Coupling reactions of indole-3-acetic acid derivatives. Synthesis of arcyriaflavin A

Article abstract of DOI:10.1039/b004029k

The bisindolesuccinic acid methyl ester 10 was obtained by an iodine-promoted coupling of the dianion 9. The diester was converted to the N-benzylimide 12, which was oxidatively cyclized to the indolo[2,3-a]pyrrolo[3,4-c]-carbazole 15. The diester 10 coul

Full text of DOI:10.1039/b004029k

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Coupling reactions of indole-3-acetic acid derivatives. Synthesis of
arcyriaflavin A
Jan Bergman,* Eva Koch† and Benjamin Pelcman†
1
Department of Biosciences of Novum, Karolinska Institute, Novum Research Park,
SE-141 57 Huddinge, Sweden and Södertörn University College, SE-141 04 Huddinge,
Sweden
Received (in Cambridge, UK) 19th May 2000, Accepted 9th June 2000
Published on the Web 28th July 2000
The bisindolesuccinic acid methyl ester 10 was obtained by an iodine-promoted coupling of the dianion 9. The
diester was converted to the N-benzylimide 12, which was oxidatively cyclized to the indolo[2,3-a]pyrrolo[3,4-c]-
carbazole 15. The diester 10 could be directly transformed to the known indolocarbazole diester 27 via acid-induced
intramolecular cyclization in TFA. The same methodology gave arcyriaflavin A 4 from the succinimide 18b.
Introduction
The interesting biological activities of indolocarbazole alka-
loids, such as the protein kinase C inhibitor staurosporine1 and
the tumour-growth inhibitor rebeccamycin,2 have stimulated
the development of a number of synthetic approaches towards
indolo[2,3-a]pyrrolo[3,4-c]carbazoles such as the aglycon of 1,
staurosporinone 3, and arcyriaflavin A 4.3–7
Both staurosporine 1 and rebeccamycin 2 have been shown
by labelling experiments to be biosynthetically derived from
two tryptophan units.8,9 This notion has been used by us10,11
and others12 in the synthetic strategy to this type of com-
pounds.
Results and discussion
Our first approach towards arcyriaflavin A 4 involves the oxid-
ative coupling of anions α to the carbonyl group of either
indole-3-acetic acid or its methyl ester as shown in Scheme 1.
Sequential addition of 2 eq. of BuLi and 1 eq. of t-BuLi to
† Present address: Karo Bio, SE-141 57 Huddinge, Sweden.
Scheme 1
DOI: 10.1039/b004029k
J. Chem. Soc., Perkin Trans. 1, 2000, 2609–2614
This journal is © The Royal Society of Chemistry 2000
2609

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indole-3-acetic acid 5 afforded the trianion 6. Quenching an
aliquot of the reaction mixture with D2O and subsequent exam-
1
ination of the reaction product with H NMR showed 95%
incorporation of deuterium α to the carbonyl group. It was also
found that 6 was stable at Ϫ40 ЊC in THF for at least 18 h.
Addition of 0.5 eq. of iodine to a solution of 6 in THF at
Ϫ70 ЊC followed by an acidic work-up gave 2,3-di(indol-3-
yl)succinic acid 7. The reaction mixture was treated, without
any attempts to purify the diacid, with diazomethane or acetic
anhydride to give a diastereomeric mixture (the -pair and
the meso-form) of the diester 10 or the diastereomerically pure
anhydride 11, respectively. However, the yields of 10 and 11
were not satisfactory (38% and 32%, respectively). Fortunately,
the diester 10 could be obtained in a much higher yield (85%),
as a diastereomeric mixture (1:1), by the iodine-promoted
coupling of the dianion 9, prepared from indole-3-acetic acid
methyl ester 8 and lithium diisopropylamide (LDA). Heating
(200 ЊC; N2) of the diester 10 or the anhydride 11 with ben-
zylamine gave the bisindolesuccinimide 12 together with some
of the bisamide 13 (Scheme 2). The imide 12 was readily
Scheme 3
that the pure dimer 10b, obtained by crystallization of the
diastereometric mixture of 10 from 1,4-dioxane, is the meso-
form.
