Synthesis of Novel Pyrrolo[3,2- c ]carbazole and Dipyrrolo[3,2- c:2′,3′- g ]carbazole Derivatives

Article abstract of DOI:10.1055/s-0035-1560601

Pyrrolocarbazole and dipyrrolocarbazoles have been synthesized via the Hemetsberger indole synthesis, starting from 9-ethyl carbazole-3-carbaldehyde and 9-ethylcarbazole-3,6-dicarbaldeyde, respectively. The pyrrolocarbazole structures were confirmed through ¹H NMR, ¹³C NMR, IR, mass spectrometry and single crystal X-ray diffraction techniques. The targeted compounds showed potent in vitro cytotoxicity against human colon cancer HT29 cells.

Full text of DOI:10.1055/s-0035-1560601

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
A
letter
Synlett
I. F. Sengul et al.
Letter
Synthesis of Novel Pyrrolo[3,2-c]carbazole and Dipyrrolo[3,2-c:
′,3′-g]carbazole Derivatives
2
Ibrahim Fazil Sengula
Erhan Astarcib
Hakan Kandemir*c
a
Department of Chemistry, Gebze Technical University,
P.O. Box. 141, 41400 Kocaeli, Turkey
Mudurnu Sureyya Astarci Vocational School, Abant Izzet
b
Baysal University, Bolu, Turkey
Department of Chemistry, Faculty of Art and Science,
c
Namık Kemal University, Tekirdag, Turkey
hknkandemir@gmail.com
Received: 18.11.2015
Accepted after revision: 30.12.2015
Published online: 02.02.2016
many heterocyclic skeletons. The overall process to form an
indole by the Hemetsberger strategy involves three steps;
the synthesis of an alkyl azidoacetate, a base-promoted
Knoevenagel condensation between an azidoacetate and an
aromatic aldehyde to form a vinyl azide and the thermolysis
of the vinyl azide in an intramolecular cyclization to form
the indole skeleton.12 Recently, Liotta reported a new ap-
proach to Hemetsberger indolization using ethyl trifluoro-
acetate as a sacrificial electrophile in order to increase the
DOI: 10.1055/s-0035-1560601; Art ID: st-2015-d0896-l
Abstract Pyrrolocarbazole and dipyrrolocarbazoles have been synthe-
sized via the Hemetsberger indole synthesis, starting from 9-ethyl car-
bazole-3-carbaldehyde and 9-ethylcarbazole-3,6-dicarbaldeyde, respec-
1
tively. The pyrrolocarbazole structures were confirmed through H NMR,
13
C NMR, IR, mass spectrometry and single crystal X-ray diffraction
techniques. The targeted compounds showed potent in vitro cytotoxici-
ty against human colon cancer HT29 cells.
13
overall yield of the Knoevenagel condensation. Our aim
was to investigate the Hemetsberger indole synthesis as a
synthetic route for the construction of novel pyrrolo[3,2-
c]carbazole and dipyrrolo[3,2-c:2′,3′-g]carbazole systems.
As part of an ongoing investigation into the chemistry of
pyrrolocarbazoles, it was decided to use the Hemetsberger
strategy in the preparation of monomeric and dimeric pyr-
role derivatives based on structurally rigid carbazole ring
systems as precursors. As other pyrrolocarbazole systems
have also shown cytotoxic activity, it was decided to evalu-
ate their cytotoxicity against the HT29 colon adenocarcino-
ma cell line.
