Efficient synthesis of some new antiproliferative N-fused indoles and isoquinolines via 1,3-dipolar cycloaddition reaction in an ionic liquid

Article abstract of DOI:10.1039/c4nj02308k

Syntheses of some new pyrrolo-fused pyrrolo[1,2-a] indole derivatives have been achieved by combining N-allyl-indole-2-carbaldehyde with a variety of N-alkyl-glycine esters as well as tetrahydroisoquinolines in an ionic liquid, triethylammonium acetate (TEAA), a recyclable reaction medium, via intramolecular [3+2] cycloaddition reaction. This new method is highly efficient, and the ionic liquid employed is recyclable. The stereochemistry of all the compounds was confirmed by 2D NMR NOESY and in some cases single crystal X-ray diffraction data. The in vitro screening of all new candidates against various bacterial strains and representative human solid tumor cell lines, A549 (lung), HeLa (cervix), SW1573 (lung), T-47D (breast) and WiDr (colon), revealed that many of them have good antibacterial, antifungal and antitubercular and antiproliferative activities.

Full text of DOI:10.1039/c4nj02308k

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DOI: 10.1039/C4NJ02308K
ARTICLE TYPE
Efficient synthesis of some new antiproliferative N-fused indoles and
isoquinolines via 1,3-dipolar cycloaddition reaction in ionic liquid
a
a
a*
b
b
Tushar R. Sutariya , Balvantsingh M. Labana , Narsidas J. Parmar , Rajni Kant , Vivek K.Gupta ,
c
c
Gabriela B. Plata and José M. Padrón
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Syntheses of some new pyrrolo–fused pyrrolo[1,2-a] indole derivatives have been achieved by combining
N-allyl-indole-2-carbaldehyde with a variety of N-alkyl‒glycine esters as well as tetrahydroisoquinolines
in an ionic liquid, triethylammonium acetate (TEAA), a recyclable reaction medium, via intramolecular
[3+2] cycloaddition reaction. This new method is highly efficient, and the ionic liquid employed is
recyclable. The stereochemistry of all the compounds was confirmed by 2D NMR NOESY and in some
cases single crystal X-ray diffraction data. The in vitro screening of all new candidates against various
bacterial strains and representative human solid tumor cell lines; A549 (lung), HeLa (cervix), SW1573
1
0
(lung), T-47D (breast) and WiDr (colon), revealed that many of them have good antibacterial, antifungal
1
5
and antitubercular and antiproliferative activities.
Introduction
5
5
6
6
7
0
5
0
5
0
In addition, the members of the trolline family are active against
respiratory Staphylococcus aureus and pneumonia bacteria. Like
The heterocycles with N-fused indole/isoquinoline‒heterocyclic
framework as one of their integral structural units constitute an
important class of bioprofiles, and have attracted interest of many
in the research fields of medicines and pharmaceuticals.
Containing pyrrolo–indole nucleus, terpenoidal alkaloids and
9
trolline, (+)-crispine A (Fig. 1D) also incorporates an analogous
heterocyclic framework and has potential anti-proliferative
1
2
2
3
3
0
5
0
5
12
activity against SKOV3, KB, and HeLa human cancer lines.
2
Finally, the pyrrolizidine occurring in many heterocycles
represents another useful framework of biological interest. In
addition to anti-inflammatory and analgesic properties, it confers
heterocycles with effective aromatase and tumour growth
3
mitomycins exhibited antitumor activity (Fig.1A). With
pyrrolo[1,2-a]indole as a specific fusion, cyclopropamitosenes
revealed cytotoxicity through bacterial cell division and DNA
4
5
alkylation. Likewise, antimalarial Flinderole B, bioactive
13
inhibition action. Besides, 5-HT2c receptor agonists, known to
6
Isatisine A (Fig.1B) and hallucinogenic Yuremamine (Fig.1C),
which are potential candidates of this class have attracted interest
of many chemists and biochemists.
Pyrrolo-isoquinoline alkaloids, on the other hand, showed
promising results for depression in animals, with pyrrolo-
isoquinoline nucleous.
isoquinoline is a key fused-ring systems of (2)-trolline structure,
which can be derived from Trollius Chinese flowers and its
be effective in hyperglycaemia and other diseases, come from the
same family and make it interesting source of bioactive
7
14
scaffolds.
In view of the above, it follows that incorporation of N-fused
indole, N-fused isoquinoline and pyrrolizidine into a molecular
assembly helps generate a new and useful class of heterocycles,
8
A
tricyclic hydropyrrolo [2,1-a]
finding
a great importance in the medicinal chemistry.
9
Development and enlargement of a molecular library of these
heterocycles is thus desirable and worth studying too.
1
0,11
Portulaca oleracea L weed-derived antipode (+)-oleracein E.
Studies showed that (2)-trolline has remarkable activity against
influenza viruses A and B, and so revealed antiviral property. (+)-
<< Figure: 1 Some biologically active heterocycles containing pyrrolo-
indole and pyrrolo-isoquinoline units >>
10
Oleracein E displayed DPPH-radical scavenging activity.
1
5
16
a
Intermolecular alkylation,
radical cyclization,
trans
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar-
388120. Dist. Anand, Gujarat, India. Tel.:+91-2692-226858;fax:+91-
692-236475;e-mail:njpchemdeptspu@yahoo.co.in
17
18
4
4
0
5
annulation reaction carbene–based rearrangement etc. are
general synthetic approaches for N-fused indoles. Cycloaddition
reaction involving in situ azomethine ylide generation,
nevertheless, seems to be seldom studied for kind of this
heterocycles. The protocol is highly atom economic, and.used
so far for many complex heterocyclic systems. It is witness of
2
b
Post-Graduate Department of Physics, University of Jammu, Jammu
7
5
Tawi-180006, India.
c
BioLab, Instituto Universitario de Bio-Orgánica “Antonio González”
19
(IUBO-AG), Centro de Investigaciones Biomédicas de Canarias
(
§
9
CIBICAN), C/ Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain
Electronic supplementary information (ESI) available. CCDC
60921and 1018001.
20
many aldehyde reacted with amino acid derivatives to design 6-
5 fused-ring systems. Indole-based substrates however remained
80
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[journal], [year], [vol], 00–00 | 1

New Journal of Chemistry
Page 2 of 15
24c
with a very few in number in the protocol for designing of 5-5 55 takes relatively less reaction times (3 h) than others . It should
2
1
fused-ring systems. The ring system exists in biotin, an
be noted further that the present combination allows pyrrolizidine
21d
View Article Online
important naturally occurring heterocycle.
As part of our research program, we have reported synthesis of
many pyran‒heterocycles.
via 1,3 dipolar cycloaddition. Here, we describe pyrrolo-indole
and pyrrolo-isoquinoline derivatives as new bioprofiles,
constructed from N–allyl‒3–chloro–indole‒2‒carbaldehyde 1
as highly significant, bioactive unit to incorporate effectively into
DOI: 10.1039/C4NJ02308K
N-fused indole/isoquinoline heterocycles.
20-h
20h-is
5
0
5
0
including aminobenzopyrans
<
< Table 1: Optimization of conditions of the reaction between amine 3a
60
and aldehyde 1>>
<
<Scheme 2: Synthesis of all newly pyrrolo-fused-indoles and
o
with
a
variety of ꢀ-amino acid esters as well as
isoquinolines (1) TEAA, 100 C>>
1
1
2
tetrahydroisoquinolines, in ionic liquid TEAA as an effective
reaction medium.
<
<Table 2: Synthesis of all newly pyrrolo-fused-indoles and
Use of ionic liquids (ILs) helped translate many synthetic
routes into green methodologies, with adopting requisite practice
isoquinolines >>
22
not only as economic one, but as environmentally friendly too.
To the best of our knowledge, very few reports appeared on use
6
7
7
5
0
5
A plausible mechanism of the reaction has been depicted in
Scheme 3. Addition of electron from the tethered-alkene terminal
carbon on imine follows the addition of the enolized ester on the
other end of the alkene via semi bicyclic transition state that may
force system to adopt the most favoured cis-fusion product. The
exo or endo attack of dipolarophile alkene on azomethine ylide
dipole determines the stereoselectivity of the reaction. The
spectral data support the cis-fusion between central pyrrolidine
rings in all heterocycles, hence favouring the endo transition
state. In 11’a-b, however, the Cis-fusion may involve a further
23
of ionic liquid in 1,3-dipolar cycloaddition reaction. And those
reported in ILs still suffer from preparation cost, use and
23-c
recyclability of ILs, and, of course, promotion of the reaction.
Conventional methods in general suffers from many
disadvantages like use of conventional solvent, longer reaction
24
time and tedious work-up procedure.
Results and discussion
27
isomerization of the ylide.
Chemistry
All requisite secondary amines 2–6, except tetrahydro-
isoquinolines 6; N–methyl/ethyl/benzyl/(4‒morpholinyl) ethyl
glycine esters, are liquids and prepared by methods reported
elsewhere. Teterahydroisoquinolines 6 were used as received
from commercial sources. The substrate, N–allyl–3–chloro–
indole–2–carbaldehyde 1, was obtained by reacting 3–chloro–
indole–2–carbaldehyde with ally bromide in the presence of
<<Scheme 3: A plausible mechanism of the reaction between aldehyde 1
and secondary amine via 1,3-dipolar cycloaddition reaction >>
2
5
25
The proposed structures of all newly synthesized
heterocycles fully agreed with the observed elemental analyses,
1
8
8
9
9
0
5
0
5
mass, IR and NMR spectral data. In the H NMR spectra, all
3
0
compounds except 7a showed a multiplet in the region ꢀ 2.93–
anhydrous K CO3, suspended in DMF (dimethylformamide)
2
4
.09 ppm, due to diastereotopic methylene protons of the
solution (Scheme 1), in 95% yield. 3–Chloro–indole–2–
carbaldehyde was obtained as Vilsmeier–Haack product of
pyrrolidine ring. In 7a, instead N-methyl proton appeared as a
singlet at ꢀ ~2.75 ppm. The carbonyl group in 7-10 showed a
26
(phenylglycine)–O–carboxylic acid, with excellent purity.
