.0, 28.4, 27.5; νmax/cm
(
film): 3103, 2981, 2821, 1745, 1669, 1607, 1571, 1454, 1317,
228, 1153, 1134; HRMS calcd for C20 S: 369.1035,
1
H19NO
4
+
found: 369.1029; MS: m/z 369 (M , 10%), 340 (13), 326 (22),
2
69 (17), 254 (14), 240 (72), 226 (100), 57 (91), 41 (16).
tert-Butyl 4-Methyl-10H-thieno[3,2-a]carbazole-10-car-
boxylate 20. Into a 50-mL two-necked round-bottom flask
(oven dried, under Ar) was placed MePPh
3
Br (2.90 g, 8.12
mmol) followed by dry Et O (30 mL). The white suspension
2
was cooled to -10 °C, and then nBuLi (1.4 M, 5.8 mL, 8.1
mmol) was added dropwise, thus forming a yellow solution.
The solution was allowed to warm to room temperature and
stirred for another 1.5 h. Stirring was stopped, and the white
salt was allowed to settle, leaving a yellow solution. Into a
separate 100-mL round-bottom flask fitted with a dropping
funnel (oven dried, under Ar) was placed the dicarbonyl 18
as a bright yellow solid (2.335 g, 99%). mp 102-104 °C; δ
ppm (300 MHz): 12.29 (1H, brs), 7.69 (1H, d, J ) 5.3 Hz),
.62 (1H, d, J ) 7.9 Hz), 7.53 (1H, d, J ) 5.3 Hz), 7.49 (1H, d,
J ) 8.2 Hz), 7.26-7.21 (1H, m), 7.13-7.08 (1H, m), 6.96 (1H,
brs), 2.70 (3H, s); δ /ppm (75 MHz): 192.1, 138.7, 136.0, 133.0,
32.4, 131.0, 130.7, 128.1, 123.3, 120.7, 120.1, 112.1, 103.9,
H
/
7
C
1
3
1
-1
0.4; νmax/cm (film): 3178, 3119, 3055, 1645, 1611, 1570, 1537,
487, 1405, 1377, 1220; HRMS calcd for C14 11NOS: 241.0561,
(300 mg, 0.812 mmol) followed by dry Et O (60 mL), and the
2
H
solution was cooled to 0 °C by means of an ice bath. The ylide
solution from the first flask was transferred by cannula into
+
found: 241.0564; MS: m/z 241 (M , 100%), 226 (26), 224 (12),
1
98 (12), 171 (10), 154 (8), 121 (9), 89 (5).
the second flask containing the dicarbonyl 18 in Et O over a
2
tert-Butyl 2-(2-Acetyl-3-thienyl)-3-formyl-1H-indole-1-
10-min period. The reaction mixture was stirred for 30 min at
0 °C and then quenched by the addition of water (60 mL). The
carboxylate 18. Into a two-necked 250-mL round-bottom
flask fitted with a dropping funnel (dried and under Ar) was
placed DMF (5.80 mL, 5.48 g, 74.9 mmol). The flask was then
Et
× 100 mL), then brine (100 mL). After drying the Et
with MgSO , the crude intermediate diene was adsorbed onto
2
O layer was separated, washed successively with water (2
2
O layer
cooled by means of an ice bath, and POCl
2.5 mmol) was added dropwise by syringe. The formation of
the Vilsmeier salt was allowed to proceed for 30 min under
Ar at 0 °C. The dropping funnel was then charged with CH
Cl (100 mL), and this was added over a 10-min period to dilute
the newly formed reagent. This solution was left to cool to 0
C for another 15 min. Meanwhile, the dropping funnel was
once again charged with CH Cl (50 mL) and the indole 17
2.15 g, 8.91 mmol). This yellow solution was then added
3
(1.15 mL, 1.92 g,
4
1
silica gel and purified hastily by column chromatography. The
diene, now suspended in EtOAc/hexane, was then concentrated
by removing 80% of the solvent mixture in vacuo, and then
toluene was added (150 mL), and the mixture was again
concentrated in vacuo to about 80% of its original volume.