Key words carbazole, pyrrolocarbazole, Hemetsberger indolization,
HT29 cells, cyctotoxicity
Carbazole and its derivatives are an important class of
aromatic heterocyclic compounds in the area of medicinal
1
chemistry. In particular, heteroannulated carbazole alka-
loids are found in numerous natural products and play an
2–4
important role in pharmaceuticals. Significant effort has
been focused on the preparation of pyrrolocarbazole scaf-
folds due to their promising biological activities, such as an-
tidepressant, anticancer and antibacterial activities.5 For
example, pyrrolo[2,3-a]carbazole derivatives show inhibi-
tory activity towards topoisomerase I expression, cell via-
bility of glioma and endothelial cells in vitro and angiogen-
,6
Carbazole ring systems are easily functionalized and co-
valently linked to other molecules.1
4,15
Therefore, this sys-
tem was chosen as the precursor to the targeted mono- and
dipyrrolocarbazoles. The synthesis of pyrrolocarbazoles be-
gan with the formylation of 9-ethylcarbazole 1 via the Vils-
7
esis in vivo. Having a pyrrolo[2,3-c]carbazole core, dictyo-
dendrin A was isolated from Dictyodendrilla verongiformis,
and was the first marine natural product with telomerase
inhibitory properties, showing 100% inhibition at 50
meier–Haack formylation, using POCl /DMF to obtain mo-
3
no- and diformylcarbazoles 2 (Scheme 1) and 6 (Scheme
16,17
2).
With the carbazole-3-carbaldehyde 2 and carbazole-
8
mg/mL. Furthermore, dipyrrole and its derivatives are as-
3,6-dicarbaldehyde 6 in hand, it was of interest to use a mo-
nomeric model for the preparation of monopyrrolocarba-
zole 4 before extending the chemistry to dipyrrolocarba-
zoles. Accordingly, the preparation of the targeted pyrrolo-
carbazole under the Hemetsberger conditions was
undertaken. Methyl azidoacetate was synthesized by the
method of Liotta, via treatment of anhydrous sodium azide
sociated with antifungal, antibacterial, antimalarial, antitu-
9
mor and anticancer properties.
Many synthetic approaches have been reported for the
10,11
synthesis of pyrrolocarbazoles.
The Hemetsberger reac-
tion is potentially an important method for the synthesis of
indole derivatives, providing the foundation for access to
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Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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I. F. Sengul et al.
Letter
O
OMe
HN
O
OMe
c
O
N3
N
H
a
b
4
N
N
N
O
OMe
1
2
3
NH
N
5
Scheme 1 Reagents and conditions: (a) DMF, POCl , reflux, 12 h, 60%; (b) N CH CO Me, NaOMe, anhyd MeOH, –15 °C, 4 h, 71%; (c) 1,2-dichloroben-
3
3
2
2
zene, reflux, 3 h, 83%.
with methyl bromoacetate in a mixture of acetone/water
c]carbazole 4, which crystallizes in the monoclinic space
13
10
(50:50) at room temperature. The carbazole-3-carbalde-
group P2 /n. The bond lengths and angles are within nor-
1
hyde 2 was subsequently reacted with seven equivalents of
methyl azidoacetate in the presence of sodium methoxide
to afford the azido ester intermediate 3.
mal ranges. The pyrrolocarbazole skeleton is almost planar,
consistent with the geometry found in similar com-
pounds,21 as shown in Figure 1. The NH group forms a linear
intermolecular N–H···O hydrogen bonding interaction with
a N···O distance of 2.9430 (19) Å along the b axis in the crys-
tal structure.
Interestingly, when closely monitoring the reaction by
thin layer chromatography, it was noticed that the reaction
did not proceed to completion, and some starting material
remained unreacted even after 24 hours. The source of the
problem was thought to be the solubility of carbazole-3-
carbaldehyde 2 in cold methanol. Tetrahydrofuran, in which
carbazole 2 has no such solubility issue, was subsequently
18
used and the problem was successfully solved.
The most significant features in the IR spectrum of com-
pound 3 were the characteristic N and C=O peaks that ap-
3
–1
–1
peared at 2100 cm and 1700 cm , respectively.
In the next step, thermal decomposition of azido ester 3,
followed by intramolecular cyclization in 1,2-dichloroben-
zene at reflux could result in the formation of regioisomers
4
or 5. Investigation of the reaction mixture afforded only
one product in which insertion had occurred at C4 showing
19
the formation of 4. A previous report on a similar ring clo-
sure also supported the conclusion that insertion had taken
20
place at C4 rather than at C2.
