Visible-light-induced oxidation/[3+2] cycloaddition/oxidative aromatization sequence: A photocatalytic strategy to construct pyrrolo[2,1-a]isoquinolines

Article abstract of DOI:10.1002/anie.201102306

A ray of sunshine: The title reaction sequence using ethyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)acetates with a series of electron-deficient alkenes and alkynes provides rapid and efficient access to pyrrolo[2,1-a] isoquinolines (see scheme; bpy=2,2′-bipyri

Full text of DOI:10.1002/anie.201102306

DOI: 10.1002/anie.201102306
Photochemistry
Visible-Light-Induced Oxidation/[3+2] Cycloaddition/Oxidative
Aromatization Sequence: A Photocatalytic Strategy To Construct
Pyrrolo[2,1-a]isoquinolines**
You-Quan Zou, Liang-Qiu Lu, Liang Fu, Ning-Jie Chang, Jian Rong, Jia-Rong Chen,
and Wen-Jing Xiao*
The development of new and highly efficient strategies for the
rapid construction of intricate molecular architectures is of
great importance and remains a preeminent goal in current
synthetic chemistry.[1] Compared with traditional stepwise
chemical processes, tandem reactions have proven to be
extremely useful in achieving these goals owing to their high
reaction efficiency, atom economy, and operational simplic-
ity.[2] In this context, a considerable number of tandem
reactions for the synthesis of complex molecular systems have
been established over the past century.[2,3] However, one
fundamental impediment associated with the chemical indus-
tries is the exhaustion and nonrenewal of fossil fuels. The
search for clean and renewable energy[4] in the preparation of
valuable synthetic building blocks and biologically important
molecules has become one of the most challenging tasks in
this century. In this endeavor, photocatalysis using visible
light represents a unique strategy because of its inherent
“green chemistry” features.[5] In 2008 a milestone was reached
in the field of catalysis using visible light when two seminal
publications appeared almost simultaneously: one on direct
asymmetric alkylation of aldehydes,[6] and one on intra-
molecular formal [2+2] cycloaddition.[7] Since then, photo-
chemical synthesis using visible light has received much
attention,[8] and some fundamental chemical transformations
have been elegantly carried out under irradiation with visible
light.[9] Despite these advances, tandem reactions initiated by
visible light remain largely unexplored, and the development
of such methods for the highly efficient and practical synthesis
of natural products and analogues is greatly desirable.
For example, lamellarin alkaloids, a new family of marine
natural products that contain a pyrrolo[2,1-a]isoquinoline
core, were found to exhibit a wide spectrum of biological
activities (Figure 1).[11] For instance, lamellarin D, which was
Figure 1. Representative examples of novel marine natural lamellarin
alkaloids.
isolated from prosobranch mollusk Lamellaria sp., is a potent
inhibitor of human topoisomerase I,[12] and lamellarin a 20-
sulfate is a drug candidate for the inhibition of HIV
integrase.[13] Other members of this family, such as lamellar-
in I and lamellarin K, displayed potential antitumor activi-
ties.[14] This biological activity has made the synthesis of these
compounds attractive, and several straightforward and robust
methods for their syntheses have been established.[15] Notably,
Wang and co-workers have recently disclosed a highly
efficient approach to the core structure of lamellarin by
employing a copper(II)-catalyzed oxidation/[3+2] cycloaddi-
tion/aromatization cascade.[16] As part of our ongoing
research program addressing carbo- and heterocycle-oriented
method development,[17] we herein report a mechanistically
distinct method for the construction of pyrrolo[2,1-a]isoqui-
nolines using a photoredox strategy. We envisioned that ethyl
2-(3,4-dihydroisoquinolin-2(1H)-yl) acetate (1a) could be
oxidized to generate the iminium ion II in the presence of
[Ru(bpy)3]2+ under irradiation by visible light.[5d,e] Subse-
quently, the iminium intermediate II affords 1,3-dipole
azomethine III by a deprotonation process; III then under-
goes [3+2] cycloaddition reactions and sequential oxidation
The vast majority of biologically active molecules and
pharmaceutical compounds contain nitrogen heterocycles.[10]
[*] Y.-Q. Zou, L.-Q. Lu, L. Fu, N.-J. Chang, J. Rong, Dr. J.-R. Chen,
Prof. Dr. W.-J. Xiao
Key Laboratory of Pesticide & Chemical Biology
Ministry of Education, College of Chemistry
Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
Fax: (+86)27-6786-2041
E-mail: wxiao@mail.ccnu.edu.cn
Homepage: http://chem-xiao.ccnu.edu.cn/default.aspx
[**] We are grateful to the National Science Foundation of China
(NO.20872043, 21072069 and 21002036), the National Basic
