Chlorophyll-catalyzed tandem oxidation /[3+2] cycloaddition reactions toward the construction of pyrrolo[2,1-a]isoquinolines under visible light

Article abstract of DOI:10.1016/j.jphotochem.2020.112877

Chlorophyll as a green, cheap, and affordable natural pigment was used in the one-pot synthesis of pyrrolo[2,1-a]isoquinoline scaffold under visible light. This photocatalytic approach has handled oxidation/[3 + 2] cycloaddition/aromatization cascade reac

Full text of DOI:10.1016/j.jphotochem.2020.112877

Journal of Photochemistry & Photobiology, A: Chemistry 404 (2021) 112877
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Journal of Photochemistry & Photobiology, A: Chemistry
journal homepage: www.elsevier.com/locate/jphotochem
Chlorophyll-catalyzed tandem oxidation /[3+2] cycloaddition reactions
toward the construction of pyrrolo[2,1-a]isoquinolines under visible light
Mehdi Koohgard, Mona Hosseini-Sarvari*
Department of Chemistry, Shiraz University, Shiraz, 7194684795, Iran
A R T I C L E I N F O
A B S T R A C T
Keywords:
Chlorophyll as a green, cheap, and affordable natural pigment was used in the one-pot synthesis of pyrrolo[2,1-a]
isoquinoline scaffold under visible light. This photocatalytic approach has handled oxidation/[3 + 2] cycload-
dition/aromatization cascade reaction using air as the final oxidant. Under this condition, a vast variety of N-
substituted tetrahydroisoquinolines were treated with dipolarophiles in good to excellent yields.
Chlorophyll
Green chemistry
[3+2] Cycloaddition
Pyrrolo[2,1-a]isoquinolines
Visible light
1. Introduction
Although Ru (II) and Ir (III) polypyridine are versatile effective
photocatalysts, some drawbacks such as toxicity, high price ([Ru(bpy)3]
After a great milestone in 2008 [1,2], the photoinduced electron
transfer (PET) process was extensively followed as an efficient, envi-
ronmentally benign, and versatile strategy to construct the complex
scaffolds under visible light [3,4]. Thus, in recent years tremendous
advances in the field of visible-light-driven photoredox catalysis have
been achieved. In this context, photocatalytic reaction based on inor-
ganic complexes, e.g., Ru(II) and Ir (III) polypyridine turned out to be
robust alternative tools in current synthetic chemistry [5–7].
Cl2; 1 kg ~ 122000 USD, from Sigmaaldrich website) and difficult
separation are associated with Ru(II), Ir (III) polypyridine photo-
catalysis. In comparison with these inorganic complexes, chlorophyll is
cheap (1 kg ~ 45-60 USD; chlorophyll extracted powder, the price is
from commercial website), safe, biodegradable, and abundant natural
inorganic complex. Considering some environmental problems associ-
ated with using organic dyes [13] (e.g. eosin Y: 25 g = 168.0 USD and
methylene blue: 25 g = 78.0 USD, www.sigmaaldrich.com), chlorophyll
as natural pigment might also be a low-price alternative. Redox poten-
tials and selected photophysical properties of these photocatalysts have
been summarized in Fig. 1.
Chlorophyll has known as the most abundant natural photocatalyst
in our world which triggers the PET process toward the synthesis of
carbohydrates in photosynthesis. Hence, green leave is an efficient fac-
tory for solar energy conversion by using this natural inorganic complex
[8,9]. Up to now, six types of chlorophylls (a-f) have been known which
chlorophyll-a is the most abundant type of chlorophyll in nature [10].
Inspired by photosynthesis in green plants, vast efforts on artificial
photosynthesis and solar fuels are going on [11]. Moreover, chlorophyll
as a safe, cheap, and natural pigment has been applied in modern
luminescence materials, cosmetic, food, and textile industry [9]. How-
ever, there are just two reports to survey the potential of this natural
photosensitizer in the organic transformations. First, Boyer et al. re-
ported the PET process for polymerization via chlorophyll, in 2015 [11].
Then, He et al. developed the chlorophyll-catalyzed synthesis of tetra-
hydroquinolines through triplet energy transfer under visible light, in
2017 [12]. Hence, it is highly demanded to explore the potential of this
green and efficient photosensitizer in the more organic transformations.
Compounds containing pyrrolo[2,1-a]isoquinoline have been found
to be very prominent building blocks in synthetic chemistry and natural
compounds due to several biological activities like anti-depressant [17]
and cardiotonics [18–20]. Other alkaloids containing this scaffold, ma-
rine lamellarin alkaloids, shows prominent pharmacological properties.
For example, lamellarin I and lamellarin K exhibit the competency of
antitumor activities [21,22] and lamellarin
α-20-sulfate inhibits HIV
integrase selectively [23,24]. In this regard, some preparation methods
of pyrrolo[2,1-a]isoquinoline scaffolds have been established so far [25,
26]. Early methods went through Diels-Alder cycloaddition, oxidative
dimerization, and double-barreled Heck cyclization [27]. Later, due to
facility and atom economy, a tandem reaction based on dipolar [3 + 2]
cycloadditions between azomethines and active alkenes was established
as an effective straightforward strategy for the rapid synthesis of pyrrolo
* Corresponding author.
E-mail address: Hossaini@shirazu.ac.ir (M. Hosseini-Sarvari).
https://doi.org/10.1016/j.jphotochem.2020.112877
Received 23 May 2020; Received in revised form 27 August 2020; Accepted 27 August 2020
Available online 1 September 2020
1010-6030/© 2020 Elsevier B.V. All rights reserved.

