Access to Diverse Seleno-spirocyclohexadienones via Ag(II)-Catalyzed Selenylative ipso-Annulation with Se and Boronic Acids

An efficient and straightforward synthesis of diversified seleno-azaspiro-2,5-cyclohexadienones from N-(4-methoxy aryl)propiolamides using elemental selenium and boronic acids has been demonstrated. The reaction proceeds through silver-catalyzed oxidative dearomatization in the presence of potassium persulfate (K2S2O8) as the oxidant. Further, this approach was extended to N-(4-methoxy aryl)propiolates and biaryl ynones to access the corresponding selenylated oxospiro-2,5-cyclohexadienones and spiro[5,5]trienones, respectively. The present three-component method offers the diverse substitutions on selenium involving two C–Se and one C–C bond formations.


■ INTRODUCTION
Spirocarbocycles appear widely as privileged structural frameworks in many natural products and pharmacologically active molecules with interesting bioactive and pharmaceutical properties ( Figure 1). 1 Hence, these frameworks have gained attention of synthetic organic chemists. 2 Concurrently, in the past decade numerous methods have been established for the construction of functionalized spirocyclohexadienones from N-(p-methoxy aryl)propiolamides via a tandem electrophilic or radical addition/ipso-annulation/dearomatization reactions. 3−8 These annulation reactions were either depend on the carbonheteroatom (C−X, X= I, Br, Cl, F, S, Se, N, P, Si) bond formation or carbon−carbon (C−C) bond formation on the alkyne. Among the C−X bond forming reactions, the selenylation (C−Se bond) followed by dearomative ipsoannulation, is one of the significant transformations to accomplish the selenylated spiro-cyclohexadienones (Scheme 1a). In spite of this elegant progress, the commonly used diarl/ alkyl selenides or arylselenium halides as the selenium source under various reaction conditions would result in the narrow structural diversity of the selenylated spiro-cyclohexadienones. 8 Besides, these procedures require the preinstallation of an aryl/ alkyl group on the selenium for the preparation of these diselenide or selenium halide reagents. Hence, the development of alternative efficient approaches for rapid access to distinctly selenylated-spiro cyclohexadienones still remains desirable.
On the other hand, organo-selenium compounds have attracted considerable attention due to their important pharmacological activities, as well as their applications in organic materials, agrochemicals, catalysis, and organic syn-thesis. 9−12 Consequently, extensive efforts have been dedicated to introduce selenium into the various functionalities employing diselenides and selenium halides as selenium sources. 13 However, very recently the usage of selenium powder as the source of selenium in the presence of boronic acids is gaining prominence in cyclization reactions to accomplish diversely (aryl/heteroaryl/alkyl) selenylated annulated products in onepot avoiding the preparation of selenylated reagents. 14 It is noteworthy to mention that selenium powder has been progressively regarded as an attractive selenium source, as it is moisture insensitive, less toxic, bench stable and readily accessible in comparison with other selenium sources. In continuation of our efforts on ipso-annulations, 15 we became intrigued to explore the selenylative ipso-annulation of propiolamides using elemental selenium and boronic acid (Scheme 1b). To the best of knowledge, ipso-annulation approach to spirocycles using selenium powder in the presence of boronic acids is unfamiliar. The developed method has been further extended to dearomative ipso-cyclization of arylpropiolates and biaryl ynones.

