Intramolecular Diels-Alder reaction for the synthesis of tetracyclic carbazoles and isocanthines

Article abstract of DOI:10.1016/j.tet.2013.10.054

One pot intramolecular Diels-Alder reaction has been efficiently used as a new route for the synthesis of four tetracyclic carbazoles and four isocanthine analogues where a dialdehyde is utilised as a common intermediate for both the scaffolds. Biological activity was evaluated for some molecules, which demonstrated moderate activity against HeLa cervical cancer cell lines.

Full text of DOI:10.1016/j.tet.2013.10.054

Tetrahedron xxx (2013) 1e6
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular DielseAlder reaction for the synthesis of tetracyclic
carbazoles and isocanthines
*
Prajakta N. Naik, Ayesha Khan, Radhika S. Kusurkar
Department of Chemistry, University of Pune, Pune, 411 007, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
One pot intramolecular DielseAlder reaction has been efficiently used as a new route for the synthesis of
four tetracyclic carbazoles and four isocanthine analogues where a dialdehyde is utilised as a common
intermediate for both the scaffolds. Biological activity was evaluated for some molecules, which dem-
onstrated moderate activity against HeLa cervical cancer cell lines.
Received 19 September 2013
Received in revised form 11 October 2013
Accepted 17 October 2013
Available online xxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Intramolecular DielseAlder reaction
Isocanthine
Tetracyclic carbazole
a,b-Unsaturated hydrazone
1. Introduction
in Fig 1. These alkaloids are known to act as cardiovascular agent7
and 5HT3 receptor antagonist.8 Palladium-catalysed intra-
Tetracyclic carbazole analogue X (Fig. 1) has carbazole as a basic
skeleton, which is a common artifact of many natural products
having biological activity, such as inhibitory activity against cyclin-
dependent kinase 4 and antiproliferative activity in a human colon
carcinoma cell line,1 antiplatelet aggregation activity,2 inhibition
against pRb phosphorylation3 etc. Several routes are available for
the synthesis of derivatives of tetracyclic carbazole X, which in-
volve mainly photocyclisation,4 Heck coupling5 and DielseAlder
reactions as key steps.6
molecular annulation9 and hetero DielseAlder reaction10 have
been used for the synthesis of isocanthines in the past. Recently,
a one pot electrocyclisation strategy and intramolecular aza-Diel-
seAlder (ADA) reaction approach have been developed in our
group for the synthesis of
g
-carboline derivatives11 and for new
canthine analogues,12 respectively.
In continuation with this, the present work describes the use of
intramolecular DielseAlder strategy for an efficient and short
synthesis of substituted tetracyclic carbazole and isocanthine an-
alogues using dialdehyde as a common intermediate.
2. Results and discussion
The synthesis was planned as shown in the retrosynthetic
analysis (Scheme 1) where in, dialdehyde would be a common in-
termediate to achieve both the target scaffolds.
The scheme towards tetracyclic carbazole started with for-
mylation of indole 1, using VilsmeiereHaack conditions (Scheme 2).
3-Formyl indole 2 was then treated with 4-chloro-butan-1-ol, to
get the N-alkylated 3-formyl indole 3. Compound 3 was oxidised
using o-iodoxybenzoic acid (IBX) to deliver the intermediate dia-
ldehyde 4. Refluxing dialdehyde 4 in toluene with excess of car-
Fig. 1. Tetracyclic carbazole and isocanthine skeleton.
Isocanthines are heterocyclic analogues of carbazoles, which are
-carboline alkaloids possessing a tetracyclic skeleton Y as shown
bethoxymethylenetriphenyl phosphorane (4 equiv), for
8 h,
g
afforded trans olefin 5. Further, the DielseAlder reaction of com-
pound 5 was attempted by refluxing in toluene for about 60 h.
However, starting material was recovered in this case. Changing the
solvent from toluene to o-dichlorobenzene, refluxing for 36 h and
* Corresponding author. E-mail address: rsk@chem.unipune.ac.in (R.S. Kusurkar).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.054
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P.N. Naik et al. / Tetrahedron xxx (2013) 1e6
Scheme 1. Retrosynthetic analysis.
further purification led us to the desired cycloadduct 5a in 78%
yield. This compound was then characterised and was shown to be
a single diastereomer from 1H NMR spectral data. Nevertheless, the
geometry of the isomer could not be fixed from the available data.
This cycloadduct was further dehydrogenated using DDQ in o-di-
chlorobenzene to get the product6 6 as one of the targeted tetra-
cyclic carbazoles in 75% yield. It was then thought to carry out the
cycloaddition and dehydrogenation reaction in one pot with an aim
to reduce the reaction time. Thus, compound 5 was refluxed in o-
dichlorobenzene in presence of DDQ. As expected, tetracyclic car-
bazole 6 was produced after 36 h in 75% yield. From these experi-
ments, it was revealed that a one pot reaction sequence having
cycloaddition and dehydrogenation together was an efficient route
considering the time and the yield of the reaction (Scheme 2).
isocanthine analogue. Thus, compound 4 was refluxed with
2 equiv of carbethoxymethylenetriphenyl phosphorane to fur-
nish trans olefin 7 after 2 h. In subsequent step, use of imino
diene system in the form of
a,b-unsaturated hydrazone was
envisioned in an aza-DielseAlder reaction. Thus, compound 7
was refluxed for 60 h in toluene in presence of excess hydrazine
hydrate. Instead of the expected hydrazone as the product,
a new isocanthine derivative 8 was obtained in 72% yield. For-
mation of product 8 could be explained by initial in situ for-
mation of hydrazone 7a, followed by intramolecular aza-
DielseAlder reaction and dehydrogenation of the cycloadduct
along with loss of ammonia. The efforts to isolate the in-
termediate hydrazone were unsuccessful because of the in-
stability of the hydrazone.
Scheme 2. Reagents and conditions: a) DMF, POCl3, rt, 5 h; b) KOH, DMSO, ClCH2(CH2)nCH2OH, rt, 5 h; c) IBX, EtOAc, 80 ꢀC, 8 h; d) PPh3CHCOOEt (4 equiv), toluene, reflux, 8 h (for
R¼CO2Et) or PPh3CH3I (4 equiv), nBuLi, THF, rt, 2 h (for R¼H); e) o-dichlorobenzene, reflux, 36 h, 78%; f) DDQ, o-dichlorobenzene, reflux, 12 h, 75%; g) DDQ, o-dichlorobenzene,
reflux, 36 h; h) PPh3CHCOOEt (2 equiv), toluene, reflux, 2 h or PPh3CH3I (2 equiv), nBuLi, THF, 30 min (R¼H); i) NH2eNH2$H2O, toluene, reflux, 60 h.