Figure 1 Ortep diagram of the pyrrolo[3,2-c]carbazole 4. Displace-
ment ellipsoids are drawn at the 50% probability level. H atoms are
shown as small spheres of arbitrary radii.
The structure of compound 4 was determined through
NMR spectroscopy, with the H NMR spectrum showing a
1
singlet at δ = 9.54 ppm, corresponding to the pyrrolo NH
proton, and the disappearance of the H4 proton of com-
pound 3, confirming that cyclization had taken place. The IR
spectrum also showed no absorption in the region of 2100–
Having successfully used this method to prepare mono-
meric pyrrolocarbazoles, preparation of related dipyrrolo-
carbazole systems was next examined. The Hemetsberger
reaction was again employed for the preparation of dipyrro-
locarbazoles 9 (Scheme 2).
–1
2
200 cm , indicating that no N bonds were present. A
3
suitable single crystal led to X-ray crystallographic determi-
nation, further confirming the formation of pyrrolo[3,2-
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I. F. Sengul et al.
Letter
O
R
NH
O
R
NH
N
8
O
O
O
O
R
R
R
R
N3
O
N3
O
NH HN
H
H
a
b, b1
c
N
N
N
N
1
6
7
9
7
a
b
–10
R
OMe
OEt
O
O
R
R
HN
NH
N
10
Scheme 2 Reagents and conditions: (a) DMF, POCl , reflux, 24 h, 58%; (b) N CH CO Me, NaOMe, anhyd MeOH, –15 °C, 4 h, 15%; (b1) N CH CO Et,
3
3
2
2
3
2
2
CF COOEt, NaOEt, absolute EtOH, –5 °C, 3 h, 42%; (c) 1,2-dichlorobenzene, reflux, 3 h, 58–60%.
3
Condensation of carbazole-3,6-dicarbaldehyde 6 with
fourteen equivalents of methyl azidoacetate in THF gave the
corresponding methyl vinyl ester 7a in 15% yield; whereas
the use of methyl azidoacetate in the presence of sodium
ethoxide and ethanol gave ethyl vinyl ester 7b in 28% yield.
This confirms that the yield of ester depends on the choice
of base, rather than azidoacetate. The problem associated
with the low yield of 7b was partially overcome by the use
of ethyl trifluoroacetate as a sacrificial electrophile. Accord-
ingly, to a solution of carbazole-3,6-dicarbaldehyde 6 in
THF, fourteen equivalents of ethyl azidoacetate and four
equivalents of ethyl trifluoroacetate were added and this
mixture was subsequently added to sodium ethoxide solu-
tion at –5 °C in two or three portions. In this manner, the
Double indolization via nitrene insertion of 7a and 7b in
1,2-dichlorobenzene was subsequently investigated. The
thermal cyclization of vinyl esters 7a,b could give a mixture
of three isomeric pyrrolocarbazoles, namely, dipyrrolo[2,3-
b:2′,3′-g]carbazoles 8a,b, dipyrrolo[3,2-c:2′,3′-g]carbazoles
9a,b and dipyrrolo[2,3-b:3′,2′-h]carbazoles 10a,b as shown
in Scheme 2. However, when vinyl esters 7a,b were treated
with 1,2-diclorobenzene at reflux for three hours, dimeric
pyrrolocarbazoles 9a and 9b23 were found to be the exclu-
sive products of the reaction and were isolated in 58% and
60% yields, respectively.
The symmetrical structure of 9a was confirmed through
examination of its 1H NMR spectrum, which displayed a
singlet at δ = 10.7 ppm corresponding to the pyrrole NH
protons, while the pyrrole ring CH protons appeared at δ =
7.32 ppm. The structure of compound 9a was confirmed by
X-ray crystallography as shown in Figure 2, which revealed
that the planar dipyrrolocarbazole co-crystallized with a
22
reaction yield of 7b was increased to 42%. Quite surpris-
ingly, no reaction occurred when a methyl trifluoroacetate
and sodium methoxide combination was used. Consequent-
ly, the yield of 7a could not be increased further.
