New approaches to the synthesis of benzo[h]pyrroloisoquinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.151264

An effective strategy for the synthesis of benzo[h]pyrrolo[2,1-a]isoquinoline derivatives has been developed. The process can be described as a one-pot domino reaction that consists of an initial Michael addition, intramolecular cyclization, and subsequen

Full text of DOI:10.1016/j.tetlet.2019.151264

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New approaches to the synthesis of benzo[h]pyrroloisoquinoline derivatives
Anastasia A. Ershova, Anna D. Zinoveva, Tatiana N. Borisova, Alexander A.
Titov, Alexey V. Varlamov, Leonid G. Voskressensky, Van Tuyen Nguyen,
Tuan Anh Le
PII:
S0040-4039(19)31044-5
DOI:
https://doi.org/10.1016/j.tetlet.2019.151264
TETL 151264
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 August 2019
23 September 2019
10 October 2019
Please cite this article as: Ershova, A.A., Zinoveva, A.D., Borisova, T.N., Titov, A.A., Varlamov, A.V.,
Voskressensky, L.G., Tuyen Nguyen, V., Anh Le, T., New approaches to the synthesis of
benzo[h]pyrroloisoquinoline derivatives, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.151264
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New
approaches
to
the
synthesis
of
Leave this area blank for abstract info.
benzo[h]pyrroloisoquinoline derivatives
Anastasia A. Ershova, Anna D. Zinoveva, Tatiana N. Borisova, Alexander A. Titov, Alexey V. Varlamov,
Leonid G. Voskressensky, Van Tuyen Nguyen, Tuan Anh Le
1
2
R
EWG
solvent
reflux/MW
R
X
= H, OR , CO2R ; = Ar, O
N
N
O
Ar
= C6H5, 4-MeC6H4,
4-MeOC6H4, 4-BrC6H4
R
Ar
Ar
2
X
23 examples
34-98% yield
EWG
R1=
= CHO, COMe, CO2R
EWG
R2
= Me, CH2CF3;
= Me, Et

1
Tetrahedron Letters
journal homepage: www.elsevier.com
New approaches to the synthesis of benzo[h]pyrroloisoquinoline derivatives
Anastasia A. Ershova,a Anna D. Zinoveva,a Tatiana N. Borisova,a Alexander A. Titov,*,a Alexey V. Varlamov,a
Leonid G. Voskressensky,a Van Tuyen Nguyen,b Tuan Anh Lec
a
Organic Chemistry Department, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow, 117198, Russian Federation
b Institute of Chemistry, Graduate University of Science and Technology Vietnam Academy of Science and Technology, N. 18, Hoang Quoc Viet street, Can Giay,
Hanoi, 100 000, Vietnam
c Faculty of Chemistry, VNU University of Science, N. 19, Le Thanh Tong street, Hanoi, 100 000, Vietnam
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An effective strategy for the synthesis of benzo[h]pyrrolo[2,1-a]isoquinoline derivatives has
been developed. The process can be described as a one-pot domino reaction that consists of an
initial Michael addition, intramolecular cyclization, and subsequent transformations leading to
the formation of the desired products. A wide range of structurally diverse hydrogenated
benzo[h]pyrrolo[2,1-a]isoquinolines were obtained in 34-98% yield. This strategy represents an
efficient catalyst-free procedure that allows the synthesis of previously inaccessible compounds.
2019 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Alkaloids
Anticancer activity
Benzo[h]pyrroloisoquinoline derivatives
Domino reaction
Introduction
Lamellarin D, a natural alkaloid which was isolated from the
marine mollusk Lamellaria sp., is a topoisomerase I inhibitor.