M. Koohgard and M. Hosseini-Sarvari
Journal of Photochemistry & Photobiology, A: Chemistry 404 (2021) 112877
Fig. 1. Redox potentials (vs the saturated calomel electrode in acetonitrile) and selected photophysical properties of [Ru(bpy)3](Cl)2 [3] and chlorophyll-a [14–16].
[2,1-a]isoquinoline scaffolds [28–30]. Xiao’s group developed the first
visible-light-driven dipolar [3 + 2] cycloadditions report for the syn-
thesis of pyrrolo[2,1-a]isoquinoline via [Ru(bpy)3]Cl2 as photosensitizer
[31]. Then, some more photosensitizers namely C60-Bodipyhybrids
[32], iodo-Bodipy immobilized on the support [33] and two organic
dyes [27,34] were investigated in this methodology. These protocols
proceeded through single electron transfer (SET) between photoredox
catalyst and N-substituted tetrahydroisoquinoline followed by the stoi-
chiometric addition of extra oxidants such as N-bromosuccinimide
(NBS) which they were usually required to aromatize the pyrrolidines to
the pyrroles.
Model 8452A diode-array spectrophotometer. Elemental analysis was
performed on a 2400 series PerkinElmer analyzer. 1H NMR and 13C NMR
spectra were recorded in DMSO-d6 or CDCl3 using Bruker Avance DPX
FT 250 MHz and Bruker Ultrashield 400 MHz spectrometry respectively,
with TMS as an internal standard (multiplicity: s = singlet, d = doublet, t
= triplet, dd = doublet of doublets, m = multiplet), coupling constants:
Hz). (FT-IR) spectra were obtained by a Shimadzu FT-IR 8300 spectro-
photometer. The products purified by hand-made column chromatog-
raphy: short columns of SiO2 60 (230–400 mesh) in glass columns (1.0
–1.5 cm); 10 ꢀ 20 g of SiO2 per nearly 0.4-gram crude mixture. The re-
actions were monitored by thin-layer chromatography (TLC): silica gel
PolyGram SIL G/UV 254 plates.
2. Experimental
2.2. Extraction of chlorophyll-a
2.1. Materials and methods
Chlorophyll-a extracted from leaves of spinach according to the re-
ported procedure [35,36]. First, fresh leaves of spinach (50 g) were
washed with cold water, cut and crushed. Then, it was extracted with 25
mL of 80 % aqueous acetone (four times). The combined extracts (100
Unless otherwise noted, starting materials were purchased from
Acros and Merck chemical companies and used without further purifi-
cation. UV-Vis absorptions were recorded using a Hewlett-Packard
Scheme 1. The proposed reaction mechanism.
2

