Regio- And Diastereoselective Synthesis of Novel Polycyclic Pyrrolo[2,1- a ]isoquinolines Bearing Indeno[1,2- b ]quinoxaline Moieties by a Three-Component [3+2]-Cycloaddition Reaction

Article abstract of DOI:10.1055/s-0039-1690768

A regio- and diastereoselective synthesis of 2,3-dihydro-10b′ H -spiro[indeno[1,2- b ]quinoxaline-11,1′-pyrrolo[2,1- a ]isoquinoline]-2′,3′-diylbis(phenylmethanone) derivatives containing four contiguous chiral stereocenters was achieved through 1,3-dipolar cycloaddition of isoquinolinium N -ylides in a one-pot three-component reaction. The desired products were obtained in short reaction times and in moderate to high yields (up to 92percent) under relatively mild reaction conditions. The structure and relative stereochemistry of the desired product was confirmed by X-ray diffraction analysis.

Full text of DOI:10.1055/s-0039-1690768

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
F. M. Moghaddam et al.
Letter
Synlett
Regio- and Diastereoselective Synthesis of Novel Polycyclic
Pyrrolo[2,1-a]isoquinolines Bearing Indeno[1,2-b]quinoxaline
Moieties by a Three-Component [3+2]-Cycloaddition Reaction
Firouz Matloubi Moghaddam*a
Atiyeh Moafia
Behzad Jafarib
0
0
0
0-0
0
0
2-
8
4
1
8-9
8
8
8
Ar1
O
Ar2
N
H
O
Alexander Vilingerb
Peter Langerb
N
O
Et3N
CH3CN
N
Ar2
R1
O
+
Br
a Laboratory of Organic Synthesis and Natural Products,
Department of Chemistry, Sharif University of Technology,
Azadi Street, PO Box 11155-9516, Tehran, Iran
matloubi@sharif.edu
b Institut für Chemie, Universität Rostock, Albert-Einstein-Str.
3a, 18059 Rostock, Germany
N
+
R2
Ar1
N
11 Examples
Reflux
R1
Regio- and diastereoselectivity
Moderate to high yield (up to 92%)
Use of available starting materials
Relatively mild reaction conditions
Short reaction time
Ar2
N
N
Ar1
Ar1 = Ph
Tol
Ar2 = Ph
Tol
O
R2
O
N
Easy workup
4-MeOC6H4
4-BrC6H4
4-MeOC6H4
4-BrC6H4
R1 = H, Me
R2 = H, Me
N
R1
R2
Received: 23.09.2019
H
MeO
MeO
Accepted after revision: 28.11.2019
Published online: 12.12.2019
DOI: 10.1055/s-0039-1690768; Art ID: st-2019-k0505-l
HO
HO
O
N
N
10b
(10bR)-(+)-Oleracein
(10bS)-(–)-Trolline
(+)-Crispine
Abstract A regio- and diastereoselective synthesis of 2,3-dihydro-
10b′H-spiro[indeno[1,2-b]quinoxaline-11,1′-pyrrolo[2,1-a]isoquino-
line]-2′,3′-diylbis(phenylmethanone) derivatives containing four con-
tiguous chiral stereocenters was achieved through 1,3-dipolar cycload-
MeO
MeO
OSO2Na
OH
HO
HO
MeO
MeO
dition of isoquinolinium N-ylides in
a one-pot three-component
O
O
MeO
reaction. The desired products were obtained in short reaction times
and in moderate to high yields (up to 92%) under relatively mild reaction
conditions. The structure and relative stereochemistry of the desired
product was confirmed by X-ray diffraction analysis.