A compound claimed to be the trans-imide 18a has been
reported in the literature.14 This purported compound was
obtained in a low reported yield (6%) by reaction of indolyl-
magnesium chloride with bromomaleimide followed by acidic
(2 M HCl) work-up. Repetition of this experiment showed,
however, that this product is in fact 3,3-di(indol-3-yl)succin-
imide 21 which was first indicated by the appearance of a CH2
group in the 13C NMR spectrum. The previous workers did not
report any 13C NMR data and interpreted the CH2 singlet in the
1H NMR spectrum as two coinciding CH signals. This result
can be rationalized as initial formation of 20 followed by acid-
catalyzed addition of a second molecule of indole during the
acidic work-up (Scheme 4).
In harmony with this scheme it was found that interaction of
20 with indole under acidic conditions indeed gave 21. The
structure of 21 was also confirmed by an independent synthesis
starting with the known diester 22, which readily underwent
cyclization with hydrazine yielding 23, which in turn upon
treatment with Raney nickel in 1,4-dioxane gave the imide 21
(Scheme 5).15 It should also be noted that compound 21, still
written as 18b, recently has been tested for activity against
human cytomegalovirus.16 The discussion in this paper thus at
this point might be somewhat misleading.
Scheme 2
dehydrogenated with one equivalent of DDQ at room temper-
ature to give the bisindolemaleimide 14. Compound 12 could
also serve as precursor for the indolocarbazole 15, by the use of
two equivalents of DDQ and a catalytic amount of p-TsOH
in refluxing benzene.
The same set of transformations could be exerted on the
anhydride 11, thus establishing a route to compounds 1613 and
17. A somewhat higher temperature (refluxing chlorobenzene,
132 ЊC) was, however, required.
The diester 10 was formed as a mixture of the -pair and the
meso-form. On trituration with 1,4-dioxane one of them crys-
tallized in pure form. When the mixture of 10 was treated with
ammonium formate in refluxing triglyme only one of the two
diastereomers cyclized to the imide 18. The other diastereomer
of 10, identical with the one obtained from trituration with 1,4-
dioxane, could be recovered intact from the reaction mixture.
To assign the structure of the diastereomers we synthesized
the cis-succinimide 18b from arcyriarubin A 19 (see Scheme 3),
an experiment previously described by Davis.14 The cis-
succinimide 18b was not identical with our sample obtained
from the diester and thereby we can conclusively ascertain
the trans stereochemistry of the imide 18a and thus deduce
The trans-imide 18a could be dehydrogenated to arcyriarubin
A 19, but arcyriaflavin A 4 could not be obtained with the same
methodology which gave 15 and 17. Whereas indole in acidic
media dimerizes to 2-(indol-3-yl)indoline, 3-substituted indoles
will form 2,2Ј-coupled dihydrodimers by rearrangement.17–19
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upon treatment with TFA, and indeed 10 gave the tetra-
hydroindolocarbazole 27 (Scheme 7) in excellent yield.
Scheme 7
Gentle warming of a TFA solution of the tetrahydro com-
pound 27 gave the known, fully aromatized diester 28.22 The
imide 18b similarly gave the tetrahydroindolocarbazole 29 when
treated with TFA. Here it might be added that some related
dehydrogenations leading to indolo[3,2-a]pyrrolo[3,4-c]-
carbazoles have recently been described by us.23
Scheme 4
Arcyriaflavin A 4 was obtained in quantitative yield by
refluxing a TFA solution of 29 for 8 h.
Scheme 5
Such couplings are known for simple indoles, e.g. skatole, and,
as we presented in an earlier communication,11 for indole-3-
acetic acid and several related derivatives (see Scheme 6).
It was shown that the dimer 24b was readily formed by
treatment of methyl indole-3-acetate with trifluoroacetic acid
(TFA) and readily underwent cyclization to the lactam 25,
whose structure has been confirmed by X-ray crystallography.20
Interestingly, unsuccessful attempts to prepare the dimer 24b
had been reported as early as 1965.21 Dehydrogenation of
24b with DDQ readily gave the corresponding 2,2Ј-biindolyl
derivative 26.