–1
13
characteristic IR band at ~1730 cm , and a C NMR signal ~ꢀ
173 ppm. In all compounds, a doublet in the ꢀ 4.00–4.80 ppm
range, with J value in the 7.6–8.4 Hz range, can be attributed to a
bridge-head proton 10b or 12b, suggestive of the cis-fusion
between central pyrrolidine rings. Another bridge-head proton 3a
or 5a appeared as a multiplet at ꢀ ~3.80 ppm is therefore
orientated cis to this 10b or 12 b proton. Analysing cross-peaks in
3
5
<< Scheme 1: Synthesis of N-allyl‒3-chloro–indole‒2-carbaldehyde 1,
The reagents and conditions (1) K CO , allyl bromide, DMF, 10 – 12 h,
room temp. >>
2
3
The reaction between amine 3a and aldehyde 1 was taken as a
model to optimize the reaction conditions (Table 1). Initially, we
heated the aldehyde and amine in refluxing methanol (entry 1),
acetonitrile (entry 2), toluene (entries 3 and 4) and xylene (entries
2
D NMR NOESY (nuclear Overhauser effect spectroscopy) and
4
4
5
0
5
0
DQF-COSY (double quantum filtered correlation spectroscopy)
of representative 8a (Fig. 2 and 3), the similar relationship
between these protons could be confirmed. The bridge-head
proton 2 or 4b is however trans with respect to proton 10b or
5
, 6), in presence and absence of Na SO . Although results in
2 4
toluene and xylene using Na CO were good, prolonged heating
2
3
was discouraging to accept this method (6 h). Even, when tried
reported methods, they failed to run present conversion
1
2b, appeared at ꢀ 4.00–4.40 ppm, except in 11’a-b. In 11’a-b, it
is cis oriented.
22c-d
effectively.
Thus, we opted for heating under solvent‒free
Finally, with the single-crystal X-ray diffraction data of 9b and
00 11’b, we could be able to establish important stereo-chemical
considerations (Fig. 4).
environment at 100 ℃. Here, the reaction time could be improved
but not the yields (entry 7). The conventional way was thus
abandoned in favour of the TEAA promoted one (entry 8). It
showed improved results in yield and reaction time at 80 ℃ that
were improved further at 100 ℃ (entry 9). Above 100 ℃,
however no further improvement was seen. This improved
method was then generalised to receive other products, too
1
<
< Fig. 2 Characteristic NOESY interactions in 8a>>
1
05
<< Fig. 3 Characteristic COSY interactions in 8a >>
(Scheme 2, Table 2). Advantage of the present protocol is that it
2
| Journal Name, [year], [vol], 00–00
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Page 3 of 15
New Journal of Chemistry
particular context, compounds 7–8 showed more activity against
HeLa cells, with GI50 values in the range 3.1–14 ꢀM and
<
< Fig. 4 The ORTEP views of compounds 9b and 11’b, with
displacement ellipsoids at the 40% probability level >>
View Article Online
comparable to those of cisplatin (2.0 ꢀM) or etoposide (3.3 ꢀM).
DOI: 10.1039/C4NJ02308K
60
No significant differences were observed between methyl and
ethyl ester derivatives. In contrast, the presence of a benzyl group
(9) or a morpholine substituent (10) on the pyrrol nitrogen
produced a severe loss in activity. From the pyrrolo-fused-
isoquinolines 11 obtained in our investigations, the best results of
Biological results
5
0
5
0
5
0
5
0
5
Table 3 summarizes in vitro antimicrobial screening test
results of all the compounds. The majority of compounds
displayed good resistance against bacteria, at least, in line with
one of the standard reference drugs ampicillin. The activity of 65 antiproliferative activity were obtained for adduct 11b, which
some of them was found to be equal to that of more potent drug.
Analyzing results in terms of maximum how many bacterium
species a compound can kill effectively, it revealed the compound
can cover a maximum five species at least with the potency
showed active against all the cell lines with GI50 values in the
range 9.5–18 ꢀM. This is a relevant result, since the class of
adduct correlates to selectivity towards cancer cell lines.
1
1
2
2
3
3
4
4
Analysing N-fused indoles derived from amino acid esters,
equivalent to ampicillin. Examples include 7c, 9c, 10e and 11b. 70 structurally, it reveals that methyl at pyrolidine nitrogen confers
Among them, 7c revealed excellent activity against Gram-
positive Clostridium tetani (reaching to potency of even more
potent norfloxacin) and Gram-negative Escherichia coli bacteria
heterocycles with enhanced resistivity against Clostridium tetani
and Escherichia coli bacteria, when carbpropoxy moiety is
present at carbon next to this nitrogen. Pyrrolidin with
morpholine or ethyl moieties at nitrogen in combination with
(reaching to the potency of even more potent chloramphenicol).
Similarly, compound 9c resembled more potent standard 75 carbmethoxy group also had a similar effect against these
norfloxacin drug in activity, against Gram-positive Bacillus
subtilis bacteria. Compounds 7a, 7d, 8a, 8c, 8d, 9e, 10a, 10b, 10c
and 11a, on the other hand, had recorded better resistance against
at least four types of bacteria. Among them, 7a, 7d, 8c, and 10a
bacteria. Carbbutoxy moiety, on the other hand, had very less
effect on activity, irrespective of substituent present at pyrrolidine
nitrogen. Antiproliferative activity, nevertheless, seemed to be
altered very less taking any ester component with N-methyl/N-
registered excellent activity against Gram-positive Clostridium 80 ethyl pyrrolidine ring, against HeLa (cervix) cell lines. In
tetani bacteria, with MIC values in line with ciprofloxacin which
is more potent than ampicillin. Compounds 7d and 10a with
chloramphenicol–equivalent potency had good results against
Bacillus subtilis and Salmonella typhi bacteria respectively. It is
noted that both ciprofloxacin and compound 7d recorded similar 85 electron releasing methoxy substituted‒tetrahyderoisoquinoline
MIC value against Bacillus subtilis bacteria. Next, those with at
least activity against three types of bacterium species include 7b,
addition, N-ethyl pyrrolidine with any ester component had
similar effect against Widr(colon) cell lines. The N-fused indoles
derived from tetrahydreoisoquinolines showed remarkable
bioactivities as well. In general, heterocycles derived from
are excellent in antibacterial, antitubercular, antioxidant and
antiproliferative activities, compared to the ones derived from
simple tetrahydro isoquinoline.
7
e, 8b, 8e, 9b, 9d and 10d. Among them 8b, 8c and 9d are very
close to standard ciprofloxacin in potency, against Clostridium
tetani bacteria. Further, a few of the compounds showed good
antifungal activity, particularly against Candida albicans fungus.
Examples include 7a, 7e, 8c, 8e, 9c and 10d all having
griseofulvin-equivalent power. As anti-fungal agents,
compounds 7d, 10a and 10b are relatively more active.
9
0
<< Table 4: Antiproliferative activity (GI50) against human solid tumor
cells. >>
Conclusions
Anti-tubercular activity study shows that compounds 9d and
10b have highest M. tuberculosis H37Rv bacterial resistance,
with growth inhibition in the 90-100% range. Compounds 8a, 9a,
Thus, we synthesized N-fused indole and isoquinoline
derivatives as new bioactive compounds via 1,3-dipolar
cycloaddition reaction, using an ionic liquid, TEAA as
inexpensive, environmentally friendly and recyclable reaction
medium. The resistance power of 7c, 7d, 8a and 10a at least
against one of the bacterial species studied is highest with
00 resembling Chloramphenicol in activity with MIC 62.5 µg/L.
Antiproliferative activity of 11b, on the other hand, found
excellent against all cell lines, with GI50 values laying in the 9.5–
18 ꢀM range, comparable with standard drugs used. Besides, 10b,
with FRAP value of 225 (mmol/100 gm), showed excellent ferric
05 reducing anti-oxidant power.
95
9
c, 10a and 11’b have growth inhibition in the 80-90% range.
FRAP values of majority of the heterocycles are around 225
(mmo/100 gm), indicating that they are moderate in anti-oxidant
power. However, compound 10b revealed remarkable activity.
1
<
< Table 3: Antimicrobial, antitubercular and antioxidant activities test
result. >>
The antiproliferative activity of 7–11 was evaluated against a
panel of representative human tumor cell lines including A549
1
5
0
(
lung), HeLa (cervix), SW1573 (lung), T-47D (breast) and WiDr
28
(colon), using the SRB assay. The experimental GI50 values are
summarized in Table 4 and compared to those of cisplatin,
etoposide and camptothecin after 48 h of treatment. Taken as a
whole, pyrrolo-fused-indoles 7–8 was the most active class of
compounds, with activity against all cell lines tested. In this
5
5
This journal is © The Royal Society of Chemistry [year]
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New Journal of Chemistry
Page 4 of 15
+
Experimental
138.5(Ar-C), 172.87(C=O). ESI-MS (m/z): 304.97 (M) , Anal
Calcd for C H ClN O : C, 63.05; H, 5.62; N, 9.19; Found: C,
16
17
2
2
Materials and methods
View Article Online
6
3.35; H, 5.27; N, 9.42.
DOI: 10.1039/C4NJ02308K
All solvents and reagents were used as supplied from
commercial sources. The recorded melting points are uncorrected.
IR spectra were recorded in KBr on Shimadzu FT-IR 8401
60
Ethyl
(2S,3aS,10bS)-10-chloro-1-methyl-1,2,3,3a,4,10b
5
0
5
0
5
hexahydropyrrolo[2',3':3,4] pyrrolo[1,2-a]indole-2-
carboxylate(7b). yield 82%, mp 102-104℃, IR (ν , cm ):
3059, 2983, 1730, 1631, 1455, 1177, 1038, 732, 602; H NMR
-
1
1
-1
spectrometer and are reported in wave numbers (cm ). H NMR
max
1
13
and C NMR spectra were recorded on a Bruker Avance 400
1
spectrometer operating at 400 MHz for H NMR and 100 MHz 65 (400 MHz, CDCl ): δ 1.33(3H, t, J = 6.4 Hz, -OCH CH ),
3
2
3
13
for C NMR as solutions in CDCl , unless otherwise indicated.