■ RESULTS AND DISCUSSION
In order to define the appropriate reaction conditions for the proposed seleno ipso-annulation, our study commenced by employing N-(4-methoxyphenyl)-N-methyl-3-phenyl-propiolamide (1a) and phenyl boronic acid (2a) as substrates in the initial reaction with selenium powder (Table 1). An initial experiment in the presence of AgNO 2 as a catalyst in CH 3 CN failed to progress the reaction, while in 1,4-dioxane formation of 3a was observed in 10% yield (entries 1 and 2, Table 1). Pleasingly, it was observed that the three-component reaction in the presence of AgNO 2 (10 mol %), using K 2 S 2 O 8 as an oxidant in 1,4-dioxane as a solvent under air at 120°C, exhibited the best performance, providing the spiro-product 3a in 85% yield (entry 3). Fortified by this result, a few other oxidants were screened, wherein the reaction with Na 2 S 2 O 8 and (NH 4 ) 2 S 2 O 8 gave reasonably good yield of 3a, while there is no reaction with oxone (Table 1, entries 4−6). Next, the replacement of AgNO 2 with other silver salts, such as AgOAc, AgOTf, and AgNO 3 , led to either no reaction or lower yield of product (Table 1, entries 7−9). Other solvents, such as DMF, toluene, and DMSO (entries 10−12), were found to be less effective. However, the selenylative ipso-annulation did not progress efficiently under nitrogen atmosphere (45% yield, entry 13). Further, when the amount of AgNO 2 was reduced to 5 mol %, decreasing the yield of 3a was observed, while in the absence of silver catalyst the reaction found to be futile ( Table  1, entries 14 and 15). While the reaction at 80°C was unsuccessful, reducing the reaction time to 8 h led to a low yield of the product (Table 1, entries 16 and 17). From the above outcomes, the ideal conditions were established as AgNO 2 (10 mol %) and K 2 S 2 O 8 in 1,4-dioxane at 120°C (Table 1, entry 3).
Having established the optimal reaction conditions, we next moved our attention to evaluate the generality of the threecomponent reactions of N-arylpropiolamides, Se powder, and arylboronic acids. First, the scope of boronic acids was examined. A series of boronic acids were employed in this conversion, and the reaction proceeded smoothly to provide the corresponding seleno-spirocyclohexadienones in good to excellent yields (Scheme 2). Phenylboronic acids bearing electron-donating as well as electron-withdrawing groups were found to be effective to furnish the spirocyclic products 3b to 3f in 72−85% yields. Similarly, multisubstituted boronic acids participated well in the reaction with 1a and Se powder to deliver the selenylated spiro-[4,5]trienones holding 3,5dimethylphenyl (3g) and 2,4,5-trifluorophenyl selenyl (3h) groups. Additionally, bicyclic (1-naphthyl) and heterocyclic (3thiophenyl) boronic acids were well endured in this procedure to give the products 3i (80%) and 3j (73%), respectively. It is noteworthy that the aliphatic (cyclopropyl) boronic acid was also amenable to this selenylative ipso-annulation, affording the desired product 3k in 65% yield. However, methyl (2l) and trans-2-phenylvinyl (2m) boronic acids failed to participate in the reaction.
Subsequently, the scope of N-(4-methoxyphenyl)-N-methylpropiolamides with diverse substitutions tethered to alkynes was studied. The electron-releasing (Me, OMe), as well as   electron-withdrawing (Cl, F, NO 2 ) groups on para-position of phenyl ring on alkyne of propiolamide were suitable in this reaction and furnished the spirocyclic products 3l to 3p with good competence. In addition, the reaction of 1-naphthyl propiolamide (1g) proceeded well to obtain the selenoproduct 3q in 72% yield. The ipso-cyclization of propiolamide having N-benzyl-protected (1h) gave the spiro[4,5]-trienone 3r in 68% yield, but unprotected propiolamide (1i) failed to take part in the reaction. From the study, it was found that the propiolamides having a terminal alkyne (1j) and alkyl (methyl) tethered alkyne (1k) were not suitable for the present method. A gram-scale reaction of 1a with 2a ensued efficiently to deliver the spiro[4,5]-trienone 3a in 82% yield, which exhibit the scalability of the developed approach. Enthused by the above results, we then set out to investigate the ipso-cyclization of 4-methoxyphenyl propiolates to selenyl oxaspiro[4.5]trienones (Scheme 3). Worthy to state that, to the best of our knowledge there are only two reports are known to access these products. 8a,c The three-component reaction of 4-methoxyphenyl 3-phenylpropiolate with phenylboronic acids bearing methyl (Me), methoxy (OMe), halo (Br and Cl), and trifluoromethyl (CF 3 ) on the para position of the benzene ring were reacted efficiently in the presence of optimal reaction conditions to yield oxaspiro[4.5]trienones 5a to 5f in good yields. Likewise, 3,5-dimethylphenyl and 1-naphthyl seleno-spiro products 5g and 5h were isolated in 81% and 77% yields, respected from the reaction of 4a with the respective boronic acids.
