Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
TBAI/TBHP-Mediated Cascade Cyclization toward Sulfonylated Indeno[1,2‑c]quinolines Jatuporn Meesin,† Manat Pohmakotr,† Vichai Reutrakul,† Darunee Soorukram,† Pawaret Leowanawat,† Saowanit Saithong,‡ and Chutima Kuhakarn*,† †
Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH−CIC), Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand ‡ Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH−CIC), Faculty of Science, Prince of Songkla University, Hat Yai, Songkla 90112, Thailand S Supporting Information *
ABSTRACT: Treatment of ortho-amino-substituted aryldiyne derivatives with sulfonyl hydrazides in the presence of tetrabutylammonium iodide (TBAI) and tert-butyl hydroperoxide (TBHP) led to a cascade cyclization reaction to yield sulfonylated indeno[1,2-c]quinolines in moderate to good yields. The features of the methodology include metal-free reaction, the ease of reagent handling, and a broad functional group tolerance.
T
Scheme 1. Cascade Cyclization Reaction
here are increasingly high demands for an atomeconomical synthesis and straightforward strategy for the construction of highly functionalized carbocyclic and heterocyclic compounds due to their unique physical properties and their applications in several fields.1 One of the attractive synthetic strategies that serves these needs is a cascade or tandem cyclization reaction.2 Through this strategy, compounds with high molecular complexity, including functionalized polycyclic and heterocyclic skeletons, can be constructed in highly efficient way.3 Numerous approaches have been continually developed to access highly functionalized nitrogencontaining tetracyclic molecules of chemical and biological importance via tandem reactions.4 Despite their significance, available synthetic routes to access indene-fused quinoline analogues are rare.5 Therefore, there have been tremendous efforts to search for novel and facile methods for accessing these scaffolds. Sulfone-containing molecules exhibit unique and diverse ranges of behaviors including both chemical and biological features. For instance, the sulfonyl group was found to be a key structural motif in a wide variety of bioactive compounds,6 drug molecules,7 and versatile synthetic intermediates.8 As a consequence, novel and efficient methods for the installation of a sulfonyl motif into organic frameworks to access sulfonylated compounds have received much attention. Recently, Schipper and co-workers reported a copper(II) mediated nucleophilic addition/cascade cyclization reaction of aryl 1,6-diynes with sulfinate salts to allow for the synthesis of sulfonylated tetracyclic compounds [Scheme 1, (a)].9 The reaction was proposed to proceed through a rare ionic mechanism through nucleophilic addition of a sulfinate salt to a Cu(II) activated diyne leading to the formation of two new C−C bonds and a C−S bond formation. © XXXX American Chemical Society
More recently, Jiang and co-workers described visible-light photocatalytic bicyclization of 1,7-enynes with sulfinic acids using eosin Y as a catalyst and the reaction proceeded through a radical process [Scheme 1, (b)].10 The reaction is metal-free and provided a wide range of sulfone-containing benzo[a]fluoren-5-ones. According to these elegant examples as well as our recent report on the chemistry of 2-alkynyl-N,N-dialkylanilines,11 we describe herein tetrabutylammonium iodide (TBAI)/tert-butyl hydroperoxide (TBHP)-mediated the synthesis of sulfonylated indeno[1,2-c]quinolines from orthoamino-substituted aryldiyne derivatives 1 using sulfonyl hydrazides 2 as the sulfur source [Scheme 1, (c)]. The reaction Received: October 19, 2017
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DOI: 10.1021/acs.orglett.7b03246 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
mL, 0.083 M) (Table 1, entry 11). Finally, it is worth noting that the reaction did not occur in the absence of TBAI (Table 1, entry 12). After achieving the optimal reaction conditions (Table 1, entry 11), we next evaluated the scope and the generality of the reaction. First, the reactions of 1a with a collection of sulfonyl hydrazides were explored and the results are summarized in Scheme 2. Under the optimized reaction conditions,
is metal-free and facile, involving the formation of C−S, C−C, and C−N bonds via a cascade strategy and can accommodate a wide range of substrate scopes. Exploratory studies were carried out employing N,Ndimethyl-2-((2-(phenylethynyl)phenyl)ethynyl)aniline (1a) and toluenesulfonyl hydrazide (2a) as benchmarking substrates to screen for optimized reaction conditions. On the basis of our previous report, we first exposed 1a (0.25 mmol) and 2a (5 equiv) to I2 (1.2 equiv), TBHP (6 equiv) in EtOAc at refluxing temperature for 2 h.11 Unfortunately, although 1a was consumed, the crude products showed multiple spots (TLC analysis). Extensive investigations were carried out to search for optimized reactions and the results are summarized in Table 1.
