Oxidative bicyclization of N-tethered 1,7-enynes toward polycyclic 3,4-dihydroquinolin-2(1H)-ones via site-selective decarboxylative C(sp3)–H functionalization

A new Ag-catalyzed oxidative bicyclization of N-tethered 1,7-enynes with alkylcarboxylic acids for forming 41 examples of polycyclic 3,4-dihydroquinolin-2(1H)-ones has been established using readily accessible K2S2O8 as an oxidant. The reaction pathway involves a silver-catalyzed decarboxylation/in situ-generated C-center radical-triggered a,b-conjugated addition/6-exo-dig cyclization/H-abstraction/5-endo-trig cyclization/SET sequence, allowing direct site-selective decarboxylative C(sp)–H functionalization toward the formation of multiple C–C bonds and rapid construction of complex spiroheterocycles.


Introduction
Molecules containing all-carbon quaternary stereocenters are ubiquitously distributed in natural products and bioactive substances, which have been found to exhibit a variety of biological and pharmacological activities. 1 Accordingly, the construction of sterically restricted quaternary stereocenters has attracted the interest of synthetic chemists because of their special structural features and their tendency to tightly bind to target molecules. 2 As a result, numerous efforts have been devoted to develop efficient methodologies for their direct construction, 3 which generally involved pericyclic, 4 alkylation, 5 photochemical, 6 transition metal-catalyzed, 7 radical, 8 and semipinacol rearrangement reactions. 9 Among which, oxidative radical reactions have been proved to be a high-efficient synthetic strategy toward these molecules contained all-carbon quaternary stereocenters. 10 For instance, Nevado and co-workers reported radical-triggered aryl migration strategies to construct all-carbon quaternary stereocenters via desulfonylative bi-functionalization of N-aryl-N-arylsulfonyl methacrylamides. 11 However, to the best of our knowledge, catalytic decarboxylative C(sp 3 )-H functionalization for the construction of spiro-quaternary stereocenters through radical-triggered bicyclization is virtually unexplored. 1,7-Enynes are types of competent reactants endowed with multiple reactive sites, which could be used as versatile and synthetically useful feedstocks for the construction of molecules containing multiple functionalities. 12 Specically, oxidative radical 1,7-enyne-cyclizations have gradually become a powerful platform for rapid collection of cyclic compounds with all-carbon quaternary stereocenters via synergistic processes across the C]C and C^C bond systems in a single step fashion. 13 These reactions feature annulation efficiency, extreme convergence while minimizing the generation of waste. Recently, we reported the addition of various C-centered radicals to N-tethered 1,7enynes, which underwent a radical addition-cyclization/Habstraction/radical coupling sequence to access spiro-fused cyclopenta [c]quinolones (Scheme 1a). 14 Meanwhile, Li and coworkers presented a metal-free radical [2 + 2 + 1] carbocyclization reaction of N-tethered 1,7-enynes with two C(sp 3 )-H bonds adjacent to a heteroatom to build similar spirocyclic compounds (Scheme 1b), but only trace amount of spirocyclic compound was observed when R is a strong electron-withdrawing Ts group. 15 For this reaction, we attempted to employ N-Ts tethered 1,7-enyne 1a to react with 2,3-dihydrobenzo[b] [1,4]dioxine under the above reported conditions. 