Regio- And Stereoselectivity in the 1,3-Dipolar Cycloaddition Reactions of Isoquinolinium Ylides with Cyclopenta[ a ]acenaphthylen-8-ones

Article abstract of DOI:10.1055/s-0040-1706750

A convenient regio- and diastereoselective synthesis of functionalized 5a,5b-dihydro-5 H,13 H -naphtho[1′′,8′′:4′,5′,6′]pentaleno[1′:3,4]pyrrolo[2,1- a ]isoquinolin-5-ones via 1,3-dipolar cycloaddition reaction of 8 H -cyclopenta[a]acenaphthylen-8-ones wi

Full text of DOI:10.1055/s-0040-1706750

SYNLETT0936-52141437-2096
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–E
letter
A
en
I. Yavari et al.
Letter
Synlett
Regio- and Stereoselectivity in the 1,3-Dipolar Cycloaddition Reac-
tions of Isoquinolinium Ylides with Cyclopenta[a]acenaphthylen-
8-ones
Issa Yavari* 0176-982
O
O
O
Z
Parisa Ravaghi
Maryam Safaei
Jasmine Kayanian
Ar
O
Z
Ar
H
Z
Z
N
H
N
Department of Chemistry, Tarbiat Modares University, PO Box
14115-175, Tehran, Iran
yavarisa@modares.ac.ir
Z = CO2Me, CO2Et
Ar = Ph, 4-MeC6H4, 4-ClC6H4,
4-MeOC6H4, 4-O2NC6H4,
10 examples
84–92% yield
IDesMesapaaYilratyvmaaverainrtisoaf@Cmheomdaisretrsy.a, cT.airrbiat Modares University, PO Box 14115-175, Tehran, Iran
Received: 02.04.2020
Accepted after revision: 20.07.2020
Published online: 11.08.2020
to the formation of bridged carbonyl compounds, which can
lose carbon monoxide upon heating. The catalytic reactivity
of iron cyclopentadienone complexes have been reported.6
The synthesis, reactions, and physical properties of cyclo-
pentadienones have been extensively reviewed.3
DOI: 10.1055/s-0040-1706750; Art ID: st-2020-v0187-l
Abstract A convenient regio- and diastereoselective synthesis of
functionalized 5a,5b-dihydro-5H,13H-naphtho[1′′,8′′:4′,5′,6′]pentale-
no[1′:3,4]pyrrolo[2,1-a]isoquinolin-5-ones via 1,3-dipolar cycloaddition
reaction of 8H-cyclopenta[a]acenaphthylen-8-ones with carbonyl-sta-
bilized isoquinolinium N-ylides, is described. Based on DFT calculations
at b3lyp/6-311+g(d,p) level of theory, a nonconcerted mechanism is
proposed to explain the regioselectivity of this reaction. The structure
of a typical product was confirmed by X-ray crystallographic analysis.
O
O
Ar
RO2C
Ar
CO2R
O
O
Ar
Ar
Ar
Ar
Key words regioselective synthesis, 1,3-dipolar cycloaddition, iso-
1
2
3
4
quinolinium ylide, cyclopentadienones, DFT calculations
Figure 1 Cyclopentadienone and its monomeric derivatives
Cyclopentadienone (1) represents an unusual system of
crossed conjugated double bonds in a five-membered ring.1
Cyclopentadienones are antiaromatic dienes having low
HOMO–LUMO energy gaps.2 Although 1 and nearly all of
the simple cyclopentadienones that have been prepared are
dimeric, tetraarylcyclopentadienones 2 and fused-ring cy-
clopentadienones, such as disubstituted 8H-cyclo-
pent[a]acenaphthylen-8-ones (3 and 4), are monomeric
(Figure 1).3 The factors that determine whether a monomer
or a dimer is formed appear to be steric in nature. All of the
monomeric cyclopentadienones are colored and many have
been studied for the effect of substituents and fused rings
on the ultraviolet and visible absorption.4 The tetraaryl de-
rivatives 2 are powerful dienes in a Diels–Alder reaction
and have been used for the synthesis of highly arylated
compounds.5 With alkenes or alkynes the reaction can lead
The cyclopentadienone system has been proved to be a
privileged and peculiar dipolarophile. Thus, in the cycload-
dition of tetrasubstituted cyclopentadienones with nitrile
oxides, the 1,3-dipole attacks the ring C=C double bond,7a
whereas with nitrile imines7b and nitrile ylides,7c the dipole
attacks the carbonyl double bond (Scheme 1). It was of in-
terest, therefore, to study the cycloaddition of the ring-
fused 7,9-bis(alkoxycabonyl)-8H-cyclopent[a]acenaphth-
ylen-8-ones8 with carbonyl-stabilized isoquinolinium
ylides,9 to examine the position of attack by this dipole and
the regioselectivity of the cycloadducts. As shown in
Scheme 1, the 1,3-dipole attacks the ethylene double bond
of cyclopentadienone derivative to afford a heptacyclic ad-
duct.