Toluene (150 mL) was added once again, and the volume was
2
-
2
°
3
2
2
reduced in vacuo to 20 cm , thus removing most of the EtOAc/
(
hexane without ever fully concentrating the diene (which is
unstable when neat). The solution was transferred to a 50-
mL round-bottom flask, degassed several times in vacuo, and
then Grubbs II catalyst was added (50 mg, 0.059 mmol). After
degassing once more, the flask was covered in aluminum foil,
and the reaction was allowed to proceed under Ar at room
temperature for 3 h. Analysis of the reaction mixture by TLC
dropwise over a period of 5-10 min to the flask still at 0 °C.
After the addition was complete, the reaction was carefully
monitored by TLC (every 5 min), and after about 15 min all of
the starting material had been converted to the salt (only a
highly UV active spot on the baseline if the TLC was run in
4
0% EtOAc/hexane). The reaction was immediately quenched
10478 J. Org. Chem., Vol. 70, No. 25, 2005

Reactions for the Synthesis of Ring-Fused Carbazoles
indicated that not all of the diene had reacted, and therefore
a further quantity of Grubbs II catalyst was added (30 mg,
0.035 mmol), and the reaction mixture was degassed again
tert-Butyl 2-(2-acetylfuran-3-yl)-1H-indole-1-carboxy-
late 22. Into a two-neck round-bottom flask fitted with a
dropping funnel and a condenser was placed Pd(PPh ) (1.73
3 4
and left for 18 h. The solvent was then removed in vacuo, and
the crude material was purified by column chromatography
to afford the desired product 20 as a white solid (109 mg, 40%
g, 1.50 mmol), and the reaction vessel was degassed and
refilled with Ar gas five times. The dropping funnel was
charged with DME (28 mL) and 1-(tert-butoxycarbonyl)-1H-
indol-2-yl-2-boronic acid 14 (2.90 g, 11.1 mmol). Ar gas was
then bubbled into the dropping funnel by means of a pasteur
pipet, and dissolution of the boronic acid occurred almost
immediately. During this period of degassing, 2-acetyl-3-
bromofuran (1.20 g, 6.34 mmol) was added to the dropping
funnel and degassing was continued for another 5 min. The
solution was then discharged into the reaction vessel, and the
over two steps). mp 111-115 °C; δ
.12 (2H, m), 7.95 (1H, d, J ) 7.4 Hz), 7.70 (1H, s), 7.47 (1H,
d, J ) 5.7 Hz), 7.44-7.42 (1H, m), 7.39-7.31 (1H, m), 2.67
3H, s), 1.76 (9H, s); δ /ppm (75 MHz): 151.2, 141.2, 138.4,
H
/ppm (300 MHz): 8.17-
8
(
C
1
1
2
1
32.2, 127.7, 127.2, 126.3, 126.0, 125.9, 123.9, 123.3, 122.9,
-
1
19.1, 115.8, 115.7, 84.2, 28.3, 20.5; νmax/cm (film): 2978,
932, 1732, 1595, 1471, 1452, 1428, 1365, 1316, 1295, 1240,
154; HRMS calcd for C20
H
19NO
2
S: 337.1136, found: 337.1138;
2 3
dropping funnel was recharged with an aqueous Na CO
+
MS: m/z 337 (M , 39%), 281 (96), 237 (100), 118 (6), 57 (54),
solution (2.0 M, 3.3 g, 31 mmol). This solution was similarly
degassed for 10 min and then discharged into the reaction
vessel. The two-phase mixture was heated and left to reflux
for 3 d. During this time the solution became homogeneous,
and a color change from yellow to pale brown occurred. The
reaction mixture was cooled and decanted into a dropping
funnel and then diluted with EtOAc (200 mL) and water (200
mL). After thorough mixing, the organic phase was separated,
and the aqueous phase was extracted three times with EtOAc
4
1 (11).