M. Koohgard and M. Hosseini-Sarvari
Journal of Photochemistry & Photobiology, A: Chemistry 404 (2021) 112877
Table 1
Table 2
Screening optimization condition for the reaction between 1a and 2aa.
The scope of oxidation/[3 + 2] cycloaddition/aromatization cascade reactiona.
Entry
Solvent
CH3CN
Acetone
THF
Yield 3a/4a (%)[b]
trace/0
12/0
1
2
3
14/0
4
EtOAc
CHCl3
EtOH
9/0
5
0/0
6
0/0
7
DMF
26/0
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
69/0
9[c]
86/0
10[d]
11[e], [c]
12[f], [c]
13[g], [c]
14[h]
15[i], [c]
16[j] [f]
87/0
85/0
92/0
0/0
trace/0
0/0
74
[a] Reaction conditions: Dihydroisoquinoline ester 1a (1.0 mmol), maleimide 2a
(1.0 mmol) and photocatalyst (2.0 mg) in solvent (4.0 mL) was irradiated by 15
W white LED for 30 h at room temperature. [b] Isolated product. [c] 4.0 mg of
photocatalyst [d] 8.0 mg of photocatalyst. [e] 1.0 mmol 1a and 1.2 mmol 2a. [f]
1.2 mmol 1a and 1.0 mmol 2a. [g] In the dark. [h] Without chlorophyll-a. [i] The
degassed reaction mixture was carried out under Ar. [j] 8.0 mg of chopped and
crushed spinach leaves.
mL) were concentrated under vacuum to about 25 mL and washed with
10 mL of hot petroleum ether (three times). The aqueous acetone phase,
containing carotenes and other plant constituents, was removed and
thrown away. The petroleum ether phase was washed with H2O: MeOH
(65:35 v/v) and it was loaded on a silica gel column. The column was
eluted with petroleum ether and then with petroleum ether: n-propanol
(95:5 v/v) to afford chlorophyll-a.
2.3. Typical Procedure for synthesis of Pyrrolo[2,1-a]isoquinoline
derivatives
[a]
Reaction condition: Dihydroisoquinoline 1 (1.2 mmol), dipolarophile 2 (1.0
mmol) and chlorophyll-a (4.0 mg) in toluene (4.0 mL) were irradiated by 15 W
white LED for 30 h at rt, the yield of the isolated product. [b] The value in the
bracket is belonged to [Ru(bpy)3]Cl2-catalyzed [3 + 2] cycloaddition reaction
[31]. [c] The value in the bracket is belonged to methylene blue-catalyzed [3 +
2] cycloaddition reaction [27].
In a test tube, a mixture of dihydro isoquinoline ester 1a (0.263 g, 1.2
mmol), maleimide 2a (0.097 g, 1 mmol), and chlorophyll-a (4.0 mg) in
toluene (4.0 mL) was irradiated under air atmosphere by 15 W white
LED (λ > 410 nm, distance app. 9.0 cm) at rt. The reaction was moni-
tored by TLC and after completion (30 h), the reaction mixture
concentrated under reduced pressure and the residue was purified by
flash column chromatography on silica gel with petroleum ether/ethyl
acetate as eluent (9:1).
followed by oxidation/aromatization, the corresponding pyrrolo[2,1-a]
isoquinoline derivative (3) was provided. Not surprisingly, in situ
generated singlet oxygen or peroxide are highly likely to become
involved in the last step of this reaction.
3. Results and discussion
Our study commenced with the extraction of chlorophyll-a from
spinach leaves as cheap and renewable feedstock. Chlorophyll-a was
extracted and mostly purified by column chromatography according to
the previous reports [35] (See SI, UV-Vis spectrum). Next, one-pot
synthesis of pyrrolo [2, 1-a] isoquinoline was examined through the
treatment between dihydro isoquinoline ester 1a and maleimide 2a
under visible light (Table 1). Accordingly, when the reaction was con-
ducted in CH3CN, EtOH, and CHCl3, no desired products were found
after 30 h under visible light (entries 1, 5, and 6). However, the reaction
exhibited slight progress in acetone, THF, and EtOAc up to 14 % of
dihydropyrrolo[2,1-a]isoquinoline 3a (entries 2, 3, and 4) in the pres-
ence of atmospheric dioxygen as the terminal oxidant. Then, the reac-
tion was performed in DMF and delivered 26 % of 3a without any 4a.
Delightfully, the reaction in toluene showed significant improvement in
the desired product up to 69 % of 3a, upon isolation (entry 8). In com-
parison with most previous reports, this chlorophyll-a-catalyzed dipolar
We envisioned to survey the merit of chlorophyll in this dipolar [3 +
2] cycloadditions and study whether chlorophyll as natural pigment
would afford the criteria of green chemistry such as the tolerance of a
vast range of functional groups, low waste, the decrease in the reaction
time and catalyst amount, and low toxicity. Chlorophyll is known as a
good producer of singlet dioxygen through triplet energy transfer (TET)
[37,38]. So, based on related works [12,31], we hypothesized a plau-
sible mechanism to handle the reaction as shown in Scheme 1. After light
irradiation, chlorophyll-a becomes excited (chlorophyll-a*) and this
photosensitizer transfers its energy to the ground state of molecular
oxygen, generating the singlet oxygen. Then, the singlet oxygen oxidizes
N-substituted tetrahydroisoquinoline (1) through the SET process to
generate a radical cation (I) followed by two steps affording azomethine
ylide (III). Subsequently, azomethine ylide (III) undergoes the [3 + 2]
cycloaddition with dipolarophile to afford pyrrolidine cycloadduct (4),
3

