Synthesis of arylsulfonyl-substituted indolo[2,1-a]isoquinolin-6(5H)-one derivatives via a TBAI-catalyzed radical cascade cyclization

Shengxin Zhi,Shuxin Qiu,Shui Yng,Bingyn Hu,Yongsheng Niu,?,Chuchu Hn,Youzhu Yu,Yucho Li,Hongbin Zhi

aCollege of Chemistry &Environmental Engineering,Anyang Institute of Technology,Anyang 455000,China

bDepartment of Chemistry,Guangdong University of Education,Guangzhou 510303,China

cState Key Laboratory of Chemical Oncogenomics and Key Laboratory of Chemical Genomics,Shenzhen Engineering Laboratory of Nano Drug Slow-Release,Shenzhen Graduate School of Peking University,Shenzhen 518055,China

1These authors contributed equally to this work.

ABSTRACT We have developed a metal-free radical cascade reaction of N-substituted 2-aryl indoles with readily available sulfonyl hydrazides for the rapid construction of arylsulfonyl-substituted indolo[2,1-a]isoquinolin-6(5H)-one derivatives.With the TBAI–TBHP catalytic system,a broad series of structurally diverse indolo[2,1-a]isoquinolin-6(5H)-one derivatives were obtained in moderate to excellent yields.The reaction features mild reaction conditions,operationally easiness,scaled-up feasibility,and high functional-group-tolerance.

Keywords:TBAI-catalyzed Metal-free Radical cascade Cyclization Nitrogen-containing heterocycles Fused-indole derivatives

Nitrogen-containing heterocycles,particularly fused-indole derivatives,are prevalent in numerous biologically significant natural products and pharmaceuticals[1-3].As an important species of fused-indole derivatives,indolo[2,1-a]isoquinolines with a fused tetracyclic core structure have drawn considerable attention due to their wide existence in bioactive compounds(Fig.1)[4-12].For example,the indolo[2,1-a]isoquinoline derivatives C-E can act as an inhibitor of tubulin polymerization and estrogen receptor[7-11]and a melatonin antagonist[12],respectively.As a consequence,considerable efforts have been devoted to the construction of this type of polycyclic skeleton[13-21].As for the assembly of indolo[2,1-a]isoquinolin-6(5H)-ones,several elegant works have been reported in the past few years[22-33].For instance,in 2015,Nevado and coworkers developed a one-pot synthesis of CF3-,SCF3-,Ph2(O)P-,N3-containing indolo[2,1-a]isoquinolin-6(5H)-onesviaa radical tandem reaction[25].Subsequently,various functionalized indolo[2,1-a]isoquinolin-6(5H)-ones were successfully obtained with Fe(II)/(III)[26,27],Pd(II)[28,29],or Mn(III)[30,31]as a catalyst,or Ir(III)[32]as a photocatalyst.Despite all these achievements,the vast majority of the reported reactions are mediated by metal catalysts[24],which might limit their further synthetic applications.Therefore,development of a metal-free approach for the preparation of indolo[2,1-a]isoquinolin-6(5H)-ones remains highly desirable.

Synthesis of sulfone-containing compounds is a hot topic in the fields of pharmaceutical chemistry and agrochemistry because of their unique anti-HIV,anticancer,and antibacterial bioactivities[33-36].In addition,sulfones can serve as versatile building blocks in organic synthesis[37-41].Over the past few decades,sulfonyl hydrazides have been widely utilized to install sulfonyl functional group into organic molecules[42-52].Most importantly,they behave as a sulfonyl radical precursor to furnish sulfonyl-substituted heterocyclesviasulfonyl radicalinitiated addition/cyclization cascade reactions[53-62].And a series of sulfonyl-substituted compounds,including oxindoles[53-56],isoquinoline-1,3(2H,4H)-diones[57,58],3,4-dihydroquinolin-2(1H)-ones[59],disubstituted oxazoles[60],thioflavones[56,61]and quinoline-2,4(1H,3H)-diones[56,62]were successively synthesized from sulfonyl hydrazides involving a sulfonyl radical intermediate.As part of our continuing interest in pursuing new methodology for heterocycle compound synthesis[63-69],herein,we report further application of readily accessible sulfonyl hydrazides to generating indolo[2,1-a]isoquinolin-6(5H)-ones withN-substituted 2-aryl indoles as starting materials under metal-free conditions,in which a sulfonyl group was introduced simultaneously.To the best of our knowledge,synthesis of arylsulfonyl-substituted indolo[2,1-a]isoquinolin-6(5H)-ones using sulfonyl hydrazides as free-radical precursors has never been reported.