4
-Methyl-10H-thieno[3,2-a]carbazole 21. The carbazole
2
0 (93 mg, 0.28 mmol) in dry CH
2
Cl
2
(15 mL) was treated at
room temperature with TFA (0.63 mL, 93 mg, 0.82 mmol). The
reaction mixture was then heated to reflux for 2 h, and after
this time analysis of the reaction mixture by TLC indicated
that not all of the starting material had reacted. Another
addition of TFA was made (0.63 mL, 93 mg, 0.82 mmol), and
after another hour of stirring the reaction mixture at room
temperature the reaction was complete. The reaction mixture
(
3 × 100 mL). The combined organic fractions were then
washed with brine (200 mL) and dried over anhydrous MgSO
4
.
After evaporation of the solvent in vacuo, the crude material
was purified by column chromatography (5-10% EtOAc/
hexane), affording the desired tert-butyl 2-(2-acetylfuran-3-yl)-
was then diluted with CH
2
Cl
2
(30 mL) and washed with water
(
50 mL) before the two layers were separated. The water layer
was extracted with CH
2
Cl
2
(2 × 50 mL), and the combined
1
H-indole-1-carboxylate 22 (1.61 g, 78%) as well as a small
organic extracts were washed with brine (100 mL) and then
amount of 2-(2-acetylfuran-3-yl)-1H-indole 23. mp 98-99 °C;
4
dried over anhydrous MgSO . Purification of the product by
δ
1
7
H
/ppm (300 MHz): 8.20 (1H, d, J ) 8.4 Hz), 7.57 (1H, d, J )
column chromatography afforded 4-methyl-10H-thieno[3,2-a]-
carbazole 21 as a white solid (48 mg, 72%). mp 189-191 °C
.6 Hz), 7.55 (1H, d, J ) 7.9 Hz), 7.37-7.31 (1H, m), 7.27-
.21 (1H, m), 6.67 (1H, s), 6.61 (1H, d, J ) 1.6 Hz), 2.37 (3H,
δ
7
7
H
/ppm (300 MHz): 8.39 (1H, brs), 8.09 (1H, d, J ) 7.8, Hz),
s), 1.45 (9H, s); δ
C
/ppm (75 MHz): 186.8, 149.6, 148.4, 144.1,
.84 (1H, s), 7.63 (1H, d, J ) 5.5 Hz), 7.54 (1H, d, J ) 5.5 Hz),
.51 (1H, d, J ) 8.2 Hz), 7.49-7.38 (1H, m), 7.29-7.25 (1H,
1
1
1
37.0, 130.0, 128.7, 125.6, 124.8, 122.8, 120.6, 115.4 (2×),
-1
11.4, 85.5, 27.7, 26.9; νmax/cm (film): 3020, 1732, 1674, 1532,
470, 1452, 1370, 1328, 1217; HRMS calcd for C19
m), 2.71 (3H, s); δ
c
/ppm (75 MHz): 139.2, 138.6, 132.9, 125.4,
H
4
19NO :
1
1
1
24.8, 124.1, 123.9, 123.3, 119.9, 119.9, 119.7, 119.6, 116.8,
10.9, 20.5; νmax/cm (film): 3413 (NH str), 1609, 1452, 1360,
249; HRMS calcd for C15 11NS: 237.0612, found: 237.0606;
+
-
1
325.1314, found: 325.1296; MS: m/z 325 (M , 18%), 226 (15),
225 (100), 224 (31), 210 (8), 154 (10), 57 (49).
H
+
MS: m/z 237 (M , 100%), 204 (5), 191 (3), 118.5 (17).
