Domino Reactions of 1-Aroyl-3,4-dihydroisoquinolines with α,β-Unsaturated Aldehydes

Article abstract of DOI:10.1055/s-0036-1588486

An efficient synthesis of pyrrolo[2,1- a ]isoquinolines by a domino reaction from a variety of 3,4-dihydropyrrolo[2,1- a ]isoquinolines and α,β-unsaturated aldehydes in the absence of catalyst in good yields under microwave irradiation, is reported.

Full text of DOI:10.1055/s-0036-1588486

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
en
M. D. Matveeva et al.
Paper
Synthesis
Domino Reactions of 1-Aroyl-3,4-dihydroisoquinolines with
α,β-Unsaturated Aldehydes
Maria D. Matveevaa
R5
R5
R5
R1
R2
R1
R2
R5
Tatiana N. Borisovaa
Alexander A. Titova
Lada V. Anikinab
Svetlana V. Dyachenkoa
Grigorii S. Astakhova
Alexey V. Varlamova
Leonid G. Voskressensky*a
CHO
R6
N
R6
N
O
CHO
CF3CH2OH
R3
MW, 150 °C, 15–90 min
R3
R4
R4
55–91%
R6 = H, Me, Ph, 4-MeOC6H4
a Peoples’ Friendship University of Russia (RUDN University),
6, Mikluho-Maklaya St., Moscow 117198, Russian Federation
lvoskressensky@sci.pfu.edu.ru
b Institute of Physiologically Active Compounds, Russian
Academy of Sciences, Chernogolovka, Russian Federation
18 examples
up to 90% yield
Received: 16.04.2017
Accepted after revision: 12.06.2017
Published online: 22.08.2017
phosphodiesterase 10А,7 are follicle-stimulating hormone
(FSH) receptor activators,8 and exhibit antiplasmodial9 and
antitumor10 activities.
DOI: 10.1055/s-0036-1588486; Art ID: ss-2017-t0260-op
There are two principle approaches to construct the
skeleton of 3,4-dihydropyrrolo[2,1-a]isoquinolines. The
first, most common method is annulation of the pyrrole
ring to isoquinoline derivatives by oxidative/cycloaddi-
tion/aromatization.11 The second approach involves forma-
tion of an isoquinoline fragment based on pyrrole deriva-
tives.12
Abstract An efficient synthesis of pyrrolo[2,1-a]isoquinolines by a
domino reaction from a variety of 3,4-dihydropyrrolo[2,1-a]isoquino-
lines and α,β-unsaturated aldehydes in the absence of catalyst in good
yields under microwave irradiation, is reported.
Key words domino reaction, dihydroisoquinolines, aldehydes, micro-
wave irradiation, cytotoxic activity
In this paper, we describe results of domino reactions of
1-p-fluorobenzoyl (1), 1-p-chlorobenzoyl (2), and 3',4'-di-
methoxybenzoyl (3) 6,7-dimethoxy-3,4-dihydroisoquino-
lines, drotaveraldine (4) and 3,3,7-trimethyl-3,4-dihy-
droisoquinoline (5) with α,β-unsaturated aldehydes in
2,2,2-trifluoroethanol (Figure 1). 1-Aroylisoquinolines 1–3
were prepared by the Bischler–Napieralski reaction,13,14 and
the intermediate 1-benzyl-3,4-dihydroisoquinolines were
oxidized by sparging with oxygen gas in ethyl acetate.
Michael addition of the sp3-hybridized nitrogen atom is
a well-studied process1 that is widely used in chemistry, in-
cluding for the construction of heterocyclic compounds.2
The addition of an sp2-hybridized nitrogen atom to activat-
ed double and triple bonds has been much less studied. 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU) and 4-(N,N-dime-
thylamino)pyridine (DMAP) with an sp2-hybridized nitro-
gen atom are used as catalysts in the Baylis–Hillman reac-
tion between electron-deficient olefins and carbonyl com-
pounds or their derivatives.3 The presence of a carbonyl
group in the α-position to the sp2-hybridized nitrogen atom
may lead to the formation of a pyrrole ring. According to
this scheme, the attachment of electron-deficient alkenes
to 1-aroyl-3,4-dihydroisoquinolines with an iminoketone
fragment for the formation of 3,4-dihydropyrrolo[2,1-a]iso-
quinolines is possible. This type of transformation can be
regarded as a domino reaction. Related precedence was
published by Basavaiah et al. using aromatic isoquinoline
derivatives in the reaction with activated ketones in the
presence of Lewis acid.4
MeO
MeO
MeO
MeO
N
O
N
O
F
Cl
1
2
Me
N
MeO
MeO
EtO
EtO
Me
N
N
O
Me
O
O
MeO
EtO
The heterocyclic system of 3,4-dihydropyrrolo[2,1-
a]isoquinolines is a structural fragment of the alkaloids
criptaustoline and cryptovoline,5 as well as lamellarin-type
alkaloids, which were first isolated from the prosobranch
mollusc Lamellaria.6 Pyrrolo[2,1-a]isoquinolines inhibit
OMe
OEt
3
4
5
Drotaveraldine
Figure 1 1-Aroyl-3,4-dihydroisoquinolines 1–5
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
M. D. Matveeva et al.
Paper
Synthesis
benzene. Replacement of the solvent with methanol, etha-
nol, 2,2,2-trifluoroethanol, or hexafluoroisopropanol re-
sulted in the interaction, but in trifluoroethanol the reac-
tion proceeds faster and with an increased yield of 24.