Further, dialdehyde 4 formed in the above reaction sequence
Having the dialdehyde 4 in hand, unsubstituted tetracyclic car-
was used as a common starting material in order to obtain
bazole and isocanthine derivatives were synthesised, following the
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P.N. Naik et al. / Tetrahedron xxx (2013) 1e6
3
Table 1
same sequence of reactions. To accomplish this synthesis, Wittig
IC50 values for carbazole analogues
reaction was performed with dialdehyde 4 using iodo(methyl)tri-
phenylphosphorane (4 equiv) to get the olefin 9 after 2 h. It was
then refluxed in o-dichlorobenzeneeDDQ system, to furnish the
known13 target compound 10 as a tetracyclic carbazole derivative
in a one pot sequence. The isocanthine analogue of this was also
synthesised starting from the same dialdehyde 4 by treating it with
iodo(methyl)triphenylphosphorane (2 equiv) for 30 min to give
olefin 11. This olefin, on treatment with hydrazine hydrate and
further refluxing for 60 h gave the required isocanthine10 derivative
12 in 75% yield in a similar one pot reaction sequence as shown
earlier (Scheme 2).
Compound no.
IC50/m
Ma
6
16
24
19.80ꢂ0.06
17.46ꢂ0.05
18.76ꢂ0.01
a
IC50 values calculated from linear response from linear regression of the dose log
response curves after 72 h exposure to the compound, determined by MTT assay on
HeLa cell lines. Values are meanꢂSD of three experiments.
3. Conclusion
As per our previous experience,12 the size reduction of ring ‘D’
played an important role in increasing the biological activity of the
compound. Thus, it was then planned to synthesise derivatives
having a five-membered ‘D’ ring. For this purpose, indole-3-
aldehyde 2 was initially N-alkylated with 3-chloro-propanol to
give compound 13, which on subsequent oxidation furnished the
required intermediate dialdehyde 14. Treatment of 14 with
4 equiv carbethoxymethylenetriphenyl phosphorane for 8 h
afforded trans olefin 15, whose treatment with DDQ in o-di-
chlorobenzene gave the targeted tetracyclic carbazole 16. The
isocanthine derivative with five-membered ‘D’ ring was obtained
by initial reaction between dialdehyde 14 and carbethox-
ymethylenetriphenyl phosphorane (2 equiv) for 2 h giving trans
olefin 17. Further olefin 17 was refluxed with hydrazine hydrate in
toluene to produce successfully a new unknown isocanthine de-
rivative 18 in an aza-DielseAlder reaction of the intermediate
hydrazone (Scheme 2).
Review of the literature reports of canthine alkaloids indicated
that, presence of methoxy substituent on the ‘A’ ring helps in
increasing the biological activity. Taking into consideration the
similarity of canthine framework with the isocanthine and tet-
racyclic carbazole moiety, we decided to synthesise analogues
having methoxy substituent on ‘A’ ring. Starting with 5-methoxy
indole 19, the required dialdehyde intermediate 22 was ob-
tained by sequentially following VilsmeiereHaack formylation, N-
alkylation with 4-chlorobutanol and IBX oxidation reactions.
Similar to the set of reactions mentioned in above cases, com-
Thus, a new intramolecular DielseAlder strategy using simple
diene as well as its aza analogue in the form of hydrazone was
successfully employed for the synthesis of four tetracyclic carba-
zoles and four isocanthines, respectively, in a clean and efficient
manner. Some of the carbazoles were tested for activity against
HeLa cervical cancer cell lines, which showed moderate activity
with IC50 value of about 18 mM.
4. Experimental
4.1. General information
All reactions were carried out under an inert atmosphere with
dry solvents, unless otherwise stated. Reactions were monitored by
thin layer chromatography (TLC) on silica gel plates (Kieselgel 60
F254, Merck). Visualisation of the spots on TLC plates was achieved
either by UV light or by staining the plates in 2,4-dini-
trophenylhydrazine/anisaldehyde and charring on hot plate. All
products were characterised by 1H NMR and 13C NMR, IR and
HRMS/elemental analysis. 1H NMR and 13C NMR were recorded on
Varian Mercury 300 MHz and 75 MHz instrument, respectively.
Chemical shifts are expressed in parts per million values and 1H
NMR spectra are referenced to 0.00 ppm for Me4Si (TMS) and 13C
NMR spectra are referenced to 77.00 ppm for CDCl3. Peak multi-
plicities are designated by the following abbreviations: s, singlet; br
s, broad singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m,
multiplet; exch, D2O exchangeable; J, coupling constant in Hertz. IR
spectra were recorded on Bruker instrument as ATR. HRMS spectra
were obtained on a Micromass Q-TOF apparatus. Melting points
recorded are uncorrected. Column chromatography on silica gel
(100e200 mesh) was performed with reagent grade ethyl acetate
and hexane as an eluent.
pound 22 was treated with
4 equiv carbethoxymethylene-
triphenyl phosphorane furnishing trans olefin 23 followed by
refluxing with DDQ in o-dichlorobenzene to get the known6 tet-
racyclic carbazole derivative 24. The corresponding new iso-
canthine derivative 26 was obtained from dialdehyde 22, by
treating with 2 equiv carbethoxymethylenetriphenyl phosphor-
ane to give trans olefin 25, followed by refluxing with hydrazine
hydrate in toluene.
4.2. Synthesis of formylated indoles 2 and 20
Prepared according to literature procedure.14
2.1. Biological assay
4.2.1. 1H-Indole-3-carbaldehyde (2). White solid (95%); mp14
After completing the synthesis of the targeted analogues, bi-
ological evaluation of some representative compounds was un-
dertaken to evaluate cytotoxicity against HeLa cervical cancer cell
lines, since the activity of these carbazoles was not studied earlier.
The compounds chosen varied in the size of ring ‘D’ and sub-
stitution on ‘A’ ring. Thus the compounds 6, 16 and 24 were dis-
solved in 2% DMSO (volume made up by PBS buffer) and diluted to
micro molar (mM) concentration. The cell viability study was per-
formed at an interval of 24 h, 48 h and 72 h. The IC50 values were
obtained at the end of 72 h and are shown in Table 1. All the three
195 ꢀC.