1
21
The H NMR spectrum of ethyl vinyl ester 7b in CDCl3
water molecule. The water molecule, which acts as both a
showed only one stereoisomer, indicating a singlet corre-
sponding to the alkenyl CH at δ = 7.17 ppm and a 6H multi-
plet assigned to the CH2 protons between δ = 4.37–4.43
ppm. The formation of compound 7b was further con-
hydrogen donor and an acceptor, was bound to the dipyrro-
locarbazole with double O–H···O and N–H···O hydrogen
bonding interactions.
An exploratory investigation into the reactivity of pyr-
rolocarbazoles 5, 9a and 9b was also carried out. It was re-
vealed from the literature that pyrrolocarboxylic acid mo-
tifs, commonly found in natural products, possess many
firmed by the IR spectrum, showing the azide (N ) band ab-
3
–1
sorption at 2108 cm .
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I. F. Sengul et al.
Letter
rolocarbazoles against human colon cancer (HT29) cell lines
of compounds 4, 9a,b, 11 and 12 was evaluated at different
concentrations (0, 5, 10, 25, 50, 100, 250 ng/mL). The cyto-
toxic activity of the targeted compounds was assessed by
calculating the concentration that inhibited the HT29 cell
by 50% (IC ) and the results are shown in Table 1. Although
50
the mechanism of compounds 4, 9a,b, 11 and 12 in terms of
their toxic effect has not yet been studied for this cell type,
these results are promising.
Table 1 Cytotoxic Activity of Pyrrolocarbazoles
Compound
IC50 Values (μM)
4
0.019
0.73
9
9
a
b
0.39
1
1
1
2
0.069
0.013
Figure 2 Ortep diagram of the dipyrrolocarbazole 9a. Displacement
ellipsoids are drawn at the 50% probability level. H atoms are shown as
small spheres of arbitrary radii.
In conclusion, the Hemetsberger reaction provides an
effective approach for the synthesis of pyrrolocarbazole
systems. The thermal cyclization of the vinyl ester precur-
sors to give the pyrrolocarbazoles was found to be regiose-
lective. A preliminary screening of the targeted compounds
developed throughout this body of work displayed reason-
able cytotoxic activity against human colon cancer HT29
cell lines. Work is currently underway to prepare further
bioactive monomeric and dimeric fused carbazole deriva-
tives and to use them further in anticancer studies.
useful chemical and electronic features that are readily ex-
ploited in biological contexts.24 The hydrolysis of the pyrro-
locarbazoles was successfully achieved by heating 5, 9a and
9
b in ethanolic sodium hydroxide under reflux to afford the
25
corresponding carboxylic acids 11 and 12, respectively
(Scheme 3).
O
O
OMe
OH
Acknowledgment
HN
HN
This work was funded by TUBITAK grant 113Z159 to E.A., İ.F.S., and
H.K. We thank the NMR facility of Gebze Technical University.
N
N
Supporting Information
11
4
Supporting information for this article is available online at
O
R
O
O
O
HO
R
OH
http://dx.doi.org/10.1055/s-0035-1560601.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
NH HN
NH HN
References and Notes
(1) Zhang, F. F.; Gan, L. L.; Zhou, C. H. Bioorg. Med. Chem. Lett. 2010,
N
N
20, 1881.
(2) Molina, P.; Fresneda, P. M.; Almendros, P. Tetrahedron 1993, 49,
1
223.
8
12
(
3) Kirsch, G. H. Curr. Org. Chem. 2001, 5, 507.
(
4) Bergman, J.; Janosik, T.; Wahlstrom, N. Adv. Heterocycl. Chem.
Scheme 3 Reagents and conditions: EtOH, KOH, reflux, 3 h, 65–77%.
2001, 80, 1.