2.21(1H, m, H-3’), 2.40(1H, ddd, J = 13.2, 8.4, 5.2 Hz, H-3),
2.75(3H, s, N-CH ), 3.66(1H, t, J = 5.6 Hz, H-2), 3.79(1H, m, H-
3a), 3.96 (1H, ddd, J = 9.9, 4.0, 1.2 Hz, H-4), 4.18-4.28(3H, m,
2H of -COOCH CH and 1H of H-4’), 4.82(1H, d, J = 7.6 Hz, H-
3
1
1
2
2
Chemical shifts are reported as parts per million (ppm, d) and
referenced to the residual protic solvent. Coupling constants are
reported in Hertz (Hz). Splitting patterns are designated as s,
3
2
3
1
3
singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet. 70 10b), 7.18(3H, m, Ar-H.), 7.6(1H, dd, J = 7.8, 0.8 Hz, H-9);
The degree of substitution (C, CH, CH , and CH ) was
NMR (100 MHz, CDCl3): 14.3(OCH CH ), 36.7(C-3),
37.1(NCH ), 45.3(C-3a), 50.8(C-4), 60.6(OCH CH ), 64.8(C-
C
2
3
δ
2
3
determined by the DEPT-135 method. The ESI mass spectra were
measured on Shimadzu LCMS-2010 spectrometer. Elemental
analysis (% C, H, N) was carried out by Perkin-Elmer 2400
3
2
3
10b), 67.0(C-2), 98.2(C-10), 110.0(C-6), 118.6, 120.1, 122.2,
130.2, 131.9, 138.5 (Ar-C), 172.8(C=O). ESI-MS (m/z): 319.10
+
series-II elemental analyzer (Perkin-Elmer, USA). TLC was 75 (M) , Anal Calcd for C H ClN O : C, 64.05; H, 6.01; N, 8.79;
17
19
2
2
performed on Merck 60 F254 precoated silica plates, spots were
detected either by UV (254 nm, 366 nm) or dipping into a
permanganate [KMnO (3 g), K CO (20 g), NaOH (5 mL, 5 % in
Found: C, 64.21; H, 6.17; N, 8.62.
4
2
3
Propyl
(2S,3aS,10bS)-10-chloro-1-methyl-1,2,3,3a,4,10b-
pyrrolo[1,2-a]indole-2-
H O), H2O (300 mL)] or an anisaldehyde solution [3 % p-
hexahydropyrrolo[2',3':3,4]
2
-
1
methoxybenzaldehyde and 1 %H SO in MeOH] or 2,4 dinitro 80 carboxylate(7c). yield 77%, mp 106-108℃, IR (ν , cm ):
2
4
max
1
phenyl hydrazine solution [2,4-DNP (12 g), conc. H SO (6 mL),
3059, 2984, 1732, 1630, 1457, 1179, 1039, 730, 599; H NMR
(400 MHz, CDCl3):
2
4
water (8 mL), EtOH (20 mL)] followed by heating.
δ 0.99(3H, t, J = 7.8 Hz, -
COOCH CH CH ), 1.75(2H, m, -COOCH CH CH ), 2.19(1H,
m, H-3’), 2.42(1H, ddd, J = 13.8, 8.2, 5.4 Hz, H-3), 2.74(3H, s, -
2
2
3
2
2
3
General procedure for the synthesis of N-fused indoles and
isoquinolines:
8
9
9
5
0
5
NCH ), 3.70(1H, t, J = 5.4 Hz, H-2), 3.79(1H, m, H-3a), 3.98
3
A mixture of an aldehyde 1 (1 equiv.) and an acyclic secondary
amine 2-5 (1 equiv.) or isoquinoline 6a-b (1 equiv.) in 2 mL of
ionic liquid TEAA in a round bottom flask was heated at 100 ℃
and completion of the reaction was confirmed through the TLC.
The reaction mass was cooled to room temperature and poured
into ice species. The oily product thus emulsified was then
extracted with three 10 mL diethyl ether portions. It yielded crude
products in quantitative amounts on removal of ether. Finally, the
product was purified by column chromatography using a 90:10 n-
hexane-ethyl acetate mixture as an eluent. The yields were in the
(1H, ddd, J = 9.6, 4.0, 1.6 Hz, H-4), 4.17 (3H, m, 2H of -
COOCH CH CH , 1H of H-4’), 4.83(1H, d, J = 7.8 Hz, H-10b),
2
2
3
3
3
4
0
5
0
13
7
(
.16(3H, m, Ar-H), 7.71(1H, dd, J = 7.6, 1.0 Hz, H-9); C NMR
100 MHz, CDCl3): 10.4(-COOCH CH CH ), 22.1(-
COOCH CH CH ), 36.6(C-3), 37.0(-NCH ), 45.3(C-3a), 50.7(C-
δ
2
2
3
2
2
3
3
4
1
1
), 64.8(C-10b), 66.7(-COOCH CH CH ), 67.0(C-2), 98.2(C-10),
2 2 3
10.0(C-6), 118.5, 120.1, 122.2, 130.2, 131.9, 138.1(Ar-C),
+
72.8(C=O). ESI-MS (m/z): 332.92 (M) , Anal Calcd for
C H ClN O : C, 64.96; H, 6.36; N, 8.42; Found: C, 64.75; H,
18
21
2
2
6.47; N, 8.62
7
5-85 % range. The TEAA was recovered quantitatively by
heating the aqueous layer–left after the ether extraction of
product–under the reduced presser at 80 ℃. The recovered ionic
liquid can be used again for the same. It was noticed that TEAA
can be recycled at least four-time with its unaltered efficiency.
Isopropyl (2S,3aS,10bS)-10-chloro-1-methyl-1,2,3,3a,4,10b-
hexahydropyrrolo [2',3':3,4]pyrrolo[1,2-a]indole-2-
-1
carboxylate(7d). yield 84%, mp 107-109℃; IR (ν , cm ):
max
1
1
1
1
00 3058, 2984, 1732, 1632, 1456, 1179, 1038, 732, 599; H NMR
(
400 MHz, CDCl ): δ 1.30(3H, d, J = 2.4 Hz, CH of isopropyl),
3
3
1
2
3
.32(3H, d, J = 2.4 Hz, CH of isopropyl), 2.20(1H, m, H-3’),
.39(1H, ddd, J = 12.8, 8.2, 5.0 Hz, H-3), 2.74(3H, s, N-CH3),
.67(1H, t, J = 5.8Hz, H-2), 3.80(1H, m, H-3a), 3.96 (1H, ddd, J
Spectroscopy data of compounds (7-11)
3
4
5
5
5
0
5
Methyl
hexahydropyrrolo[2',3':3,4]pyrrolo[1,2-a]indole-2-
carboxylate (7a). yield 82%, mp 118-120 ℃, IR (νmax, cm ):
(2S,3aS,10bS)-10-chloro-1-methyl-1,2,3,3a,4,10b-
05 = 9.8, 4.0, 1.2 Hz, H-4), 4.18(1H, dd, J = 16.8, 7.8 Hz, H-4’),
.81(1H, d, J = 7.4 Hz, H-10b), 5.12(1H, septet, J = 6.4 Hz, –
CH(CH ) ), 7.18(3H, m, Ar-H), 7.61(1H, dd, J = 7.6, 0.8 Hz, H-
-
1
4
1
3
058, 2983, 1732, 1630, 1455, 1178, 1039, 731, 600; H NMR
3
2
(
400 MHz, CDCl ): δ 2.20(1H, m, H-3’), 2.41(1H, ddd, J = 13.6,
13
3
9
3
); C NMR (100 MHz, CDCl ): δ 21.2(-OCH(CH ) ), 36.7(C-
3 3 2
8.2, 5.6 Hz, H-3), 2.76(3H, s, -NCH ), 3.68(1H, t, J = 5.8Hz, H-
3
), 37.0(-NCH ), 45.2(C-3a), 50.7(C-4), 64.8(C-10b), 67.0(C-2),
3
2
9
), 3.78(4H, m, 3H of –COOCH , 1H, H-3a), 3.97 (1H, ddd, J =
.8, 4.2, 1.4 Hz, H-4), 4.19 (1H, m, H-4’), 4.81(1H, d, J = 7.4
3
10 68.0(-CH(CH ) ), 98.2(C-10), 110.0(C-6), 118.5, 120.1, 122.2,
3
2
1
30.2, 131.9, 138.6(Ar-C), 172.87(C=O). ESI-MS (m/z): 332.94
Hz, H-10b), 7.17(3H, m, Ar-H), 7.70(1H, dd, J = 7.6, 1.0 Hz, H-
+
(M) , Anal Calcd for C H N O , C, 64.96; H, 6.36; N, 8.42;
18 21 2 2
13
9
); C NMR (100 MHz, CDCl ): δ 36.7(C-3), 37.1(-NCH ),
3 3
Found: C, 64.88; H,6.25; 8.34.
45.3(C-3a), 50.8(C-4), 51.3(-COOCH ), 64.8(C-10b), 67.0(C-2),
3
9
8.2(C-10), 110.0(C-6), 118.6, 120.1, 122.2, 130.2, 131.9,
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 15
New Journal of Chemistry
-
1
Butyl
(2S,3aS,10bS)-10-chloro-1-methyl-1,2,3,3a,4,10b-
carboxylate(8c); yield 84%, mp 64-66℃, IR (ν , cm ): 3050,
max
1
hexahydropyrrolo[2',3':3,4]
carboxylate(7e). yield 77%, mp 92-94℃, IR (ν , cm ): 3060,
pyrrolo[1,2-a]indole-2- 60 2976, 1730, 1632, 1452, 1198, 1168, 739, 648; H NMR (400
-
1
View Article Online
MHz, CDCl ): δ 0.99 (3H, t, J = 7.4 Hz, –COO(CH ) CH ),
3 2 2 3
DOI: 10.1039/C4NJ02308K
max
1
2
982, 1732, 1630, 1456, 1178, 1039, 731, 600; H NMR (400
1.21(3H, t,
J = 7.4 Hz, –NCH CH ), 1.72(2H, m, -
2 3
5
0
5
0
5
0
5
0
5
0
5
MHz, CDCl ): δ 0.99(3H, t, J = 7.8 Hz, -COO(CH ) CH ),
3 2 3 3
COOCH CH CH ), 2.22(1H, m, H-3’), 2.41(1H, ddd, J = 12.6,
9.2, 3.4 Hz, H-3), 2.95(1H, m, 1H of -NCH CH ), 3.30(1H, m,
2 3
2
2
3
1
.43(2H, sextet, J = 7.6 Hz, -COO(CH ) CH CH ), 1.68(2H,
2
2
2
3
quintet, J = 7.2 Hz, -COOCH CH CH CH ), 2.22(1H, m, H-3’), 65 1H of -NCH CH ), 3.78(1H , m, H-3a), 3.97(2H, m, 1H of H-2
2
2
2
3
2
3
2
3
.39(1H, ddd, J = 13.6, 8.4, 5.6 Hz, H-3), 2.73(3H, s, -NCH3),
.70(1H, t, J = 5.4 Hz, H-2), 3.78(1H, m, H-3a), 3.97 (1H, ddd, J
and 1H of H-4), 4.16-4.21(3H, m, 1H of H-4’ and 2H of -
COOCH ), 4.79(1H, d, J = 7.8 Hz, H-10b), 7.21(3H, m, Ar-H),
2
13
1
1
2
2
3
3
4
4
5
5
=
9.4, 4.2, 1.8 Hz, H-4), 4.19 (3H, m, 2H of
-
7.62(1H, dd, J = 7.4, 1.6 Hz, H-9); C NMR (100 MHz, CDCl3):
10.4(–COO(CH ) CH ), 13.8(-NCH CH ), 22.1(-
70 COOCH CH CH ) 35.9(C-3), 44.2(-NCH CH ), 45.0(C-3a),
COOCH (CH ) CH , 1H of H-4’), 4.81(1H, d, J = 7.6 Hz, H-
δ
2
2 2
3
2 2
3
2
3
13
1
0b), 7.17(3H, m, Ar-H), 7.70(1H, dd, J = 7.4, 1.2 Hz, H-9);
C
2
2
3
2
3
NMR (100 MHz, CDCl ): δ 10.4(-COO(CH ) CH ), 19.2(-
50.5(C-4), 63.9(C-2), 64.1(C-10b), 66.3(-COOCH CH CH ),
3
2 3
3
2
2
3
COOC(CH ) CH CH ), 30.7(-COOCH CH CH CH ), 36.7(C-3),
97.7(C-10), 112.0(C-6), 118.5, 120.0, 122.1, 130.1, 131.8, 139.4
2
2
2
3
2
2
2
3
+
37.1(-NCH3), 45.3(C-3a), 50.7(C-4), 64.7(C-10b), 66.7(-
COOCH (CH ) CH ), 67.0(C-2), 98.2(C-10), 110.0(C-6), 118.5,
(Ar-C), 173.8(C=O); ESI-MS (m/z): 346.87 (M) , Anal Calcd for
C H ClN O : C, 65.79; H, 6.68; N, 8.08; Found: C, 65.89; H,
2
2 2
3
19 23
2
2
1
20.1, 122.2, 130.2, 131.9, 138.5(Ar-C), 172.8(C=O). ESI-MS 75 6.43; N, 7.89.