This alkaloid reverses multidrug resistance and induces apoptosis
in a large number of cancer cell lines.4 Crispine A is an antitumor
active pyrrolo[2,1-a]isoquinoline alkaloid (Fig. 1).5
Pyrrolo[2,1-a]isoquinolines have attracted considerable
attention due to their biological activities. For example, the
antidepressant JNJ-7925476, which belongs to the pyrrolo[2,1-
a]isoquinolines series, is at the last stage of development by
Johnson & Johnson©.1 Pyrrolo[2,1-a]isoquinoline derivatives
have potential antibacterial and antifungal activity.2 Use of the
commercial program ADMET Predictor allowed prediction of the
potential anti-inflammatory and anticancer activity on the MCF-7
cell line for the alkaloid Trolline.3
3-Hydroxy- and 3-chloropyrrolo[2,1-a]isoquinolines possess
excellent cytotoxic activity.6 Pyrrolo[2,1-a] dihydroisoquinolines
that inhibit Phosphodiesterase (PDE) 10A and exhibit
antiproliferative activity were obtained and patented by
Niewoehner’s group.7 Synthetic 5,6-dihydropyrroloisoquinolines
showed inhibitory activity toward the growth of six cancer cell
lines.8 In addition, the pyrrolo[2,1-a]isoquinoline skeleton can be
used as a chemosensor for the detection of Ag+ in aqueous
solutions.9
O
HO
HO
O
H
N
O
H
N
Crispine A
Trolline
R1O
Benzo[h]pyrrolo[2,1-a]isoquinoline derivatives have a unique
nitrogen-containing tetracyclic structure, the synthesis of which
has been poorly represented in the scientific literature.
Unsubstituted benzo[h]pyrrolo[2,1-a]isoquinoline was obtained
via electrophilic cyclization of the N–acylpyrrolidine ion.10-11
Benzo[f]pyrrolo[1,2-b]isoquinoline and naphthalindolizidine
alkaloids are rare in Nature; for example, (-)-Fistulosine, 2,3-
dimethoxy-6-(3-oxobutyl)-7,9,10,11,11a,12-
O
O
N
MeO
R2O
MeO
OR3
MeO
Lamellarin D: R1=R2=R3=H
hexahydrobenzo[f]pyrrolo[1,2-b]isoquinoline, and Vincetene
were isolated from Ficus fistulosa, Cynanchum vincetoxicum and
Cynanchum komarovii, respectively (Fig. 2).12-14 At the same
Figure 1. Pyrrolo[2,1-a]isoquinoline alkaloids.

2
Tetrahedron Letters
time, analogous structures of the natural alkaloids Tylophorine
naphthylethylamine with aroyl formic acids, and then the amides
were cyclized using phosphorous oxychloride. Cyclization occurs
with the formation of 1-aroyl-3,4-dihydrobenzo[h]isoquinolines,
having an angular structure, which corresponds to the previously
described results.21
and Vincetene exhibit anticancer and antiarrhythmic activities.
Recent investigations have revealed several additional
alkaloids of the benzo[f]pyrrolo[1,2-b]isoquinoline series.15 The
study of the biological activity of these compounds showed good
cytotoxic activity on the MDA-MB-468 cell line (IC50 7.4 μM)
for Tengerensine and on the MDA-MB-468, MDA-MB-231 and
MCF7 cell lines (IC50, from 0.038 to 0.91 μM) for
Tengechlorenine (Fig. 2). MDA-MB-231 line is considered as
one of the most dangerous groups of cells (breast cancer).
The obtained 1-aroyl-3,4-dihydrobenzo[h]isoquinolines were
studied in domino reactions with electron-deficient alkynes and
alkenes.
O
H
N
NH2
a
MeO
O
MeO
R1
H
N
H
N
52-72%
+
R1PhCOCOOH
b
HO
R1= H, Me, OMe, Br
OH
N
Vincetene
(-)-Fistulosine
O
Ac
Ac
N
OMe
MeO
MeO
OMe
OMe
R1
MeO
1a-d
50-70%
Cl
N
Scheme 1. Synthesis of benzo[h]isoquinolines 1a-d. Reagents and
conditions: a) SOCl2 (2.3 mmol, 2.3 equiv.), Et3N (2.3 mmol, 2.3
equiv.), CH2Cl2 (30 mL), under Ar, rt, 2 d; b) POCl3 (25 mmol, 25
equiv.), 50 oC, under Ar, 6 d.