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B
I. Yavari et al.
Letter
Synlett
To determine the scope of this approach, a number of
phenacyl bromides 6 were tested under the reaction condi-
tions. As shown in Table 2, phenacyl bromides bearing elec-
tron-donating or electron-withdrawing substituents pro-
vided the functionalized pyrrolo[2,1-a]isoquinoline deriva-
tives 8 in good yields (84–92%).10
Previous work:
a)
Ph
Ph
Ph
Ph
C
C
N
N
N-Ph
Ph
Ph
Ph
Ph
O
C6H6, r.t.
+
O
N
N
Ph
Ph
N-Ph
Ph
Ph
b)
Ph
Ph
Ph
Ph
C
N
CH-Ar
CH-Ar
Ph
Ph
H
Ph
O
C6H6, r.t.
Ar
Table 2 Synthesis of Fused Pyrrolo[2,1-a]isoquinolines 8a
+
O
N
Ph
Ph
C
N
Ph
Ph
Ar = 4-O2NC6H4
O
Br
+
This work:
N
Ar
O
O
O
5
6
Z
O
Ph
H
O
O
N
rt
Z
Z
Z
MeCN
O
Z
Z
Z
Z
Ar
Z
Z
N
Br
MeCN
O
Et3N
MeCN
O
N
+
H
N
Et3N
Ar
N
Ar
COAr
4
7
8
9 (not observed)
Z = CO2Me, CO2Et
Scheme 1 Dipolar cycloaddition of fused cyclopentadienones with: a)
diphenylnitrilimine, b) benzonitrile-4-nitrobenzylide, and carbonyl-sta-
bilized isoquinolinium ylide.
Entry
Z
Ar
Product 8
Yield (%)b
1
2
3
4
5
6
7
8
9
10
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
Ph
Ph
8a
8b
8c
8d
8e
8f
86
88
85
90
87
86
92
85
90
84
4-ClC6H4
Initially, the reaction between 7,9-bis(methoxycabon-
yl)-8H-cyclopent[a]acenaphthylen-8-one (4a) and 2-(2-
oxo-2-phenylethyl)isoquinolin-2-ium bromide (7a), pre-
pared in situ from isoquinoline (5) and phenacyl bromide
(6a), was investigated in the presence of Et3N. The reaction
proceeded smoothly in MeCN at room temperature (25 °C)
and afforded dimethyl 4-benzoyl-5-oxo-4H,12cH-naph-
tho[1′′,8′′:4′,5′,6′]pentaleno[1′:3,4]pyrrolo[2,1-a]isoquino-
line-4a,6(5H)-dicarboxylate (8a) in 80% yield (Table 1). In
order to optimize the reaction conditions for the formation
of 8a, the effects of solvent and temperature were studied.
As shown in Table 1, H2O, MeOH, DMF, MeCN, and CH2Cl2
were examined. Ultimately, MeCN was found to be the best
solvent at 80 °C.
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
4-O2NC6H4
8g
8h
8i
8j
a Reaction conditions: 4 (1 mmol), 7 (1 mmol), Et3N (1 mmol), solvent (6
mL).
b Isolated yield.