(
5) Akue-Gedu, R.; Rossignol, E.; Azzaro, S.; Knapp, S.;
Filippakopoulos, P.; Bullock, A. N.; Bain, J.; Cohen, P.;
Prudhomme, M.; Anizon, F.; Moreau, P. J. Med. Chem. 2009, 52,
6369.
The anticancer activity of mono- and dipyrrolocarba-
zoles was investigated in an attempt to understand their bi-
ological properties. A preliminary in vitro evaluation of pyr-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
Synlett
I. F. Sengul et al.
Letter
(
6) Hugon, B.; Anizon, F.; Bailly, C.; Golsteyn, R. M.; Pierre, A.;
Hickman, S. L. J.; Prudhomme, B. P. M. Bioorg. Med. Chem. 2007,
5, 5965.
120.6, 120.6, 121.2, 121.2, 124.2, 124.8, 132.1, 138.5, 138.8,
+
162.5 (aryl C). Maldi (TOF): m/z = 293 [M + H] . HRMS (ESI, +ve):
+
1
m/z [M + H] calcd for C18H16N O : 293.1290; found: 293.1291.
2
2
(
7) Lampropoulou, E.; Manioudaki, M.; Fousteris, M.; Koutsourea,
(20) Rodriguez-Salvador, L.; Zaballos-Garcia, E.; Gonzales-Rosende,
E.; Testa, M. L.; Sepulveda-Arques, J.; Jones, R. A. Tetrahedron
2000, 56, 4511.
(21) CCDC 1049555 (for 4) and 1400624 (for 9a) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
A.; Nikolaropoulos, S.; Papadimitriou, E. Biomed. Pharmacother.
2
011, 65, 142.
8) Ayats, C.; Soley, R.; Albericio, F.; Alvarez, M. Org. Biomol. Chem.
009, 7, 860.
(
(
2
9) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P. RSC
Adv. 2015, 5, 15233.
(
10) Viji, N.; Nagarajan, R. RSC Adv. 2012, 2, 10544.
(22) A solution of sodium ethoxide was prepared via the portionwise
addition of metallic sodium (0.6 g, 26.09 mmol) to pre-cooled
anhyd EtOH (50 mL) with stirring under nitrogen. The sodium
ethoxide solution was stirred and cooled to –5 °C in an ice-salt
slurry before the addition of a solution containing the carba-
zole-3,6-dicarbaldehyde 6 (1.87 g, 7.42 mmol), methyl azidoac-
etate (9.83 g, 85.55 mmol) and ethyl trifluoroacetate (2.9 mL,
24.44 mmol) in anhyd THF (11 mL). The mixture was stirred for
a further 3 h with cooling and then poured onto crushed ice.
The resulting precipitate was filtered and purified (only for
characterization) by flash column chromatograpy using CH2-
(
11) Fousteris, M. A.; Papakyriakou, A.; Koutsourea, A.; Manioudaki,
M.; Lampropoulou, E.; Papadimitriou, E.; Spyroulias, G. A.;
Nikolaropoulos, S. J. Med. Chem. 2008, 51, 1048.
(12) Bingul, M.; Cheung, B. D.; Kumar, N.; Black, St. C. D. Tetrahedron
2014, 70, 7363.
(
13) Heaner, W. L. IV.; Gelbaum, C. S.; Gelbaum, L.; Pollet, P.;
Richman, K. W.; Dubay, W.; Butler, J. D.; Wells, G.; Liotta, C. L.
RSC Adv. 2013, 3, 13232.
(14) Pawluc, P.; Franczyk, A.; Walkowiak, J.; Hreczycho, G.; Kubicki,
M.; Marciniec, B. Org. Lett. 2011, 13, 1976.
(
15) Asakawa, M.; Ashton, P. R.; Brown, C. L.; Fyfe, M. C. T.; Menzer,
S.; Pasini, D.; Scheuer, C.; Spencer, N.; Stoddart, J. F.; White, A. J.