Scheme 2. Scope of Sulfonyl Hydrazide 2
Table 1. Optimization of Reaction Conditionsa
entry
TBAI (equiv)
oxidant
solvent
yieldb (%)
c
1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.0 2.0 1.5 −
TBHP TBHP TBHP TBHP TBHPd H2O2 DTBP TBPB TBHP TBHP TBHP TBHP
EtOAc THF H2O MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOHe MeOHe
46 48 60 74 63 18 0 28 69 64 80 −
1 2c 3c 4 5 6 7 8 9 10 11 12
arenesulfonyl hydrazides bearing electron-donating substituent groups on the phenyl ring including p-CH3 and p-CH3O readily underwent the reaction and gave the corresponding sulfonylated indeno[1,2-c]quinolines 3a−3c in good yields (62−80% yields). The electronic nature of the substituents imposed significant effects on the chemical yields, and in the case of electron-withdrawing substituted arenesulfonyl hydrazides including p-Br, p-Cl, p-NO2, and m-F, the corresponding products 3d−3g were obtained in low to moderate yields (18− 51% yields). Sterically demanding 2,4-dimethylbenzenesulfonyl hydrazide was successfully engaged in the reaction and smoothly gave the desired product 3h in 46% yield. Unfortunately, alkanesulfonyl hydrazides were somewhat incompatible under the reaction conditions. While ethanesulfonyl hydrazide provided product 3i in low yield (24% yield), methanesulfonyl hydrazide failed to yield the desired product; trace amount of 3j was detected (TLC analysis). Next we set out to evaluate the scope of substrates 1 with different substituted patterns and electronic properties on the aniline moiety (R2) and the arylethynyl moiety (R1) toward the sulfonylated indeno[1,2-c]quinoline formation (Scheme 3). A broad range of 1 readily reacted with toluenesulfonyl hydrazide to give access to the corresponding sulfonylated indeno[1,2c]quinolines 3 with structural diversity in acceptable yields (37−89% yields). As depicted in Scheme 3, a collection of substituents on the aniline moiety (R2), including methyl, bromo, chloro and fluoro groups were well tolerated leading to the desired products 3k−3o in good to excellent yields (60− 89% yields). It is worth mentioning here that in cases where products 3 were isolated in poor yields, the reactions gave complex crude mixtures (TLC analysis). Notably, the corresponding C3-sulfonylated indole products were not observed, and in some cases, the starting aryldiynes were recovered in the range of 15−25% yields.11 Electronic characteristics and substituted patterns of substituents on the arylethynyl moiety (R1) did not impede the reaction leading to the desired sulfonylated indeno[1,2c]quinolines 3p−3x in moderate to good yields (57−79% yields). Notably, sterically encumbered α-naphthyl- and 2thienyl-substituted sulfonylated indeno[1,2-c]quinolines 3y and 3z were also successfully prepared in 44% and 37% yields, respectively. Finally, alkylethynyl substrate readily reacted to
a Reaction conditions: 1a (0.25 mmol), 2a (2 equiv), 70% TBHP in H2O (3.0 equiv) in solvent (2 mL), reflux, open air, 2 h. bIsolated yields. cReaction was carried out at 80 °C. dTBHP in decane (5.5 M). e MeOH (3 mL) was employed.