4.2.2. 5-Methoxy-1H-indole-3-carbaldehyde
(93%); mp15 180e182 ꢀC; FTIR (ATR cmꢁ1) 3032, 2726, 1609, 1582,
1436, 1257, 1130, 1063; 1H NMR (300 MHz, CDCl3)
: 11.4 (1H, br s,
(20). White
solid
d
eNH), 9.86 (1H, s, eCHO), 7.75 (1H, s, ArH), 7.63 (1H, d, J¼2.2 Hz,
ArH), 7.28 (1H, d, J¼9.2 Hz, ArH), 6.81 (1H, dd, J¼2.2, 8.8 Hz, ArH),
3.77 (3H, s, eOCH3); 13C NMR (75 MHz, CDCl3)
d: 184.7, 155.7, 136.8,
131.6, 124.7, 118.1, 113.4, 112.6, 102.5, 55.2.
compounds exhibited similar IC50 values ranging from 17 to 20 mM.
The IC50 values indicate that, five membered D-ring is preferred
over the six membered ring. Also, though the IC50 values are almost
similar, a slightly lower IC50 value was shown by the compound 24,
compared to compound 6, which may be owed to the presence of
methoxy group on ring ‘A’.
4.3. General procedure for N-alkylindoles, 3, 13, 21
To a solution of DMSO (10 ml) taken in a round bottom flask was
added KOH (2 equiv) and the solution was stirred at room tem-
perature for 15 min. The indole derivative 2 or 20 (1 equiv) was
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4
P.N. Naik et al. / Tetrahedron xxx (2013) 1e6
then added and the mixture was further stirred for 1 h, after which
4-chlorobutan-1-ol or 3-chloropropan-1-ol (1.5 equiv) was added
dropwise to the reaction mixture. The reaction was monitored by
TLC to completion within 5 h. The reaction mixture was then
quenched by adding water and was extracted with ethyl acetate.
Evaporation of the solvent under reduced pressure followed by
column chromatography gave the required N-alkylated com-
pounds, 3/13/21.
117.9, 114.5, 110.8, 103.3, 55.7, 46.1, 40.1, 22.1; HRMS (ESI) (MþNa)
268.0950; calculated for C14H15NO3Na 268.0950.
4.5. General procedure for synthesis of compounds 5, 15, 23
To a solution of suitable dialdehyde 4/14/22 (1 equiv) in dry
toluene was added carbethoxymethylenetriphenyl phosphorane
(4 equiv) and refluxed for 8 h under inert atmosphere. After the
completion of reaction, toluene was concentrated under reduced
pressure and the residue was extracted with ethyl acetate. Evapo-
ration of the solvent under reduced pressure followed by column
chromatography (0.5:9.5, EA/Hexane) gave corresponding com-
pounds 5/15/23.
4.3.1. 1-(4-Hydroxybutyl)-1H-indole-3-carbaldehyde
(3). White
solid (85%); mp12 75e77 ꢀC.
4.3.2. 1-(3-Hydroxypropyl)-1H-indole-3-carbaldehyde (13). Sticky
solid12 (86%).
4.5.1. (E)-Ethyl 6-(3-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-1H-indol-
1-yl)hex-2-enoate (5). White solid (75%); mp 67e68 ꢀC; Rf (30% EA/
Hexane) 0.80; FTIR (ATR cmꢁ1) 2978, 2938, 1718, 1697, 1620, 1572,
4.3.3. 1-(4-Hydroxybutyl)-5-methoxy-1H-indole-3-carbaldehyde
(21). Off white solid (84%); mp 89e91 ꢀC; Rf (40% EA/Hexane)
0.35; FTIR (ATR cmꢁ1) 3299, 3094, 2929, 2856, 1638, 1620, 1529,
1530, 1165, 1144; 1H NMR (300 MHz, CDCl3)
d: 7.85e7.93 (2H, m,
1435, 1194, 1043; 1H NMR (300 MHz, CDCl3)
d
: 9.86 (1H, s, eCHO),
ArCH]CHe, ArH), 7.21e7.34 (4H, m, ArH), 6.84e6.94 (1H, m,
eCH2eCH]CHe), 6.41 (1H, d, J¼15.8 Hz, eCHCOOEt), 5.81 (1H, d,
J¼15.3 Hz, eCHCOOEt), 4.26 (2H, q, J¼7 Hz, eCH2CH3), 4.11e4.21
(4H, m, eNCH2, eCH2CH3), 2.20 (2H, q, J¼7.1 Hz, eCH2eCHe), 2.02
(2H, quint, J¼7.1 Hz, eCH2e), 1.34 (3H, t, J¼7 Hz, eCH2CH3), 1.28
7.76 (1H, d, J¼2.4 Hz, ArH), 7.65 (1H, s, ArH), 7.25 (1H, d, J¼9 Hz,
ArH), 6.94 (1H, dd, J¼2.4, 8.6 Hz, ArH), 4.16 (2H, t, J¼7.1 Hz,
eNCH2), 3.87 (3H, s, eOCH3), 3.65 (2H, t, J¼6.2 Hz, eOCH2), 2.28
(1H, br s, exch, eOH), 1.97 (2H, quint, J¼7.6 Hz, eCH2e), 1.56 (2H,
quint, J¼6.7 Hz, eCH2e); 13C NMR (75 MHz, CDCl3)
d
: 184.5, 156.5,
(3H, t, J¼7 Hz, eCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 168.1, 166.1,
138.5, 131.9, 126.0, 117.6, 114.2, 110.9, 103.3, 61.8, 55.7, 47.1, 29.5,
26.3; HRMS (ESI) (MþNa) 270.1104; calculated for C14H17NO3Na
270.1106.
146.6, 137.7, 137.1, 131.8, 126.1, 122.9, 122.5, 121.2, 120.7, 112.8, 112.2,
109.9, 60.2, 59.9, 45.7, 29.0, 28.0, 14.3, 14.1; HRMS (ESI) (MþNa)
378.1684; calculated for C21H25NO4Na 378.1681.