N
MeO
Tengechlorenine
Tengerensine
O
The
three-component
reactions
of
1-aroyl-3,4-
N
dihydrobenzo[h]isoquinolines 1a-d with methyl propiolate were
performed in 2,2,2,-trifluoroethanol and methanol. Methyl 1-
aroyl-3-alkoxy-5,6-dihydrobenzo[h]pyrrolo[2,1-a]isoquinoline-2-
carboxylates 2a-h were obtained in low and moderate yields
(Table 1).
1,2,3,12c-tetrahydrobenzo[h]-
pyrrolo[2,1-a]isoquinolin-5(6H)-one
Figure 2. Benzoisoquinoline alkaloids.
Thus, further investigation of the biological activities of
benzo[h]pyrrolo[2,1-a]isoquinoline derivatives can reveal useful
effects. Due to this, the research and development of new
methods for the synthesis of their derivatives represents an
attractive goal.
Table 1. Reactions of 1-aroyl-3,4-dihydrobenzo[h]isoquinolines 1a-
d with methylpropiolate in different alcohols.
CO2Me R2OH
,
N
N
reflux or MW
OR2
O
Three new approaches to the synthesis of pyrrolo[2,1-a]
isoquinolines, which are based on the domino reaction of 1-aroyl-
3,4-dihydroisoquinolines with electron-deficient alkynes and
CO2Me
R1
R1
2a-h
alkenes have been developed by Voskressensky’s group.16-19
A
1a-d
significant number of these compounds exhibit cytotoxic activity
on several cell lines. Some of them proved to be in vitro
inhibitors of P-gp with selectivity over the MRP1 efflux pump,
and several compounds attained submicromolar P-gp inhibition
potency.20
Entry R1
R2
Conditions
Product
Yield
Time
(d)
10
5
(%)
46
60
58
62
47
59
37
60
1
2
3
4
5
6
7
8
H
H
Me
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
2a
2b
2c
2d
2e
2f
CH2CF3
Me
Me
Me
10
5
The successful synthesis of such compounds using domino
processes led us to the benzo analogues of pyrrolo[2,1-
a]isoquinolines - benzo[h]pyrrolo[1,2-a]isoquinolines via the
transformations of 1-aroyl-3,4-dihydrobenzo[h]isoquinolines
with activated alkynes and alkenes.
CH2CF3
OMe Me
8
OMe CH2CF3
5
Br
Br
Me
2g
2h
12
7
CH2CF3
Results and Discussion
Reagents and conditions: 1a-d (0.5 mmol, 1 equiv.), methyl
The synthesis of the starting 3,4-dihydrobenzo[h]isoquinolines
1a-d involves several stages. Initially, for introduction of the
aroyl substituent, benzoyl, p-methylbenzoyl, p-methoxybenzoyl
and p-bromobenzoyl formic acids were synthesized by oxidizing
the corresponding acetophenone with selenium dioxide or by
hydrolyzing the aroylnitrile obtained from the corresponding acid
chloride (Scheme 1). Further acylation was performed using 2-
propiolate (1.5 mmol, 3 equiv.), alcohol (5 mL).
The proposed mechanism for the three-component reaction of
1-aroyl-3,4-dihydrobenzo[h]isoquinolines 1a-d with methyl
propiolate in various alcohols is shown in Scheme 2. In the first
stage, Michael addition generates zwitterion A. After
nucleophilic attack of the anionic center onto the carbonyl group,

3
closure of the five-membered ring and the formation of
intermediate В occurs. Subsequent addition of the corresponding
alcohol (intermediate C), dehydration, and aromatization leads to
the synthesis of 5,6-dihydrobenzo[h]pyrrolo[2,1-a]isoquinolines
2a-h through intermediates D and E (Scheme 2). Annulation of
the benzene ring to the tetrahydroisoquinoline core and the
X
X
N
N
O
X
toluene, 150 oC, MW
O
X
R1
R1
1a-d
3a-g
angular
structure
of
the
starting
3,4-
Entry
1
R1
Х
Product Yield (%)
Time (min)
15
dihydrobenzo[h]isoquinolines, obviously, leads to the fact that
the aroyl substituent is non-coplanar to the hydrogenated
benzoisoquinoline fragment. This complicates intramolecular
cyclization and the formation of intermediate B. Further addition
of alcohols is likely to be reversible for the same reason. All of
this leads to a significant reduction in yields, and the variation of
conditions is not conducive to optimization of the process.