-Acetyl-3-bromofuran. Into a 100-mL three-neck round-
bottom flask, under N , fitted with two dropping funnels was
placed CH Cl (15 mL), and the solvent was cooled by means
of an ice bath. AlCl (1.355 g, 10.16 mmol) was added in one
portion, and the solution was stirred at 0 °C for 15 min, during
which time partial dissolution of the AlCl took place. A
dropping funnel was charged with more CH Cl (15 mL) and
2-(2-Acetylfuran-3-yl)-1H-indole 23. Method 1: Using
AlCl . Into a two-neck round-bottom flask under nitrogen was
3
2
placed tert-butyl 2-(2-acetylfuran-3-yl)-1H-indole-1-carboxylate
2 (925 mg, 2.84 mmol) followed by CH Cl (70 mL). After the
solid had dissolved completely the flask was cooled by means
of an ice bath, and then AlCl (455 mg, 3.41 mmol) was added
in one portion. The reaction was allowed to proceed for 2 h at
°C, during which time the color of the solution changed to
2
2
2
2
2
2
3
3
3
0
2
2
bright red. The reaction was quenched by the careful addition
of ice water, and the red color immediately disappeared. The
freshly distilled acetyl chloride (0.750 mL, 828 mg, 11.0 mmol).
The acetyl chloride solution was then added over a 5-min
2 2
reaction mixture was diluted with more CH Cl (100 mL),
period to the AlCl
3
solution, and the reaction was left to
followed by water (100 mL), and the phases were mixed and
then separated. The aqueous phase was extracted three times
proceed at 0 °C for 30 min. During this time, complete
dissolution of the AlCl
was charged with CH
3
occurred. The second dropping funnel
Cl (15 mL) and 3-bromofuran (0.310
with CH
were washed with brine and then dried over anhydrous
MgSO . After filtration and evaporation of the solvent, the
crude material was purified by column chromatography (5-
2
Cl
2
(3 × 50 mL), and the combined organic fractions
2
2
mL, 507 mg, 3.45 mmol), and this was added over a 5-min
period to the reaction mixture, still at ice bath temperature.
The reaction was left to proceed for 20 min and then allowed
to warm to room temperature over a 10-min period. After
cooling once again using an ice bath, water (50 mL) was added
slowly, and then the reaction mixture was decanted to a
4
2
0% EtOAc/hexane) to afford the desired product 23 as a bright
yellow solid (536 mg, 84%).
2
Method 2: Using Microwave and SiO . The boc-
dropping funnel before being diluted by the addition of CH
Cl (150 mL) and water (200 mL). After thoroughly mixing
the phases, the organic layer was separated and the aqueous
layer was extracted with CH Cl
(3 × 100 mL). The combined
organic fractions were washed with saturated NaHCO solu-
tion (200 mL), followed by brine (200 mL). After the organic
layer was dried over anhydrous MgSO , the solvent was
2
-
protected indole 22 (500 mg, 1.54 mmol) was suspended in
EtOAc (200 mL), and silica was added (200 g). The slurry was
concentrated in vacuo until a dry off-white powder was
obtained. This mixture was then placed into a conventional
microwave (500 W) for 30-s bursts with 2 min of cooling
between each burst. After each burst the adsorbate was mixed
to ensure that the reaction progressed evenly through the
adsorbate, and a small sample was removed for analysis by
TLC (a small amount of the silica was placed into EtOAc to
dissolve the adsorbed material and this was analyzed by TLC).
In total, approximately 3 min of microwave heating was
required to complete the reaction. As the reaction proceeded,
the silica gradually became more yellow in color. Once the
2
2
2
3
4
evaporated in vacuo. The crude product was then purified by
column chromatography (5% EtOAc/hexane) followed by distil-
lation (approx 120 °C, 10 mbar) to afford the desired compound
as a white waxy solid (561 mg, 86%). δ
H
/ppm: (300 MHz): 7.50
(
1H, d, J ) 1.7 Hz), 6.63 (1H, d, J ) 1.7, Hz), 2.55 (3H, s);
C
δ /ppm (75 MHz): 186.4, 148.3, 145.3, 117.4, 106.9, 27.4.
J. Org. Chem, Vol. 70, No. 25, 2005 10479

Pelly et al.
