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

Lau, Jonathan

Rueping, Magnus

Vila Descals, Carlos

PubMed

Vila, Carlos

Rüping, Magnus

Publikationsserver der RWTH Aachen University

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

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1233Visible-light photoredox catalyzed synthesis ofpyrroloisoquinolines via organocatalytic oxidation/[3 + 2] cycloaddition/oxidative aromatizationreaction cascade with Rose BengalCarlos Vila, Jonathan Lau and Magnus Rueping*Letter Open AccessAddress:Institute of Organic Chemistry, RWTH Aachen University,Landoltweg 1, D-52074 Aachen, GermanyEmail:Magnus Rueping* - magnus.rueping@rwth-aachen.de* Corresponding authorKeywords:alkaloids; [3 + 2] cycloaddition; organocatalysis; oxidation;photochemistry; photoredox catalysis; Rose Bengal; visible-lightBeilstein J. Org. Chem. 2014, 10, 1233–1238.doi:10.3762/bjoc.10.122Received: 20 February 2014Accepted: 30 April 2014Published: 27 May 2014This article is part of the Thematic Series "Organic synthesis usingphotoredox catalysis".Guest Editor: A. G. Griesbeck© 2014 Vila et al; licensee Beilstein-Institut.License and terms: see end of document.AbstractPyrrolo[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 beenobtained in good yields under mild and metal-free reaction conditions.IntroductionPyrrolo[2,1-a]isoquinolines constitute the core structure of thenatural products family lamellarin alkaloids (Figure 1) [1-4].These alkaloids display numerous biological activities such asinhibitor of human topoisomerase I by lamellarin D [5] or inhi-bition of HIV integrase by lamellarin α-20-sulfate [6,7]. More-over lamellarin I and lamellarin K also showed potential anti-tumor activities [8,9]. Due to their potential biological activi-ties, the synthesis of pyrrolo[2,1-a]isoquinolines has become avery interesting, important and attractive goal in organic syn-thesis [10-20]. For example, dipolar [3 + 2] cycloaddition usingazomethine ylides [21] is a powerful class of reactions thatpermits the synthesis of structural complex molecules in astraightforward way and has been used for the efficient syn-thesis of this type of compounds [22-26]. Recently, severalmetal mediated syntheses using a [3 + 2] cycloaddition reactionhave been described in the literature. Porco Jr. et al. [27]described a silver-catalyzed cycloisomerization/dipolar cyclo-addition for the synthesis of the pyrrolo[2,1-a]isoquinolines.Wang and co-workers described a copper catalyzedoxidation/[3 + 2] cycloaddition/aromatization cascade [28].Also, Xiao disclosed a very elegant oxidation/[3 + 2] cyclo-addition/aromatization cascade catalyzed by [Ru(bpy)3]3+ underBeilstein J. Org. Chem. 2014, 10, 1233–1238.1234Figure 1: Representative examples of lamellarin alkaloids.Scheme 1: Photocatalytic metal free construction of pyrrolo[2,1-a]isoquinolines.irradiation with visible light [29]. In this context, very recentlyZhao reported the same reaction using C60-Bodipy hybrids [30]and porous material immobilized iodo-Bodipy [31] as photocat-alysts, obtaining in both cases good yields for differentpyrrolo[2,1-a]isoquinolines. Finally, Lu presented in 2013 adirhodium complex for the synthesis of these compounds [32].Despite these elegant and important syntheses of pyrrolo[2,1-a]isoquinolines through dipolar [3 + 2] cycloaddition, the devel-opment of metal-free syntheses using visible light photoredoxcatalysis with simple organic dyes remained unexplored.Visible-light photoredox catalysis has emerged as an importantfield and has attracted increasing attention in recent years [33-42]. Thus, in the last years spectacular advances in visible-lightphotoredox catalysis have been made and this kind of catalysishas become a powerful tool in organic synthesis. In this context,the use of organic dyes as photoredox catalysts [40-42] has beendemonstrated by several groups [43-61] and became a usefulalternative to the inorganic photoredox catalysts that are expen-sive and sometimes toxic. The organic dyes have very impor-tant qualities such as being inexpensive, environmentallyfriendly and