4.4. General procedure for oxidation using IBX
4.5.2. (E)-Ethyl 5-(3-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-1H-indol-
1-yl)pent-2-enoate (15). White solid (82%); mp 109e111 ꢀC; Rf (30%
EA/Hexane) 0.84; FTIR (ATR cmꢁ1) 2974, 1713, 1697, 1618, 1470,
To a solution of suitable hydroxyl compound 3/13/21 (1 equiv) in
dry ethyl acetate (20 ml) was added o-iodoxybenzoic acid
(1.5 equiv) under inert atmosphere. The contents were refluxed for
8 h and the reaction was followed by TLC. After completion of re-
action, the reaction mixture was filtered through Celite bed on
a sintered funnel and washed with ethyl acetate. Evaporation of the
solvent under reduced pressure followed by column chromatog-
raphy gave corresponding aldehydes 4/14/22.
1152, 1046, 733; 1H NMR (300 MHz, CDCl3)
d: 7.84e7.93 (2H, m,
ArCH]CHe, ArH), 7.22e7.37 (4H, m, ArH), 6.84e6.94 (1H, m,
eCH2eCH]CHe), 6.41 (1H, d, J¼16.4 Hz, eCHCOOEt), 5.83 (1H, dt,
J¼15.8 and 0.9 Hz, eCHCOOEt), 4.13e4.30 (6H, m, eNCH2, eCH2CH3
ꢃ2), 2.72 (2H, qd, J¼7.1 and 0.9 Hz, eCH2eCH]), 1.34 (3H, t,
J¼7.1 Hz, eCH2CH3), 1.26 (3H, t, J¼7.1 Hz, eCH2CH3); 13C NMR
(75 MHz, CDCl3) d: 168.1, 165.7, 143.2, 137.7, 137.0, 131.6, 126.1, 124.2,
123.0, 121.3, 120.7, 113.0, 112.4, 109.7, 60.4, 59.9, 45.2, 32.5, 14.4,
14.1; HRMS (ESI) (MþNa) 364.1526; calculated for C20H23NO4Na
364.1525.
4.4.1. 1-(4-Oxobutyl)-1H-indole-3-carbaldehyde
(93%); Rf (30% EA/Hexane) 0.53; FTIR (ATR cmꢁ1) 2936, 2813, 2725,
1718, 1650, 1576, 1467, 1165; 1H NMR (300 MHz, CDCl3)
: 9.95 (1H,
(4). Thick
oil
d
s, eCHO), 9.75 (1H, s, eCHO), 8.27 (1H, dd, J¼6.2, 2.4 Hz, ArH), 7.67
(1H, s, ArH), 7.28e7.41 (3H, m, ArH), 4.22 (2H, t, J¼7.1 Hz, eNCH2),
2.49 (2H, t, J¼7.1 Hz, eCH2CHO), 2.18 (2H, quint, J¼7.1 Hz, eCH2e);
4.5.3. (E)-Ethyl 6-(3-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-5-
methoxy-1H-indol-1-yl)hex-2-enoate (23). White solid (78%); mp
85e87 ꢀC; Rf (30% EA/Hexane) 0.78; FTIR (ATR cmꢁ1) 2922, 1714,
1692, 1605, 1519, 1456, 1320, 1156, 1034, 986; 1H NMR (300 MHz,
13C NMR (75 MHz, CDCl3)
d: 200.4, 184.5, 138.1, 136.9, 125.3, 124.1,
122.9, 122.1, 118.1, 109.9, 45.9, 40.1, 22.1; HRMS (ESI) (MþNa)
CDCl3)
d
: 7.87 (1H, d, J¼15.8 Hz, ArCH]CHe), 7.32 (2H, m, ArH),
238.0848; calculated for C13H13NO2Na 238.0844.
7.22 (1H, d, J¼8.6 Hz, ArH), 6.84e6.95 (2H, m, eCH2eCH]CHe,
ArH), 6.32 (1H, d, J¼15.7 Hz, eCHCOOEt), 5.81 (1H, dt, J¼15.7 and
1.4 Hz, eCHCOOEt), 4.26 (2H, q, J¼7.1 Hz, eCH2CH3), 4.15 (2H, q,
J¼7.1 Hz, eCH2CH3), 4.10 (2H, t, J¼7.1 Hz, eNCH2), 3.89 (3H, s,
eOCH3), 2.18 (2H, bq, J¼6.7 Hz, eCH2eCHe), 2.00 (2H, quint,
J¼7.1 Hz, eCH2e), 1.34 (3H, t, J¼7.1 Hz, eCH2CH3), 1.27 (3H, t,
4.4.2. 1-(3-Oxopropyl)-1H-indole-3-carbaldehyde (14). Thick oil
(94%); Rf (40% EA/Hexane) 0.55; FTIR (ATR cmꢁ1) 2946, 2820, 2729,
1720, 1656, 1577, 1468, 1169; 1H NMR (300 MHz, CDCl3)
d: 9.85 (1H,
s, eCHO), 9.68 (1H, s, eCHO), 8.23e8.25 (1H, m, ArH), 7.72 (1H, s,
ArH), 7.23e7.30 (3H, m, ArH), 4.41 (2H, t, J¼6.6 Hz, eNCH2), 3.00
J¼7.1 Hz, eCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 168.2,166.2, 155.4,
(2H, t, J¼6.6 Hz, eCH2CHO); 13C NMR (75 MHz, CDCl3)
d
: 198.6,
146.6, 137.8, 132.2, 131.9, 126.7, 122.5, 112.9, 112.1, 111.8, 110.7, 102.6,
60.2, 60.0, 55.9, 45.9, 29.1, 28.1, 14.4, 14.1; HRMS (ESI) (MþNa)
408.1786; calculated for C22H27NO5Na 408.1787.
184.5, 139.4, 136.5, 125.1, 123.9, 122.8, 121.9, 117.9, 109.6, 42.7, 39.5;
HRMS (ESI) (MþH) 202.0868; calculated for C12H12NO2 202.0868.