Research Program of China (2011CB808600), and the Program for
Changjiang Scholars and Innovative Research Team in University
(IRT0953) for support of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102306.
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Communications
delight, the proposed reaction between 1a and
2a does indeed occur in the presence of [Ru-
(bpy)3Cl2] (5 mol%) and dioxygen in DMF
(N,N’-dimethylformamide) under irridation by
visible light to afford dihydropyrrolo[2,1-a]iso-
quinoline 3a and hexahydropyrrolo[2,1-a]iso-
quinoline 4a in 26% and 15% yields, respec-
tively, upon isolation (Table 1, entry 1). Encour-
aged by these results, we then started to
optimize the reaction conditions to improve
the chemical yield. With CH3CN as the solvent,
the yield of 3a was increased to 47%, although
there was still a significant amount of 4a formed
as well (Table 1, entry 2). In order to further
Scheme 1. Photocatalytic oxidation/cycloaddition/aromatization sequence. EWG=elec-
tron-withdrawing group.
improve the reaction efficiency and selectivity,
to form the pyrrolo[2,1-a]isoquinoline (Scheme 1). Although
N-bromosuccinimide (1.1 equiv) was added to the crude
reaction mixture when 2a was completely consumed.
Remarkably, this tandem reaction was completed within 9–
10 hours and gave the corresponding product 3a in high yield
(Table 1, entries 3–5). Under the same reaction conditions,
[Ir(ppy)2(dtbbpy)]PF6 can also catalyze this transformation to
give an 86% yield, but with a prolonged reaction time
(Table 1, entry 6). Interestingly, when the catalyst loading was
reduced to 2.5 mol% or even 1 mol%, the reaction also gave
comparable results (Table 1, entries 7 and 8). Notably no
reaction occurred in the absence of a photocatalyst, such as
visible light or oxygen, thus indicating that the photoredox
catalysis is essential for this tandem process (Table 1,
entries 9–11).
the reductive quenching of the excited species [Ru(bpy)3]2+
*
by tertiary amines has been applied in a few synthetic
methods,[8,9] this strategy, to the best of our knowledge, has
not been examined in a tandem reaction involving a [3+2]
cycloaddition.
Our initial investigations were focused on examining the
feasibility of the reaction of dihydroisoquinoline ester 1a with
N-phenylmaleimide (2a) and optimizing the reaction con-
ditions for application to a variety of dihydroisoquinoline
derivatives and electron-deficient components. To our
Table 1: Optimization of the reaction conditions.[a]
With the optimal reaction conditions established, we then
examined the substrate scope of this tandem reaction. As
highlighted in Table 2, a variety of N-substituted maleimides
2a–2e can react efficiently with 1a to give the corresponding
products in good to excellent yields upon isolation (Table 2,
entries 1–5). The reaction appears quite general with respect
to the dipolarophile components. It was found that the
reaction proceeded smoothly with nitroolefins 2 f–2h bearing
electron-neutral, electron-donating, and electron-withdraw-
ing groups on the aromatic ring and the corresponding
products were obtained in 53–64% yields (Table 2, entries 6–
8). More importantly, other dipolarophiles, such as activated
alkynes, acrylates, and maleic anhydrides, reacted smoothly
even without the addition of NBS (Table 2, entries 9–11).
Notably, this tandem reaction exhibited excellent regioselec-
tivity and only one regioisomer was formed in the reaction of
1a and the unsymmetrical dipolarphiles (e.g. 2h, 2i, etc.). The
structures of products 3h and 3i were unambiguously
established by X-ray crystallographic analysis.[18,19]
Entry
Catalyst
Solvent
t [h]
Yield [%][b]
3a/4a
1
2
5 (5 mol%)
5 (5 mol%)
5 (5 mol%)
5 (5 mol%)
5 (5 mol%)
6 (5 mol%)
5 (2.5 mol%)
5 (1 mol%)
5 (5 mol%)
–
DMF
72
72
9
26/15
47/27
94/0
69/0
60/0
86/0
90/0
90/0
0/0
CH3CN
CH3CN
DMF
3[c]
4[c]
5[c]
6[c]
7[c]
8[c]
9[d]
10[e]
11[f]
10
10
24
13
13
72
72
72
EtOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0/0
0/0
5 (5 mol%)
[a] Reaction conditions: 1a (0.36 mmol), 2a (0.20 mmol), catalyst 5 or 6
(1–5 mol%), O2 balloon, visible-light irradiation, and solvent (3.0 mL).
[b] Yield of the isolated product. [c] NBS (1.1 equiv) was added to the
reaction mixture when 2a was completely consumed, and stirring
continued for another 1 h. [d] Reaction was carried out in the dark.
[e] Reaction was carried out without catalyst. [f] Reaction mixture was
degassed and the reaction was carried out under an inert atmosphere.
bpy=2,2’-bipyridine, dtbbpy=4,4’-di-tert-butyl-2,2’-bipyridine, NBS=N-
bromosuccinimide.
Scheme 2. Reaction system was open to air.
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Angew. Chem. Int. Ed. 2011, 50, 7171 –7175