Microwave (MW) activation can significantly reduce the re-
action time. Soft acid catalysis under microwave conditions
was ineffective. Finally, optimal conditions were estab-
lished at 150 °C for 80 minutes, leading to 80% yield of the
desired pyrrolo[2,1-a]isoquinoline 24 (Table 1, entry 9).
Table 1 Optimization of the Reaction Conditionsa
EtO
EtO
EtO
CHO
Ph
N
O
N
EtO
EtO
8
Ph
CF3CH2OH
CHO
EtO
EtO
EtO
24
4
R5
R5
N
R1
R2
R5
R1
R2
R5
Entry
Conditions
Yield (%)
CHO
R6
N
R6
1
2
MeOH, reflux, 48 h
53
64
69
39
70
68
72
76
80
68
60
6–9
EtOH, reflux, 24 h
O
CF3CH2OH
CHO
3
TFE, reflux, 3 h
R3
MW, 150 °C, 15–90 min
R3
4
(CF3)2CHOH, reflux, 24 h
EtOH, MW, 100 °C, 1 h
EtOH, АсОН, MW, 100 °C, 1 h
TFE, MW, 100 °C, 1 h
TFE, MW, 150 °C, 1 h
TFE, MW, 150 °C, 80 min
TFE, MW, 180 °C, 1 h
R4
R4
5
1–5
10–26
6
R6 = H, Me, Ph, 4-MeOC6H4
7
8
Scheme 1 Synthesis of pyrrolo[2,1-a]isoquinolines 10–26 under MW
9
The optimal conditions were used in the reactions of 1-
benzoylisoquinolines 1–5 with acrolein (6), crotonaldehyde
(7), cinnamaldehyde (8), and 4-methoxycinnamaldehyde
(9) (Scheme 1). Yields of pyrrolo[2,1-a]isoquinolines 10–26
in the reaction with unsaturated aldehydes 6–9 carried out
in TFE under MW conditions for 15–90 minutes at 150 °C
are shown in Table 2.
The reaction begins with nucleophilic addition by the
imine nitrogen onto the activated double bond of alde-
hydes, which generates zwitterion A. Next follows the clo-
sure of the five-membered ring and the formation of zwit-
terion B. The process is completed by the formation of ylide
C, the dehydration of which leads to the synthesis of pyrro-
lo[2,1-a]isoquinolines 10–26 (Scheme 2).
10
11
TFE, АсОН, MW, 150 °C, 80 min
a Reaction conditions: 4 (0.24 mmol), 8 (0.36 mmol).
Drotaveraldine 4 was recovered from drotaverine hydro-
chloride, which was spontaneously oxidized by air oxygen.
Isoquinoline 5 was synthesized through the Ritter reaction
of 2-methyl-1-(4-methylphenyl)propan-2-ol and benzoyl
cyanide.15
Reaction conditions were optimized by the reaction of
drotaveraldine (4) and cinnamaldehyde (8) to produce pyr-
rolo[2,1-a]isoquinoline 24 (Table 1). It was found that the
reactions do not occur in such aprotic solvents as ether and
R5
N
R5
N
R5
R1
R2
R5
R1
R2
R5
R1
R2
R5
R6
O
R6
N
O
O
R6
Ar
Ar
O
HO
O
R3
R4
B
1–5
A
6–9
R5
R5
N
R1
R2
R5
R1
R2
R5
N
R6
R6
Ar
HO
– H2O
O
O
R3
C
R4
10–26
Scheme 2 Proposed mechanism for the formation of pyrrolo[2,1-a]-isoquinolines 10–26
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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M. D. Matveeva et al.
Paper
Synthesis
Table 2 Yields of Products 10–26a
Entry
R1
OMe
R2
OMe
R3
R4
R5
R6
Product
MW time (min)
Yield (%)
1
2
F
F
F
F
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
20
30
90
90
25
30
80
80
10
20
50
60
10
30
80
90
20
60
65
70
55
91
68
80
60
86
75
80
63
80
72
80
69
61
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
3
H
Ph
4
H
p-MeOC6H4
5
Cl
H
H
6
Cl
H
Me
7
Cl
H
Ph
8
Cl
H
p-MeOC6H4
9
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OEt
H
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OEt
H
H
10
11
12
13
14
15
16
17
Me
Ph
p-MeOC6H4
H
OEt
OEt
Me
OEt
OEt
Ph
OEt
OEt
p-MeOC6H4
H
Me
H
a Reaction conditions: benzoylisoquinoline (1.0 mmol), aldehyde (1.5 mmol), 2,2,2-trifluoroethanol (3 mL), MW (300 W, 150 °C).
The substituent R6 in the reagent affects the rate of for-
mation of the target products 10–26. Reactions with acrole-
in progress rapidly for 0.5 hour, but reactions with 4-me-
thoxycinnamicaldehyde take about a week without micro-
wave radiation. The reaction is sensitive, first of all, to the
steric biases of substituent R6, which correlates with the
proposed reaction mechanism. This is confirmed by the ob-
servation that 3,3-dimethyl-1-benzoyl-3,4-dihydroisoquin-
oline 5 reacts only with acrolein. With other α,β-unsaturat-
ed aldehydes, the reaction does not begin because of steric
hindrance during the formation of intermediate A.