Experimental
General
NMR spectra were recorded on a Bruker DPX 300 (300 MHz)
spectrometer and a Bruker VP-200. IR spectra were recorded
with a Perkin-Elmer 1600 FT-IR. J-values are in Hz. HRMS
analyses were performed by Sveriges Lantbruksuniversitet
(SLU), Uppsala, Sweden, MS ESI analyses were obtained on a
Perkin-Elmer API 150 EX spectrometer. MS (EIϩ) analyses
were performed on a Micromass Platform II spectrometer or a
LKB-9000, both with a direct inlet at 70 eV. Mps were taken on
a Büchi Melting Point B-545 apparatus or a Reichert WME
Kofler hot stage and are uncorrected. All solvents were purified
by distillation or were HPLC grade. Diisopropylamine (DIPA)
As compounds 10 and 18b each have two unsubstituted
2-positions they should (cf. Scheme 6) be able to undergo
intramolecular acid-promoted ring closure as they also did
Scheme 6
J. Chem. Soc., Perkin Trans. 1, 2000, 2609–2614
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and THF were distilled immediately before use from CaH2 and
benzophenone ketyl, respectively. Chromatography was
performed on Merck Silica Gel 60. All reactions, except the
TFA-induced dimerizations and the DDQ dehydrogenations,
were performed under a positive pressure of nitrogen.
122.3 (d), 119.8 (d), 119.5 (d), 112.6 (d), 108.1 (s), 46.1 (d);
νmax(KBr)/cmϪ1 3410, 3390, 1860, 1775, 1455, 1420, 1340, 1250,
1180, 1025, 935, 920, 795, 740; m/z (EIϩ) 330. Found: HRMS
(EI) m/z 330.1025. C20H14N2O3 requires M, 330.1004.
N-Benzyl-3,4-di(indol-3-yl)succinimide 12
Dimethyl 2,3-di(indol-3-yl)succinate 10 from 8
A mixture of 10 (1.47 g, 3.9 mmol) and benzylamine (6 ml) was
heated at 200 ЊC for 18 h. The orange solution which solidified
on cooling was dissolved in EtOH. The EtOH solution was
added dropwise with stirring to aq. HCl (2 M; 100 ml), and the
precipitate which formed was collected, washed with ethanol
and dried. Purification by chromatography (CH2Cl2–MeOH,
98:2) gave 12 (1.30 g, 80%), mp 184–187 ЊC; δH (200 MHz;
DMSO-d6) 10.95 (2H, s, NH), 7.4–7.3 (11H, m, ArH), 7.07 (2H,
m, ArH), 6.89 (2H, m, ArH), 4.78 (2H, s, CH2), 4.62 (2H, s,
CH); δC (75 MHz; DMSO-d6) 176.9 (s), 136.5 (s), 136.35 (s),
128.6 (d), 128.0 (d), 127.7 (d), 126.1 (s), 124.3 (d), 121.4 (d),
118.8 (d), 118.6 (d), 111.8 (d), 109.7 (s), 67.3 (d), 42.1 (t);
νmax(KBr)/cmϪ1 3400, 1775, 1695, 1460, 1430, 1395, 1345, 1155,
740 and 700; m/z (ESI) [M ϩ H]ϩ 420. Found: HRMS (EI) m/z
419.1627. C27H21N3O2 requires M, 419.1634.
To a solution of LDA [prepared from DIPA (5.61 ml, 40
mmol), n-BuLi (10 M; 4 ml, 40 mmol) and THF (100 ml)] was
added a solution of 8 (3.78 g, 20 mmol) in THF (40 ml) over a
period of 75 min, keeping the temperature below Ϫ65 ЊC
(sometimes a viscous precipitate formed, making stirring dif-
ficult). After 2 h at Ϫ75 ЊC, the mixture was allowed to come to
Ϫ40 ЊC, kept at that temperature for 30 min and recooled to
Ϫ75 ЊC. A solution of iodine (2.53 g, 10 mmol) in THF (40 ml)
was added over a period of 75 min at Ϫ70 ЊC whereafter the
mixture was stirred at Ϫ75 ЊC for 1 h and then allowed to reach
room temperature overnight. The purple solution was poured
into NaHSO3 (aq., saturated) and, after separation, the aque-
ous phase was extracted with EtOAc. The combined organic
phases were washed successively with water and brine and dried
with MgSO4. Concentration gave a brown foam, which was
triturated with hot 1,4-dioxane to give dimer 10b (0.79 g) as fine
white needles (only one diastereomer), mp 270–273 ЊC; δH (200
MHz; DMSO-d6) 11.10 (2H, s, NH), 7.74 (2H, d, J 7, ArH),
7.41 (2H, d, J 2, ArH), 7.36 (2H, d, J 8, ArH), 7.01–7.13 (4 H,
m, ArH), 4.77 (2H, s, CH), 3.26 (6H, s, CH3); δC (50 MHz;
DMSO-d6) 172.0 (s), 136.0 (s), 126.1 (s), 123.6 (d), 121.2 (d),
118.8 (2d), 111.5 (d), 110.1 (s), 51.4 (q), 45.4 (d); νmax(KBr)/cmϪ1
3350, 1714, 1432, 1313, 1161, 749; m/z (ESI) [M ϩ Hϩ] 377.