MeO
HO
N
O
N
O
HO
Lamellarin D-α-20-sulfate
Lamellarin D
Figure 1 Examples of pyrrolo[2,1-a]isoquinoline-containing alkaloids
Key words pyrroloisoquinolines, indenoquinoxalines, spiro com-
pounds, diastereoselectivity, 1,3-dipolar cycloaddition, multicompo-
nent reaction
macrocyclic receptors for molecular recognition,18 and as
chemically controllable switches.19 Indenoquinoxalines are
a major group of polycyclic quinoxalines that are widely
used as precursors for the synthesis of biologically active
spiro compounds.20
Pyrrolo[2,1-a]isoquinolines, which have a broad range
of applications, are attractive target structures in synthesis
and in medicinal chemistry.1a Furthermore, these heterocy-
cles are important frameworks in such natural products as
(+)-oleracein,1b (–)-trolline,1c (+)-crispine,1d and lamellarin
alkaloids, for example, lamellarin D and lamellarin -20-
sulfate1e (Figure 1).1f Most alkaloids containing pyrrolo[2,1-
a]isoquinoline residues exhibit significant antitumor,2 anti-
bacterial, antiviral,1c,3 antiinflammatory,4 antidepressant,5
or cardiovascular activities.6
Quinoxaline and its derivatives are also important het-
erocycles that have a wide range of biological activities,
such as antimicrobial,7 antihypertensive,8 antitubercular,9
antidepressant,10 antimalarial,11 antiinflammatory,12 anti-
convulsant,13 anti-HIV,14 antidiabetic, or anticancer activi-
ties15,16 (Figure 2). In addition, they have been used in syn-
theses of organic semiconductors,17 as rigid subunits of
H
N
Me
O
O
H
N
Me
O
N
N
N
N
Me
Anticancer Agent
HO
Antiinflammatory Agent
O
N
H
N
O
O
N
F
Me
Antimicrobial Agent
Figure 2 Examples of biologically active quinoxalines
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
F. M. Moghaddam et al.
Letter
Synlett
Heteroaromatic N-ylides such as pyridinium, thiazoli-
um, quinolinium, or isoquinolinium methylides are useful
reactive intermediates that are extensively used in 1,3-di-
polar cycloaddition reactions for syntheses of N-bridgehead
heterocyclic compounds.21–23 The reaction of isoquinolini-
um N-ylides with various activated alkynes or olefins con-
stitutes an efficient method for the regio- and stereoselec-
tive synthesis of structurally complex pyrrolo[2,1-a]iso-
quinolines with multiple contiguous stereogenic centers
that have many applications in medicinal chemistry and
drug discovery.24,25 For example, Yan and co-workers re-
ported the synthesis of spiro[indoline-3,3′-pyrrolo[1,2-
a]isoquinolines] by a 1,3-dipolar cycloaddition reaction of
N-phenacylquinolinium bromides with 3-phenacylidene-
oxindoles as dipolarophiles.24
purpose, a mixture of isoquinoline and phenacyl bromide
(5a) was stirred in acetonitrile at room temperature for 15
minutes. Ketone 3a and triethylamine were then added, and
the mixture was stirred under reflux conditions for two
hours. After a simple workup, product 6a was obtained in
moderate yield (Scheme 2).
Ph
O
O
Ph
Ph
N
H
O
O
Et3N
Br
N
+
N
+
Ph
N
CH3CN
Reflux
N
N
3a
5a
6a
Scheme 2 Three-component synthesis of diastereoisomer 6a
Because of the biological importance of pyrrolo[2,1-
a]isoquinolines and quinoxaline structures, and in continu-
ation of related studies and our growing interest in develop-
ing 1,3-dipolar cycloaddition reactions,26–28 we decided to
synthesize spiroheterocycles containing both pyrrolo[2,1-
a]isoquinoline and quinoxaline moieties. To the best of our
knowledge, this is the first report of a 1,3-dipolar cycloaddi-
tion of N-phenacylquinolinium bromides with 1-aryl-2-
To survey the scope of this reaction, various substituted
phenacyl bromides 5 containing either electron-donating
or electron-withdrawing groups on the aromatic ring were
treated with isoquinoline and various 1-aryl-2-(11H-inde-
no[1,2-b]quinoxalin-11-ylidene)ethanones
3 under the
Table 1 Synthesis of 2′,3′-Dihydro-10b′H-spiro[indeno[1,2-b]quinox-
aline-11,1′-pyrrolo[2,1-a]isoquinoline]-2′,3′-diylbis(phenylmethanone)
Derivatives 6a
(11H-indeno[1,2-b]quinoxalin-11-ylidene)ethanones
in
which electron-deficient alkenes act as dipolarophiles to
give functionalized spiropyrrolo[2,1-a]isoquinoline deriva-
tives bearing four stereogenic centers.