1
reaction was complete, the adsorbed product was purified by
column chromatography (5-10% EtOAc/hexane), affording 23
in 83% yield (288 mg) as a bright yellow solid. mp 137-138
120.2, 116.4, 115.2, 85.1, 27.6, 26.6; νmax/cm- (film): 2981,
1747, 1672, 1607, 1529, 1479, 1453, 1418, 1383, 1346, 1316,
5
1275, 1232; HRMS calcd for C20H19NO : 353.1263, found:
+
°
C; δ
Hz), 7.55 (1H, d, J ) 1.6 Hz), 7.50 (1H, d, J ) 8.2 Hz), 7.25
1H, t, J ) 7.1 Hz), 7.11 (1H, t, J ) 7.4 Hz), 7.01 (1H, d, J )
H
/ppm (300 MHz): 11.91 (1H, brs), 7.63 (1H, d, J ) 7.9
353.1269; MS: m/z 353 (M , 1%), 310 (10), 254 (29), 225 (13),
224 (26), 211 (16), 210 (100), 57 (67).
(
tert-Butyl-2a-methyl-1,2,2a,10c-tetrahydro-6H-cyclob-
uta[c]furo[3,2-a]carbazole-6-carboxylate 26. Part A. Into
a 250-mL two-neck round-bottomed flask under Ar was placed
methyl triphenylphosphonium bromide (3.00 g, 8.40 mmol)
followed by dry diethyl ether (150 mL). The phosphonium salt
was not soluble in this solvent and thus formed a white
suspension. The solution was cooled to 0 °C under Ar, and then
nBuLi (1.4 M, 6.0 mL, 8.4 mmol) was added dropwise over a
period of 5 min. The solution rapidly changed color to yellow
as the nBuLi was added; however, a white solid remained
insoluble in the solution (LiBr). After the addition of the
nBuLi, the solution was stirred at 0 °C for 30 min and then
warmed to room temperature for 30 min. Stirring was then
stopped, and the insoluble LiBr salt was allowed to settle to
the bottom of the flask.
1
1
1
1
C
.6 Hz), 6.91 (1H, s), 2.66 (3H, s); δ /ppm (75 MHz): 189.7,
46.2, 145.8, 136.2, 128.9, 128.3, 126.9, 123.3, 120.6, 120.0,
-
1
12.4, 111.9, 103.4, 27.2; νmax/cm (film): 3253, 3019, 1656,
573, 1523, 1475, 1397, 1360, 1250, 1216; HRMS calcd for
+
C
1
14
H
11NO
2
: 225.0787, found: 225.0789; MS: m/z 225 (M ,
00%), 224 (40), 210 (8), 196 (11), 182 (7), 154 (26).
tert-Butyl 2-(2-Acetylfuran-3-yl)-3-formyl-1H-indole-1-
carboxylate 24. Into a 100-mL two-neck round-bottom flask
(
dried, under Ar), fitted with a dropping funnel, was placed
DMF (1.00 mL, 944 mg, 12.9 mmol), and the flask was cooled
by means of an ice bath. POCl (0.200 mL, 334 mg, 2.18 mmol)
3
was added via a syringe, and the reaction was left to proceed
for 10 min at 0 °C. By means of the dropping funnel, to the
2 2
newly formed reagent was added CH Cl (20 mL), and this
solution was allowed to cool to 0 °C for 10 min. The dropping
Part B. Into a 250-mL two-neck round-bottom flask fitted
with a dropping funnel was placed tert-butyl 2-(2-acetylfuran-
3-yl)-3-formyl-1H-indole-1-carboxylate 24 (300 mg, 0.849 mmol)
followed by diethyl ether (50 mL). The ylide as prepared in
Part A was transferred by cannula into the dropping funnel.
The contents of the round-bottom flask were cooled to 0 °C
under Ar, and then the ylide was added in small portions (ca.
