Visible-light photoredox catalyzed synthesis of pyrroloisoquinolines via organocatalytic oxidation/ [3 + 2] cycloaddition/oxidative aromatization reaction cascade with Rose Bengal

Article abstract of DOI:10.3762/bjoc.10.122

Pyrrolo[2,1-a]isoquinoline alkaloids have been prepared via a visible light photoredox catalyzed oxidation/[3 + 2] cycloaddition/ oxidative aromatization cascade using Rose Bengal as an organo-photocatalyst. A variety of pyrroloisoquinolines have been obtained in good yields under mild and metal-free reaction conditions.

Full text of DOI:10.3762/bjoc.10.122

Visible-light photoredox catalyzed synthesis of
pyrroloisoquinolines via organocatalytic oxidation/
[3 + 2] cycloaddition/oxidative aromatization
reaction cascade with Rose Bengal
Carlos Vila, Jonathan Lau and Magnus Rueping*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1233–1238.
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, D-52074 Aachen, Germany
doi:10.3762/bjoc.10.122
Received: 20 February 2014
Accepted: 30 April 2014
Published: 27 May 2014
Email:
Magnus Rueping* - magnus.rueping@rwth-aachen.de
* Corresponding author
This article is part of the Thematic Series "Organic synthesis using
photoredox catalysis".
Keywords:
alkaloids; [3 + 2] cycloaddition; organocatalysis; oxidation;
photochemistry; photoredox catalysis; Rose Bengal; visible-light
Guest Editor: A. G. Griesbeck
© 2014 Vila et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Pyrrolo[2,1-a]isoquinoline alkaloids have been prepared via a visible light photoredox catalyzed oxidation/[3 + 2] cycloaddition/
oxidative aromatization cascade using Rose Bengal as an organo-photocatalyst. A variety of pyrroloisoquinolines have been
obtained in good yields under mild and metal-free reaction conditions.
Introduction
Pyrrolo[2,1-a]isoquinolines constitute the core structure of the permits the synthesis of structural complex molecules in a
natural products family lamellarin alkaloids (Figure 1) [1-4]. straightforward way and has been used for the efficient syn-
These alkaloids display numerous biological activities such as thesis of this type of compounds [22-26]. Recently, several
inhibitor of human topoisomerase I by lamellarin D [5] or inhi- metal mediated syntheses using a [3 + 2] cycloaddition reaction
bition of HIV integrase by lamellarin α-20-sulfate [6,7]. More- have been described in the literature. Porco Jr. et al. [27]
over lamellarin I and lamellarin K also showed potential anti- described a silver-catalyzed cycloisomerization/dipolar cyclo-
tumor activities [8,9]. Due to their potential biological activi- addition for the synthesis of the pyrrolo[2,1-a]isoquinolines.
ties, the synthesis of pyrrolo[2,1-a]isoquinolines has become a Wang and co-workers described a copper catalyzed
very interesting, important and attractive goal in organic syn- oxidation/[3 + 2] cycloaddition/aromatization cascade [28].
thesis [10-20]. For example, dipolar [3 + 2] cycloaddition using Also, Xiao disclosed a very elegant oxidation/[3 + 2] cyclo-
azomethine ylides [21] is a powerful class of reactions that addition/aromatization cascade catalyzed by [Ru(bpy)3]3+ under
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Beilstein J. Org. Chem. 2014, 10, 1233–1238.
irradiation with visible light [29]. In this context, very recently Results and Discussion
Zhao reported the same reaction using C60-Bodipy hybrids [30] Initially, we focused on the reaction between methyl dihy-
and porous material immobilized iodo-Bodipy [31] as photocat- droisoquinoline ester 1a and N-methylmaleimide (2a) catalyzed
alysts, obtaining in both cases good yields for different by Rose Bengal. Although the [3 + 2] cycloaddition occurs
pyrrolo[2,1-a]isoquinolines. Finally, Lu presented in 2013 a smoothly in the presence of Rose Bengal (5 mol %) in acetoni-
dirhodium complex for the synthesis of these compounds [32]. trile under irradiation with visible light, the reaction was not
Despite these elegant and important syntheses of pyrrolo[2,1- selective affording the dihydropyrrolo[2,1-a]isoquinoline 3aa in
a]isoquinolines through dipolar [3 + 2] cycloaddition, the devel- 35% yield and the hexahydropyrrolo[2,1-a]isoquinoline 4aa in
opment of metal-free syntheses using visible light photoredox 26% yield, after column chromatography (Scheme 1).
catalysis with simple organic dyes remained unexplored.
Visible-light photoredox catalysis has emerged as an important In order to improve the selectivity of the reaction to the aroma-