14,15 Unluckily, the reaction hardly proceeded with observation of trace amount of the expected product 3a as most of the starting materials remained unreacted. These unsatisfactory results led us to change synthetic strategy for spiro-fused 3,4-dihydroquinolin-2(1H)-one preparation. 16 A survey revealed that decarboxylative coupling reactions have become a powerful tool for the collection of functionalized molecules through direct carbon-carbon bond formation. 17 Considering Ag-catalyzed decarboxylation oen trapped by a radical process, 17 we envisaged that 2,3-dihydrobenzo[b] [1,4] dioxine-2-carboxylic acid as a potential radical donor was subjected to the reaction with N-Ts tethered 1,7-enynes in Agcatalysis, enabling decarboxylative C(sp 3 )-H functionalization to access the expected spiro-fused 3,4-dihydroquinolin-2(1H)ones. Herein, we report the successful implementation of this idea with these special and practical transformations in which a wide range of spiro-fused 3,4-dihydroquinolin-2(1H)-ones 3 were achieved through Ag-catalyzed decarboxylative bicyclizations of N-tethered 1,7-enynes 1 and 2,3-dihydrobenzo[b] [1,4] dioxine-2-carboxylic acid 4a. Using cycloalkyl-(e.g. cyclopentyl 4b, cyclohexyl 4c, 4-methylcyclohexyl 4d, cyclobutyl 4e) and alkylsubstituted (e.g. pentan-3-yl 4f, isopropyl 4g, and sec-butyl 4h) carboxylic acids as radical donors to expand the synthetic utility of this methodology, the reaction smoothly proceeds through a similar decarboxylative bicyclizations, delivering a series of important fused 3,4-dihydroquinolin-2(1H)-ones 5 with two quaternary stereocenters. To the best of our knowledge, this is the rst site-selective decarboxylative C(sp 3 )-H functionalization of alkylcarboxylic acids for the assemble of these special polycyclic 3,4-dihydroquinolin-2(1H)-ones with excellent diastereoselectivity through an oxidative silver-catalysis.

Results and discussion
Our initial investigation was started with the treatment of N-Ts tethered 1,7-enyne 1a (1.0 equiv.) by 2,3-dihydrobenzo[b] [1,4] dioxine-2-carboxylic acid (4a, 2.0 equiv.) under air conditions in a 1 : 1 ratio of MeCN-H 2 O mixture at 80 C. The reaction in the presence of AgNO 3 (20 mol%) and K 2 S 2 O 8 (4.0 equiv.) led to the selective formation of the expected product 3a as a sole diastereoisomer in 48% yield (dr > 99 : 1 established on the basis of 1 H NMR) ( Table 1, entry 1). Lowering the loading of AgNO 3 to 10 mol% gave a higher yield of 59% (entry 2). In contrast, increasing the dosage of K 2 S 2 O 8 to 5.0 equivalents resulted in an inferior outcome (entry 3). The relatively lower conversion into 3a was detected when temperature was elevated to 100 C (entry 4) whereas ne-tuning the ratio of 1a with 4a to 1 : 2.5 still decreased the yield of 3a (entry 5). The use of 4 : 1 mixture of MeCN and H 2 O completely suppressed the reaction process (entry 6). As the next optimization step, we performed the screening of a variety of silver salts, including AgOAc, Ag 2 CO 3 , AgNTf 2 , AgOTf, and AgF, for this bicyclization at 80 C by using 4.0 equiv. of K 2 S 2 O 8 as an oxidant (entries 7-11). Unfortunately, all of these silver catalysts did not show higher catalytic activity than AgNO 3 . Changing mixed solvents of 1,2dichloroethane (DCE)-H 2 O, tetrahydrofuran (THF)-H 2 O, 1,4dioxane-H 2 O, and acetone-H 2 O revealed that all these media cannot further enhance yields (entries 12-15). Without AgNO 3 , the reaction did not work under oxidative conditions (entry 16).