Gratifyingly, the cascade reaction was achieved when molecular iodine was replaced by TBAI. Thus, when 1a (0.25 mmol) and 2a (2 equiv) were treated with TBAI (1.5 equiv) and TBHP (70% in H2O, 3 equiv) and the reaction mixture was stirred in ethyl acetate (EtOAc, 2 mL, 0.125 M) at refluxing temperature for 2 h, the reaction readily took place and the desired tetracyclic indeno[1,2-c]quinoline-3-sulfonylindole 3a was obtained in moderate yield (46% yield) (Table 1, entry 1). The product 3a was identified and characterized by means of spectroscopic techniques and its structure was further confirmed by single-crystal X-ray crystallography (see Supporting Information). Under similar reaction conditions, the reaction performed in either THF or water resulted in slightly better yields (Table 1, entries 2 and 3). The reaction proceeded more efficiently and delivered 74% yield of 3a when the reaction was carried out in MeOH at refluxing temperature (Table 1, entry 4). Next, different types of oxidants including 5.5 M TBHP in decane, 30% aqueous hydrogen peroxide, ditert-butyl peroxide (DTBP), and tert-butyl peroxybenzoate (TBPB), were screened but the results were less satisfactory (Table 1, entries 5−8). A decreased or increased stoichiometry of TBAI did not appreciably effect to the reaction efficiency (Table 1, entries 9 and 10). The best yield (80% yield) of 3a was obtained when the reaction was performed using MeOH (3 B
DOI: 10.1021/acs.orglett.7b03246 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 3. Scope of N,N-Dimethyl-2-((2(arylethynyl)phenyl)ethynyl)aniline Derivatives 1
is proposed as described in Scheme 5. First, TBAI interacts with TBHP to generate radical species which then react with Scheme 5. Plausible Mechanism
sulfonyl hydrazide 2 to generate a sulfonyl radical with the extrusion of nitrogen gas. Next, the sulfonyl radical regioselectively inserts to an alkynyl moiety of 1 producing a vinyl radical intermediate A. Subsequent 5-exo-dig cyclization leads to a vinyl radical intermediate B. Radical-initiated cyclization can proceed into two pathways. In path A, a vinyl carbon radical and an electron of nitrogen atom recombines forming a C−N bond leading to a radical cation intermediate C.13 Alternatively, in path B, nucleophilic addition by the nitrogen lone pair onto the vinyl radical carbon of B leads to a radical-zwitterion intermediate D.14 Both C and D can readily be oxidized by TBHP generating a quinolinium intermediate E. Next, iodide ion promotes dealkylation to finally yield sulfonylated indeno[1,2-c]quinolines 3. In conclusion, we have disclosed a novel and concise synthetic route for the construction of sulfonylated indeno[1,2c]quinolines via a cascade annulation of sulfonyl hydrazide and ortho-amino-substituted aryldiyne derivatives. The reaction is smoothly promoted by TBAI and aqueous TBHP as a primary oxidant under metal-free conditions. Our approach involves concomitant production of C−S, C−C, and C−N bonds leading to two new rings in a single step. A wide range of functionalized substrates are proved to be tolerant and compatible under the reaction conditions providing the desired products in moderate to good yields. Evaluation of biological activities of the synthesized sulfony-containing indeno[1,2c]quinoline derivatives is ongoing in our laboratory.
yield alkyl-substituted sulfonylated indeno[1,2-c]quinoline 3a′ although in low yield (38% yield). In order to shed some light on the reaction mechanism toward an access of sulfonylated indeno[1,2-c]quinoline formation from ortho-amino-substituted aryldiyne derivatives 1, a series of control experiments were carried out (Scheme 4). Scheme 4. Control Experiments
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Consumption of 1a was observed when it was exposed to the standard reaction conditions but in the absence of sulfonyl hydrazide [Scheme 4, (a)]. Product 3a was not obtained when TBHP was excluded from the reaction [Scheme 4, (b)]. This result highlighted the important role of TBHP in the present conversion. Next, to validate whether 1a reacted with 2a in the present reaction via a radical cascade process, radical trapping experiments were also conducted by employing TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl and BHT (2,6-di-tertbutyl-4-methylphenol) as radical scavengers [Scheme 4, (c)]. The reaction was suppressed by both TEMPO and BHT affording 3a in a trace amount and low yield, respectively. This observation indicated the possibility of a radical mechanism. On the basis of our preliminary mechanistic investigation and the previously reported work,12 a possible reaction mechanism
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03246. Experimental details and characterization data (PDF) Accession Codes
CCDC 1579071 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. C
DOI: 10.1021/acs.orglett.7b03246 Org. Lett. XXXX, XXX, XXX−XXX
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Chutima Kuhakarn: 0000-0003-4638-4356 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Thailand Research Fund (BRG5850012 and IRN58W0005), the Center of Excellence for Innovation in Chemistry (PERCH−CIC), the Office of the Higher Education Commission, Mahidol University under the National Research Universities Initiative, PICS6663 ISMA (France/Thailand), and the Franco−Thai Cooperation Program in Higher Education and Research (PHC Siam 2017) for financial support. The Institute for the Promotion of Teaching Science and Technology and Science Achievement Scholarship of Thailand (SAST) for financial support through student scholarship to J.M. are also gratefully acknowledged.
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DOI: 10.1021/acs.orglett.7b03246 Org. Lett. XXXX, XXX, XXX−XXX