Found: HRMS (EI) m/z 376.1410. C22H20N2O4 requires M,
376.1423. Concentration of the 1,4-dioxane solution followed
by flash chromatography (CH2Cl2–MeOH, 99:1) gave 10
(2.44 g) as a mixture of diastereomers. Total yield of 10a plus
10b: 85%.
N-Benzyl-3,4-di(indol-3-yl)maleimide 14
DDQ (0.16 g, 0.069 mmol) was added at room temperature in
small portions to a stirred solution of 12 (0.29 g, 0.69 mmol) in
benzene (10 ml). After 1 h at room temperature the mixture
was concentrated and subjected to chromatography (CH2Cl2–
MeOH, 98:2) to give 14 (0.27 g, 94%) as a red solid, δH (200
MHz; Me2CO-d6) 10.9 (2H, br s, NH), 7.89 (2H, s, ArH), 7.5-
7.3 (7H, m, ArH), 7.0–6.9 (4H, m, ArH), 6.63 (2H, m, ArH),
4.84 (2H, s, CH2); νmax(KBr)/cmϪ1 3400, 1760, 1685, 1530, 1400,
1345, 1245, 810, 750, 700. These data are in agreement with
those published.24
N-Benzylarcyriaflavin A 15
DDQ (1 g, 4.4 mmol) and a catalytic amount of p-TsOH were
added to a solution of 12 (0.82 g, 1.96 mmol) in benzene (20
ml). The red mixture was stirred at room temperature for 1 h
and heated at reflux for 2 h. Concentration and chrom-
atography (CH2Cl2–MeOH, 98:2) gave 15 (0.73 g, 90%) as red
solid, mp >260 ЊC; δH (DMSO-d6) 11.75 (2H, s, NH), 8.99 (2H,
d, J 7, 8, ArH), 7.82 (2H, d, J 8.1, ArH), 7.56 (2H, app t, ArH),
7.56–7.30 (7H, m, ArH), 4.92 (2H, s, CH2); νmax(KBr)/cmϪ1
3315, 1750, 1680, 1570, 1380, 750, 700. MS (EIϩ) m/z 415.
These data are in agreement with those published.24
Dimethyl 2,3-di(indol-3-yl)succinate 10 from 5
n-BuLi (1.6 M; 25 ml, 40 mmol) was added to a solution of
5 (3.50 g, 20 mmol) in THF (150 ml) over a period of 15 min,
keeping the temperature below Ϫ60 ЊC. After 20 min at Ϫ75 ЊC
the mixture was treated with t-BuLi (1.6 M; 13 ml, 20 mmol)
over a period of 15 min, keeping the temperature below
Ϫ70 ЊC. After 2 h at Ϫ75 ЊC the yellow solution was allowed to
come to Ϫ40 ЊC, kept at that temperature for 30 min, and
recooled to Ϫ75 ЊC. A solution of iodine (2.53 g, 10 mmol) in
THF (10 ml) was added over a period of 10 min at Ϫ70 ЊC,
whereafter the mixture was stirred at Ϫ75 ЊC for 1 h and was
then allowed to reach room temperature overnight. The purple
solution was poured into NaHSO3 (aq., saturated) and, after
separation, the aqueous phase was extracted with EtOAc. The
combined organic phases were washed successively with water
and brine and dried with MgSO4. A solution of diazomethane
(≈30 mmol) in diethyl ether was added and after 1 h unchanged
diazomethane was quenched with acetic acid. Concentration
and chromatography (CH2Cl2–MeOH, 99:1) gave 10 as a
mixture of diastereomers; m/z (EIϩ) 376. IR and NMR data as
above.