easy to handle. As a part of our ongoing researchon photoredox catalysis [62-72], we herein present a synthesisof pyrrolo[2,1-a]isoquinolines through an oxidation/[3+2]cycloaddition/aromatization cascade catalyzed by Rose Bengalunder irradiation with green LEDs.Results and DiscussionInitially, we focused on the reaction between methyl dihy-droisoquinoline ester 1a and N-methylmaleimide (2a) catalyzedby Rose Bengal. Although the [3 + 2] cycloaddition occurssmoothly in the presence of Rose Bengal (5 mol %) in acetoni-trile under irradiation with visible light, the reaction was notselective affording the dihydropyrrolo[2,1-a]isoquinoline 3aa in35% yield and the hexahydropyrrolo[2,1-a]isoquinoline 4aa in26% yield, after column chromatography (Scheme 1).In order to improve the selectivity of the reaction to the aroma-tized product 3aa, N-bromosuccinimide was added to the reac-tion mixture when the starting materials were completelyconsumed [29-31,73]. In this case the desired product 3aa wasobtained in 72% yield (Table 1, entry 1). Other organic dyessuch as Rhodamine B or Eosin Y were less efficient comparedto Rose Bengal (Table 1, entries 2 and 3, respectively). Severalsolvents were tested without an improvement in the yield of theproduct (Table 1, entries 4–9). Finally, after tuning the relativeamounts of the reagents, the product 3aa was isolated in 76%yield (Table 1, entry 12).With the optimal conditions in hand, we examined the substratescope for the photoreaction catalyzed by Rose Bengal(Scheme 2). Various tetrahydroisoquinolines with differentBeilstein J. Org. Chem. 2014, 10, 1233–1238.1235Table 1: Optimization of the reaction conditions.aEntry Catalyst Solvent Yield (%)b1 Rose Bengal CH3CN 722 Rhodamine B CH3CN 113 Eosin Y CH3CN 404 Rose Bengal THF 295 Rose Bengal CH2Cl2 266 Rose Bengal toluene 147 Rose Bengal DMF 658 Rose Bengal MeOH 529 Rose Bengal EtOAc 1610c Rose Bengal CH3CN 6411d Rose Bengal CH3CN 6012e Rose Bengal CH3CN 76aReaction 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) wasadded to the reaction mixture and stirring was continued for 1 hour. bYields of the isolated products after column chromatography. c1.25 equiv of 1awas used. d1.25 equiv of 2a was used. e1.1 equiv of 1a was used.Scheme 2: Evaluation of the substrate scope.Beilstein J. Org. Chem. 2014, 10, 1233–1238.1236Scheme 3: Evaluation of the substrate scope with activated alkynes.electron-withdrawing groups (R2) such as methyl ester (1a),ethyl ester (1b), tert-butyl ester (1c), cyano (1d) or aromaticketone (1e) were reacted with N-methylmaleimide (2a) andgave the corresponding products 3 in moderate to good yields.In addition, different N-substituted maleimides were testedunder the optimized reaction conditions to give the corres-ponding products with good yields. Incorporation of methoxygroups at C-6 and C-7 in the dihydroisoquinoline core was welltolerated, affording the corresponding product 3fa in 68% yield.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 additionof NBS was not necessary, and the corresponding products 6were isolated in moderate yields (Scheme 3).ConclusionIn conclusion, we have developed a metal-free photoredox oxi-dation/[3 + 2] dipolar cycloaddition/oxidative aromatizationcascade catalyzed by Rose Bengal using visible-light. Thisprotocol offers a “green” and straightforward synthesis ofpyrrolo[2,1-a]isoquinolines starting from readily availablemaleimides and tetrahydroisoquinolines. 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Chem. 2014, 10, 1233–1238.1238License and TermsThis is an Open Access article under the terms of theCreative Commons Attribution License(http://creativecommons.org/licenses/by/2.0), whichpermits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.The license is subject to the Beilstein Journal of OrganicChemistry terms and conditions:(http://www.beilstein-journals.org/bjoc)The definitive version of this article is the electronic onewhich can be found at: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

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

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