The structures of pyrrolo[2,1-a]isoquinolines 10–26
Figure 2 Molecular structure of 17 presented in ADP ellipsoids at 50%
probability
were confirmed based on 1H and 13C NMR, IR spectroscopy,
and mass spectrometry. Additionally, the structure of com-
pound 17 was established by using single-crystal X-ray dif-
fraction data (Figure 2).
pounds 22 and 25 show a more pronounced effect, which
allows them to be considered as prospective objects of fur-
ther study.
It has been shown16 that 2-aryl-5,6-dihydropyrrolo[2,1-
a]isoquinolines exhibit cytotoxic activity against certain
lines of human cancer cells, such as breast cancer in wom-
en, liver, and lung cancer. In this report, compounds 22–25
were tested on human cell cultures A549 (lung carcinoma),
HCT116 (intestinal carcinoma), RD (rhabdomyosarcoma),
and HeLa (cervical adenocarcinoma). The obtained data are
presented in Table 3.
Comparing the data, it can be concluded that pyrro-
lo[2,1-a]isoquinolines 22–25 possess some cytotoxicity, al-
though not sufficient to compete with the structures
known in this pharmacological group. However, com-
To determine the synthetic limits of the reaction, 1-ben-
zoyl-3,4-dihydro-β-carboline 2717 was reacted with acrole-
in in trifluoroethanol heated at reflux. Indoloindolizine 28
was obtained as a result with a 35% yield (Scheme 3). The
structure of indoloindolizine 28 was confirmed using 1H
and 13C NMR, IR spectroscopy, and mass spectrometry.
Thus, we have confirmed the possibility of the formation of
the pyrrole ring with an imino-ketone moiety and unsatu-
rated aldehydes.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
M. D. Matveeva et al.
Paper
Synthesis
Table 3 IC50 Values
Compound
IC50 (μM)
RD
HCT116
HeLa
44.54 ± 1.98
А549
22
21.31 ± 1.22
61.13 ± 1.60
365.20 ± 22.95
12.25 ± 0.90
2.45 ± 0.07
11.82 ± 0.03
66.60 ± 0.90
183.35 ± 0.03
23.87 ± 1.12
0.21 ± 0.00
0.19 ± 0.01
19.69 ± 0.26
251.27 ± 20.77
228.51 ± 20.83
43.66 ± 2.35
1.44 ± 0.31
–
23
–
24
–
25
103.69 ± 6.5
daunorubicin
doxorubicin
–
–
0.53 ± 0.03
13C NMR (СDCl3, 150 MHz): δ = 186.0, 162.4 (d, J = 247.1 Hz, 1 C),
147.9, 147.8, 132.6 (d, J = 7.2 Hz, 2 C), 130.4 (d, J = 4.3 Hz, 1 C), 127.7,
126.0, 124.5, 124.2, 121.0, 120.3, 115.6 (d, J = 21.7 Hz, 2 C), 111.3,
107.7, 56.0, 52.3, 45.4, 29.2.
CHO
N
N
N
N
H
H
MS (LCMS): m/z = 352 [M + Н]+.
O
CHO
CF3CH2OH
Anal. Calcd for C21H18FNO3: C, 71.78; H, 5.16; N, 3.99. Found: C, 71.44;
H, 5.05; N, 3.82.
27
28, 35%
1-(4-Fluorophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrro-
lo[2,1-a]isoquinoline-2-carbaldehyde (11)
Scheme 3 Synthesis of 1-phenyl-6,11-dihydro-5H-indolizino[8,7-b]-in-
dole-2-carbaldehyde 28
Yield: 231 mg (65%); beige solid; mp 168–169 °C.
1H NMR (СDCl3, 600 MHz): δ = 9.64 (s, 1 Н), 7.39–7.37 (m, 2 Н), 7.13–
7.11 (m, 2 Н), 6.68 (s, 1 H), 6.43 (s, 1 H), 3.99 (t, J = 6.4 Hz, 2 H), 3.85
(s, 3 H), 3.36 (s, 3 H), 3.02 (t, J = 6.4 Hz, 2 H), 2.63 (s, 3 H).
13C NMR (СDCl3, 150 MHz): δ = 187.0, 162.3 (d, J = 247.1 Hz, 1 C),
147.8, 147.6, 135.4 (d, J = 7.2 Hz, 2 C), 132.7, 130.5 (d, J = 4.3 Hz, 1 C),
125.7, 124.1, 121.2, 121.1, 120.6, 115.6 (d, J = 20.2 Hz, 2 C), 111.1,
107.5, 56.0, 55.2, 40.8, 28.9, 11.0.
In summary, a new method for the synthesis of pyrro-
lo[2,1-a]isoquinolines by the domino reaction of 1-aroyl-
substituted 3,4-dihydroisoquinolines with α,β-unsaturated
aldehydes has been developed. The simple reaction setup
and the variety of commercially available starting materials
are additional merits of this method.
MS (LCMS): m/z = 366 [M + Н]+.
Anal. Calcd for C22H20FNO3: C, 72.31; H, 5.52; N, 3.83. Found: C, 72.15;
H, 5.24; N, 3.75.