1
The structures of products 8a–j were elucidated by H
NMR, 13C NMR, IR, and mass spectral data. The 1H NMR
spectrum of 8a exhibited four sharp singlets for the me-
thoxy ( = 3.51 and 3.86 ppm) and methine ( = 4.82 and
6.13 ppm) protons. The aromatic protons show characteris-
Table 1 Optimization of Reaction Conditions for the Formation of 8aa
O
Br
+
Ph
N
MeO
O
O
tic multiplets ( = 6.37–8.27 ppm) in the spectrum. The 13
C
O
6a
5
H
O
MeCN
Br
O
O
O
Ph
NMR spectrum of 8a showed 34 signals in agreement with
the proposed structure. The mass spectrum of 8a displayed
the molecular ion peak at m/z = 567. The NMR spectra of
compounds 8b–j were similar to those of 8a, except for the
substituents, respectively.
MeO
N
OMe
MeO
H
Et3N
O
+
N
MeCN
Ph
4a
7a
8a
Entry
Solvent
Temp (°C)
Yield (%)b
Clear evidence for the structure of 8e was obtained from
single-crystal X-ray analysis.11 The ORTEP diagram of 8e is
shown in Figure 2. There are eight molecules of 8e in the
unit cell, which are arranged in a centrosymmetric manner.
The structure obtained from the crystallographic data, and
those of 8a–d and 8f–j were assumed to be analogous on
account of their similar NMR spectra.
1
2
3
4
5
6
H2O
60
60
25
25
25
80
trace
15
MeOH
CH2Cl2
DMF
50
20
MeCN
MeCN
80
86
a Reaction conditions: 4a (1.0 mmol), 7a (1.0 mmol), Et3N (1.0 mmol), sol-
vent (6 mL), 2 h.
b Yield of isolated product.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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I. Yavari et al.
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Figure 4 Frontier orbital diagram for isoquinolinium ylides 10 (left) and
cyclopentadienone 4 (right). The HOMO–LUMO energy levels are given
in eV.
DFT has been accepted by chemists as a reliable ap-
proach for computation of molecular structures and ener-
gies of chemical systems.14 To estimate the molecular reac-
tivities of 4 and 10, the values of global chemical reactivity
descriptors such as electronic chemical potentials (),15
chemical hardness (η),16 and electrophilicity ()17 for reac-
tants 4 and 10 are calculated by this method. As shown in
Table 3, the chemical hardness for the reactants is almost
the same, but the electronic chemical potential value of 10
is higher than that of 4. Therefore, charge transfer is expect-
ed to take place from isoquinolinium ylide 10 to 4. Also, the
comparison of the nucleophilicity and the electrophilicity
of the reactants showed that the dipolar species 10 would
act as the nucleophile in this cycloaddition reaction.
Figure 2 X-ray crystal structure of compound 8e
The 13C NMR spectra of compounds 8a–j showed five
signals above  = 160 ppm. Two of these signals which ap-
pear between  = 160–170 ppm are assigned to the ester
C=O groups, and two of the remaining peaks appearing
above  = 190 ppm are attributed to the ketone carbonyl
groups. In order to assign the last signal appearing above  =
190 ppm, we turned to DFT calculations at the b3lyp/6-
311+g(d,p) level of theory.12 Thus, the NMR calculations
performed to estimate the chemical shifts of the five 13C
signals in compound 8e that appear above  = 160 ppm are
shown in Figure 3.
Table 3 Frontier MO Energies and Reactivity Descriptors for Reactants
4 and 10 Calculated at the b3lyp/6-311+G(d,p) Level of Theorya
Comp EHOMO
ELUMO

η
N

165.7 (170.9)
MeO
198.3 (203.2)
O
10
4
–5.20
–6.32
–2.42
–3.54
–3.80
–4.93
1.395
1.390
4.24
3.17
5.19
8.74
O
O
2
O
193.3 (197.5)
4
161.5 (166.2)
5
p-Tol
a All energetics are given in eV.