H
CO2Me 3a
CO2Et 3b
CO2Me 3c
68
2
3
4
5
6
7
8
H
72
61
54
-
58
Me
Me
60
CO2Et
CO2Me
CO2Et
3d
-
205
-
OMe
OMe
Br
3e
44
71
76
100
90
CO2Me 3f
CO2Et 3g
N
N
OR2
CO2Me
2a-h
CO2Me
R2OH
Br
135
O
Reagents and conditions: 1a-d (0.35 mmol, 1 equiv.), DMAD or
diethyl acetylenedicarboxylate (0.70 mmol, 2 equiv.), toluene (5
mL).
R1
R1
R1
R1
1a-d
CO2Me
N
N
O
N
OR2
X
N
O
X
X
O
X
CO2Me
CO2Me
R1
1a-d
3a-g
A
R1
E
R1
-H2O
X
X
R2OH
N
OR2
CO2Me
N
OR2
H
N
N
O
X
X
N
O
CO2Me
O
CO2Me
OH
H
X
R1
R1
B
C
D
O
X
Scheme 2. Proposed reaction mechanism.
R1
R1
B
A
Another direction for the transformations of 1-aroyl-3,4-
dihydrobenzo[h]isoquinolines 1a-d is the reaction with
symmetrical alkynes such as dimethyl acetylenedicarboxylate
(DMAD) and diethyl acetylenedicarboxylate. The reactions were
carried out in dry toluene at 150 °C under microwave activation.
1,5,6,12c-Tetrahydrobenzo[h]pyrrolo[2,1-a]isoquinolines 3a-g
with an aryl group at position 12c and a cross-conjugated system
were obtained in moderate yields after crystallization from the
reaction mixtures (Table 2). In the reaction of 3,4-dihydro-
benzo[h]isoquinoline 1c with DMAD, we encountered
unexpected difficulties, since we could not isolate the product in
an individual form (Entry 5, Table 2).
Scheme 3. Plausible reaction mechanism.
Unlike 1-aroylisoquinolines, which reacted smoothly with α,β-
unsaturated aldehydes and ketones forming 2-carbonyl
substituted pyrrolo[2,1-a]isoquinolines,18-19 their benzo[h]-
annulated analogs 1a-d only reacted in trifluoroethanol under
MW with acrolein and methyl vinyl ketone (MVK). The
reactions with crotonic, cinnamic and 4-methoxycinnamic
aldehydes did not proceed at reflux or under MW at 200 ºС
(Entries 3,4,5,8,9,10, Table 2).
5,6-Dihydrobenzopyrroloisoquinolines 4a-h were isolated
from the reaction with acrolein under MW at 150 °C with
excellent yields and with methyl vinyl ketone with moderate
yields, respectively. The reaction rate with acrolein exceeds the
reaction rate with MVK by approximately 5 times (Table 3).
Scheme 3 shows a possible mechanism for the synthesis of
1,5,6,12c-tetrahydrobenzo[h]pyrrolo[2,1-a]isoquinolines
3a-g.
The first two stages coincide with the previously described
mechanism. After the generation of intermediate B, stabilization
of the structure is achieved due to the transfer of the aryl group to
the 12c position and the formation of a cross-conjugated five-
membered fragment. This type of rearrangement was recently
observed in our work on the reactions of 1-aroylisoquinolines
with symmetric alkynes.17
Table 3. Reactions of 1-aroyl-3,4-dihydrobenzo[h]isoquinolines 1a-
d with activated alkenes.