P. Chem. Eur. J. 1997, 3, 1136.
Cl /hexane (5:5) as eluent to give the title compound 7b as a
2
yellow solid (1.47 g, 42%); mp 131–133 °C. IR (KBr): 3382, 2981,
2108, 1699, 1590, 1483, 1365, 1304, 1228, 1196, 1157, 1129,
–1 1
(
16) Budreckiene, R.; Buika, G.; Grazulevicius, J.; Jankauskas, V.;
Staniskiene, B. J. Photochem. Photobiol. A: Chem. 2006, 181, 257.
17) Kandemir, H.; Sengul, I. F. Synth. Commun. 2015, 22, 2583.
18) A solution of sodium methoxide was prepared via the portion-
wise addition of metallic sodium (1.2 g, 52.17 mmol) to pre-
cooled anhyd MeOH (40 mL) with stirring under nitrogen. The
sodium methoxide solution was stirred and cooled to –15 °C in
an ice-salt slurry before the dropwise addition of a solution
containing the carbazole-3-carbaldehyde 2 (1.064 g, 4.77
mmol) and methyl azidoacetate (5.37 g, 46.5 mmol) in anhyd
THF (6 mL) over 1 h. The mixture was stirred for a further 3 h
with cooling and then poured onto crushed ice. The resulting
precipitate was filtered and purified by flash column chromato-
grapy using CH Cl /hexane (5:5) as eluent to give the title com-
1078, 1018, 899, 801 cm . H NMR (500 MHz, CDCl ): δ = 1.43–
3
1.49 (m, 9 H, 3 × Me), 4.37–4.43 (m, 6 H, 3 × CH ), 7.17 (s, 2 H,
2
(
(
alkyl H), 7.42 (d, J = 8.9 Hz, 2 H, aryl H), 8.03 (t, J = 7.5 Hz, 2 H,
aryl H), 8.62 (s, 2 H, aryl H). Maldi (TOF): m/z = 418 [M – 4 N].
(23) The azidocinnamate 7b (1.47 g, 3.11 mmol) was dissolved in
1,2-dichlorobenzene (30 mL) and the resulting mixture was
heated at reflux for 3 h. The solvent was then removed under
reduced pressure and the residue was purified by flash column
chromatograpy using CH Cl /hexane (8:2) as eluent to give the
2
2
title compound 9b (0.77 g, 60%); mp 227–229 °C. IR (KBr): 3477,
3361, 2975, 1698, 1670, 1633, 1532, 1499, 1388, 1345, 1300,
–1
1
1257, 1198, 1154, 1017, 782, 743 cm
. H NMR (500 MHz,
CDCl ): δ = 1.63 (d, J = 5.7 Hz, 9 H, 3 × Me), 4.54–4.65 (m, 6 H, 3
3
× CH ), 7.49 (s, 2 H, aryl H), 7.62 (s, 2 H, aryl H), 7.84 (d, 2 H, aryl
2
2
2
13
pound 3 as a yellow solid (1.08 g, 71%); mp 107–109 °C. IR
H), 10.82 (s, 2 H, pyrrolo NH). C NMR (125 MHz, CDCl ): δ =
3
(
1
KBr): 3071, 2983, 2950, 2120, 1708, 1592, 1497, 1471, 1430,
14.3, 14.4 (Me), 38.6, 61.0 (CH ), 105.2, 119.5, 119.6, 121.7,
2
371, 1336, 1250, 1228, 1155, 1078, 915, 807, 744 cm–1
.
1
H
124.8, 132.0, 137.4, (aryl C), 163.3 (C=O). Maldi (TOF): m/z = 418
+
+
NMR (500 MHz, CDCl ): δ = 1.46 (m, 3 H, Me), 3.95 (s, 3 H, OMe),
[M + H] . HRMS (ESI, +ve): m/z [M + Na] calcd for C24H23N O :
3
3 4
4
.40 (d, J = 7.0 Hz, 2 H, CH ), 7.19–7.31 (m, 2 H, aryl H), 7.40–
440.1586; found: 440.1577.