All reagents were purchased from Merck, J.T. Baker, or Sigma–Aldrich
1
Chemical Co. and used without further purification. H and 13C NMR
spectra were recorded in CDCl3 solutions at 25 °C, with a 600 MHz
NMR spectrometer; peak positions are given in parts per million (δ)
referenced to the appropriate solvent residual peak. Mass spectra
were recorded with an LCMS-8040 Triple quadrupole liquid chro-
matograph–mass spectrometer from Shimadzu.
1-(4-Fluorophenyl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrro-
lo[2,1-a]isoquinoline-2-carbaldehyde (12)
Yield: 299 mg (70%); beige solid; mp 230–232 °C.
1H NMR (СDCl3, 600 MHz): δ = 9.62 (s, 1 Н), 7.52–7.48 (m, 3 Н), 7.47–
7.45 (m, 2 Н), 7.45–7.42 (m, 2 Н), 7.13–7.11 (m, 2 Н), 6.69 (s, 1 H),
6.49 (s, 1 H), 3.97 (t, J = 6.3 Hz, 2 H), 3.85 (s, 3 H), 3.37 (s, 3 H), 2.96 (t,
J = 6.3 Hz, 2 H).
13C NMR (СDCl3, 150 MHz): δ = 186.5, 162.3 (d, J = 247.1 Hz, 1 C),
148.0, 147.7, 141.4, 132.5 (d, J = 8.7 Hz, 2 C), 131.2 (d, J = 4.3 Hz, 1 C),
131.0 (s, 2 C), 129.23, 129.16, 128.6 (s, 2 C), 127.5, 125.2, 121.5, 121.0,
119.3, 115.4 (d, J = 21.7 Hz, 2 C), 111.0, 108.2, 56.0, 55.2, 42.5, 29.3.
Pyrrolo[2,1-a]isoquinolines 10–26; General Procedure
1-Benzoylisoquinoline (1.0 mmol), the corresponding aldehyde (1.2
mmol), and 2,2,2-trifluoroethanol were added to a flask that was suit-
able for a microwave oven. The mixture was irradiated at 150 °C for
10–90 min. The reaction progress was monitored by TLC (Sorbfil, 2:1
EtOAc–hexane). The solvent was removed under vacuum, and the res-
idue was recrystallized from EtOAc–hexane to give pyrroloisoquino-
lines 10–26.
MS (LCMS): m/z = 428 [M + Н]+.
Anal. Calcd for C27H22FNO3: C, 75.86; H, 5.19; N, 3.28. Found: C, 75.59;
H, 4.96; N, 3.07.
1-(4-Fluorophenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]iso-
quinoline-2-carbaldehyde (10)
1-(4-Fluorophenyl)-8,9-dimethoxy-3-(4-methoxyphenyl)-5,6-di-
hydropyrrolo[2,1-a]isoquinoline-2-carbaldehyde (13)
Yield: 211 mg (60%); beige solid; mp 155–157 °C.
1H NMR (СDCl3, 600 MHz): δ = 9.61 (s, 1 Н), 7.42–7.40 (m, 2 H), 7.38
(s, 1 H), 7.15–7.09 (m, 2 H), 6.69 (s, 1 H), 6.49 (s, 1 H), 4.12 (t, J =
6.5 Hz, 2 H), 3.85 (s, 3 H), 3.37 (s, 3 H), 3.04 (t, J = 6.5 Hz, 2 H).
Yield: 251 mg (55%); beige solid; mp 203–205 °C.
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M. D. Matveeva et al.
Paper
Synthesis
1H NMR (СDCl3, 600 MHz): δ = 9.61 (s, 1 Н), 7.44–7.42 (m, 2 H), 7.39
(d, J = 8.7 Hz, 2 Н), 7.13–7.10 (m, 2 H), 7.03 (d, J = 8.7 Hz, 2 Н), 6.68 (s,
1 H), 6.47 (s, 1 H), 3.96 (t, J = 6.3 Hz, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H),
3.37 (s, 3 H), 2.96 (t, J = 6.3 Hz, 2 H).
1H NMR (СDCl3, 600 MHz): δ = 9.61 (s, 1 Н), 7.41–7.39 (m, 4 H), 7.38
(d, J = 8.4 Hz, 2 Н), 7.03 (d, J = 8.4 Hz, 2 Н), 6.68 (s, 1 H), 6.45 (s, 1 H),
3.96 (t, J = 6.4 Hz, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.37 (s, 3 H), 2.95 (t,
J = 6.4 Hz, 2 H).
13C NMR (СDCl3, 150 MHz): δ = 186.5, 162.3 (d, J = 247.1 Hz, 1 C),
160.4, 147.9, 147.7, 141.4, 132.5 (d, J = 8.7 Hz, 2 C), 132.3 (s, 2 C),
131.2 (d, J = 4.3 Hz, 1 C), 127.3, 125.2, 121.4, 121.2, 121.1, 119.2, 115.4
(d, J = 20.2 Hz, 2 C), 114.1 (s, 2 C), 111.0, 108.1, 56.0, 55.2, 55.5, 42.3,
29.3.
13C NMR (СDCl3, 150 MHz): δ = 186.4, 160.4, 147.9, 147.7, 141.7,
133.9, 133.1, 132.3 (s, 2 C), 132.3 (s, 2 C), 128.6 (s, 2 C), 127.4, 125.2,
121.2, 121.1, 120.9, 118.9, 114.1 (s, 2 C), 111.0, 106.2, 56.0, 55.5, 55.2,
42.3, 29.3.
MS (LCMS): m/z = 474 [M + Н]+.