4.4.3. 5-Methoxy-1-(4-oxobutyl)-1H-indole-3-carbaldehyde
4.6. Synthesis of 1-(pent-4-en-1-yl)-3-vinyl-1H-indole (9)
(22). Thick oil (92%); Rf (40% EA/Hexane) 0.54; FTIR (ATR cmꢁ1
)
2934, 2832, 1718, 1648, 1618, 1579, 1460, 1260, 1040; 1H NMR
(300 MHz, CDCl3) : 9.92 (1H, s, eCHO), 9.75 (1H, s, eCHO), 7.78
To a solution of iodo(methyl)triphenylphosphorane (3.76 g,
9.3 mmol) in dry THF (50 ml) was added 1.6 M n-butyllithium
(5.8 ml, 9.3 mmol) at 0 ꢀC under nitrogen atmosphere. A yellow
coloured anion was formed after which a solution of 1-(4-
oxobutyl)-1H-indole-3-carbaldehyde (4) (0.5 g, 2.3 mmol) in dry
THF (15 ml) was added dropwise to the above mixture. After the
d
(1H, s, ArH), 7.67 (1H, s, ArH), 7.27 (1H, d, J¼8.6 Hz, ArH), 6.96 (1H, d,
J¼8.6 Hz, ArH), 4.18 (2H, t, J¼7.1 Hz, eNCH2), 3.88 (3H, s, eOCH3),
2.49 (2H, t, J¼6.7 Hz, eCH2CHO), 2.18 (2H, quint, J¼7.1 Hz, eCH2e);
13C NMR (75 MHz, CDCl3)
d: 200.4, 184.4, 156.6, 138.1, 131.8, 126.1,
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P.N. Naik et al. / Tetrahedron xxx (2013) 1e6
5
completion of reaction, the mixture was quenched by addition of
saturated ammonium chloride solution and then extracted with
ethyl acetate. Evaporation of the solvent under reduced pressure
followed by column chromatography on neutral alumina (0.5:9.5,
EA/Hexane) gave compound 9 as an unstable pale yellow oil
(0.41 g, 85%). Rf (30% EA/Hexane) 0.81; 1H NMR (300 MHz, CDCl3)
136.9, 125.2, 123.9, 122.8, 122.5, 122.0, 120.8, 118.1, 117.6, 114.2,
109.8, 46.2, 28.9, 27.8.
4.8.3. Diethyl 4,5-dihydropyrrolo[3,2,1-jk]carbazole-2,3-
dicarboxylate (16). Viscous oil (74%); Rf (30% EA/Hexane) 0.85;
FTIR (ATR cmꢁ1) 2924, 1725, 1612, 1463, 1282, 1120, 744; 1H NMR
d
: 7.88 (1H, d, J¼7.6 Hz, ArH), 7.33 (1H, d, J¼8.1 Hz, ArH), 7.24 (1H,
(300 MHz, CDCl3)
d
: 8.59 (1H, s, ArH), 8.12 (1H, d, J¼7.7 Hz, ArH),
m, ArH), 7.14e7.21 (2H, m, ArH), 6.88 (1H, dd, J¼10.9, 17.6 Hz,
ArCH]CH2), 5.64e5.84 (2H, m, eCH2eCH]CH2, ArCH]CHH),
5.02e5.16 (3H, m, eCH2eCH]CH2, ArCH]CHH), 4.09 (2H, t,
J¼7.1 Hz, eNCH2), 2.08 (2H, q, J¼7.1 Hz, eCH2eCH]), 1.93 (2H,
quint, J¼7.1 Hz, eCH2e).
7.49e7.54 (1H, m, ArH), 7.25e7.32 (1H, m, ArH), 7.17e7.21 (1H, m,
ArH), 4.26 (2H, q, J¼7.1 Hz, eCH2CH3), 4.11e4.21 (4H, m, eNCH2,
eCH2CH3), 3.06 (2H, t, J¼6.2 Hz, ArCH2), 1.34 (3H, t, J¼7.1 Hz,
eCH2CH3), 1.28 (3H, t, J¼7.1 Hz, eCH2CH3); 13C NMR (75 MHz,
CDCl3) d: 169.3, 166.9, 140.8, 139.3, 130.4, 126.4, 122.5, 121.4, 121.3,
120.3, 119.9, 119.0, 118.6, 108.8, 61.4, 61.0, 40.7, 22.5, 14.3, 14.2;
HRMS (ESI) (MþH) 338.1397; calculated for C20H20NO4 338.1392.
4.7. Synthesis of diethyl 2,3,3a,4,5,6-hexahydro-1H-pyrido
[3,2,1-jk]carbazole-2,3-dicarboxylate (5a)
4.8.4. Diethyl
10-methoxy-5,6-dihydro-4H-pyrido[3,2,1-jk]carba-
zole-2,3-dicarboxylate (24). Thick brown oil6 (78%); FTIR (ATR
A solution of (E)-ethyl 6-(3-((E)-3-ethoxy-3-oxoprop-1-en-1-
yl)-1H-indol-1-yl)hex-2-enoate (5) (0.5 g, 1.4 mmol) in o-di-
chlorobenzene was refluxed under inert atmosphere for 36 h.
After completion of reaction, water was added to the reaction
mass and it was extracted with ethyl acetate. Evaporation of the
solvent under reduced pressure followed by column chromatog-
raphy (1:1, DCM/Hexane) gave compound 5a as an off white solid
(0.39 g, 78%). Mp 66e68 ꢀC; Rf (30% EA/Hexane) 0.81; FTIR (ATR
cmꢁ1) 2932, 1727 (br s), 1450, 1185, 1026, 742; 1H NMR (300 MHz,
cmꢁ1) 2955, 2921, 1725, 1615, 1461, 1259, 1018; 1H NMR (300 MHz,
CDCl3)
d
: 8.51 (1H, s, ArH), 7.77 (1H, d, J¼2.9 Hz, ArH), 7.47 (1H, d,
J¼7.2 Hz, ArH), 7.3e7.4 (1H, m, ArH), 4.13e4.30 (6H, m, eNCH2,
eCH2CH3 ꢃ2), 3.87 (3H, s, eOCH3), 3.08 (2H, t, J¼6.2 Hz, ArCH2),
2.68e2.76 (2H, m, eCH2e), 1.34 (3H, t, J¼7.1 Hz, eCH2CH3),1.26 (3H,
t, J¼7.2 Hz, eCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 168.2, 166.1,
146.6, 138.2,137.1, 131.8, 126.0, 123.0, 122.5,121.3, 120.7, 112.8, 112.3,
109.8, 60.2, 59.9, 55.8, 45.7, 29.1, 28.2, 14.3, 14.1.