+
(
m/z): 347.04 (M) , Anal Calcd for C H ClN O : C, 65.79; H,
19 23 2 2
6
.68; N, 8.08; Found: C, 65.55; H, 6.57; N, 8.22
Isopropyl
hexahydropyrrolo[2',3':3,4]
carboxylate (8d); yield 78%, mp 62-63℃, IR (νmax, cm ):
(2S,3aS,10bS)-10-chloro-1-ethyl-1,2,3,3a,4,10b
pyrrolo[1,2-a]indole-2-
-
1
Methyl
(2S,3aS,10bS)-10-chloro-1-ethyl-1,2,3,3a,4,10b-
1
hexahydropyrrolo
carboxylate(8a); yield 85%, mp 84-86℃, IR (ν , cm ): 3051,
[2',3':3,4]
pyrrolo[1,2-a]indole-2- 80 3054, 2967, 1733, 1631, 1456, 1373, 1185, 1107, 737, 656; H
-
1
NMR (400 MHz, CDCl ): δ 1.2(3H, t, J = 7.2 Hz, –CH CH ),
3 2 3
max
1
2
975, 1728, 1631, 1453, 1197, 1169, 738, 650; H NMR (400
1.31(3H, d, J = 2.4 Hz, CH of isopropyl), 1.32(3H, d, J = 2.4 Hz,
3
MHz, CDCl ): δ 1.20(3H, t, J = 7.2 Hz, –NCH CH ), 2.19(1H, m,
CH of isopropyl), 2.19(1H, m, H-3’), 2.39(1H, ddd, J = 13.4,
3
2
3
3
H-3’), 2.40(1H, ddd, J = 12.8, 9.4, 3.2 Hz, H-3), 2.95(1H, m, one
9.2, 2.8 Hz, H-3), 2.93(1H, m, 1H of -NCH CH ), 3.37(1H, m,
2
3
of NCH CH ), 3.35(1H, m, another of -NCH CH ), 3.78(4H, m, 85 1H of -NCH CH ), 3.81(1H, m, H-3a), 3.93(1H, dd, J = 7.2, 2.8
2
3
2
3
2
3
3
1
H of –COOCH , and 1H of H-3a), 3.96(2H, m, 1H of H-2, and
H of H-4), 4.18(1H, dd, J = 10, 8.4 Hz, H-4’), 4.82(1H, d, J =
Hz, H-4), 3.98(1H, dd, J = 10.2, 4.0 Hz, H-2),4.20(1H, dd, J =
17.2, 8.0 Hz, H-4’), 4.82(1H, d, J = 8.4 Hz, H-10b), 5.12(1H,
septet, J = 6.4 Hz, -OCH(CH ) ), 7.19(3H, m, Ar-H), 7.59(1H,
3
8Hz, H-10b), 7.20(3H, m, Ar-H), 7.60(1H, dd, J = 7.6, 1.6 Hz, H-
3
2
1
3
13
9
4
6
1
); C NMR (100 MHz, CDCl ): δ 13.8(-NCH CH ), 35.9(C-3),
dd, J = 7.8, 1.2 Hz, H-9); C NMR (100 MHz, CDCl ): δ 13.5(-
3
3
2
3
4.2(-NCH CH ), 45.0(C-3a), 50.5(C-4), 51.3(CH ), 63.9(C-2), 90 NCH CH ), 21.2(Me of iso propyl), 35.9(C-3), 44.6(-NCH CH ),
4.1(C-10b), 97.7(C-10), 110.0(C-6), 118.5, 120.0, 122.1, 130.1,
31.8, 139.4(Ar-C), 173.8(C=O); ESI-MS (m/z): 319.10 (M) ,
2
3
3
2
3
2
3
45.7(C-3a), 50.7(C-4), 64.1(C-2), 64.2(C-10b), 68.0(-
OCH(CH ) ) 97.4(C-10), 110.0, 118.1, 120.1, 122.2, 130.1,
+
3
2
+
Anal Calcd for C H ClN O : C, 64.05; H, 6.01; N, 8.79; Found:
131.6, 139.6(Ar-C.), 173.4(C=O); ESI-MS (m/z): 346.00 (M) ,
17
19
2
2
C, 63.88; H, 6.23; N, 8.94.
Anal Calcd for C H ClN O : C, 65.79; H, 6.68; N, 8.08; Found:
19
23
2
2
95
C, 65.88; H, 6.73; N, 8.16.
Ethyl
hexahydropyrrolo[2',3':3,4]
carboxylate(8b); yield 82%, mp 92-94℃, IR (νmax, cm ): 3053,
(2S,3aS,10bS)-10-chloro-1-ethyl-1,2,3,3a,4,10b-
pyrrolo[1,2-a]indole-2-
Butyl
hexahydropyrrolo[2',3':3,4]
carboxylate (8e); yield 89%, mp 60-62℃, IR (νmax, cm ): 3052,
(2S,3aS,10bS)-10-chloro-1-ethyl-1,2,3,3a,4,10b-
-
1
pyrrolo[1,2-a]indole-2-
1
-1
2
973, 1730, 1630, 1450, 1248, 1198, 1170, 739, 652; H NMR
1
(
400 MHz, CDCl ): δ 1.22(3H, t, J = 7.2 Hz, –NCH CH ), 100 2976, 1729, 1630, 1451, 1198, 1170, 1130, 740, 648; H NMR
3
2
3
1
2
.32(3H, t, J = 6.8 Hz, –COOCH CH ), 2.20(1H, m, H-3’),
.42(1H, ddd, J = 12.4, 9.6, 3.4 Hz, H-3), 2.94(1H, m, 1H of -
(400 MHz, CDCl ): δ 0.98 (3H, t, J = 7.6 Hz, –COO(CH ) CH ),
3 2 3 3
1.19(3H, t, J = 7.8 Hz, –NCH CH ), 1.42(2H, sextet, J = 7.2 Hz,
2 3
2
3
NCH CH ), 3.32(1H, m, 1H -NCH CH ), 3.79(1H , m, H-3a),
–COO(CH ) CH CH ), 1.68(2H, quintet,
J
=
7.2 Hz,
-
2
3
2
3
2 2
2
3
3
.98(2H, m, 1H of H-2 and 1H of H-4), 4.18-4.22(3H, m, 1H of
COOCH CH CH CH ), 2.21(1H, m, H-3’), 2.41(1H, ddd, J =
2
2
2
3
H-4’ and 2H of -COOCH ), 4.80(1H, d, J = 8.2 Hz, H-10b), 105 12.8, 9.6, 3.2 Hz, H-3), 2.94(1H, m, 1H of -NCH CH ), 3.32(1H,
2
2
3
13
7
.22(3H, m, Ar-H), 7.62(1H, dd, J = 7.8, 1.4 Hz, H-9); C NMR
m, 1H of -NCH CH , 3.79(1H, m, H-3a), 3.96(2H, m, 1H of H-2,
2 3)
and 1H of H-4), 4.18-4.21(3H, m, 1H of H-4’ and 2H of -
(
100 MHz, CDCl ): δ 13.8(-NCH CH ), 14.3(-COOCH CH )
3
2
3
2
3
35.9(C-3),
44.2(-NCH CH ),
45.0(C-3a),
50.4(C-4),
COOCH ), 4.80(1H, d, J = 7.6 Hz, H-10b), 7.20(3H, m, Ar-H),
2
3
2
13
6
1
1
0.3(COOCH CH ), 63.9(C-2), 64.1(C-10b), 97.7(C-10),
7.61(1H, dd, J = 7.2, 1.8 Hz, H-9); C NMR (100 MHz, CDCl3):
10.4(-COO(CH ) CH ), 13.8(-NCH CH ), 19.2(-
COO(CH ) CH CH ), 30.7(-COOCH CH CH CH ) 35.9(C-3),
2
3
12.0(C-6), 118.5, 120.0, 122.1, 130.1, 131.8, 139.4(Ar-C), 110
δ
2
3
3
2
3
+
73.8(C=O); ESI-MS (m/z): 332.82 (M) , Anal Calcd for
2
2
2
3
2
2
2
3
C H ClN O : C, 64.96; H, 6.36; N, 8.42; Found: C, 64.86; H,
44.2(-NCH CH ), 45.0(C-3a), 50.5(C-4), 63.9(C-2), 64.1(C-10b),
2 3
66.8(-COOCH (CH ) CH ), 97.7(C-10), 112.0(C-6), 118.5,
2 2 2 3
18
21
2
2
6.53; N, 8.74.