MS (LCMS): m/z = 458 [M + Н]+.
Anal. Calcd for C28H24ClNO4: C, 70.96; H, 5.10; N, 2.96. Found: C,
71.87; H, 5.21; N, 3.12.
Anal. Calcd for C28H24FNO4: C, 73.51; H, 5.29; N, 3.06. Found: C, 73.40;
H, 5.12; N, 2.96.
1-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-5,6-dihydropyrrolo-
1-(4-Chlorophenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]iso-
[2,1-a]isoquinoline-2-carbaldehyde (18)
quinoline-2-carbaldehyde (14)
Yield: 338 mg (86%); beige solid; mp 177–179 °C.
Yield: 334 mg (91%); beige solid; mp 244–247 °C.
1H NMR (СDCl3, 600 MHz): δ = 9.67 (s, 1 Н), 7.40 (s, 1 H), 7.03 (dd, J =
1.8, 8.3 Hz, 1 Н), 6.98 (d, J = 1.8 Hz, 1 Н), 6.96 (d, J = 8.3 Hz, 1 Н), 6.71
(s, 1 H), 6.67 (s, 1 H), 4.14 (t, J = 6.5 Hz, 2 H), 3.93 (s, 3 H), 3.87 (s, 3 H),
3.84 (s, 3 H), 3.41 (s, 3 H), 3.07 (t, J = 6.5 Hz, 2 H).
1H NMR (СDCl3, 600 MHz): δ = 9.63 (s, 1 Н), 7.41–7.38 (m, 4 H), 7.38
(s, 1 H), 6.69 (s, 1 H), 6.48 (s, 1 H), 4.12 (t, J = 6.5 Hz, 2 H), 3.85 (s, 3 H),
3.38 (s, 3 H), 3.04 (t, J = 6.5 Hz, 2 H).
13C NMR (СDCl3, 150 MHz): δ = 185.9, 148.0, 147.8, 133.5, 133.0, 132.3
(s, 2 C), 128.8 (s, 2 C), 127.8, 126.2, 124.6, 124.1, 121.0, 120.0, 111.3,
107.7, 56.0, 55.3, 45.4, 29.1.
13C NMR (СDCl3, 150 MHz): δ = 186.6, 149.0, 148.5, 147.7, 127.3,
126.6, 125.1, 124.4 (s, 2C), 124.3, 123.3, 121.7, 121.2, 114.0, 111.4,
111.2, 107.8, 56.09, 56.06, 56.0, 55.4, 45.4, 29.2.
MS (LCMS): m/z = 368 [M + Н]+.
MS (LCMS): m/z = 394 [M + Н]+.
Anal. Calcd for C21H18ClNO3: C, 68.57; H, 4.93; N, 3.81. Found: C,
68.91; H, 5.18; N, 3.62.
Anal. Calcd for C23H23NO5: C, 70.21; H, 5.89; N, 3.56. Found: C, 72.05;
H, 5.56; N, 3.41.
1-(4-Chlorophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrro-
1-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-
lo[2,1-a]isoquinoline-2-carbaldehyde (15)
pyrrolo[2,1-a]isoquinoline-2-carbaldehyde (19)
Yield: 259 mg (68%); beige solid; mp 231–232 °C.
Yield: 305 mg (75%); beige solid; mp 163–165 °C.
1H NMR (СDCl3, 600 MHz): δ = 9.65 (s, 1 Н), 7.40 (d, J = 8.4 Hz, 2 Н),
7.35 (d, J = 8.4 Hz, 2 Н), 6.68 (s, 1 H), 6.42 (s, 1 H), 3.99 (t, J = 6.4 Hz,
2 H), 3.85 (s, 3 H), 3.36 (s, 3 H), 3.02 (t, J = 6.4 Hz, 2 H), 2.63 (s, 3 H).
13C NMR (СDCl3, 150 MHz): δ = 186.8, 147.8, 147.7, 135.6, 133.4,
133.2, 132.5 (s, 2 C), 128.8 (s, 2 C), 125.8, 124.2, 121.1, 120.7, 120.4,
111.1, 107.6, 56.0, 55.2, 40.9, 29.0, 11.0.
1H NMR (СDCl3, 600 MHz): δ = 9.66 (s, 1 Н), 6.96 (dd, J = 1.8, 8.1 Hz,
1 Н), 6.94 (s, 1 Н), 6.92 (d, J = 8.1 Hz, 1 Н), 6.68 (s, 1 H), 6.59 (s, 1 H),
3.99 (t, J = 6.6 Hz, 2 H), 3.90 (s, 3 H), 3.86 (s, 3 H), 3.81 (s, 3 H), 3.36 (s,
3 H), 3.02 (t, J = 6.6 Hz, 2 H), 2.64 (s, 3 H).
13C NMR (СDCl3, 150 MHz): δ = 187.7, 149.0, 148.4, 147.7, 147.4,
135.0, 126.8, 125.4, 124.0, 123.5, 122.2, 121.4, 120.6, 114.1, 111.4,
110.9, 107.5, 56.1, 56.06, 55.98, 55.4, 40.8, 28.9, 11.1.
MS (LCMS): m/z = 382 [M + Н]+.
MS (LCMS): m/z = 408 [M + Н]+.
Anal. Calcd for C22H20ClNO3: C, 69.20; H, 5.28; N, 3.67. Found: C,
69.41; H, 5.05; N, 3.77.