trans-3,4-Di(indol-3-yl)succinimide 18a from 10
A diastereomeric mixture of 10 (0.75 g, 2 mmol), HCO2NH4
(10 g) and triglyme (5 ml) was refluxed for 4 days. The solution
was allowed to cool and was then poured into water. The pre-
cipitate formed was collected by filtration. Chromatography
(CH2Cl2–MeOH, 95:5) gave 18a (0.36 g, 55%) as a colourless
foam, mp 239–242 ЊC; δH (300 MHz; DMSO-d6) 11.56 (1H, s,
NH), 11.05 (2H, d, J 1.5, ArH), 7.42–7.35 (6H, m, ArH), 7.08
(2H, app t, ArH), 6.86 (2H, app t, ArH), 4.56 (2H, s, CH);
δC (75 MHz; DMSO-d6) 178.5 (s), 136.5 (s), 126.3 (s), 124.1 (d),
121.3 (d), 118.8 (d), 118.6 (d), 111.7 (d), 110.0 (s), 47.0 (d);
νmax(KBr)/cmϪ1 3430, 3340, 3180, 3060, 1770, 1700, 1550, 755,
740; m/z (ESI) [M ϩ Hϩ] 330. Found: HRMS (EI) m/z
329.1155. C20H15N3O2 requires M, 329.1164.
3,4-Di(indol-3-yl)succinic anhydride 11
The diacid 7 was prepared as above but the combined organic
phases were concentrated, and dissolved in acetic anhydride (50
ml). After reflux for 5 h, the dark brown solution was allowed to
cool and after concentration it was triturated with hot ethanol
to give 11 (1.07 g, 32%) as a slightly reddish solid, mp 250–
255 ЊC; δH (300 MHz; DMSO-d6) 11.16 (2H, s, NH), 7.57 (2H,
d, J 8, ArH), 7.51 (2H, d, J 2, ArH), 7.38 (2H, d, J 8, ArH), 7.10
(2H, app t, ArH), 6.99 (2H, app t, ArH), 5.28 (2H, s, CH);
δC (75 MHz; DMSO-d6) 172.7 (s), 137.1 (s), 127.2 (s), 125.5 (d),
Further elution gave unchanged 10b (0.11 g, 15%).
cis-3,4-Di(indol-3-yl)succinimide 18b. The experiment (hydro-
genation14 of 19) by Davis et al. was repeated. Yield 33% (lit.,
70%); δH (300 MHz; DMSO-d6) 11.59 (1H, s), 10.64 (2H, s),
7.39 (2H, d, J 8), 7.12 (2H, d, J 8), 6.95–6.8 (6H, m), 4.9 (2H, s);
δC (75 MHz; DMSO-d6) 179.6, 135.4, 127.0, 124.4, 120.7, 118.5,
118.3, 111.3, 108.2, 44.7.
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General procedure for dimerization of the 3-substituted indoles
ArH), 6.98–7.15 (4H, m, ArH), 6.70–6.80 (2H, m, ArH), 5.05
(1H, d, J 7.8, CH), 4.27 (1H, d, J 5.4, CH), 4.08 (1H, dd, J 11.5
and 5.4, CH), 3.67 (3H, s, CH3), 3.60 (3H, s, CH3), 3.03 (1H, dd,
J 11.5 and 7.8, CH); δC (DMSO-d6) 172.2 (s), 171.6 (s), 149.2 (s),
136.1 (s), 133.5 (s), 130.4 (s), 128.3 (d), 125.1 (s), 125.1 (d), 121.7
(d), 119.4 (d), 119.1 (d), 118.0 (d), 111.5 (d), 110.8 (d), 105.8 (s),
54.2 (d), 51.8 (q), 51.7 (q), 45.2 (d), 40.4 (d), 39.7 (d); νmax(KBr)/
cmϪ1 3442, 1733, 1663, 1434, 1200, 1137, 757, 745, 723; m/z
(ESI) [M ϩ Hϩ] 377. Found: HRMS (EI) m/z 376.1405.
C22H22N2O4 requires M, 376.1423.