CDCl3)
d
: 7.49 (1H, d, J¼7.2 Hz, ArH), 7.24e7.26 (1H, m, ArH),
4.9. General procedure for synthesis of compounds 7, 17, 25
7.08e7.19 (2H, m, ArH), 4.21e4.35 (3H, m, eCH2CH3, eCHCOOEt),
4.06e4.19 (2H, m, eCH2CH3), 3.61e3.71 (2H, m, eNCH2),
3.28e3.40 (2H, m, eCH2CHCOOEt), 2.98e3.06 (1H, m,
eCH2CHCOOEt), 2.58e2.66 (2H, m, eCH2e), 2.16e2.25 (2H, m,
eCH2CHe), 1.34 (3H, t, J¼7.1 Hz, eCH2CH3), 1.22 (3H, t, J¼7.1 Hz,
eCH2CH3), 1.11e1.17 (1H, m, eCHCHCOOEt); 13C NMR (75 MHz,
To a solution of suitable dialdehyde 4/14/22 (1 equiv) in dry
toluene was added carbethoxymethylenetriphenyl phosphorane
(2 equiv) or and refluxed for 2 h under inert atmosphere. After the
completion of reaction, toluene was concentrated under reduced
pressure and the residue was extracted with ethyl acetate. Evapo-
ration of the solvent under reduced pressure followed by column
chromatography (2:8, EA/Hexane) gave corresponding compounds
7/17/25.
CDCl3)
d: 172.9, 172.5, 137.9, 135.4, 127.3, 120.8, 119.3, 117.9, 109.1,
104.9, 60.7, 60.6, 46.9, 42.5, 41.8, 32.0, 26.6, 23.2, 23.1, 14.1, 14.0;
HRMS (ESI) (MþNa) 378.1673; calculated for
C21H25NO4Na
378.1676.
4.9.1. (E)-Ethyl 6-(3-formyl-1H-indol-1-yl)hex-2-enoate (7). Pale
4.8. General procedure for synthesis of tetracyclic carbazoles
6/10/16/24
yellow viscous oil (80%); Rf (30% EA/Hexane) 0.50; FTIR (ATR cmꢁ1
)
2933, 1710, 1655, 1530, 1467, 1389, 1152, 1037, 744; 1H NMR
(300 MHz, CDCl3) : 9.97 (1H, s, eCHO), 8.27e8.30 (1H, m, ArH),
d
To a stirred solution of 5/9/15/23 (1 equiv) in o-dichlorobenzene,
was added DDQ (2.5 equiv) under inert atmosphere. The contents
were refluxed for 36 h. After completion of reaction, water was
added to the reaction mass and it was extracted with ethyl acetate.
Evaporation of the solvent under reduced pressure followed by
column chromatography (1:1, DCM/Hexane) gave compound 6/10/
16/24.
7.66 (1H, s, ArH), 7.25e7.33 (3H, m, ArH), 6.82e6.92 (1H, m,
eCH2eCH]CHe), 5.80 (1H, d, J¼15.8 Hz, eCHCOOEt), 4.12e4.18
(4H, m, eNCH2, eOCH2CH3), 2.20 (2H, q, J¼7.1 Hz, eCH2eCHe), 2.03
(2H, quint, J¼6.7 Hz, eCH2e), 1.25 (3H, t, J¼7.2 Hz, eCH2CH3); 13C
NMR (75 MHz, CDCl3) d: 184.4, 166.0, 146.2, 138.1, 136.9, 125.2,
123.9, 122.8, 122.5, 122.0, 118.0, 109.8, 60.2, 46.2, 28.9, 27.8, 14.1;
HRMS (ESI) (MþNa) 308.1265; calculated for
C17H19NO3Na
308.1263.
4.8.1. Diethyl 5,6-dihydro-4H-pyrido[3,2,1-jk]carbazole-2,3-
dicarboxylate (6). Thick oil6 (75%); FTIR (ATR cmꢁ1) 2924, 1711,
4.9.2. (E)-Ethyl 5-(3-formyl-1H-indol-1-yl)pent-2-enoate
(17). Viscous oil (83%); Rf (30% EA/Hexane) 0.57; FTIR (ATR cmꢁ1
2977, 2935, 1694, 1619, 1527, 1276, 1039, 740; 1H NMR (300 MHz,
CDCl3)
1599, 1578, 1475, 1261, 1140, 771; 1H NMR (300 MHz, CDCl3)
d
: 8.57
)
(1H, s, ArH), 8.13 (1H, d, J¼7.7 Hz, ArH), 7.49e7.54 (1H, m, ArH),
7.25e7.32 (1H, m, ArH), 7.17e7.21 (1H, m, ArH), 4.36e4.50 (4H, m,
eCH2CH3 ꢃ2), 4.20 (2H, t, J¼5.7 Hz, eNCH2), 3.06 (2H, t, J¼6.2 Hz,
ArCH2), 2.31 (2H, quint, J¼5.7 Hz, eCH2e), 1.39e1.44 (6H, m,
d
: 9.98 (1H, s, eCHO), 8.31 (1H, m, ArH), 7.70 (1H, d, J¼7.6 Hz,
ArH), 7.26e7.38 (3H, m, ArH), 6.85e7.06 (1H, m, eCH2eCH]CHe),
5.94 (1H, d, J¼15.7 Hz, eCHCOOEt), 4.14e4.33 (4H, m, eNCH2,
eCH2CH3), 2.50 (2H, q, J¼7.1 Hz, eCH2eCHe), 1.25 (3H, t, J¼6.7 Hz,
eCH2CH3 ꢃ2); 13C NMR (75 MHz, CDCl3)
d: 169.3, 166.9, 140.8,
139.3, 130.4, 126.4, 122.5, 121.4, 121.3, 120.3, 119.9, 119.0, 118.6,
108.8, 61.4, 61.0, 40.7, 22.6, 21.8, 14.3, 14.2.
eCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 184.4, 172.3, 146.2, 138.1,
137.1, 125.4, 124.0, 122.9, 122.5, 122.1, 118.2, 109.9, 60.7, 46.1, 30.7,
14.1; HRMS (ESI) (MþNa) 294.1109; calculated for C16H17NO3Na
294.1106.