Anal. Calcd for C24H25NO5: C, 70.74; H, 6.18; N, 3.44. Found: C, 70.96;
H, 6.07; N, 3.58.
1-(4-Chlorophenyl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrro-
lo[2,1-a]isoquinoline-2-carbaldehyde (16)
1-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-3-phenyl-5,6-dihydro-
pyrrolo[2,1-a]isoquinoline-2-carbaldehyde (20)
Yield: 354 mg (80%); beige solid; mp 206–208 °C.
Yield: 375 mg (80%); beige solid; mp 150–152 °C.
1H NMR (СDCl3, 600 MHz): δ = 9.62 (s, 1 Н), 7.52–7.48 (m, 3 Н), 7.46–
7.45 (m, 2 Н), 7.42–7.39 (m, 4 Н), 6.69 (s, 1 H), 6.46 (s, 1 H), 3.97 (t, J =
6.2 Hz, 2 H), 3.85 (s, 3 H), 3.38 (s, 3 H), 2.96 (t, J = 6.2 Hz, 2 H).
13C NMR (СDCl3, 150 MHz): δ = 186.4, 148.0, 147.7, 141.7, 133.9,
133.2, 132.3 (s, 2 C), 131.0 (s, 2 C), 129.3, 129.0, 128.7 (s, 2 C), 128.6
(s, 2 C), 127.6, 125.3, 121.3, 120.8, 118.9, 111.0, 108.2, 56.0, 55.2, 42.5,
29.2.
1H NMR (СDCl3, 600 MHz): δ = 9.64 (s, 1 Н), 7.53–7.42 (m, 5 Н), 7.03
(dd, J = 1.9, 8.3 Hz, 1 Н), 7.01 (d, J = 1.9 Hz, 1 Н), 6.94 (d, J = 8.3 Hz,
1 Н), 6.68 (s, 1 H), 6.63 (s, 1 H), 3.96 (t, J = 6.4 Hz, 2 H), 3.90 (s, 3 H),
3.85 (s, 3 H), 3.83 (s, 3 H), 3.38 (s, 3 H), 2.96 (t, J = 6.4 Hz, 2 H).
13C NMR (СDCl3, 150 MHz): δ = 186.6, 149.0, 148.4, 147.8, 147.7,
140.6, 131.0, 129.4, 129.1, 128.5 (s, 3C), 127.4, 127.3, 125.0, 123.2,
121.5, 121.3, 120.7, 114.0, 111.1, 110.9, 108.2, 56.06, 56.05, 55.98,
55.4, 42.5, 29.3.
MS (LCMS): m/z = 444 [M + Н]+.
Anal. Calcd for C27H22ClNO3: C, 73.05; H, 5.00; N, 3.16. Found: C,
72.95; H, 5.27; N, 3.28.
MS (LCMS): m/z = 470 [M + Н]+.
Anal. Calcd for C29H27NO5: C, 74.18; H, 5.80; N, 2.98. Found: C, 74.09;
H, 5.90; N, 2.85.
1-(4-Chlorophenyl)-8,9-dimethoxy-3-(4-methoxyphenyl)-5,6-di-
hydropyrrolo[2,1-a]isoquinoline-2-carbaldehyde (17)
Yield: 284 mg (60%); beige solid; mp 201–203 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
M. D. Matveeva et al.
Paper
Synthesis
1-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-3-(4-methoxyphenyl)-
MS (LCMS): m/z = 526 [M + Н]+.
5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carbaldehyde (21)
Anal. Calcd for C33H35NO5: C, 75.40; H, 6.71; N, 2.66. Found: C, 75.18;
H, 6.37; N, 2.22.
Yield: 314 mg (63%); beige solid; mp 147–149 °C.
1H NMR (СDCl3, 600 MHz): δ = 9.64 (s, 1 Н), 7.39–7.37 (m, 2 H), 7.03–
7.01 (m, 3 H), 7.00 (d, J = 2.1 Hz, 1 Н), 6.94 (d, J = 8.3 Hz, 1 Н), 6.67 (s,
1 H), 6.62 (s, 1 H), 3.95 (t, J = 6.4 Hz, 2 Н), 3.90 (s, 3 H), 3.87 (s, 3 H),
3.85 (s, 3 H), 3.83 (s, 3 H), 3.37 (s, 3 H), 2.95 (t, J = 6.4 Hz, 2 Н).
1-(3,4-Diethoxyphenyl)-8,9-diethoxy-3-(4-methoxyphenyl)-5,6-
dihydropyrrolo[2,1-a]isoquinoline-2-carbaldehyde (25)
Yield: 383 mg (69%); beige solid; mp 99–102 °C.
13C NMR (СDCl3, 150 MHz): δ = 186.7, 160.3, 149.0, 148.3, 147.7,
147.6, 140.6, 132.2 (s, 3 C), 127.5, 127.0, 125.0, 123.2, 121.5, 121.4,
120.6, 114.1 (s, 2 C), 114.0, 111.4, 110.9, 108.2, 56.06, 56.05, 55.98,
55.5, 55.4, 42.3, 29.3.