The indole (1 mmol) was dissolved in TFA (2.5 ml) and the
solution was kept at room temperature for 3 h, when water
(15 ml) was added. The pH of the opaque solution was adjusted
to 4 with 2 M NaOH and the crude product was collected
by filtration. The precipitate can be recrystallized from propan-
2-ol.
2-(Indol-2Ј-yl)indoline-3,3Ј-diacetic acid 24a. Yield 91%; mp
156–160 ЊC; δH (300 MHz; DMSO-d6) 11.12 (1H, s, NH), 7.46
(1H, d, J 7.8, ArH), 7.33 (1H, d, J 8.0), 7.11–6.96 (4H, m), 6.79–
6.71 (2H, m, ArH), 4.92 (1H, d, J 7.5, CH), 3.78 (1H, m, CH),
3.73 (2H, s, CH2), 2.61 (1H, dd, J 8.4 and 16.4, CHH), 2.70 (1H,
dd, J 4.5 and 16.4, CHH); δC (300 MHz; DMSO-d6) 173.4 (s),
173.4 (s), 149.0 (s), 135.9 (s), 135.5 (s), 131.6 (s), 127.9 (s), 127.9
(d), 123.6 (d), 121.5 (d), 119.4 (d), 118.6 (d), 118.5 (d), 111.3 (d),
110.3 (d), 106.8 (s), 60.4 (d), 45.5 (d), 36.7 (t), 29.9 (t);
νmax(KBr)/cmϪ1 3089 br, 1703, 1682, 1200, 745; m/z (ESI)
[M ϩ Hϩ] 351.
Compound 28
Dissolution of 10b (10 mg) in TFA (1 ml) at 40 ЊC gave the
known22 indolocarbazole 28 as a precipitate (8 mg).
Tetrahydroarcyriaflavin A 29
The succinimide25 18b (15 mg) was dissolved in TFA (2.5 ml).
After 15 min at room temperature 5 ml of water was added. The
product of 28 (13 mg, 87%) was collected by filtration and
washed with diethyl ether; δH (DMSO-d6) 11.16 (1H, s), 10.90
(1H, s), 7.8 (1H, br s), 7.71 (1H, d, J 7.8), 7.29 (1H, d, J 7.9),
7.17 (1H, d, J 7.2), 7.04 (1H, app t), 6.94 (1H, app t), 6.88 (1H,
app t), 6.58 (1H, app t), 6.50 (1H, d, J 7.6), 4.74 (1H, d, J 7.9),
4.29 (1H, dd, J 7.5 and 2), 4.10 (1H, dd, J 7.9 and 2), 4.01 (1H,
d, J 7.5); δC (DMSO-d6) 179.9 (s), 178.0 (s), 149.7 (s), 136.1 (s),
134.5 (s), 128.9 (s), 127.8 (d), 125.6 (s), 122.5 (d), 121.8 (d),
120.3 (d), 119.0 (d), 117.9 (d), 111.1 (d), 109.3 (d), 104.7 (s), 53.2
(d), 40.9 (d), 40.0 (d), 39.7 (d); m/z (ESI) [M ϩ Hϩ] 330.
These data are in agreement with those published.20
Dimethyl 2-(indol-2Ј-yl)indoline-3,3Ј-diacetate 24b. Yield
97%, mp 112–114 ЊC; δH (DMSO-d6) 11.14 (1H, s, NH), 7.41
(1H, d, J 8, ArH), 7.31 (1H, d, J 8, ArH), 6.94–7.1 (4H, m,
ArH), 6.62–6.70 (2H, m, ArH), 4.85 (1H, d, J 11, CH), 3.79
(2H, s, CH2), 3.71 (1H, dd, J 6 and 11, CHH), 3.58 (3H, s, CH3),
3.51 (3H, s, CH3), 2.72 (2H, d, J 6, CH); δC (DMSO-d6) 29.3 (t),
36.0 (t), 45.5 (d), 51.3 (q), 51.5 (q), 60.4 (d), 105.6 (s), 109.5 (d),
111.1 (d), 116.1 (d), 116.5 (d), 121.3 (d), 123.2 (d), 127.6 (s),
127.7 (d), 130.5 (s), 135.7 (s), 136.0 (s), 149.8 (s), 172.0 (2s);
νmax(KBr)/cmϪ1 3361, 2522 br, 1722, 1655, 1618, 1415, 1206,
744; m/z (ESI) [M ϩ Hϩ] 379. Found: HRMS (EI) m/z
378.1562. C22H22N2O4 requires M, 378.1580.
Arcyriaflavin A 4
The succinimide25 18b (15 mg) was dissolved in TFA (5 ml).