Table 2: Oxidation/[3+2] cycloaddition/aromatization sequence.[a]
Structural variation in dihy-
droisoquinoline esters can also be
realized without loss in reaction
efficiency. Incorporation of two
methoxy substituents at the C6-
and C7-positions in the dihydro-
isoquinoline, and a bromo group at
the C7-position reveals that elec-
tronic modification of the substrate
can be accomplished (Table 2,
entries 13 and 14). Importantly,
the photocatalytic system also
works well when the oxygen is
replaced by air (Scheme 2).
Entry Dihydroisoquinoline
Dipolarophile 2
Product 3
t
[h]
Yield[b]
[%]
esters 1
1
2
12
94
12.5 81
Notably the cycloadduct 4 f was
isolated when nitroolefins were
3
12.5 68
employed
as
dipolarphiles
(Scheme 3). The formation of 4a
(Table 1, entries 1 and 2) and 4 f
revealed that this tandem reaction
proceeds through [3+2] cycloaddi-
tion with a subsequent oxidative
aromatization. To get more insight
into the mechanism of the present
transformation (Scheme 1), the
kinetic isotopic effect (KIE) was
investigated by the reaction of
deuterated ethyl 2-(3,4-dihydro-
isoquinolin-2(1H)-yl) acetate (1a’)
with nitrostyrene (2 f; Scheme 2).[19]
Results showed that the abstrac-
tion of a hydrogen in the a position
of the radical cation I by the super-
oxide radical anion is 5.7 times
faster than the abstraction of deu-
terium; this result revealed that
this process might play an impor-
tant role in the current visible-
light-induced reaction. A precise
reaction mechanism awaits further
study.
4
5
11
11
94
76
6
15
12
12
24
24
22
64(16)[c]
62(13)[c]
53(11)[c]
52
7
8
9[d]
10[d]
11[d]
In conclusion, we have devel-
oped a photocatalytic tandem oxi-
dation/[3+2] cycloaddition/oxida-
tive aromatization sequence using
visible light. This novel protocol
52
provides
access to biologically important
pyrrolo[2,1-a]isoquinolines in
a rapid and efficient
a
65
highly concise fashion. The appli-
cation of this powerful strategy to
the synthesis of natural products,
lamellarin I and K, and more
detailed mechanistic investigations
are currently underway in our
laboratory.
12
25
51
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Communications
Table 2: (Continued)
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Entry Dihydroisoquinoline
Dipolarophile 2
Product 3
t
[h]
Yield[b]
[%]
esters 1
13
14
24
15
93
89
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Scheme 3. Mechanistic studies.
Experimental Section
Representative procedure: N-Phenylmaleimide (2a; 0.30 mmol) was
added to a mixture of ethyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)
acetate (1a; 0.36 mmol) and [Ru(bpy)3Cl2] (5; 0.015 mmol) in
CH3CN (3.0 mL) under an oxygen atmosphere. The solution was
stirred at room temperature under irridation by visible light (distance
app. 10 cm). After 2a was completely consumed (monitored by TLC),
the light source was removed and N-bromosuccinimide (1.1 equiv)
was added to the reaction mixture. The resulting mixture was stirred
for another 1 h. The crude mixture was concentrated under reduced
pressure and then purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate 10:1) to furnish the desired compound
3a.
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Received: April 3, 2011
Published online: June 22, 2011
Keywords: alkaloids · oxygen · photochemistry ·
.
tandem reactions · visible light
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[20] Structures
of
the
oxidation
products
of
3 f–3h:
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