1
20.0, 122.1, 130.1, 131.8, 139.4(Ar-C), 173.8(C=O); ESI-MS
+
Propyl
(2S,3aS,10bS)-10-chloro-1-ethyl-1,2,3,3a,4,10b- 115 (m/z): 360.88 (M) , Anal Calcd for C H ClN O : C, 66.56; H,
20 25 2 2
hexahydropyrrolo[2',3':3,4]
pyrrolo[1,2-a]indole-2-
6.98; N, 7.76; Found: C, 66.78; H, 6.54; N, 7.98.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

New Journal of Chemistry
Page 6 of 15
1
H NMR (400 MHz, CDCl ): δ 1.31(3H, d, J = 2.4 Hz, Me of
3
Methyl
hexahydropyrrolo
carboxylate (9a); yield 80%, mp 154-156℃, IR (νmax, cm ):
(2S,3aS,10bS)-1-benzyl-10-chloro-1,2,3,3a,4,10b- 60 isopropyl), 1.33(3H, d, J = 2.4 Hz, Me of isopropyl), 2.18(1H, m,
View Article Online
[2',3':3,4]pyrrolo[1,2-a]indole-2-
H-3’), 2.36(1H, ddd, J = 12.8, 9.2, 3.2 Hz, H-3), 3.69(1H, t, J =
DOI: 10.1039/C4NJ02308K
-
1
6.0 Hz, H-2), 3.84(1H, m, H-3a), 4.03(2H, m, -NCH Ph),
2
5
0
5
0
5
0
5
0
5
0
5
3055, 2980, 1723, 1581, 1455, 1369, 1195, 1028, 739, 705, 598;
4.20(1H, m, H-4), 4.82(1H,d, J = 13.4 Hz, H-4’), 5.02(1H, d, J =
1
H NMR (400 MHz, CDCl ): δ 2.16(1H, m, H-3’), 2.35(1H, ddd,
8.4 Hz, H-10b), 5.14(1H, septet, J = 6.4 Hz, –CH(CH ) ),
3
3 2
13
J = 12.4, 9.0, 3.2 Hz, H-3), 3.67(1H, t, J = 6.2 Hz, H-2), 3.77(3H, 65 7.25(8H, m, Ar-H), 7.65(1H, d, J = 7.8 Hz, H-9); C NMR (100
s, -COOCH ), 3.84(1H, m, H-3a), 4.06(2H, m, -NCH Ph), MHz, CDCl ): δ 21.3(-COOCH(CH ) ), 35.8(C-3), 45.4(C-3a),
3
2
3
3 2
4
.21(1H, m, H-4), 4.79(1H, d, J = 13.4 Hz, H-4’), 5.01(1H, d, J =
50.2(C-4), 54.0(-NCH Ph), 63.8(C-10b), 64.3(C-2), 68.0(–
2
1
1
2
2
3
3
4
4
5
5
8.2 Hz, H-10b), 7.25(8H, m, Ar-H), 7.62(1H, d, J = 7.4 Hz, H-9);
CH(CH ) ), 97.2(C-10), 110.0(C-6), 118.6, 120.0, 122.1, 127.1,
3
2
13
C NMR (100 MHz, CDCl ): δ 35.8(C-3), 45.4(C-3a), 50.1(C-4),
128.2, 129.0, 130.1, 131.7, 138.8, 140.3(Ar-C), 173.4(-C=O);
3
+
5
9
1
1.3(-COOCH3), 54.0(-NCH Ph), 63.9(C-10b), 64.4(C-2), 70 ESI-MS (m/z): 408.90 (M) , Anal Calcd for C H ClN O : C,
7.2(C-10), 110.0(C-6), 118.6, 120.0, 122.1, 127.1, 128.2, 129.0,
2
24 25
2
2
70.49; H, 6.16; N, 6.85; Found: C, 70.54; H, 6.28; N, 6.73
30.2, 131.7, 138.8, 140.3(Ar-C), 173.4(-C=O); ESI-MS (m/z):
+
380.87 (M) , Anal Calcd for C H ClN O : C, 69.38; H, 5.56; N,
Butyl
(2S,3aS,10bS)-1-benzyl-10-chloro-1,2,3,3a,4,10b-
22
21
2
2
7
.36; Found: C, 69.54; H, 5.68; N, 7.42.
hexahydropyrrolo[2',3':3,4]
carboxylate (9e); yield 74%, mp 96-98℃, IR (νmax, cm ): 3052,
2981, 1722, 1584, 1453, 1372, 1194, 1028, 741, 702, 597; H
pyrrolo[1,2-a]indole-2-
-
1
75
1
Ethyl
(2S,3aS,10bS)-1-benzyl-10-chloro-1,2,3,3a,4,10b-
pyrrolo[1,2-a]indole-2-
hexahydropyrrolo[2',3':3,4]
carboxylate(9b); yield 82%, mp 124-125℃, IR (νmax, cm ):
053, 2982, 1720, 1582, 1455, 1371, 1194, 1027, 739, 700, 599;
NMR (400 MHz, CDCl ): δ 0.99(3H, t, J = 7.8 Hz, -
3
-
1
COO(CH ) CH ), 1.46(2H, sextet,
J
=
7.6 Hz,
-
-
2 3
3
3
COO(CH ) CH CH ), 1.66(2H, quintet,
J = 6.8 Hz,
2
2
2
3
1
H NMR (400 MHz, CDCl ): δ 1.30(3H, t, J = 7.2 Hz, - 80 COOCH CH CH CH ), 2.16(1H, m, H-3’), 2.34(1H, ddd, J =
3
2
2
2
3
COOCH CH ), 2.17(1H, m, H-3’), 2.34(1H, ddd, J = 12.6, 9.2,
12.6, 8.8, 3.2 Hz, H-3), 3.68(1H, t, J = 6.2 Hz, H-2), 3.87(1H, m,
2
3
3
.0 Hz, H-3), 3.68(1H, t, J = 6.0 Hz, H-2), 3.85(1H, m, H-3a),
H-3a), 4.06(2H, m, -NCH Ph ), 4.17(3H, m, 1H of H-4 and 2H of
2
4.05(2H, m, -NCH Ph), 4.2(3H, m, 2H of –COOCH CH , and 1H
-COOCH CH CH CH ), 4.79(1H, d, J = 13.4 Hz, H-4’), 4.99(1H,
2
2
3
2
2
2
3
of H-4), 4.8(1H, d, J = 13.6 Hz, H-4’), 5.0(1H, d, J = 8.0 Hz, H-
d, J = 7.6 Hz, H-10b), 7.25(8H, m, Ar-H), 7.62(1H, d, J = 7.6 Hz,
13
13
1
0b), 7.23(8H, m, Ar-H), 7.63(1H, d, J = 7.6 Hz, H-9); C NMR 85 H-9); C NMR (100 MHz, CDCl ): δ 10.4(-COO(CH ) CH ),
3 2 3 3
(
100 MHz, CDCl ): δ 14.4(-COOCH CH ), 35.8(C-3), 45.4(C-
19.2(-COO(CH ) CH CH ),
30.7(-COOCH CH CH CH ),
2 2 2 3
3
2
3
2 2
2
3
3
a), 50.1(C-4), 54.0(-NCH Ph), 60.3(-COOCH CH ), 63.9(C-
35.8(C-3), 45.4(C-3a), 50.1(C-4), 54.0(-NCH Ph), 63.9(C-10b),
2
2
3
2
10b), 64.4(C-2), 97.2(C-10), 110.0(C-6), 118.6, 120.0, 122.1,
27.1, 128.2, 129.0, 130.2, 131.7, 138.8, 140.3(Ar-C), 173.4(-
64.4(C-2), 66.7(-COOCH CH CH CH ), 97.2(C-10), 110.0(C-6),
2
2
2
3
1
118.6, 120.0, 122.1, 127.1, 128.2, 129.0, 130.2, 131.7, 138.8,
+
+
C=O); ESI-MS (m/z): 395.30 (M) , Anal Calcd for 90 140.3(Ar-C), 173.4(-C=O); ESI-MS (m/z): 422.95 (M) , Anal
C H ClN O : C, 69.95; H, 5.87; N, 7.09; Found: C, 69.74; H, Calcd for C H ClN O : C, 70.99; H, 6.43; N, 6.62; Found: C,
23
23
2
2
25 27
2
2
5
.68; N, 7.23.
70.64; H, 6.58; N, 6.92.
Propyl
hexahydropyrrolo[2',3':3,4]
carboxylate (9c); yield 78%, mp 126-128℃, IR (νmax, cm ):
054, 2981, 1725, 1582, 1457, 1369, 1196, 1029, 738, 702, 601;
(2S,3aS,10bS)-1-benzyl-10-chloro-1,2,3,3a,4,10b-
Methyl
(2S,3aS,10bS)-10-chloro-1-(2-morpholin-4-ylethyl)-
pyrrolo[2',3':3,4] pyrrolo[1,2-
pyrrolo[1,2-a]indole-2- 95 1,2,3,3a,4,10b-hexahydro
-
1
-1
a]indole-2-carboxylate (10a); yield 76%, IR (νmax, cm ): 3060,
3
2956, 1727, 1684, 1456, 1338, 1158, 1029, 745, 702, 664, 608;
1
1
H NMR (400 MHz, CDCl ): δ 1.02(3H, t, J = 7.4Hz, -
H NMR (400 MHz, CDCl ): δ 2.24(1H, m, H-3’), 2.40-2.62(7H,
3
3
COO(CH ) CH ), 1.76(2H, m, -COOCH CH CH ), 2.18(1H, m,
m, 1H of H-3 and 6H of –CH -N-(CH ) -), 3.12(1H, m, 1H of
2
2
3
2
2
3
2
2 2
H-3’), 2.33(1H, ddd, J = 12.8, 9.0, 3.0 Hz, H-3), 3.69(1H, t, J = 100 CH -11), 3.52(1H, m , 1H of CH -11), 3.70(5H, m, 1H of H-3a,
2
2
5
.8 Hz, H-2), 3.86(1H, m, H-3a), 4.09(4H, m, 2H of -NCH Ph
and 4H of –CH -O-CH -), 3.79(3H, s, -COOCH ), 3.96(1H, dd, J
2 2 3
= 10.2, 4.0 Hz, H-2), 4.07(2H, m, H-4 and H-4’), 4.86(1H, d, J =
2
and 2H of -COOCH CH CH ), 4.19(1H, m, H-4), 4.81(1H, d, J =
2
2
3
13.6 Hz, H-4’), 5.01(1H, d, J = 7.8 Hz, H-10b), 7.24(8H, m, Ar-
8.4 Hz, H-10b), 7.21(3H, m, Ar-H), 7.59(1H, d, J = 7.6 Hz, H-9);
13
13
H), 7.64(1H, d, J = 7.2 Hz, H-9); C NMR (100 MHz, CDCl ): δ
C NMR (100 MHz, CDCl ): δ 36.1(C-3), 44.8(C-3a), 46.4(C-
3
3
1
4
6
0.4(-COO(CH ) CH ), 22.1(-COOCH CH CH ), 35.8(C-3), 105 11), 50.3(C-4), 51.3(-COOCH ), 53.7(C-14), 57.7(C-12), 64.6(C-
2
2
3
2
2
3
3
5.4(C-3a), 50.1(C-4), 54.0(-NCH Ph), 63.9(C-10b), 64.4(C-2),
10b), 64.7(C-2), 66.2(C-15), 97.3(C-10), 110.0, 118.4, 120.0,
2
6.7(-COOCH CH CH ), 97.2(C-10), 110.0(C-6), 118.6, 120.0,
122.1, 130.0, 131.7, 139.7(Ar-C), 173.5(-C=O); ESI-MS (m/z):
2
2
3
+
122.1, 127.1, 128.2, 129.0, 130.1, 131.7, 138.8, 140.3(Ar-C),
404.02 (M) , Anal Calcd for C H ClN O : C, 62.45; H, 6.49; N,
21
26
3
3
+
1
73.4(-C=O); ESI-MS (m/z): 408.92 (M) , Anal Calcd for
10.40; Found: C, 62.64; H, 6.38; N, 10.02.