5-10 mL) until the formation of the diene was complete (as
determined by monitoring the reaction by TLC). Without delay,
the reaction was quenched by the addition of water (50 mL),
and the mixture was diluted by the addition of EtOAc (100
mL). After the phases were thoroughly mixed, the organic
phase was separated, and the aqueous phase was extracted
with EtOAc (3 × 50 mL). The combined organic fractions were
collected, washed with brine (100 mL), and then dried over
funnel was then charged with 2-(2-acetylfuran-3-yl)-1H-indole
2
2 2
3 (320 mg, 1.42 mmol) in dry CH Cl (30 mL), and this was
added dropwise over a period of 5 min. The reaction was left
to proceed for another 5 min, and analysis of the reaction
mixture by TLC indicated that all starting material had been
converted to the Vilsmeier salt (only a highly UV active spot
on the baseline if the TLC was run in 40% EtOAc/hexane).
Ice cold water was immediately added (40 mL), and the
2 2
reaction mixture was transferred to a beaker. CH Cl was
added (150 mL) followed by water (100 mL), and the two-phase
mixture was stirred vigorously. By means of gentle heating
2 2
the mixture was warmed to the boiling point of the CH Cl ,
and then 2 M NaOH solution was slowly added until the pH
of the solution remained slightly basic. The organic phase was
then separated, and the aqueous phase was extracted three
anhydrous MgSO . Without delay, the crude material was
4
times with CH
fractions were washed with brine (100 mL) and dried over
anhydrous MgSO . Evaporation of the solvent afforded the
2
Cl
2
(3 × 100 mL). The combined organic
adsorbed onto silica and purified by column chromatography
(5% EtOAc/hexane). The diene, now suspended in the EtOAc/
hexane solvent, was then concentrated in vacuo to 80% of its
original volume. Then toluene was added (100 mL), and the
solution was once again concentrated to 80% of its original
volume. Toluene was added once again (100 mL), and the
solution was concentrated in vacuo to approximately 10 mL.
In this way, the lower boiling solvents were essentially
removed and replaced by toluene without ever fully concen-
trating the diene. The solution was then degassed in vacuo,
and Grubbs II catalyst (72 mg, 0.085 mmol) was added. After
3 h analysis of the reaction mixture by TLC indicated that
nothing appeared to be happening, and therefore the solution
was heated to 80 °C overnight. Analysis of the reaction mixture
by TLC still indicated that only starting material was present,
and therefore another addition of Grubbs II catalyst was made
(72 mg, 0.085 mmol), and the reaction was left to proceed at
80 °C for another 5 h. Analysis by TLC indicated no change,
and therefore the mixture was adsorbed onto silica gel and
purified by column chromatography (5% EtOAc/hexane), af-
fording the unreacted diene as a clear oil (152 mg, 51% from
dicarbonyl 24). However, as soon as this oil was finally
concentrated on the high vacuum, it rapidly changed color from
clear to opaque and became waxy. After subjecting the wax
for 3 h at room temperature to high vacuum the material was
columned once again (5% EtOAc/hexane), affording tert-butyl
2a-methyl-1,2,2a,10c-tetrahydro-6H-cyclobuta[c]furo[3,2-a]car-
bazole-6-carboxylate 26 (82 mg, 28%, calculated from the
4
crude product as a dark brown solid. Purification by column
chromatography (40% EtOAc/hexane) removed most of the