1
MeO
N
3
190.0 (197.4)
A DFT diagram for mechanistic rationalization of the re-
gioselective nonconcerted formation of product 8 is given
in Figure 5. It is presumed that initially the reaction of iso-
quinoline (5) and phenacyl bromide (6a) generates the iso-
quinolinium salt (7), which is converted into the isoquino-
linium ylide (10) by Et3N. A nonconcerted regioselective ad-
dition reaction occurs between the electron deficient C2–
C3  bond of cyclopentadienone and the isoquinolinium
ylide to afford the zwitterionic intermediate 11. This inter-
mediate is converted into the heptacyclic pyrrolo[2,1-a]iso-
quinoline 8.
8e
Figure 3 Comparison of the experimental (and theoretical) values of
13C NMR chemical shifts (in ppm) for the five low-field signals (between
 = 160–200 ppm) observed in the 13C NMR spectrum of compound 8e
The frontier molecular orbital diagram for carbonyl-sta-
bilized isoquinolinium ylide 10 and cyclopentadienone 4 is
shown in Figure 4. The HOMO–LUMO energy levels are giv-
en in eV. According to this diagram, the dipolar cycloaddi-
tion reaction between 4 and 10 is controlled by the orbital
energy of isoquinolinium ylides.13
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
I. Yavari et al.
Letter
Synlett
O
O
N
TS1
Z
Ar
Z
5.60
kcal/mol
O
O
N
O
COAr
Z
Ar
Z
Z
Z
N
TS1
+
10
4
Reactants
E = 0 kcal/mol
TS2
– 3.01
kcal/mol
O
O
N
Z
Ar
Z
– 5.21
kcal/mol
intermediate 11
O
Z
O
Ar
Z
– 9.81
kcal/mol
11
N
product 8
Z = CO2Me
Ar = p-Tol
8
Reaction progress
Figure 5 DFT diagram for mechanistic rationalization of the regioselective nonconcerted formation of product 8. Relative energies (ΔE) for cycloaddi-
tion reaction are calculated according to reactants whose E = –1932.777495 Hartree at b3lyp/6-311+G(d,p) level of theory.
In summary, we have developed a regio- and diastereo-
selective synthesis of functionalized 5a,5b-dihydro-
5H,13H-naphtho[1′′,8′′:4′,5′,6′]pentaleno[1′:3,4]pyrrolo[2,1-
a]-isoquinolin-5-ones via 1,3-dipolar cycloaddition of 7,9-
bis(alkoxycabonyl)-8H-cyclopent[a]acenaphthylen-8-ones
with carbonyl-stabilized isoquinolinium ylides, derived
from isoquinoline and phenacyl bromides in the presence
of Et3N in MeCN. Based on DFT calculations at b3lyp/6-
311+g(d,p) level of theory, a nonconcerted mechanism is
proposed to explain the selectivity of this reaction. The
methodology reported here may serve as a convenient
strategy to create a wide range of functionalized heptacy-
clic pyrrolo[2,1-a]isoquinoline derivatives.
(7) (a) Argyropoulos, N. G.; Alexandrou, N. E. J. Heterocycl. Chem.
1979, 16, 731. (b) Tsatsaroni, E. G.; Argyropoulos, N. G.;
Alexandrou, N. E.; Houndas, A.; Terzis, A. J. Heterocycl. Chem.
1984, 21, 701. (c) Tsatsaroni, E. G.; Argyropoulos, N. G.;
Alexandrou, N. E.; Houndas, A.; Terzis, A. J. Heterocycl. Chem.
1984, 21, 1405.
(8) (a) Shi, R.-G.; Sun, J.; Yan, C.-G. ACS Omega 2017, 2, 7820. (b) An,
J.; Yang, Q. Q.; Wang, Q.; Xiao, W. J. Tetrahedron Lett. 2013, 54,
3834. (c) Fernández, N.; Carrillo, L.; Vicario, J. L.; Badia, D.;
Reyes, E. Chem. Commun. 2011, 47, 12313. (d) Ruano, J. L. G.;
Fraile, A.; Martin, M. R.; Gonzalez, G.; Fajardo, C.; Martin-Castro,
A. M. J. Org. Chem. 2011, 76, 3296. (e) Peng, W.; Zhu, S. J. Chem.
Soc., Perkin Trans. 1 2001, 3204.
(9) (a) Allen, C. F. H.; Van Allan, J. A. J. Org. Chem. 1952, 17, 845.