C H ClN O : C, 70.49; H, 6.16; N, 6.85; Found: C, 70.54; H, 110
24
25
2
2
6
.38; N, 6.72.
Ethyl
(2S,3aS,10bS)-10-chloro-1-(2-morpholin-4-ylethyl)-
pyrrolo[2',3':3,4] pyrrolo[1,2-
1
,2,3,3a,4,10b-hexahydro
-
1
Isopropyl
hexahydropyrrolo[2',3':3,4]
(2S,3aS,10bS)-1-benzyl-10-chloro-1,2,3,3a,4,10b-
pyrrolo[1,2-a]indole-2-
a]indole-2-carboxylate (10b); yield 78%, IR (νmax, cm ): 3059,
2954, 1729, 1685, 1454, 1336, 1151, 1028, 742, 700, 662, 612;
-
1
1
carboxylate (9d); yield 76%, mp 132-134℃, IR (νmax, cm ): 115 H NMR (400 MHz, CDCl ): δ 1.32(3H, t, J = 7.6 Hz, -
3
3
055, 2984, 1719, 1579, 1458, 1369, 1192, 1028, 740, 702, 602;
COOCH CH ), 2.23(1H, m, H-3’), 2.38-2.63(7H, m, 1H of H-3,
2 3
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 15
New Journal of Chemistry
and 6H of –CH -N-(CH ) -), 3.13(1H, m, 1H of CH -11),
1.67(2H, quintet, J = 7.2 Hz, -OCH CH CH CH ), 2.24(1H, m,
2 2 2 3
2
2 2
2
3
.51(1H, m , 1H of CH -11), 3.71(5H, m, 1H of H-3a, and 4H of 60 H-3’), 2.35-2.65(7H, m, 1H of H-3 and 6H of –CH -N-(CH ) -),
2 2
2 2
View Article Online
-CH -O-CH -), 3.97(1H, dd, J = 10, 4.2 Hz, H-2), 4.07-4.15(4H,
3.12(1H, m, 1H of CH -11), 3.50(1H, m , 1H of CH -11),
2 2
DOI: 10.1039/C4NJ02308K
2
2
m, 2H of -COOCH CH , and 2H of H-4 and H-4’), 4.85(1H, d, J
3.69(5H, m, 1H of H-3a and 4H of –CH -O-CH -), 3.98(1H, dd, J
2
3
2 2
5
0
5
0
5
0
5
0
5
0
5
= 8.2 Hz, H-10b), 7.20(3H, m, Ar-H), 7.58(1H, d, J = 7.4 Hz, H-
= 10.0, 4.0 Hz, H-2), 4.06(1H, dd, J = 7.6, 2.4 Hz, H-4), 4.18(3H,
13
9
3
6
9
); C NMR (100 MHz, CDCl ): δ 14.4(-COOCH CH ), 36.1(C-
m, 2H of –COOCH - and 1H of H-4’), 4.84(1H, d, J = 8.4 Hz, H-
3
2
3
2
1
3
), 44.8(C-3a), 46.4(C-11), 50.3(C-4), 53.7(C-14), 57.7(C-12), 65 10b), 7.19(3H, m, Ar-H), 7.58(1H, d, J = 7.6 Hz, H-9); C NMR
0.5(-COOCH CH ), 64.6(C-10b), 64.7(C-2), 66.2(C-15), (100 MHz, CDCl3): 10.4(-COO(CH ) CH ), 19.2(-
COO(CH2) CH CH ), 30.7(-COOCH CH CH CH ), 36.1(C-3),
δ
2
3
2 3
3
7.3(C-10), 110.0, 118.4, 120.0, 122.1, 130.0, 131.7, 139.7(Ar-
2
2
3
2
2
2
3
+
1
1
2
2
3
3
4
4
5
5
C), 173.6(-C=O); ESI-MS (m/z): 417.90 (M) , Anal Calcd for
44.8(C-3a), 46.3(C-11), 50.3(C-4), 53.7(C-14), 57.7(C-12),
C H ClN O : C, 63.22; H, 6.75; N, 10.05; Found: C, 63.54; H,
64.4(C-10b), 64.6(C-2), 64.9(C-15), 66.7(-COOCH ), 97.3(C-
22
28
3
3
2
6
.58; N, 10.22.
70 10), 109.9, 118.4, 120.0, 122.2, 130.0, 131.7, 139.7(Ar-C),
+
1
73.6(-C=O); ESI-MS (m/z): 446.10 (M) , Anal Calcd for
Propyl
1,2,3,3a,4,10b-hexahydro
a]indole-2-carboxylate (10c); yield 72%, IR (νmax, cm ): 3059,
(2S,3aS,10bS)-10-chloro-1-(2-morpholin-4-ylethyl)-
C H ClN O : C, 64.63; H, 7.23; N, 9.42; Found: C, 64.74; H,
24 32 3 3
7.48; N, 9.76.
pyrrolo[2',3':3,4]pyrrolo[1,2-
-
1
1
2
952, 1728, 1632, 1455, 1308, 1116, 1026, 743, 701, 612; H 75 (4bR, 5aS, 12bS)-12-chloro-4b,5,5a,12b,14,15-hexahydro-6H-
NMR (400 MHz, CDCl ): δ 1.01(3H, t, J = 7.6 Hz, -
benzo[5',6']pyrrolizino
a]isoquinoline(11a); yield 45%, mp 118-120℃, IR (ν , cm ):
3054, 2939, 2817, 1637, 1455, 1321, 1220, 740, 642, H NMR
[2',1':4,5]pyrrolo[2,1-
3
-
1
COOCH CH CH ), 1.74(2H, m, -COOCH CH CH ), 2.25(1H,
2
2
3
2
2
3
max
1
m, H-3’), 2.40-2.65(7H, m, 1H of H-3, and 6H of –CH -N-
2
(
CH ) -), 3.12(1H, m, 1H of CH -11), 3.50(1H, m , 1H of CH -
(400 MHz, CDCl ): δ 2.30(1H, m, H-5’), 2.40(1H, m, H-5),
2
2
2
2
3
1
1), 3.7(5H, m, 1H of H-3a, and 4H of –CH -O-CH -), 3.97(1H, 80 2.90(1H, m, 1H of C-14), 3.15(2H, m, 1H of C-15 and 1H of C-
2 2
dd, J = 10, 4.4 Hz, H-2), 4.15(4H, m, 2H of –COOCH CH CH ,
14), 3.66(2H, m, 1H of C-14 and 1H of H-5a), 4.00(1H, t, J = 7.6
Hz, H-4b), 4.10(1H, dd, J = 10.2, 3.2 Hz, H-6), 4.28(1H, t, J =
10.0 Hz, H-6’), 4.93(1H, d, J = 7.6 Hz, H-12b), 7.20(7H, m, Ar-
2
2
3
and 2H of H-4 and H-4’), 4.84(1H, d, J = 8.0 Hz, H-10b),
13
7.21(3H, m, Ar-H), 7.58(1H, d, J = 7.6 Hz, H-9); C NMR (100
MHz, CDCl3): 10.4(-COO(CH ) CH ), 22.1(-
COOCH CH CH ), 36.1(C-3), 44.8(C-3a), 46.8(C-11), 50.3(C- 85 δ 24.9(C-15), 34.6(C-5), 44.2(C-14), 48.4(C-5a), 51.5(C-6),
13
δ
H), 7.61(1H, d, J = 8.0 Hz, H-11); C NMR (100 MHz, CDCl3):
2 2
3
2
2
3
4
6
), 53.7(C-14), 57.7(C-12), 64.6(C-10b), 64.8(C-2), 66.1(C-15),
59.6(C-4b), 64.4(C-12b), 99.0(C-12), 109.3, 119.3, 121.3, 122.5,
123.2, 125.0, 126.8, 128.2, 128.9, 129.9, 130.8, 137.4, 139.5(Ar-
6.7(-COOCH ), 97.3(C-10), 110.0, 118.4, 120.0, 122.2, 130.0,
2
+
+
131.7, 139.7(Ar-C), 173.5(-C=O); ESI-MS (m/z): 430.90 (M) ,
C); ESI-MS (m/z): 334.20 (M) , Anal Calcd for C H ClN : C,
21
19
2
Anal Calcd for C H ClN O : C, 63.95; H, 7.00; N, 9.73; Found:
75.33; H, 5.72; N, 8.37; Found: C, 75.41; H, 5.63; N, 8.42.
23
30
3
3
C, 63.74; H, 6.78; N, 9.96.