O
Ar1
N
O
Ar2
O
H
Ar2
Et3N
CH3CN
The reaction of o-phenylenediamines 1 with ninhydrin
in refluxing EtOH gave the corresponding 11H-indeno[1,2-
b]quinoxalin-11-ones 2 in high yields.29 We then synthe-
sized 1-aryl-2-(11H-indeno[1,2-b]quinoxalin-11-ylidene)-
ethanones 3 through the reaction of 2 with 1-aryl-2-(tri-
phenylphosphoranylidene)ethanones 4 in the presence of
sodium acetate in EtOH, according to a previously reported
method (Scheme 1).30,31
O
Br
+
+
N
N
Ar1
N
Reflux
R1
N
N
R1
5
3
6
R2
R2
Product Ar1
Ar2
R1
R2
Time (h) Yieldb (%)
6a
6b
6c
6d
6e
6f
Ph
4-Tol
Ph
H
H
2
64
69
76
90
71
85
78
75
81
87
92
73
89
61
67
Ph
H
H
2
O
4-MeOC6H4
4-BrC6H4
Ph
Ph
H
H
1
O
R1
NH2
N
HO
Ph
H
H
0.5
2
EtOH
+
HO
R2
Reflux
1 h
N
NH2
R1
4-Tol
4-Tol
4-Tol
H
H
O
2
1
O
R2
4-Tol
H
H
1.5
1
O
11H-indeno[1,2-b]quinoxalin-11-one
PPh3
Ar
6g
6h
6i
4-MeOC6H4
Ph
H
H
Ar1
N
4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-BrC6H4
H
H
1.5
1
EtOH, Reflux
2 h, NaOAc
N
R1
4-Tol
H
H
3
6j
4-MeOC6H4
4-BrC6H4
Ph
H
H
0.5
0.5
1
R2
6k
6l
H
H
Scheme 1 Synthesis of 1-aryl-2-(11H-indeno[1,2-b]quinoxalin-11-
ylidene)ethanones 3
H
H
6m
6n
6o
4-MeOC6H4
4-MeOC6H4
4-BrC6H4
4-BrC6H4
H
H
0.5
2
With compounds 3 in hand, we investigated the 1,3-di-
polar cycloaddition of isoquinolinium N-ylides, generated
in situ by the reaction of isoquinoline and phenacyl bro-
mide (5a), with 2-(11H-indeno[1,2-b]quinoxalin-11-
ylidene)-1-phenylethanone (3a) as a dipolarophile. For this
4-MeOC6H4
4-MeOC6H4
Me
Me
Me
Me
1.5
a Reaction conditions: isoquinoline (1 mmol), 5 (1 mmol), 3 (1 mmol), Et3N
(1 mmol), CH3CN (3 mL), reflux.
b Isolated yields after direct filtration of the reaction mixture.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

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F. M. Moghaddam et al.
Letter
Synlett
same reaction conditions (Table 1).32 Generally, all the prod-
ucts were obtained in moderate to high yields and with ex-
cellent diastereoselectivities.
The structures of the isolated products 6a–o were fully
characterized by elemental analysis, 1H and 13C NMR spec-
troscopy, and IR spectroscopy, and confirmed by single-
crystal X-ray diffraction in the case of 6b (see below). The
1H NMR spectrum of 6a contained characteristic signals
with appropriate chemical shifts and coupling constant for
22 hydrogen atoms of the aromatic region. Two doublets at
 = 5.33 and 6.46 ppm with vicinal coupling constant J = 5.5
Hz were assigned to the protons of the dihydroisoquinoline
ring. One singlet at  = 6.36 was assigned to the benzylic CH,
and two doublets at  = 5.24 and 5.37 ppm with the vicinal
coupling constant J = 7.5 Hz were assigned to protons of the
newly formed pyrrolidine ring.
Figure 4 X-ray crystallographic structure of 6b
To identify the positions of the two methine protons in
the pyrrolidine ring for compound 6a, we performed densi-
ty functional theory (DFT) calculations with the functional
B3LYP and the 6-31+G(d) basis set. As shown in Figure 3,
the dihedral angle between these two protons is 146.960°.