The solution was refluxed for 8 h, when water was added. The
orange product (11 mg, 75%) was collected by filtration and
washed with diethyl ether, mp >260 ЊC; δH (DMSO-d6) 11.79
(2H, s), 10.97 (1H, s), 8.98 (2H, d, J 7.9), 7.79 (2H, d, J 8.2),
7.54 (2H, app t), 7.34 (2H, app t); δC (DMSO-d6) 171.3 (s), 140.3
(s), 129.1 (s), 126.8 (d), 124.3 (d), 121.6 (s), 120.2 (d), 119.9 (s),
115.5 (s), 112.0 (d). These data are in agreement with those
published.26
Diethyl 2-(indol-2Ј-yl)indoline-3,3Ј-diacetate 24c. Yield 99%,
δH (300 MHz; DMSO-d6) 11.11 (1H, s), 7.41 (1H, d, J 7.8), 7.30
(1H, d, J 8.0), 7.05–6.95 (4H, m), 6.64–6.57 (2H, m), 6.03 (1H,
d, J 3.2), 4.80 (1H, dd, J 10.8 and 3.2), 4.05–3.76 (4H, m), 3.76
(2H, s), 3.70 (1H, dd, J 10.8 and 6.6), 2.70 (2H, d, J 6.6),
1.16 (3H, t, J 7.1), 1.06 (3H, t, J 7.1); δC (DMSO-d6) 172.1 (2s),
149.8 (s), 136.3 (s), 135.4 (s), 129.6 (s), 128.3 (d), 128.0
(s), 124.0 (d), 122.3 (d), 119.6 (d), 119.3 (d), 118.5 (d), 110.9
(d), 109.4 (d), 105.8 (s), 61.2 (d), 60.9 (t), 60.6 (t), 46.1 (d),
37.4 (t), 30.1 (t), 14.1 (q), 14.0 (q); m/z (ESI) [M ϩ Hϩ] 407.
Found: HRMS (EI) m/z 406.1882. C24H26N2O4 requires M,
406.1893.
References
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Dimethyl 2,2Ј-biindolyl-3,3Ј-dicarboxylate 26
DDQ (260 mg, 1.14 mmol) in 1,4-dioxane (7 ml) was added to a
solution of the dimer 24b of indole-3-acetic acid methyl ester
(430 mg, 1.14 mmol) in 1,4-dioxane (15 ml) at room temper-
ature. After 16 h the DDQ-2H was filtered off and the solvent
was evaporated. The residue was recrystallized from propan-2-
ol and filtration gave 261 mg (61%) of the product as a white
solid, mp 196–197 ЊC; δH (DMSO-d6) 11.35 (2H, s, NH), 7.50
(2H, app d, ArH), 7.41 (2H, app d, ArH), 7.18 (2H, app t,
ArH), 7.06 (2 H, app t, ArH), 3.77 (4H, s, CH2), 3.58 (3H, s,
CH3); δC (DMSO-d6) 172.1 (q), 136.3 (q), 127.8 (q), 127.6 (q),
122.1 (s), 119.2 (s), 119.0 (s), 111.4 (s), 107.3 (q), 51.7 (q), 30.2
(t); m/z (ESI) [M ϩ Hϩ] 377. Found: HRMS (EI) m/z 376.1408.
C22H22N2O4 requires M, 376.1423.
The tetrahydroindolocarbazole 27
15 Following paper: J. Bergman, T. Janosik, E. Koch and B. Pelcman,
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solved in TFA (1.5 ml) at room temperature and the solution
stirred for 3 h. Water was added and the slightly yellow precipi-
tate 26 (18 mg, 94%) was collected by filtration and washed with
water, δH (DMSO-d6) 11.05 (1H, s, NH), 7.38–7.45 (2H, m,
J. Chem. Soc., Perkin Trans. 1, 2000, 2609–2614
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