(b) Craig, J. T.; Robins, M. D. W. Aust. J. Chem. 1968, 21, 2237.
(10) Typical Procedure for the Preparation of 8
To a stirred mixture of N-substituted isoquinolinium salts 7 (1.0
mmol) and Et3N (1.1 mmol) in MeCN (6.0 mL) was added cyclo-
pentadienone 4 (1 mmol),9a and the resulting mixture was
stirred at 80 °C for 3 h. After completion of the reaction (TLC
monitoring), the mixture was filtered, and the precipitate was
washed with cold MeCN and n-hexane to afford the products
8a–j.
Dimethyl 4-Benzoyl-5-oxo-4H,12cH-naphtho-[1′′,8′′:4′,5′,6′]-
pentaleno[1′:3,4]pyrrolo[2,1-a]isoquinoline-4a,6(5H)-dicar-
boxylate (8a)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706750. SuprtigInfrmatioSnuprtigInfrmation
References and Notes
(1) Chapman, O. L.; McIntosh, C. L. J. Chem. Soc., Chem. Commun.
1971, 770.
(2) Pal, R.; Mukherjee, S.; Chandrasekhar, S.; Guru, R. T. N. J. Phys.
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Orange crystals; yield 0.487 g (86%); mp 224–225 °C. IR (KBr):
3061, 2976, 1742, 1730, 1680, 1608, 1020 cm–1 1H NMR:  =
.
3.51 (s, 3 H), 3.86 (s, 3 H), 4.82 (d, J = 7.3 Hz, 1 H), 4.93 (s, 1 H),
5.26 (d, J = 7.3 Hz, 1 H), 6.07 (t, J = 7.3 Hz, 1 H), 6.13 (s, 1 H), 6.37
(d, J = 7.5 Hz, 1 H), 6.75 (d, J = 7.3 Hz, 1 H), 6.83 (t, J = 7.3 Hz, 1
H), 7.50 (t, J = 7.0 Hz, 1 H), 7.56 (t, J = 7.0 Hz, 1 H), 7.62 (d, J = 7.0
Hz, 2 H), 7.78 (d, J = 7.0 Hz, 1 H), 7.84 (t, J = 8.0 Hz, 1 H), 8.00 (t, J
= 8.0 Hz, 2 H), 8.15 (d, J = 8.0 Hz, 2 H), 8.27 (d, J = 7.0 Hz, 1 H). 13
NMR:  = 52.0 (MeO), 52.6 (MeO), 71.7 (CH), 73.1 (C), 73.7 (CH),
C
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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I. Yavari et al.
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75.0 (C), 103.0 (CH), 121.7 (CH), 123.4 (C) 124.3 (CH), 124.5 (2
CH), 124.8 (C), 125.7 (CH), 126.1 (CH), 127.9 (CH), 128.2 (CH),
128.8 (2 CH), 129.0 (CH), 129.1 (CH), 129.2 (CH), 130.6 (C),
130.7 (C), 131.0 (CH), 132.2 (C), 133.8 (CH), 135.3 (C), 135.4
(CH), 139.1 (C), 141.9 (C), 161.5 (C = O), 165.7 (C = O), 190.0 (C),
193.7 (C = O), 198.2 (C = O). MS (EI, 70 eV): m/z (%) = 567 (4)
[M+], 437 (50), 338 (31), 301 (54), 279 (36), 244 (45), 203 (18),
187 (27), 105 (100). Anal. Calcd for C36H25NO6 (567.60): C,
76.18; H, 4.44; N, 2.47. Found: C, 75.88; H, 4.46; N, 2.46.
(11) X-ray Crystal-Structure Determination of 8e
B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.;
Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.;
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CCDC 1969492 contains the supplementary crystallographic
data for this paper (structure 8e). The data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures..
(12) (a) Calculations
All calculations in this paper were carried out with Gaussian 09
package12a by using the DFT method. Through the comparison
of theoretical and experimental data, obtained from X-ray crys-
tallography, we found that b3lyp/6-311+g(d,p)12b,c results
were in best agreement with the experimental data. These
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dihedral angles. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.;
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E