From the 1H NMR spectrum (J = 7.5 Hz) and considering this
dihedral angle, we deduce that the two vicinal benzoyl
groups in the products are in trans-positions.
tonated by triethylamine to give the isoquinolinium ylide A.
Compound 3a contains one enone and one enimine unit, so
a 1,3-dipolar cycloaddition reaction of dipole A to the exo-
cyclic double bond of this compound might occur through
one of two pathways giving regioisomers 6a and 7a, respec-
tively. X-ray crystallographic analysis of product showed
conclusively that the reaction proceeds by Path a to give re-
gioisomer 6a exclusively.
O
O
CH3CN
Br
+
N
N
Ph
Reflux
Ph
5a
Br
Ph
isoquinolinium bromide
Path b
O
O
Ph
N
Path a
O
Ph
Path a
Et3N
N
N
N
N
3a
O
6a
Figure 3 Optimized structure of 6a calculated at B3LYP/6-31+G(d) lev-
el of theory. The dihedral angle in the optimized geometry is reported
in degrees.
N
Ph
A
Ph
N
Br
+
Et3NH
Path b
O
O
Ph
N
An X-ray crystallographic analysis of the related com-
pound 6b33 confirmed this conclusion. As shown in Figure
4, the aryl group of the indenoquinoxaline moiety and its
adjacent arylcarbonyl group exist in a trans-configuration.
This interesting result showed that this 1,3-dipolar cycload-
dition reaction proceeds with extremely high diastereose-
lectivity.
N
7a
Scheme 3 Proposed mechanism for the formation of the desired prod-
uct 6a
On the basis of the X-ray crystallography, it was clear
the cycloaddition reaction between isoquinolinium N-
ylides and unsymmetrical dipolarophile 3 is completely re-
gioselective, as only one regioisomer was obtained. Our
proposed mechanism for this reaction is shown in Scheme
3. First, the isoquinolinium bromide generated by the reac-
tion of isoquinoline and phenacyl bromide (5a) is depro-
In conclusion, we have developed a simple and efficient
method for the construction of spiropyrrolo[2,1-a]isoquin-
olines containing indenoquinoxaline moieties through a
highly regioselective and stereoselective1,3-dipolar cyclo-
addition reaction of isoquinolinium ylides, generated in situ
by the reaction of isoquinoline and phenacyl bromides in
the presence of Et3N, with 1-aryl-2-(11H-indeno[1,2-b]qui-
noxalin-11-ylidene)ethanones. The use of readily available
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

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F. M. Moghaddam et al.
Letter
Synlett
starting materials, the short reaction times, the moderate
to high yields, and the easy purification and high diversity
of the products are among the advantages of this method.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690768. Included are experimental
details, characteristic data, 1H and 13CNMR spectra of products, crys-
(21) (a) Eryazici, I.; Moorefield, C. N.; Durmus, S.; Newkome, G. R.
J. Org. Chem. 2006, 71, 1009. (b) Tu, S. J.; Jia, R. H.; Jiang, B.;
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tal data and the computational data of products.
S
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p
p
orit
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o
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p
p
orit
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gInformati
o
n
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NaOAc (1.5 mmol) was added to a solution of ninhydrin (1
mmol) and the appropriate phenylenediamine 1 (1 mmol) in
EtOH (4 mL), and the solution was stirred for 1 h at r.t. Then, the
appropriate 1-aryl-2-(triphenylphosphoranylidene)ethanone 4
(1.5 mmol) was added and the mixture was stirred at the reflux
until the reaction was complete (TLC; 2 h). The mixture was
then filtered and the product was recrystallized from EtOH.
(32) Products 6a–o: General Procedure
A mixture of isoquinoline (1 mmol) and the appropriate
phenacyl bromide 5 (1 mmol) in CH3CN (3 mL) was stirred at r.t.
for 15 min. Et3N (1 mmol) and the appropriate ketone 3 (1
mmol) were added, and the mixture was stirred under reflux
until the reaction was complete (TLC; hexane–EtOAc, 1:2). The
pure products was then simply collected by filtration and dried
in air.