1H NMR (СDCl3, 600 MHz): δ = 9.62 (s, 1 Н), 7.38–7.37 (m, 2 H), 7.02–
7.01 (m, 2 H), 6.98–6.95 (m, 2 H), 6.93 (d, J = 8.1 Hz, 1 H), 6.67 (s, 1 H),
6.63 (s, 1 H), 4.13 (q, J = 7.1 Hz, 2 H), 4.06 (q, J = 7.0 Hz, 4 H), 3.94 (t, J =
6.4 Hz, 2 H), 3.87 (s, 3 H), 3.59 (q, J = 7.0 Hz, 2 H), 2.92 (t, J = 6.4 Hz,
2 H), 1.46 (t, J = 6.9 Hz, 3 H), 1.43–1.39 (m, 6 H), 1.18 (t, J = 6.9 Hz,
3 Н).
13C NMR (СDCl3, 150 MHz): δ = 186.7, 160.2, 148.9, 148.0, 147.3,
140.1, 132.2 (s, 3 C), 127.6, 127.0, 124.8, 123.1, 121.7, 121.5, 121.3,
121.0, 116.2, 114.0 (s, 2 C), 113.7, 113.0, 110.0, 64.8, 64.7, 64.6, 63.9,
55.5, 42.4, 29.2, 15.0, 14.94, 14.91, 14.7.
MS (LCMS): m/z = 500 [M + Н]+.
Anal. Calcd for C30H29NO6: C, 72.13; H, 5.85; N, 2.80. Found: C, 72.27;
H, 6.04; N, 2.90.
1-(3,4-Diethoxyphenyl)-8,9-diethoxy-5,6-dihydropyrrolo-
[2,1-a]isoquinoline-2-carbaldehyde (22)
MS (LCMS): m/z = 556 [M + Н]+.
Yield: 359 mg (80%); beige solid; mp 125–128 °C.
1H NMR (СDCl3, 600 MHz): δ = 9.62 (s, 1 Н), 7.35 (s, 1 H), 6.95–6.92
(m, 3 H), 6.68 (s, 1 H), 6.65 (s, 1 H), 4.14–4.09 (m, 4 H), 4.07–4.02 (m,
4 H), 3.60 (q, J = 7.0 Hz, 2 H), 3.01 (t, J = 6.4 Hz, 2 H), 1.46 (t, J = 7.0 Hz,
3 Н), 1.43–1.39 (m, 6 H), 1.18 (t, J = 7.0 Hz, 3 Н).
Anal. Calcd for C34H37NO6: C, 73.49; H, 6.71; N, 2.52. Found: C, 73.17;
H, 6.57; N, 2.66.
5,5,9-Trimethyl-1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-
2-carbaldehyde (26)
13C NMR (СDCl3, 150 MHz): δ = 186.9, 148.9, 148.1, 147.37, 147.34,
127.9, 126.7, 124.7, 124.3, 124.2, 123.2, 122.0, 121.3, 116.0, 113.7,
113.2, 109.4, 64.8, 64.7, 64.6, 63.9, 45.5, 29.1, 14.94, 14.92, 14.8, 14.6.
Yield: 192 mg (61%); beige solid; mp 102–105 °C.
1H NMR (СDCl3, 600 MHz): δ = 9.61 (s, 1 Н), 7.64 (s, 1 H), 7.43–7.40
(m, 4 H), 7.40–7.37 (m, 1 H), 7.05 (d, J = 7.7 Hz, 1 H), 6.91 (dd, J = 1.1,
7.7 Hz, 1 H), 6.77 (s, 1 H), 2.94 (s, 2 H), 2.03 (s, 3 H), 1.48 (s, 6 H).
13C NMR (СDCl3, 150 MHz): δ = 187.0, 136.3, 134.1, 130.7, 128.6 (s,
2 C), 128.4, 128.3, 127.9, 127.5, 127.4 (s, 2 C), 126.9, 125.0, 124.4,
124.3, 121.1, 55.5, 43.0, 27.8 (s, 2 C), 21.3.
MS (LCMS): m/z = 450 [M + Н]+.
Anal. Calcd for C27H31NO5: C, 72.14; H, 6.95; N, 3.12. Found: C, 72.35;
H, 6.79; N, 3.23.
1-(3,4-Diethoxyphenyl)-8,9-diethoxy-3-methyl-5,6-dihydropyrro-
lo[2,1-a]isoquinoline-2-carbaldehyde (23)
MS (LCMS): m/z = 316 [M + Н]+.
Yield: 333 mg (72%); beige solid; mp 115–117 °C.
Anal. Calcd for C22H21NO: C, 83.78; H, 6.71; N, 4.44. Found: C, 83.64;
H, 6.54; N, 4.35.
1H NMR (СDCl3, 600 MHz): δ = 9.63 (s, 1 Н), 6.93–6.90 (m, 3 H), 6.67
(s, 1 H), 6.59 (s, 1 H), 4.12 (q, J = 7.0 Hz, 2 H), 4.06–4.00 (m, 4 H), 3.97
(t, J = 6.4 Hz, 2 H), 3.57 (q, J = 7.0 Hz, 2 H), 2.98 (t, J = 6.4 Hz, 2 H), 2.52
(s, 3 H), 1.45 (t, J = 7.0 Hz, 3 H), 1.42–1.38 (m, 6 H), 1.16 (t, J = 7.0 Hz,
3 Н).
13C NMR (СDCl3, 150 MHz): δ = 187.9, 148.9, 148.0, 147.3, 147.0,
134.7, 127.0, 125.4, 123.8, 123.4, 122.4, 121.6, 120.7, 116.1, 113.8,
113.0, 109.2, 64.8, 64.7, 64.6, 63.9, 40.9, 28.8, 14.9, 14.9 (s, 2 C), 14.6,
11.1.