impurities; however, complete purification was not possible
even after a second column. Recrystallization of the material
(
EtOAc/hexane mixtures) afforded the desired compound 2-(2-
acetylfuran-3-yl)-1H-indole-3-carbaldehyde as pure (247 mg);
however, by TLC it was clear that large amounts of the product
were still in the mother liquor. H NMR spectral data were
1
then collected using the pure material, and then the pure and
impure fractions were recombined and used in the next
reaction. δ /ppm (300 MHz): 12.68 (1H, brs), 10.50 (1H, s),
H
8
.29 (1H, d, J ) 7.3 Hz), 7.67 (1H, d, J ) 1.8 Hz), 7.59 (1H, d,
J ) 1.8 Hz), 7.51 (1H, dd, J ) 1.3 and 6.9 Hz), 7.40-7.27 (2H,
m), 2.70 (3H, s). The crude material (assume 1.42 mmol) was
taken up in dry THF (40 mL), and Boc O was added in one
2
portion (0.500 mL, 475 mg, 2.18 mmol) followed by DMAP (23
mg, 0.19 mmol). The reaction was left to proceed under Ar for
5
h at room temperature. Water was then added (50 mL), and
the reaction mixture was diluted with EtOAc (100 mL). The
organic phase was separated, and the aqueous phase was
extracted three times with EtOAc (3 × 100 mL). The combined
organic fractions were washed with brine (200 mL) and dried
4
over anhydrous MgSO . After filtration and evaporation of the
solvent in vacuo, the crude material was purified by column
chromatography (20-30% EtOAc/hexane), followed by recrys-
tallization from EtOAc/hexane mixtures to afford the desired
tert-butyl 2-(2-acetylfuran-3-yl)-3-formyl-1H-indole-1-carboxy-
late 24 (397 mg, 79% over the two steps starting from 23) as
dicarbonyl 24) as a white waxy solid. δ
H
/ppm (300 MHz):
7.98-7.92 (1H, m), 7.32 (1H, d, J ) 1.9 Hz), 7.32-7.29 (1H,
m), 7.21-7.15 (2H, m), 7.01 (1H, d, J ) 1.9 Hz), 3.66 (1H, t, J
) 7.5 Hz), 2.66-2.58 (1H, m), 2.46-2.36 (1H, m), 2.32-2.15
a pale yellow solid. mp 151-153 °C; δ
H
/ppm (300 MHz): 9.82
(
1H, s), 8.37-8.34 (1H, m), 8.20-8.17 (1H, m), 7.68 (1H, d, J
(2H, m), 1.72 (9H, s), 1.54 (3H, s); δ
150.5, 140.7, 136.2, 130.5, 128.5, 123.0, 122.7, 117.6, 116.0,
115.4, 111.8, 109.7, 84.0, 39.7, 39.7, 35.8, 28.3, 23.2, 26.2; νmax/
C
/ppm (75 MHz): 159.1,
)
1.7 Hz), 7.45-7.35 (2H, m), 6.72 (1H, d, J ) 1.7 Hz), 2.45
/ppm (75 MHz): 186.9, 186.7, 149.6,
48.9, 144.5, 140.0, 136.4, 126.2, 125.4, 124.7, 121.9, 121.0,
(
1
3H, s), 1.45 (9H, s); δ
C
-
1
cm (film): 2958, 1739, 1574, 1505, 1463, 1419, 1394, 1360,
10480 J. Org. Chem., Vol. 70, No. 25, 2005

Reactions for the Synthesis of Ring-Fused Carbazoles
304, 1286, 1228; HRMS calcd for C22 349.1678,
1
H
23NO
3
:
tific and Industrial Research (CSIR), Pretoria, for ad-
ditional funding.
+
found: 349.1684; MS: m/z 349 (M , 16%), 321 (5), 266 (18),
265 (100), 248 (4), 221 (55), 220 (23), 57 (30).
Supporting Information Available: Copies of H and 13C
1
Acknowledgment. This work was supported by the
NMR of 11-13, 15-18, 20-24, 26, and 2-acetyl-3-bromofuran
and the H NMR of 2-(2-acetylfuran-3-yl)-1H-indole-3-carbal-
dehyde. This material is available free of charge via the
Internet at http://pubs.acs.org.
National Research Foundation (NRF, GUN 2053652),
Pretoria, the University of the Witwatersrand (Univer-
sity Research Council and Faculty Research Council).
R. Mampa of this university is thanked for providing
the NMR service. S.C.P. thanks the Council for Scien-
1
JO051826S
J. Org. Chem, Vol. 70, No. 25, 2005 10481