M. Koohgard and M. Hosseini-Sarvari
Journal of Photochemistry & Photobiology, A: Chemistry 404 (2021) 112877
Table 3
The scope of oxidation/[3 + 2] cycloaddition/aromatization cascade reactiona.
[a]Reaction condition: Dihydroisoquinoline 1 (1.2 mmol), dipolarophile 2 (1.0 mmol) and chlorophyll-a (4.0 mg) in toluene (4.0 mL) were irradiated by 15 W white LED
for 30 h at rt, the yield of the isolated product. bThe value in the bracket is belonged to [Ru(bpy)3]Cl2-catalyzed [3 + 2] cycloaddition reaction [31]. [c] The value in the
bracket is belonged to methylene blue-catalyzed [3 + 2] cycloaddition reaction [27].
[3 + 2] cycloadditions did not need to add any extra oxidant to
aromatize the pyrrolidine ring (4a). When the photocatalyst amount was
enhanced to 4.0 mg and 8.0 mg, the reaction yielded 86 % and 87 % of
3a products, respectively (entries 9 and 10). Besides, when we changed
the molar ratio of substrates (1.2 equiv. and 1.0 equiv.) the yield of 3a
increased to 92 %, upon isolation (entries 11 and 12). So, 4.0 mg of
chlorophyll-a and 1.2 equiv. of 1a substrate were selected as optimum
values. Besides, when the reaction was separately carried out in the
absence of the visible light, chlorophyll-a, and dioxygen, corresponding
products were not observed (entries 13-15). Hence, photocatalyst, light,
and molecular oxygen were critical for this process. Interestingly, when
the reaction was performed by using chopped and crushed spinach
leaves, 74 % of the target product was isolated (entry 16). However, to
remove the effect of other plant constituents, the extracted chlorophyll
was used in the next reactions as photocatalyst.
that while the reaction for N-substituted tetrahydroisoquinolines
bearing electron-withdrawing groups proceeded with good to excellent
yields (3 cg, 3 ch, and 3 dh), the reaction was shut down by tetrahy-
droisoquinolines bearing propyl (1e). Hence, the presence of an
electron-withdrawing group on N-substituted tetrahydroisoquinolines is
essential for the progress of the reaction. Notably, in the case of un-
symmetrical dipolarphiles (2c, 2d, and 2f) the reaction displayed
regioselectivity in products that are in line with the previous reaction
catalyzed by [Ru(bpy)3]Cl2 [31]. Also, for both symmetrical and un-
symmetrical alkynes, chlorophyll-a- catalyzed reaction revealed better
efficiency than [Ru(bpy)3]Cl2-catalyzed [3 + 2] reaction (3ae and 3af).
We also surveyed the scope of N-substituted maleimides treated with
dihydro isoquinoline ester and the results were demonstrated in Table 3.
Accordingly, N-aryl maleimide bearing either electron-withdrawing or
electron-donating groups were manipulated with good to excellent
product yields (3b-3 g). Varied functional groups such as -CF3, -NO2,
-CN, -OCH3, and halogen could be well tolerated under the optimized
condition (3c-3 g). Moreover, N-alkyl maleimide containing isobutyl,
cyclohexyl, and benzyl resulted in excellent yields in this condition (3h-
3 j). Moreover, to investigate the electronic impact of substitutions on 1,
two dihydro isoquinoline core incorporating MeO and Br were examined
under optimized condition. The reaction condition well tolerated these
substrates and provided 87 % and 89 % of corresponding products,
respectively (3k and 3 l). So, the electronic modification of dihydro
isoquinoline can be accomplished. Noteworthy, a comparison between
To survey the synthetic potential of this procedure, we then
embarked upon the investigation of the generality and scope under our
optimized reaction condition (Table 2). First, we examined other dipo-
larophiles in this oxidation/[3
+ 2] cycloaddition/aromatization
cascade reaction employing 1,4-anthraquinone, acrylonitrile, nitro-
olefin, activated alkynes, and maleimides. This procedure appeared
completely general concerning various dipolarophiles and 62 % to 91%
of corresponding products were obtained, upon isolation (3ab-3af).
Then, other N-substituted tetrahydroisoquinolines incorporating nitrile,
ester, ketone, and alkyl were tested in the reaction. The results revealed
4