field and has attracted increasing attention in recent years [33- tized product 3aa, N-bromosuccinimide was added to the reac-
42]. Thus, in the last years spectacular advances in visible-light tion mixture when the starting materials were completely
photoredox catalysis have been made and this kind of catalysis consumed [29-31,73]. In this case the desired product 3aa was
has become a powerful tool in organic synthesis. In this context, obtained in 72% yield (Table 1, entry 1). Other organic dyes
the use of organic dyes as photoredox catalysts [40-42] has been such as Rhodamine B or Eosin Y were less efficient compared
demonstrated by several groups [43-61] and became a useful to Rose Bengal (Table 1, entries 2 and 3, respectively). Several
alternative to the inorganic photoredox catalysts that are expen- solvents were tested without an improvement in the yield of the
sive and sometimes toxic. The organic dyes have very impor- product (Table 1, entries 4–9). Finally, after tuning the relative
tant qualities such as being inexpensive, environmentally amounts of the reagents, the product 3aa was isolated in 76%
friendly and easy to handle. As a part of our ongoing research yield (Table 1, entry 12).
on photoredox catalysis [62-72], we herein present a synthesis
of pyrrolo[2,1-a]isoquinolines through an oxidation/[3+2] With the optimal conditions in hand, we examined the substrate
cycloaddition/aromatization cascade catalyzed by Rose Bengal scope for the photoreaction catalyzed by Rose Bengal
under irradiation with green LEDs.
(Scheme 2). Various tetrahydroisoquinolines with different
Figure 1: Representative examples of lamellarin alkaloids.
Scheme 1: Photocatalytic metal free construction of pyrrolo[2,1-a]isoquinolines.
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Beilstein J. Org. Chem. 2014, 10, 1233–1238.
Table 1: Optimization of the reaction conditions.a
Entry
Catalyst
Solvent
Yield (%)b
1
Rose Bengal
Rhodamine B
Eosin Y
CH3CN
CH3CN
CH3CN
THF
72
11
40
29
26
14
65
52
16
64
60
76
2
3
4
Rose Bengal
Rose Bengal
Rose Bengal
Rose Bengal
Rose Bengal
Rose Bengal
Rose Bengal
Rose Bengal
Rose Bengal
5
CH2Cl2
toluene
DMF
6
7
8
MeOH
EtOAc
CH3CN
CH3CN
CH3CN
9
10c
11d
12e
aReaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), organic dye (5 mol %), solvent (1 mL), green LEDs irradiation for 24 hours. NBS (1.1 equiv) was
added to the reaction mixture and stirring was continued for 1 hour. bYields of the isolated products after column chromatography. c1.25 equiv of 1a
was used. d1.25 equiv of 2a was used. e1.1 equiv of 1a was used.
Scheme 2: Evaluation of the substrate scope.
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Beilstein J. Org. Chem. 2014, 10, 1233–1238.
Scheme 3: Evaluation of the substrate scope with activated alkynes.
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ethyl ester (1b), tert-butyl ester (1c), cyano (1d) or aromatic
ketone (1e) were reacted with N-methylmaleimide (2a) and
gave the corresponding products 3 in moderate to good yields.
In addition, different N-substituted maleimides were tested
under the optimized reaction conditions to give the corres-
ponding products with good yields. Incorporation of methoxy
groups at C-6 and C-7 in the dihydroisoquinoline core was well
tolerated, affording the corresponding product 3fa in 68% yield.
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To demonstrate the synthetic utility of the oxidation/[3 + 2]
cycloaddition/aromatization cascade we examined other dipo-
larophiles such as activated alkynes 5. In this case, the addition
of NBS was not necessary, and the corresponding products 6
were isolated in moderate yields (Scheme 3).
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Conclusion
In conclusion, we have developed a metal-free photoredox oxi-
dation/[3 + 2] dipolar cycloaddition/oxidative aromatization
cascade catalyzed by Rose Bengal using visible-light. This
protocol offers a “green” and straightforward synthesis of
pyrrolo[2,1-a]isoquinolines starting from readily available
maleimides and tetrahydroisoquinolines. Further investigations
to expand the scope and potential of this methodology are
underway in our laboratory.
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Supporting Information
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Supporting Information File 1
Experimental details and characterization of the synthesized
compounds.
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