Fig.1.Selected examples of indolo[2,1-a]isoquinolines.

Our study commenced with the reaction between 2-methyl-1-(3-methyl-2-(p-tolyl)-1H-indol-1-yl)prop–2-en-1-one(1a)and tosylhydrazide(2a),using TBAI(20 mol%)as the catalyst and TBHP(70% solution in water,3.0 equiv.)as the oxidant in CH3CN under air at 80 °C for 6 h(Table 1,entry 1).Gratifyingly,the expected product,indolo[2,1-a]isoquinolin-6(5H)-one 3aa,was obtained in 40% yield.Encouraged by the preliminary results,we next investigated other solvents such as acetone,toluene,DMF,DMAc,1,4-dioxane,THF,EtOH,MeOH andiPrOH,revealing that MeOH was the best choice and afforded sulfone 3aa in a yield of 96%(entries 2–10).Subsequently,several other iodine sources commonly used in radical-triggered reactions were evaluated,all of which showed slightly decreased catalytic activities compared with TBAI(entries 11–14).Therefore,TBAI was chosen for further investigations.Upon testing a series of other oxidants like benzoyl peroxide(BPO),tert–butyl peroxybenzoate(TBPB),di–tert-butylperoxide(DTBP),tert–butyl peroxyacetate,and cumyl hydroperoxide(CHP),TBHP was identified as the optimal one(entries 15–19).When TBHP(in decane)was used instead of TBHP(70% solution in water),the yield of 3aa declined to 66%(entry 20).Ultimately,the control experiments showed that both TBAI and TBHP were essential for this radical cascade reaction(entries 21 and 22).

Table 1 Screening of reaction conditions.a

With the optimized conditions established above(Table 1,entry 9),we explored the scope of arylsulfonyl hydrazides of this raection withN-methacryloyl-2-arylindole 1a(Scheme 1).Satisfyingly,a series of sulfonyl hydrazides bearing an electron-neutral group(e.g.,H),an electron-donating group(e.g.,Me,tBu,OMe),or an electron-withdrawing group(e.g.,F,Cl,Br,CF3)at theparaposition of the aromatic ring were well tolerated,giving the desired products 3aa-3ah in 59%–96% yields.Substrate carrying a strong electron-withdrawing group NO2on the benzene ring also proceeded smoothly,providing the product 3ai in a comparable yield.Additionally,meta-Cl substituted substrate was compatible with this reaction and the yield of the corresponding product 3aj was 74%.Notably,the 2-naphthalenyl(2-Np)counterpart was proven suitable for this transformation,affording indolo[2,1-a]isoquinolin-6(5H)-one 3ak in 80% yield,whose structure was unambiguously confirmed by X-ray diffractional analysis(CCDC:2059158).

Scheme 1.Scope of the arylsulfonyl hydrazides.Reaction conditions:1a(0.2 mmol),2(2 equiv.),TBAI(20 mol%),TBHP(3 equiv.),MeOH(3 mL),air,80°C,6 h.Isolated yields.

Scheme 2.Scope of the N-substituted 2-aryl indoles.Reaction conditions:1(0.2 mmol),2a(2.0 equiv.),TBAI(20 mol%),TBHP(3.0 equiv.),MeOH(3.0 mL),air,80 °C,6 h.Isolated yields.

Next,the scope ofN-substituted 2-aryl indoles was examined for the reaction(Scheme 2).Substrates with a methoxyl,fluoro,chloro,or bromo group locating in the indole ring reacted smoothly with tosylhydrazide 2a,delivering the desired indolo[2,1-a]isoquinolin-6(5H)-one derivatives 3ba-3ea in moderate to excellent yields(62%–96%).And we confirmed the structure of 3da by X-ray crystallography(CCDC:2059157).When 2-aryl indoles containing an ethyl,n-propyl,or phenyl group at the C3 position of the indole ring were employed,the corresponding products 3fa-3ha could be isolated in 61%–75% yields.As expected,2-(4-methylphenyl)-3-phenyl-1H-indole derivatives bearing various functional groups(OMe,F,Cl and Br)in the C3-phenyl were also suitable to the reaction conditions,which could successfully be converted into sulfonated indolo[2,1-a]isoquinolin-6(5H)-ones 3ia-3la in reasonable yields.Finally,other types of substrates,such as 1-(2-(2-fluorophenyl)-3-methyl-1H-indol-1-yl)-2-methylprop-2-en-1-one(1m)and 1-(2-(4-bromophenyl)-3-methyl-1H-indol-1-yl)-2-methylprop-2-en-1-one(1n)also underwent the reaction to provide the target products 3ma and 3na in 74% and 90% yields,respectively.