90
(4bS, 5aS, 12bS)-12-chloro-4b,5,5a,12b,14,15-hexahydro-6H-
Isopropyl (2S,3aS,10bS)-10-chloro-1-(2-morpholin-4-ylethyl)-
1,2,3,3a,4,10b-hexahydro pyrrolo[2',3':3,4] pyrrolo[1,2-
a]indole-2-carboxylate (10d); yield 74%, IR (νmax, cm ): 3060,
benzo[5',6']pyrrolizino [2',1':4,5]pyrrolo[2,1-
-
1
a]isoquinoline(11’a). yield 37%, mp 152-154℃ IR (νmax, cm ):
-
1
1
3055, 2938, 2818, 1638, 1454, 1321, 1222, 1138, 742, 640; H
1
2
950, 1729, 1632, 1454, 1309, 1117, 1028, 741, 702, 614;
H
95 NMR (400 MHz, CDCl ): δ 1.89(1H, m, H-5’), 2.78(1H, m, H-5),
3
NMR (400 MHz, CDCl ): δ 1.32(3H, d, J = 2.4 Hz, Me of -
2.88(2H, m, two H of C-15), 3.16(1H, m, 1H of C-14), 3.72(2H,
m, 1H of C-14 and 1H of H-5a), 3.89(1H, dd, J = 10.8, 7.2 Hz, H-
6), 3.97(1H, dd, J = 10.0, 6.4 Hz, H-6’), 4.12(1H, d, J = 8.4 Hz,
H-12b), 4.39(1H, t, J = 9.6 Hz, H-4b), 7.16(7H, m, Ar-H),
3
COOCH(CH ) , 1.34(3H, d, J = 2.4 Hz, Me of -COOCH(CH ) ),
3
2)
3 2
2.24(1H, m, H-3’), 2.40-2.66(7H, m, 1H of H-3 and 6H of –CH2-
N-(CH ) -), 3.12(1H, m, 1H of CH -11), 3.51(1H, m, 1H of CH -
2
2
2
2
13
1
1), 3.71(5H, m, 1H of H-3a and 4H of -CH -O-CH -), 3.98(1H, 100 7.61(1H, dd, J = 7.6, 1.2 Hz, H-11); C NMR (100 MHz, CDCl3)
2 2
dd, J = 10.2, 4.6 Hz, H-2), 4.15-4.18(2H, m, H-4 and H-4’),
.85(1H, d, J = 8.2 Hz, H-10b), 5.14(1H, m, -CH(CH ) ),
δ 25.0(C-15), 34.6(C-5), 44.2(C-14), 48.2(C-5a), 51.5(C-6),
59.6(C-4b), 64.5(C-12b), 98.9(C-12), 109.3, 119.3, 121.3, 122.5,
123.2, 125.2, 127.0, 128.2, 128.9, 130.0, 130.8, 137.4, 139.8(Ar-
4
3
2
13
7.20(3H, m, Ar-H), 7.59(1H, d, J = 7.6 Hz, H-9); C NMR (100
MHz, CDCl ): δ 21.3(-COOCH(CH ) ), 36.1(C-3), 44.8(C-3a),
+
C); ESI-MS (m/z): 334.20 (M) , Anal Calcd for C H ClN : C,
3
3 2
21 19
2
4
6
1
6.8(C-11), 50.3(C-4), 53.7(C-14), 57.7(C-12), 64.6(C-10b), 105 75.33; H, 5.72; N, 8.37; Found: C, 75.39; H, 5.61; N, 8.45.
4.8(C-2), 66.1(C-15), 66.1(-CH(CH ) ), 97.3(C-10), 110.0,
3
2
18.4, 120.0, 122.2, 130.0, 131.7, 139.7(Ar-C), 173.6(-C=O);
(4bR, 5aS, 12bS)-12-chloro-2,3-dimethoxy-4b,5,5a,12b,14,15-
hexahydro-6H-benzo[5',6']pyrrolizino[2',1':4,5]pyrrolo[2,1-
+
ESI-MS (m/z): 430.94 (M) , Anal Calcd for C H ClN O : C,
23
30
3
3
-
1
6
3.95; H, 7.00; N, 9.73; Found: C, 63.86; H, 6.81; N, 9.86.
a]isoquinoline(11b); yield 46%, mp 162-164℃ IR (νmax, cm ):
1
10 2998, 2934, 2820, 1608, 1516, 1452, 1323, 1219, 1014, 746, 674;
1
Butyl
(2S,3aS,10bS)-10-chloro-1-(2-morpholin-4-ylethyl)-
pyrrolo[2',3':3,4] pyrrolo[1,2-
a]indole-2-carboxylate (10e); yield 75%, IR (νmax, cm ): 3060,
955, 1728, 1685, 1455, 1337, 1152, 1028, 744, 701, 663, 613;
H NMR (400 MHz, CDCl ): δ 2.32(2H, m, H-5 and H-5’),
3
1
,2,3,3a,4,10b-hexahydro
2.80(1H, m, 1H of C-15), 3.13(1H, m, 2H, 1H of C-15 and 1H of
C-14), 3.65(2H, m, 1H of C-14 and 1H of H-5a), 3.85(3H, s, -
OCH ), 3.87(3H, s, -OCH ), 4.01(1H, t, J = 7.2 Hz, H-4b),
-
1
2
3
3
1
H NMR (400 MHz, CDCl ): δ 0.98(3H, t, J = 8.0 Hz, -O(CH )- 115 4.09(1H, dd, J = 10.4, 3.6 Hz, H-6), 4.27(1H, dd, J = 10.2, 8.4
3
2
CH ), 1.44(2H, sextet, J = 7.6 Hz, -COO(CH ) CH CH ),
Hz, H-6’), 4.90(1H, d, J = 7.6 Hz, H-12b), 6.56 (1H, s, H-1), 6.64
3
3
2 2
2
3
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

New Journal of Chemistry
Page 8 of 15
[
2] a) I. S. Marcos, R. F. Moro, I. Costales, P. Basabe and D. Díez,
Nat. Prod. Rep., 2013, 30, 1509-1526; b) M. Somei and F.
Yamada, Nat. Prod. Rep., 2005, 22, 73-103; c) X. Yu, X. Xie and
(
1H, s, H-4), 7.20(3H, m, Ar-H), 7.60(1H, dd, J = 7.0, 1.2 Hz, H-
13
60
1
4
6
1); C NMR (100 MHz, CDCl ): δ 26.2(C-15), 36.8(C-5),
3
View Article Online
0.9(C-14), 45.7(C-5a), 50.6(C-6), 55.8(-OMe), 56.5(-OMe),
0.4(C-4b), 64.6(C-12b), 98.4(C-12), 109.7, 111.9, 117.0, 118.6,
DOI: 10.1039 4NJ02308K
S. M. Li, Appl Microbiol Biotechnol., 2011, 92, 7 3/ C7 -748; d)
Modern Alkaloids: Structure, Isolation, Synthesis, and Biology- F.
Fattorusso and O. T. Scafati, Ed, Wiley-VCH-2008; e) Marine
Pharmacognosy: Trends and Applications- S. M. Kim, Ed. CRC
Press 2012.
5
0
5
0
5
121.8, 123.2, 125.2, 128.7, 130.0, 130.3, 132.5, 147.0, 147.5(Ar-
C); ESI-MS (m/z): 394.54 (M) , Anal Calcd for C H ClN O :
C, 69.95; H, 5.87; N, 7.09; Found: C, 69.81; H, 5.93; N, 7.02.
65
+
23
23
2
2
[
3] a) S.T. Crooke and A. W. Prestayko, Ed.; Academic Press: New
York, 1981; Vol. 3, p 49; b) S. Alcaro, F. Ortuso and R. S.
Coleman, J. Med. Chem., 45, 2002, 861-870; c) N. Zein, W.
Solomon, K. L. Colson and D. R. Schroeder, Biochemistry, 1995,
34, 11591–11597; d) W. A. Remers and R. T. Dorr, In Alkaloids:
Chemical and Biological Perspectives, Ed.; S. W. Pelletier, John
Wiley & Sons, New York, 1988; vol. 6, pp. 1–74; e) R. S.
Coleman, C. H. Burk, A. Navarro, R. W. Brueggemeier and E. S.
Diaz-Cruz,. Org. Lett., 2002, 4, 3545–3548.
(
4bS, 5aS, 12bS)-12-chloro-2,3-dimethoxy-4b,5,5a,12b,14,15-
1
1
2
2
hexahydro-6H-benzo[5',6'] pyrrolizino[2',1':4,5] pyrrolo[2,1-
70
75
-
1
a]isoquinoline(11’b); yield 38%, mp 202-204℃ IR (νmax, cm ):
002, 2935, 2818, 1608, 1518, 1454, 1325, 1218, 1012, 748, 672;
3
1
H NMR (400 MHz, CDCl ): δ 1.90(1H, m, H-5’), 2.79(3H, m,
3
1
H of H-5 and 2H of C-15), 3.07(1H, m, 1H of C-14), 3.68(2H,
m, 1H of C-14 and 1H of H-5a), 3.83(4H, m, 3H of -OCH and
3
[4] a) W. Verboom, D. N. Reinhoudt, B. H. M. Lammerink, E. O. M.
Orlemans, F. C. J. M. Van Veggel and P. Lelieveld, Anti-Cancer
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1
6
4
7
H of H-6), 3.88(3H, s, -OCH ), 3.98 (1H, dd, J = 9.6, 6.4 Hz, H-
’ ), 4.13(1H, d, J = 8.0 Hz, H-12b), 4.40(1H, t, J = 9.6 Hz, H-
3
b), 6.58 (1H, s, H-1), 6.63 (1H, s, H-4), 7.18(3H, m, Ar-H),
8
0
13
.60(1H, d, J = 7.6 Hz, H-11); C NMR (100 MHz, CDCl ): δ
3
26.2(C-15), 36.9(C-5), 41.0(C-14), 45.7(C-5a), 50.5(C-6), 56.0(-
OMe), 56.6(-OMe), 60.4(C-4b), 64.5(C-12b), 99.0(C-12), 110.1,
1
1
12.0, 117.0, 118.6, 121.8, 123.3, 125.2, 128.7, 130.0, 130.4,
32.6, 147.2, 147.8(Ar-C); ESI-MS (m/z): 394.54 (M) , Anal
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Phytother. Res., 2008, 22, 1409-1412; b) D. H. Dethe, R. D.
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+
85
Calcd for C H ClN O : C, 69.95; H, 5.87; N, 7.09; Found: C,
23
23
2
2
69.91; H, 5.90; N, 7.04
90
Acknowledgements
We sincerely express our thanks to Head, Department of
Chemistry, Sardar Patel University, for providing necessary
research facilities. One of the authors, TRS, specially thanks the
UGC, New Delhi, India for providing financial assistance under
UGC Scheme of RFSMS. We thank DST, New Delhi, in general,
and the PURSE central facility for mass analysis (vide sanction
letter DO. No. SR/59/Z-23/2010/43 dated 16th march 2011).