4.8.2. 5,6-Dihydro-4H-pyrido[3,2,1-jk]carbazole (10). Pale yellow
solid (78%); mp10 86e88 ꢀC; FTIR (ATR cmꢁ1) 2917, 1595, 1465,
1244, 1147, 743; 1H NMR (300 MHz, CDCl3)
d
: 8.27 (1H, d, J¼7.2 Hz,
4.9.3. (E)-Ethyl 6-(3-formyl-5-methoxy-1H-indol-1-yl)hex-2-enoate
(25). Pale yellow oil (80%); Rf (30% EA/Hexane) 0.58; FTIR (ATR
cmꢁ1) 2948, 2786, 1706, 1650, 1514, 1265, 1097; 1H NMR (300 MHz,
ArH), 7.86e7.92 (1H, m, ArH), 7.4e7.5 (2H, m, ArH), 7.29e7.38 (3H,
m, ArH), 4.10 (2H, t, J¼6.6 Hz, eNCH2), 2.97 (2H, t, J¼6.6 Hz,
ArCH2e), 2.16 (2H, m, eCH2e); 13C NMR (75 MHz, CDCl3)
d: 138.1,
CDCl3)
d: 10.45 (1H, s, eCHO), 7.81 (1H, s, ArH), 7.22 (1H, d, J¼3.1 Hz,
Please cite this article in press as: Naik, P. N.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.054

6
P.N. Naik et al. / Tetrahedron xxx (2013) 1e6
ArH), 7.00 (1H, d, J¼8.1 Hz, ArH), 6.83e6.93 (1H, m, eCH2eCH]
CHe), 6.72, (1H, d, J¼7.7 Hz, ArH), 5.81 (1H, d, J¼15.7 Hz,
eCHCOOEt), 4.1e4.2 (4H, m, eNCH2, eCH2CH3), 3.99 (3H, s,
eOCH3), 2.20 (2H, q, J¼6.7 Hz, eCH2eCHe), 2.05 (2H, quint,
J¼6.6 Hz, eCH2e), 1.28 (3H, t, J¼6.7 Hz, eCH2CH3); 13C NMR
0.61; FTIR (ATR cmꢁ1) 2931, 1694, 1616, 1466, 1093, 738; 1H NMR
(300 MHz, CDCl3)
d
: 9.18 (1H, s, ArH), 8.29 (1H, d, J¼8.6 Hz, ArH),
7.25e7.42 (3H, m, ArH), 4.25 (2H, t, J¼7.2 Hz, eNCH2), 4.12 (2H, q,
J¼7.2 Hz, eCH2CH3), 3.06 (2H, t, J¼6.2 Hz, ArCH2), 1.23 (3H, t,
J¼7.2 Hz, eCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 167.9, 137.1, 136.5,
(75 MHz, CDCl3)
d
: 187.9, 166.2, 154.7, 146.3, 137.9, 130.8, 123.8,
131.1, 126.3, 123.5, 121.8, 121.0, 116.7, 114.1, 113.4, 109.2, 60.1, 42.1,
18.9, 14.3; HRMS (ESI) (MþH) 267.1133; calculated for C16H15N2O2
267.1133.
122.6, 118.3, 116.9, 103.4, 102.4, 60.3, 55.3, 46.5, 29.0, 28.0, 14.2;
HRMS (ESI) (MþNa) 338.1367; calculated for
C18H21NO4Na
338.1368.
4.11.4. Ethyl 10-methoxy-5,6-dihydro-4H-indolo[3,2,1-ij][1,6]naph-
thyridine-3-carboxylate (26). Viscous oil (70%); Rf (25% EA/Hexane)
0.61; FTIR (ATR cmꢁ1) 2976, 2927, 1718, 1619, 1469, 1366, 1038, 797;
4.10. Synthesis of 1-(pent-4-en-1-yl)-1H-indole-3-
carbaldehyde (11)
1H NMR (300 MHz, CDCl3)
d
: 8.86 (1H, s, ArH), 7.77 (1H, d, J¼2.4 Hz,
To a solution of iodo(methyl)triphenylphosphorane (0.75 g,
1.8 mmol) in dry THF (20 ml) was added 1.6 M n-butyllithium
(1.0 ml, 1.8 mmol) at 0 ꢀC under nitrogen atmosphere. A yellow
coloured anion was formed after which a solution of 1-(4-
oxobutyl)-1H-indole-3-carbaldehyde (4) (0.2 g, 0.9 mmol) in dry
THF (5 ml) was added dropwise to the above mixture. After the
completion of reaction, the mixture was quenched by addition of
saturated ammonium chloride solution and then extracted with
ethyl acetate. Evaporation of the solvent under reduced pressure
followed by column chromatography on neutral alumina (2:8, EA/
Hexane) gave compound 11 as an unstable pale yellow oil (0.17 g,
ArH), 7.25 (1H, d, J¼9 Hz, ArH), 6.94 (1H, dd, J¼2.4, 8.6 Hz, ArH), 4.39
(2H, q, J¼7.1 Hz, eCH2CH3), 4.16 (2H, t, J¼7.1 Hz, eNCH2), 3.87 (3H, s,
eOCH3), 3.65 (2H, t, J¼6.2 Hz, ArCH2), 1.97 (2H, m, eCH2e),1.23 (3H,
t, J¼7.1 Hz, eCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 168.3, 137.9,
137.2, 132.1, 126.0, 122.7, 121.1, 120.6, 112.4, 111.9, 110.0, 108.3, 61.9,
60.1, 46.5, 29.7, 26.5, 14.5; HRMS (ESI) (MþH) 311.1396; calculated
for C18H19N2O3 311.1395.
4.12. Cytotoxicity test
The cytotoxicity of the compounds was measured at 24, 48 and
72 h intervals in triplicate using a standard MTT assay against hu-
man cervical cell line (HeLa). The average cytotoxicity data and the
associated standard deviation (SD) obtained were then used to
calculate cell viability.16
87%); Rf (30% EA/Hexane) 0.65; 1H NMR (300 MHz, CDCl3)
d: 10.0
(1H, s, eCHO), 8.29e8.32 (1H, m, ArH), 7.71 (1H, s, ArH), 7.28e7.40
(3H, m, ArH), 5.73e5.86 (1H, m, eCH2eCH]CH2), 5.03e5.10 (2H,
m, eCH2eCH]CH2), 4.19 (2H, t, J¼7.1 Hz, eNCH2), 2.11 (2H, q,
J¼7.1 Hz, eCH2eCH]), 2.01 (2H, quint, J¼7.1 Hz, eCH2e).