To demonstrate the synthetic utility of this strategy,a scalability experiment was carried out under the standard conditions,in which a comparable yield(65%)of 3la was observed(Scheme 3a).Furthermore,three notable transformations of 3la were conducted(Scheme 3b).Specifically,Suzuki coupling of bromide 3la with 1-naphthylboronic acid 4 afforded the desired product 5 in an excellent yield.In addition,when treated with 1.5 equiv.of LiAlH4in low temperature,3la could be easily reduced to aminal 6 in a good yield of 88%.Moreover,the synthetic utility of the sulfonated indolo[2,1-a]isoquinolin-6(5H)-one was exemplified by halogenation of 3la with CCl4in the presense 3 equiv.of KOH to produce 7 in a moderate yield.

Scheme 3.Scalability experiment and representative derivatizations of 3la.

To confirm that the reaction was associated with a radical process,the radical quenching experiment was conducted as shown in Scheme 4.When the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyl-oxy(TEMPO)was added in the reaction system under the standard conditions,the cascade reaction was absolutely inhibited and the substrate 1a was recovered in 82% yield,attesting that a radical process is really involved.

Based on the control experiments and the previous reports[53,57],a plausible mechanism for the present radical cascade reaction is proposed in Scheme 5.The reaction is likely to begin with the generation of radicalst-BuO?andt-BuOO?from TBHP through the transformation between I?and I2.Then,sulfonyl hydrazide 2 reacts with the resulting radicals(t-BuO?and/ort-BuOO?)to produce the sulfonyl radical 7 by releasing N2.Following that,addition of sulfonyl radical 7 to the C=C bond of 1a leads to the formation of carbon radical intermediate 8,which subsequently undergoes an intramolecular radical cyclization to afford intermediate 9.Finally,hydrogen abstraction of intermediate 9 occurs in the presence of TBHP,giving sulfonated indolo[2,1-a]isoquinolin-6(5H)-one 3.

Scheme 4.Control experiment.

Scheme 5.Proposed mechanism.

In summary,we have developed an efficient TBAI/TBHPmediated radical cascade reaction that provides a direct access to a broad range of sulfonated indolo[2,1-a]isoquinolin-6(5H)-one derivatives from sulfonyl hydrazides with yields up to 96%.The reaction involves a sulfonyl radical intermediate generated by utilizing TBAI as the catalyst and TBHP as the oxidant.This novel protocol is characterized by metal-free conditions,easily accessible sulfonyl sources,simple operation,and broad functional group tolerance.The sulfonated indolo[2,1-a]isoquinolin-6(5H)-one derivatives should have potential applications in organic and medicinal chemistry.

Declaration of competing interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work,there is no professional or other personal interest of any nature or kind in any product,service and/or company that could be construed as influencing the position presented in the manuscript entitled.

Acknowledgments

We thank the State Key Basic Research Program of the People’s Republic of China(No.2018YFC0310900),National Natural Science Foundation of China(Nos.21871018,21801005,21732001),Shenzhen Science and Technology Innovation Committee(Nos.KQTD20190929174023858,JCYJ20180504165454447),Industry and Information Technology Bureau of Shenzhen Municipality(No.201806151622209330),Guangdong Science and Technology Program(No.2017B030314002),Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(No.2019SHIBS0004),and the National Ten Thousand Talent Program(the Leading Talent Tier)for the financial support.In addition,Shengxian Zhai thanks the Science and Technology Project of Henan Province(No.202102310328),the Henan Postdoctoral Foundation and the Postdoctoral Innovation Base of Anyang Institute of Technology for financial support.

Supplementary materials

Supplementary material associated with this article can be found,in the online version,at doi:10.1016/j.cclet.2021.06.081.