M. Koohgard and M. Hosseini-Sarvari
Journal of Photochemistry & Photobiology, A: Chemistry 404 (2021) 112877
Fig. 2. Control experiments in the presence of TEMPO (a) and DABCO (b).
Scheme 2. Oxidation/[3 + 2] cycloaddition/aromatization cascade reaction
under sun light (a), gram-scale reaction (b).
Fig. 3. “On/off” LED irradiation experiment, 1H NMR yields of 3a using 1,3,5-
the reaction.
trimethoxybenzene as an internal standard.
Then, by using typical condition, a “light/dark” experiment was
performed and the product yield was monitored during the interval on/
off light irritation after every 4 h (Fig. 3). Accordingly, the product
formation proceeded through the periods of light irradiation which
these results might support the mechanism pictured in Scheme 2.
Finally, to validate the synthetic utility of this method, we experi-
mented with sunlight as well as a gram-scale reaction, and the results
were summarized in Scheme 2. A typical reaction was carried out under
sunlight irradiation (two consecutive sunny days at Shiraz University,
May. 27,28 2019, 29◦59′ north latitude and 52◦58′ east longitude, 1500
m above the sea level); the reaction proceeded in a shorter time (20 h)
and slightly higher yield (Scheme 2a). Also, the gram-scale reaction
demonstrated this chlorophyll-based photocatalysis kept high efficiency
even for a large-scale experiment (Scheme 2b).
some obtained results with [Ru(bpy)3]Cl2-catalyzed (3ae, 3af, and 3b)
and methylene blue-catalyzed (3ab, 3af, 3a, and 3b) [3 + 2] cycload-
dition reaction [27,31] revealed that chlorophyll as a green, affordable
and natural inorganic complex provides high efficiency in this reaction.
Next, two control experiments were performed to verify the radical
mechanism, and the singlet oxygen is involved in the reaction. First, the
model reaction was carried out in the presence of 1.2 mmol of a radical
scavenger, (2,2,6,6-tetramethyl piperidine-1-yl)oxyl, known as TEMPO,
and this addition almost completely suppressed the generation of the
corresponding product (Fig. 2a). Furthermore, the various amount of
1,4-diazabicyclo[2.2.2]octane (DABCO) as a quencher of singlet oxygen
were added to the reaction vessel, followed by measuring the product
yields using 1HNMR at three given times. As depicted in Fig. 2b, by
increasing the amount of singlet oxygen quencher, the path of the target
product was gradually suppressed. Finally, the reaction was shut down
after the addition of 1.2 mmol DABCO. According to these results, a
radical pathway and singlet oxygen are highly likely to associate with
4. Conclusions
In conclusion, a sustainable, effective, and affordable procedure to
5

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Journal of Photochemistry & Photobiology, A: Chemistry 404 (2021) 112877
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authors certify that they have participated sufficiently in the work to
take public responsibility for the content, including participation in the
concept, design, analysis, writing, or revision of the manuscript.
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Conception and design of study: M. Hosseini-Sarvari, M. Koohgard;
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Declaration of Competing Interest
The authors declare that they have no known competing financial
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Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
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