2
7
.52 (m, 3 H, aryl H), 7.98 (m, 1 H, aryl H), 8.17 (d, J = 7.0 Hz, 1
(24) Walsh, C. T.; Tsodikova, S. G.; Howard-Jones, A. R. Nat. Prod. Rep.
2006, 23, 517.
13
H, alkyl H), 8.64 (s, 1 H, aryl H). C NMR (125 MHz, CDCl ): δ =
3
1
1
1
3.8 (Me), 37.7 (CH ), 52.7 (OMe), 108.8, 108.8, 119.5, 120.6,
22.2, 123.1, 123.4, 124.2, 126.1, 127.4, 128.8, 140.4 (aryl C),
68.8 (C=O). Maldi (TOF): m/z = 292 [M – 2 N].
(25) Pyrrolo carbazole 4 (1 g, 3.42 mmol) was heated to reflux in
ethanolic (30 mL) potassium hydroxide (1.15 g, 20.55 mmol) for
3 h. After cooling, the solution was acidified with 5 M HCl and
2
(
19) The azidocinnamate 3 (1 g, 3.12 mmol) was dissolved in 1,2-
dichlorobenzene (30 mL) and the resulting mixture was heated
at reflux for 3 h. The solvent was then removed under reduced
pressure and the residue was purified by flash column chro-
matograpy using CH Cl /hexane (8:2) as eluent to give the title
the resulting precipitate was filtered, washed with H O and
dried to yield the carboxylic acid 11 as a green solid (0.73 g,
2
77%); mp 232–234 °C. IR (KBr): 3432, 2961, 1669, 1638, 1545,
–
1 1
1491, 1462, 1449, 1338, 1310, 1287, 1259 cm
. H NMR (500
MHz, CDCl ): δ = 1.33 (t, J = 7.0 Hz, 3 H, Me), 4.51 (q, J = 7.5 Hz, 2
2
2
3
compound 4 (0.76 g, 83%); mp 144–146 °C. IR (KBr): 3336,
690, 1638, 1536, 1493, 1342, 1307, 1256, 1200, 1178, 1148
H, CH ), 7.22 (t, J = 7.4 Hz, 1 H, aryl H), 7.34 (d, J = 1.9 Hz, 1 H,
2
1
aryl H), 7.40–7.46 (m, 2 H, aryl H), 7.64 (d, J = 8.2 Hz, 1 H, aryl
H), 7.74 (d, J = 8.7 Hz, 1 H, aryl H), 9.02 (d, J = 7.7 Hz, 1 H, aryl H),
12.04 (s, 1 H, carboxylic OH), 12.65 (s, 1 H, pyrrolo NH). 13C NMR
(125 MHz, CDCl ): δ = 14.4 (Me), 37.7 (CH ), 105.2, 106.8, 109.2,
–1 1
cm . H NMR (500 MHz, CDCl ): δ = 1.46 (t, J = 7.1 Hz, 3 H, Me),
3
3
.97 (s, 3 H, OMe), 4.46 (q, 2 H, J = 7.1 Hz, CH ), 7.27–7.51 (m, 5
2
H, aryl H), 7.74 (d, J = 8.7 Hz, 1 H, aryl H), 8.24 (d, J = 8.7 Hz, 1 H,
3
2
13
aryl H), 9.54 (s, 1 H, pyrrolo NH). C NMR (125 MHz, CDCl ): δ =
110.7, 119.2, 120.8, 121.3, 122.9, 124.4, 126.8, 132.2, 138.3,
3
+
1
4.1 (Me), 38.0 (CH ), 51.8 (OMe), 104.9, 108.9, 110.6, 119.4,
138.6, 163.2 (aryl C). Maldi (TOF): m/z = 279 [M + H] . HRMS
2
+
(
ESI, +ve): m/z [M + H] calcd for C17H14N O : 279.1134; found:
2
2
279.1129.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E