The Ag(II)-catalyzed oxidative selenylative ipso-annulation was further expanded to the biaryl ynones holding 4-OMe group on distal phenyl ring to obtain spiro[5.5]trienones (Scheme 4). The spiro[5.5]trienones are key structural motifs present in diverse biologically active molecules. 16,17 To best of our knowledge, there are only two methods available in the literature to access selenylated spiro[5.5]trienones using diselenide as selenium source. 15b,18 Hence, the present protocol employing Se powder in the presence of boronic acid will be attractive for the assembly of various selenospiro[5.5]trienones. Agreeably, the reaction of 6a with phenyl boronic acid (2a) under the optimal reaction conditions led to seleno-spiro [5,5]trienone 7a in 90% yield. The space of the method has been studied with an array of boronic acids having substitutions, such as Me, OMe, Cl, Br, and CF 3 , were found to be suitable under the optimal conditions, providing the seleno-spiro[5,5]trienones 7b to 7f in good yields. Likewise multisubstituted boronic acids were participated well in the reaction with 6a, to deliver the selenylated spiro-[5,5]trienones holding 3,5-dimethylphenyl (7g) and 2,4,5-trifluorophenyl selenyl (7h) groups. The product 7i was given in good yield when 1-naphthylboronic acid (2i) was used in reaction with biaryl yonone 6a. Notably, cyclopropylboronic acid (2k) also reacted competently to afford spiro-trienone 7j in 62% yield. Next, a series of biarylynones holding a variety of substitutions, such as methyl, methoxy, fluoro, cyano, and trifluoromethyl on the phenyl ring tethered to C1-position of alkyne were examined for the ipso-cyclization to get the spiro[5.5]trienones 7k−7o in good yields (Scheme 4). Fascinatingly, naphthofused-spiro[5.5]trienone 7p was also successfully achieved from the corresponding biaryl ynone in 65% yield.
To gain additional understanding the mechanism of the developed ipso-annulation, a few control reactions were conducted (Scheme 6). It was found that the reaction was suppressed by the addition of TEMPO into the reaction under optimal conditions and formation of adduct-X was confirmed by HRMS, suggesting a radical pathway (Scheme 6a). In the same way, addition of diphenylethylene also suppressed the formation of 3a, instead selenide product Y was confirmed by HRMS, supporting the indication of phenylselenium radical (Scheme 6b).
On the basis of above experimental results and literature reports, a possible reaction mechanism for the radical cascade cyclization is depicted in Scheme 7. First, phenylboronic acid generates phenyl radical A in the presence of Ag(II) catalyst, which will be regenerated by K 2 S 2 O 8 as an oxidant. The aryl radical subsequently trapped by Se powder to produce an aryl selenium radical B. The propiolamide 1a reacts with the aryl selenium radical B to form vinyl radical C and subsquent dearomative ipso-cyclization led to the intermediate D, which then endures a single electron transfer (SET) with S 2 O 8 −2 to produce E. Finally, demethylation headed to deliver the spiroproduct 3a and methanol.

■ CONCLUSION
In summary, we successfully developed silver(II)-catalyzed oxidative selenyl ipso-annulation of N-aryl-propiolamides, as well as N-aryl-propiolates with boronic acids using seleniumpowder as the selenium source. This approach is valuable because a range of seleno-spirocyclohexadienones were constructed with good to excellent yields. The method has been extended to biaryl ynones delivering selenyl spiro[5.5]trienones. Further, assembly of tricyclic pyrrolo-[2,1-j]quinolone has also been established. The described protocol proceeded with the merits of mild conditions, broad substrate scope (43 examples), and operation simplicity, demonstrating a simple and expedient direct way to produce the useful selenyl spiro-trienes bearing diverse groups on selenium. ■ EXPERIMENTAL SECTION General Information. All the reactions were conducted in dried glassware; the air-and moisture-sensitive reactions were done under nitrogen atmosphere using anhydrous solvents. All reactions were monitored by thin-layer chromatography (TLC) on silica plates under UV-light. Column chromatography purification was performed on silica gel (100−200 mesh) using hexanes and ethyl acetate. 1 H NMR (500 MHz, 400 MHz) and 13 C NMR (125 MHz, 100 MHz) was recorded in CDCl 3 . The chemical shift values δ7.26 ( 1 H NMR) and δ77 ( 13 C NMR) are corresponding to CDCl 3 and δ1.56 is related to moisture present in CDCl 3. Multiplicity is showed as, s (singlet), d (doublet), t (triplet), m (multiplet), dd (doublet of doublets), etc.