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(2′-Benzoyl-2′,3′-dihydro-10b′H-spiro[indeno[1,2-b]quinox-
aline-11,1′-pyrrolo[2,1-a]isoquinolin]-3′-yl)(4-tolyl)metha-
none (6b)
Orange solid; yield: 411 mg (69%); mp 207–209 °C. IR (KBr) =
1679, 1615, 14.99, 1460, 1328, 1238, 1130 cm–1
.
1H NMR (500
3
MHz, CDCl3): H = 2.41 (s, 3 H, CH3), 5.23 (d, JHH = 7.5 Hz, 1 H,
CH pyrrolidine), 5.31 (d, 3JHH = 5.4 Hz, 1 H, olefinic CH), 5.36 (d,
3JHH = 7.7 Hz, 1 H, N–CH pyrrolidine), 6.25–6.28 (t, 3JHH = 7.5 Hz,
1 H, H–Ar), 6.38 (s, 1 H, benzylic CH), 6.43 (d, 3JHH = 5.4 Hz, 1 H,
3
olefinic CH–N), 6.53 (d, JHH = 7.5 Hz, 1 H, H–Ar), 6.56–6.60 (t,
3JHH = 7.5 Hz, 2 H, H–Ar), 6.65 (d, 3JHH = 7.5 Hz, 1 H, H–Ar), 6.70–
6.75 (m, 3 H, H–Ar), 6.99–7.02 (t, 3JHH = 7.5 Hz, 1 H, H–Ar), 7.20–
(15) Kulkarni, N. V.; Revankar, V. K.; Kirasur, B. N.; Hugar, M. H. Med.
Chem. Res. 2012, 21, 663.
(16) Amin, K. M.; Ismail, M. M. F.; Noaman, E.; Soliman, D. H.;
Ammar, Y. A. Bioorg. Med. Chem. 2006, 14, 6917.
3
3
7.23 (t, JHH = 7.5 Hz, 1 H, H–Ar), 7.32 (d, JHH = 7.5 Hz, 3 H, H–
Ar), 7.62 (d, 3JHH = 7.5 Hz, 1 H, H–Ar), 7.78–7.81 (m, 3 H, H–Ar),
3
3
8.07 (d, JHH = 9.5 Hz, 1 H, H–Ar), 8.10 (d, JHH = 8.0 Hz, 2 H, H–
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

E
F. M. Moghaddam et al.
Letter
Synlett
Ar), 8.32 (d, 3JHH = 9.4 Hz, 1 H, H–Ar). 13C NMR (125 MHz, CDCl3):
C = 21.7, 57.3, 65.3, 65.9, 69.8, 98.3, 121.2, 124.0, 124.1, 124.6,
126.1, 127.1, 127.2, 127.4, 127.6, 128.5, 128.9, 129.0, 129.1,
129.6, 129.7, 129.8, 130.9, 132.5, 132.8, 132.9, 134.0, 136.6,
137.3, 141.5, 142.2, 144.3, 144.7, 154.5, 160.4, 197.0, 197.4.
Anal. calcd for C41H29N3O2 (595.70): C, 82.67; H, 4.91; N, 7.05.
Found: C, 82.64; H, 4.96; N, 6.97.
Crystal Data for 6b: C41H29N3O2: MW = 595.67, monoclinic,
P21/c, a = 10.0450(8) Å, b = 17.0959(14) Å, c = 18.8967(15) Å,
 = 104.646(2)°, V = 3139.7(4) Å3, Z = 4, Dc = 1.293 mg/m3,
F(000) = 1281; crystal dimensions: 0.26 × 0.15 × 0.12 mm, radi-
ation, Mo K ( = 0.71073 Å), 3.424 ≤ 2θ ≤ 26.999, intensity data
were collected at 123(2) K with a Bruker APEX area-detector
diffractometer, employing the /2θ scanning technique, in the
range –12 ≤ h ≤ 12, –21 ≤ k ≤ 21, –24 ≤ l ≤ 24. The structure was
solved by a direct method; all nonhydrogen atoms were posi-
tioned and anisotropic thermal parameters were refined from
6837 observed reflections with R(into) = 0.0404 by a full-matrix
least-squares technique converging to R1 = 0.0520, and wR2 =
0.1166 [I > 2(I)].
(33) CCDC 1949927 contains the supplementary crystallographic
data for compound 6b. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E