J.M.P. thanks the EU Research Potential (FP7-REGPOT-2012-
CT2012-31637-IMBRAIN), the European Regional Development
Fund (FEDER), and the Spanish Instituto de Salud Carlos III
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Ionic Liquids: Applications in Heterocyclic Synthesis, Ionic
Liquids: Applications and Perspectives; Kokorin, Alexander, Ed.;
InTech,
ISBN
978-953-307-248-7,
2011.
115
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Journal Name, [year], [vol], 00–00 | 9

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Page 10 of 15
5
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DOI: 10.1039/C4NJ02308K
Scheme 1: Synthesis of N-allyl-3-chloro–indole-2-carbaldehyde 1, The reagents and conditions (1) K
2
CO
3
, allyl bromide, DMF, 10 – 12 h, room temp.
1
0
Cl
Cl
R
H
R , a = Me, b = Et, c = nPr,
1
H
H
d = Pr, e = nBu.
i
N
H
N
H
O
R1
O
R1
N
N
1
R O
O
O
H
OR1
O
NH
HN
7a-e, R = Me
8a-e, R = Et
9a-e
4a-
R
e
O
Cl
1
N
O
R2
R O
O
1
R2
HN
N
NH
O
2
Cl
Cl
H
2
N
N
O
H
N
H
R1
H
N
N
O
H
H
H
Cl
H
N
O
N
R2
R2
H
R2
R2
1
1'a-b
11a-b
o
Scheme 2: Synthesis of all newly pyrrolo-fused indoles and isoquinolines (1) TEAA, 100 C
1
5
1
0
| Journal Name, [year], [vol], 00–00
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New Journal of Chemistry
R
View Article Online
DOI: 10.1039/C4NJ02308K
HN
N
N
N
CO2R1
Cl
Cl
N
Cl
Cl
R
H
R
R
N
O
N
HO
N
O
1
1
CO R
CO R
2
CO R1
2
2
N
N
Cl
Cl
H
H
H
X
H
path - a
H
N
R
N
N
Cl
R
H
H
CO
2
R1
R
N
O
O
R1 trans
ExoTS
CO R1
2
N
Cl
N
Cl
H
H
R
H
H
N
Cl
H
N
N
R
path - b
H
R
N
1
H
CO R
2
O
R1
O
CO R1
2
cis
EndoTS
Scheme 3: A plausible mechanism of the reaction between aldehyde 1 and secondary amine via 1, 3-dipolar cycloaddition reaction
5
Figure 1. Some biologically active heterocycles containing pyrrolo-indole and pyrrolo-isoquinoline units
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DOI: 10.1039/C4NJ02308K
Figure 2.Characteristic NOESY interactions in 8a.
5
Figure 3. Characteristic COSY interactions in 8a.
1
0
Figure 4. The ORTEP views of compounds 9b and 11’b, with displacement ellipsoids at the 40% probability level.
1
2
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New Journal of Chemistry
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DOI: 10.1039/C4NJ02308K
5
Table.1 Optimization of the reaction conditions between amine 3a and aldehyde 1
.
Entry Solvent(reflux)
Catalyst
—
—
Temp(℃)
reflux
reflux
reflux
reflux
reflux
reflux
100
80
100
Time(h)
24
10
6.0
6.0
5.5
5.0
4
Yield (%)
trace
40
1
2
3
4
5
6
7
8
9
MeOH
ACN
toluene
toluene
xylene
xylene
—
—
68
72
70
75
70
78
85
Na
2
SO
4
—
1
0
Na
2
SO
4
a
—
TEAA
TEAA
TEAA
TEAA
3.5
2.5
a
solvent free
1
5
Table 2. Synthesis of all pyrrolo-fused-indoles and isoquinolines.
1
2
Time
h)
Entry
Compound
R
R
R
Yield (%)
(
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
10a
10b
10c
10d
10e
11a
11’a
11b
11’b
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Bn
Bn
Bn
Bn
Bn
Mp
Mp
Mp
Mp
Mp
─
Me
Et
─
─
─
─
─
─
─
─
─
─
─
─
─
─
─
─
─
─
─
─
H
H
OMe
OMe
2.75
2.75
3.0
3.0
3.5
2.5
2.75
3.0
3.0
3.0
2.5
3.0
3.0
3.5
3.5
3.0
3.0
3.0
3.5
3.0
2.75
2.75
3.0
3.0
82
80
77
84
77
85
82
84
78
79
80
82
78
76
74
76
78
72
74
75
45
37
46
38
nPr
iPr
nBu
Me
Et
nPr
iPr
nBu
Me
Et
nPr
iPr
nBu
Me
Et
nPr
iPr
nBu
─
2
2
3
3
4
0
5
0
5
0
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
─
─
─
─
─
─
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 13

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Page 14 of 15
Table. 3 Antimicrobial, antitubercular and antioxidant activities test result.
View Article Online
DOI: 10.1039/C4NJ02308K
a
-1
Anti TB
Antioxidant
Antimicrobial activity (MIC ꢀgmL )
b
Activity
Compound
Gram-positive bacteria
Gram-negative bacteria
Fungi
C
FRAP
(%)inhibition
S.p.
C.t.
B.s.
S.t.
V.c.
E.c.
A.f.
C.a.
7
7
7
7
7
8
8
8
8
8
9
9
9
9
9
a
b
c
d
e
a
b
c
d
e
a
b
c
d
e
250
200
250
100
100
125
125
100
125
200
200
250
100
250
200
125
200
500
200
500
100
500
200
250
100
125
62.5
100
250
200
100
100
200
125
200
250
250
100
250
125
200
250
250
200
200
250
125
200
250
100
200
62.5
100
200
250
250
250
200
125
200
100
200
100
100
100
250
100
250
250
100
125
200
250
500
125
200
250
200
200
250
250
200
250
250
100
100
100
62.5
125
125
125
125
100
200
125
200
125
100
125
200
250
250
200
250
250
250
250
200
125
200
125
200
125
250
250
125
200
250
100
250
100
200
62.5
100
250
62.5
200
125
125
100
200
100
200
250
250
200
250
100
250
100
250
200
100
250
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
500
500
>500
>500
250
46%
20%
13%
47%
57%
84%
59%
58%
33%
47%
80%
33%
87%
91%
12%
84%
92%
25%
74%
65%
65%
78%
58%
88%
225.11
220.49
215.27
216.87
227.32
219.28
217.28
210.25
213.26
222.90
213.46
228.72
234.95
236.35
245.99
232.14
285.15
236.15
239.37
241.37
224.51
252.22
254.23
217.28
500
>500
>500
500
>500
500
>500
>500
500
>500
>500
250
10a
10b
10c
10d
10e
11a
500
250
>500
>1000
500
>500
500
>500
500
500
1
1’a
250
500
1
1b
>500
500
>500
>500
1
1’b
[
[
[
[
[
[
[
[
A]
B]
C]
D]
E]
F]
G]
H]
0.5
100
50
50
10
—
—
—
5
250
50
100
50
—
1
250
50
50
100
—
5
100
50
25
10
—
—
—
5
100
50
25
10
—
—
—
0.05
100
50
25
10
—
—
—
—
—
—
—
—
100
100
—
—
—
—
—
—
100
500
—
—
—
—
—
—
—
—
99%
—
—
—
—
—
—
—
—
—
—
—
—
S.p.: Streptococcus pneumoniae, C.t.: Clostridium tetani, B.s.: Bacillus subtilis, S.t.: Salmonella typhi, V.c.: Vibrio cholerae, E.c.: Escherichia coli, A.f.:
Aspergillus fumigatus, C.a.: Candidaalbicans; [A]: Gentamycin, [B]: Ampicillin, [C]: Chloramphenicol, [D]: Ciprofloxacin, [E]: Norfloxacin, [F]:
5
a
Nystatin, [G]: Griseofulvin, [H]: Isoniazide. Concentration of compounds used against M. tuberculosis H37Rv bacteria = 250 ꢀg /mL, standard
b
c
antimicrobials used: isoniazide (0.2 ꢀg /mL). Concentration of compounds = 200 ꢀg /mL and standard: A.A. (ascorbic acid) = 176 ꢀg mL. A.A. mm/100
g sample.
1
0
1
5
1
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 15 of 15
New Journal of Chemistry
Table. 4. Antiproliferative activity (GI50) against human solid tumor cells
a
View Article Online
DOI: 10.1039/C4NJ02308K
Antiproliferative activity (GI50
Cell line (origin)
SW1573(lung)
68 (±45)
)
Compound
A549(lung)
>100
HeLa(cervix)
3.3 (±0.4)
5.7 (±1.6)
3.9 (±1.2)
8.3 (±3.2)
9.9 (±5.2)
14 (±1.4)
3.4 (±0.7)
3.6 (±0.3)
13 (±2.8)
3.1 (±0.4)
41 (±30)
48 (±36)
>100
T-47D(breast)
67 (±47)
84 (±29)
66 (±49)
26 (±6.5)
25 (±5.8)
27 (±4.8)
29 (±16.0)
37 (±13.0)
25 (±9.4)
26 (±4.7)
54 (±21)
57 (±43)
>100
WiDr(colon)
66 (±48)
76 (±37)
62 (±54)
22 (±4.0)
23 (±4.1)
24 (±1.7)
28 (±10)
35 (±7.8)
27 (±4.3)
24 (±8.9)
>100
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
9c
9d
9e
61 (±18)
>100
92 (±11)
53 (±26)
b
41
29 (±0.2)
32 (±2.3)
25 (±3.3)
33 (±4.6)
41 (±4.3)
27 (±3.5)
32 (±2.5)
>100
32 (±8.8)
33 (±3.0)
43 (±19)
47 (±19)
28 (±6.9)
40 (±20)
>100
>100
>100
89 (±15)
>100
>100
>100
1
1
0a
1a
>100
>100
>100
>100
>100
89 (±16)
>100
33 (±6.8)
84 (±21)
9.5 (±7.1)
2.0 (±0.3)
3.3 (±1.6)
0.6 (±0.4)
>100
53 (±14)
>100
73 (±39)
>100
1
1’a
>100
1
1b
A]
B]
C]
18 (±14)
-
17 (±1.9)
3.0 (±0.4)
14 (±1.5)
0.25 (±0.12)
15 (±7.3)
15 (±2.3)
22 (±5.5)
2.0 ±(0.5)
14 (±2.4)
26 (±5.3)
23 (±3.1)
1.8 (±0.7)
[
[
[
-
-
[
A]: cisplatin, [B]: etoposide, [C]: camptothecin.
a
b
Values are given in ꢀM and are means of two to four experiments; standard deviation is given in parentheses . Only was experiment was done
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 15