Acknowledgements
4.11. General procedure for synthesis of isocanthine ana-
logues 8/12/18/26
We are thankful to Mrs. J. P. Chowdhary and Ms. Sheetal for NMR
spectra and Mr. Yogesh for IR spectra. P.N.N. is thankful to CSIR, New
Delhi for financial assistance through fellowship.
To a solution of 7/11/17/25 (1 equiv) in toluene was added hy-
drazine hydrate in excess (1 ml). The reaction mixture was then
refluxed for 50e60 h. Toluene was then removed under reduced
pressure and the residue was extracted with ethyl acetate. Evapo-
ration of the solvent under reduced pressure followed by column
chromatography (1.5:8.5, EA/Hexane) gave compounds 8/12/18/26.
References and notes
1. Al-awar, R. S.; Ray, J. E.; Hecker, K. A.; Huang, J.; Waid, P. P.; Shih, C.; Brooks, H.
B.; Spencer, C. D.; Watkins, S. A.; Patel, B. R.; Stamm, N. B.; Ogg, C. A.; Schultz, R.
M.; Considine, E. L.; Faul, M. M.; Sullivan, K. A.; Kolis, S. P.; Grutsch, J. L.; Joseph,
S. Bioorg. Med. Chem. Lett. 2004, 14, 3217.
2. Ueno, A.; Kitawaki, T.; Chida, N. Org. Lett. 2008, 10, 10.
3. Zhu, G.; Conner, S. E.; Zhou, X.; Chan, H.-K.; Shih, C.; Engler, T. A.; Al-awar, R. S.;
Brooks, H. B.; Watkins, S. A.; Spencer, C. D.; Schultz, R. M.; Dempsey, J. A.;
Considine, E. L.; Patel, B. R.; Ogg, C. A.; Vasudevan, V.; Lytle, M. L. Bioorg. Med.
Chem. Lett. 2004, 14, 3057.
4.11.1. Ethyl 5,6-dihydro-4H-indolo[3,2,1-ij][1,6]naphthyridine-3-
carboxylate (8). Thick oil (62%); Rf (35% EA/Hexane) 0.55; FTIR
(ATR cmꢁ1) 2925, 1713, 1654, 1531, 1366, 1182, 1040; 1H NMR
(300 MHz, CDCl3)
d
: 8.97 (1H, s, ArH), 8.30 (1H, d, J¼7.7 Hz, ArH),
7.22e7.36 (3H, m, ArH), 4.22e4.29 (4H, m, eNCH2, eCH2CH3),
2.14e2.27 (4H, m, ArCH2, eCH2e), 1.34 (3H, t, J¼7.1 Hz, eCH2CH3);
4. Lu, S.; Wang, R.; Yang, Y.; Li, Y.; Shi, Z.; Zhang, W.; Tu, Z. J. Org. Chem. 2011, 76,
5661.
5. (a) Yamuna, E.; Zeller, M.; Prasad, K. J. R. Tetrahedron Lett. 2011, 52, 6030; (b)
Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J. Am. Chem. Soc. 2003,
125, 11506.
6. Haider, N.; Kaferbock, J. Tetrahedron 2004, 60, 6495.
7. Yanagisawa, H.; Shimoji, Y.; Hashimoto, T. Jpn. Kokai Tokkyo Koho, JP 05310738,
1993, Heisei; Chem. Abstr. 1994, 120, 245056.
8. Clark, R. D.; Miller, A. B.; Berger, J.; Repke, D. B.; Weinhardt, K. K.; Kowalczyk, B.
A.; Eglen, R. M.; Bonhaus, D. W.; Lee, C.-H.; Michel, A. D.; Smith, W. L.; Wong, E.
H. F. J. Med. Chem. 1993, 36, 2645.
9. (a) Zhang, H.; Larock, R. C. Org. Lett. 2002, 4, 3035; (b) Gilchrist, T. L.; Kemmitt,
P. D. Tetrahedron 1997, 53, 4447.
10. Snyder, S. A.; Vosburg, D. A.; Jarvis, M. G.; Markgraf, J. H. Tetrahedron 2000, 56,
5329.
11. Hingane, D. G.; Kusurkar, R. S. Tetrahedron Lett. 2011, 52, 3686.
12. Naik, P. N.; Naik, N. H.; Khan, A.; Kusurkar, R. S. Tetrahedron 2013, 69, 6545.
13. Markgraf, J. H.; Finkelstein, M.; Cort, J. R. Tetrahedron 1996, 52, 461.
14. Smith, G. J. Chem. Soc. 1954, 3842.
13C NMR (75 MHz, CDCl3)
d: 168.1, 137.5, 137.0, 131.7, 126.2, 123.3,
121.6, 120.9, 118.5, 113.5, 112.8, 109.8, 60.1, 44.6, 29.5, 25.7, 14.4;
HRMS (ESI) (MþH) 281.1290; calculated for C17H!7N2O2 281.1290.
4.11.2. 5,6-Dihydro-4H-indolo[3,2,1-ij][1,6]naphthyridine (12). Dark
yellow solid (75%); mp14 275 ꢀC (dec); FTIR (ATR cmꢁ1) 2920, 1620,
1574, 1478, 1242,1167, 748; 1H NMR (300 MHz, CDCl3)
d: 9.09 (1H, s,
ArH), 8.22 (1H, s, ArH), 7.90 (1H, d, J¼7.4 Hz, ArH), 7.22e7.36 (3H, m,
ArH), 4.36 (2H, t, J¼6.7 Hz, eNCH2), 3.63 (2H, t, J¼5.7 Hz, ArCH2),
2.09 (2H, quint, J¼6.2 Hz, eCH2e); 13C NMR (75 MHz, CDCl3)
d:
140.8, 137.5, 136.0, 133.5, 131.4, 125.4, 123.6, 122.3, 120.5, 110.6,
107.9, 46.8, 29.5, 26.3.
15. Coowar, D.; Bouissac, J.; Hanbali, M.; Paschaki, M.; Mohier, E.; Luu, B. J. Med.
4.11.3. Ethyl 4,5-dihydrobenzo[b]pyrido[3,4,5-gh]pyrrolizine-3-
Chem. 2004, 47, 6270.
carboxylate (18). Dark brown thick oil (68%); Rf (30% EA/Hexane)
16. Mosmann, T. J. Immunol. Methods 1983, 65, 55.
Please cite this article in press as: Naik, P. N.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.054