1-Phenyl-6,11-dihydro-5H-indolizino[8,7-b]indole-2-carbalde-
hyde (28)
The acrolein was added with stirring to a solution of 1-benzoyl-3,4-
dihydro-β-carboline 27 in 2,2,2-trifluoroethanol. The reaction was
conducted at reflux for 6 h. The reaction progress was monitored by
TLC (Sorbfil; EtOAc–hexane, 2:1). The solvent was removed under
vacuum, to give indolizino[8,7-b]indole 28 as an amorphous mass,
isolation was done by silica gel column chromatography (EtOAc–hex-
ane, 1:10).
MS (LCMS): m/z = 464 [M + Н]+.
Anal. Calcd for C28H33NO5: C, 72.55; H, 7.18; N, 3.02. Found: C, 72.32;
H, 6.97; N, 3.14.
Yield: 109 mg (35%); amorphous mass.
1H NMR (СDCl3, 600 MHz): δ = 9.71 (s, 1 Н), 7.78 (s, 1 H), 7.56–7.55
(m, 2 H), 7.54–7.51 (m, 2 H), 7.50 (s, 1 H), 7.49–7.46 (m, 2 H), 7.18 (d,
J = 8.3 Hz, 1 H), 7.13–7.09 (m, 2 H), 4.28 (t, J = 6.9 Hz, 2 H), 3.22 (t, J =
6.9 Hz, 2Н).
13C NMR (СDCl3, 150 MHz): δ = 185.8, 136.2, 133.3, 132.2, 131.0,
130.7, 130.2 (s, 2 C), 129.6, 129.1 (s, 2 C), 128.1, 128.0, 127.1, 126.1,
122.5, 120.3, 118.1, 111.3, 46.3, 29.8.
1-(3,4-Diethoxyphenyl)-8,9-diethoxy-3-phenyl-5,6-dihydropyrro-
lo[2,1-a]isoquinoline-2-carbaldehyde (24)
Yield: 420 mg (80%); beige solid; mp 107–109 °C.
1H NMR (СDCl3, 600 MHz): δ = 9.63 (s, 1 Н), 7.50–7.44 (m, 5 H), 6.99–
6.96 (m, 2 H), 6.93–6.92 (m, 1 H), 6.67 (s, 1 H), 6.64 (s, 1 H), 4.14 (q, J =
7.0 Hz, 2 H), 4.07–4.04 (m, 4 H), 3.95 (t, J = 6.2 Hz, 2 H), 3.59 (q, J =
7.0 Hz, 2 H), 2.93 (t, J = 6.2 Hz, 2 H), 1.46 (t, J = 7.0 Hz, 3 Н), 1.43–1.39
(m, 6 H), 1.19 (t, J = 7.0 Hz, 3 Н).
13C NMR (СDCl3, 150 MHz): δ = 186.6, 148.9, 148.0, 147.4, 140.1, 131.0
(s, 3C), 129.6, 129.0, 128.4 (s, 2C), 127.5, 127.2, 124.8, 123.1, 121.4,
121.3, 120.9, 116.3, 113.8, 112.9, 109.8, 64.8, 64.6, 64.5, 63.8, 42.5,
29.2, 15.0, 14.92, 14.91, 14.6.
MS (LCMS): m/z = 313 [M + Н]+.
Anal. Calcd for C21H16N2O: C, 80.75; H, 5.16; N, 8.97. Found: C, 80.54;
H, 5.36; N, 8.85.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
M. D. Matveeva et al.
Paper
Synthesis
Funding Information
(6) (a) Andersen, R. J.; Faulkner, D. J.; He, C. H.; Vanduyne, G. D.;
Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492. (b) Shen, L.; Xie, N.;
Yang, B.; Hu, Y.; Zhang, Y. Eur. J. Med. Chem. 2014, 85, 807.
(7) (a) Niewoehner, U.; Bauser, M.; Ergueden, J.-K.; Flubacher, D.;
Naab, P.; Repp, T.-O.; Stoltefuss, J.; Burkhardt, N.; Sewing, A.;
Schauer, M.; Schlemmer, K.-H.; Weber, O.; Boyer, S.; Miglarese,
M. WO Patent 02/48144, 2002. (b) Zhang, C.; Fan, D.; Wang, Y.;
Li, T.; Boyer, S.; Burke, J.; Raudenbush, B.; Wong, W.; Ying, S.;
Wang, M.; Zhao, Q.; Carter, C. A.; Burkhardt, N.; Pernerstorfer, J.;
Niewoehner, M.; Niewoehner, U. WO Patent 03/051877, 2003.
(c) Reyes-Gutiérrez, P. E.; Camacho, J. R.; Ramírez-Apan Ma, T.;
Osornio, Y. M.; Martínez, R. Org. Biomol. Chem. 2010, 8, 4374.
(8) van Rijn, R. D.; Loozen, H. J. J.; Timmers, C. M.; Anders var der
Veen, L.; Karstens, W. F. J. US patent 8394789, 2013.
This work was supported by the Russian Foundation for Basic Re-
search (grant 17-03-00605) and was financially supported by the
Ministry of Education and Science of the Russian Federation (agree-
ment no. 02.a03.21.0008).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588486.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G