O
R4
R3
N
O
N
CF3CH2OH, 150 oC, MW
R4
R3
Table 2. Reactions with symmetrical alkynes.
O
R1
R1
1a-d
4a-h

4
Tetrahedron Letters
Entry R1
R3
R4
Product Yield
(%)
Time
The
structures
of
benzo[h]pyrrolo[2,1-a]isoquinoline
derivatives 2b and 3a were established using single crystal X-ray
diffraction data (Fig. 3 and 4).
(min)
15
1
H
H
H
4a
4b
90
2
H
Me
H
H
57
105
3
H
Me
No reaction
4
H
H
Ph
No reaction
5
H
H
4-MeOPh
No reaction
6
Me
Me
Me
Me
Me
OMe
H
H
4c
98
45
7
Me
H
H
4d
47
120
8
Me
No reaction
9
H
Ph
No reaction
10
11
12
13
14
H
4-MeOPh
No reaction
H
H
H
H
H
4e
4f
90
47
70
53
50
95
50
95
OMe Me
Br
Br
H
4g
4h
Me
Figure 3. Single X-ray crystal analysis of compound 2b (CCDC:
1946241).
Reagents and conditions: 1a-d (0.24 mmol, 1 equiv.), acrolein (0.48
mmol, 2 equiv.), MVK (0.6-1.08 mmol, 2.5-5 equiv.), 2,2,2-
trifluoroethanol (4 mL).
We propose that the process includes formation of the zwitter-
ion A, which, in contrast to zwitterions in Schemes 2 and 3,
possesses sp2-hybridization of the anion center. The presence of
substituents impedes ring closure (intermediate B) and reduces
the product yields and reaction rate, which we observed in the
reactions of compounds 1a-d with MVK. The final aromatization
of the five-membered ring via dehydration through intermediates
C and D leads to the synthesis of compounds 4a-h (Scheme 4).
CH2=CH-COR3
N
N
O
R3
O
R1
R1
4a-h
1a-d
Figure 4. Single X-ray crystal analysis of compound 3a (CCDC:
CH2=CH-COR3
1946242).
Conclusion
N
N
In summary,
a
new method for the synthesis of
H
COR3
benzo[h]pyrrolo[2,1-a]isoquinoline derivatives from 1-aroyl-3,4-
dihydrobenzo[h]isoquinolines by domino reaction with activated
by electron-withdrawing groups alkynes and alkenes has been
developed. The obtained 5,6-dihydro and 1,5,6,12c-
tetrahydrobenzo[h]pyrrolo[2,1-a]isoquinolines are isomeric to
the natural alkaloids such as Tengerensine and Tylophorine, and
are of scientific interest due to their biological properties.
O
H
COR3
D
A
R1
R1
-H2O
H+
N
N
H
HO
O
H
H
COR3
COR3
B
R1
C
R1
Acknowledgements
The publication has been prepared with the support of the
«RUDN University Program 5-100». This work was supported
by the Russian Foundation for Basic Research (grant № 19-53-
54001) and Vietnam (QTRU01.02/19-20).
Scheme 4. Plausible reaction mechanism.
Previously, we described the beneficial influence of electron-
donating alkoxy groups in the benzene fragment of 1-
aroylisoquinolines. Therefore, the absence of the reaction with
crotonaldehyde, cinnamaldehyde and 4-methoxycinnamaldehyde
(Entries 3,4,5,8,9,10, Table 2) can be explained by the lack of
these groups in compounds 1a-d that obviously deactivates
nitrogen atom of imino ketone fragment to the formation of
Michael’s type zwitterion with the unsaturated aldehydes.18,20
Supplementary Material
Supplementary material [materials & methods, experimental
procedures, NMR (1H and 13C), LCMS and X-ray data] for this
article can be found online at https://doi.org/10.1016/j.tetlet...

5
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