With the established optimal conditions (Table 1, entry 2), we set out to investigate the generality of this silver-catalyzed oxidative bicyclization by using a variety of N-tethered 1,7-enynes. We found that various substituents on the aromatic ring of both the alkynyl (R 1 ) and sulfonyl (R 2 ) moieties were proven not to hamper this Ag-catalysis, and a wide range of diastereoenriched spirofused 3,4-dihydroquinolin-2(1H)-ones 3a-3bb with structural diversity can be afforded in acceptable yields and a functionalgroup-compatible fashion (dr > 99 : 1 established on the basis of 1 H NMR, Scheme 2). For instance, with the Ts protection group (R 2 ) on the amine anchor, the variant of substituents on the  arylalkynyl moiety, including MeO, F, and Cl can tolerate the catalytic conditions well. Electronic effect of substituents on the arylalkynyl moiety seems to show no impact on the reaction efficiency. However, n-butyl substituted 1,7-enyne 1e was not a good component for this reaction (Scheme 2, 3e), which may be ascribed to the relative instability of the vinyl radical intermediate (Scheme 2) generated in situ from C-centered radical triggered addition/6-exo-dig cyclization. Next, electronic nature of substituents on both N-arylalkynyl (R 1 ) and arylsulfonyl (R 2 ) moieties was probed. The reaction occurred smoothly with a variety of functional groups on both N-arylsulfonyl and arylalkynyl moieties of substrates 1. Various functional groups including methoxy, methyl, uoride, chloride, and bromide at the para-positions of the aromatic ring directly bound to N-arylsulfonyl and/or arylalkynyl moieties were well tolerated under this system, delivering the corresponding spirocyclic cyclopenta [c]quinolines 3f-3t with yields ranging from 41% to 59%. Alternatively, sterically encumbered 1-naphthalenyl (1-Np) analogues 1u-1v were successfully engaged in the current bicyclization transformations, giving access to the corresponding cyclopenta [c]quinolines 3u-3v in moderate yields. The presence of both uoro and chloro functionalities at C4 position of the internal arene rings of N-tethered 1,7-enynes proved to be more reluctant to undergo the reaction process, as diastereoenriched products 3w-3y were obtained in 35-41% yields. Similarly, replacing methyl group with aryl substituent on the terminal olen unit, N-tethered 1,7-enyne 1z was a good reaction partner, enabling radical bicyclization to access product 3z in 50% yield. Besides, N-methyl 1,7-enynes 1aa and 1bb would be accommodated, conrming the reaction efficiency, as 3aa and 3bb with high diastereopurity were generated in 75% and 67% yields, respectively. Aer the successful utilization of various N-tethered 1,7-enynes 1 with carboxylic acid 4a, we continued to explore this decarboxylative bicyclization by the adoption of other seven examples of representative cycloalkyl-and alkyl-substituted carboxylic acids 4b-h as the coupling partner (Scheme 3). As we had expected, these reactions worked well to give access to the corresponding fused cyclopenta [c]quinoline products. Various cycloalkyl carboxylic acids including cyclopentyl 4b, cyclohexyl 4c, 4-methylcyclohexyl 4d, and cyclobutyl 4e could be efficiently converted into the corresponding spiro-fused 3,4-dihydroquinolin-2(1H)ones 5a-g with yields ranging from 38% to 55% yields. Similarly, alkylcarboxylic acids such as pentan-3-yl 4f, isopropyl 4g and secbutyl 4h can tolerate the catalytic oxidation conditions well. Among them, 4-methylcyclohexyl (4d) and sec-butyl (4h) counterparts delivered the desired diastereoselective isomers 5e and 5l-5m, respectively, albeit with moderate yields of 37-45%. It is noteworthy that the protocol provides a valuable pathway for the construction of fused cyclopenta [c]quinoline derivatives 5e and 5h-m in an atom-efficient fashion, which are normally difficult to synthesize by the previously reported methods. 14,15 The stereostructural elucidation of the products was conrmed by their NMR and HRMS spectra. In the cases of 3a and 5j, both structures were unequivocally determined by X-ray analysis ( Fig. 1 and 2). To gain mechanistic insight into this reaction, several control experiments were conducted. N-Tethered 1,7-enynes 1a was subjected to reaction with 4.0 equivalents of 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO) or butylhydroxytoluene (BHT; Scheme 4), but no expected product 3a was observed with the starting material 1a remaining. For the former reaction, the TEMPO-2,3-dihydrobenzo[b] [1,4]dioxine adduct was detected by LC-MS (MS ¼ 291.2) analysis, which suggested that the reaction underwent a free-radical addition process, which is consistent with the mechanisms proposed in previous reports. 17 On the basis of our own observations and literature survey, 13 a tentative mechanism is proposed in Scheme 5. The rst step is to form the Ag(II) cation, derived from the oxidization of Ag(I) by the S 2 O 8 2À , which captures a single electron from carboxylate and subsequent decarboxylation to produce the corresponding C-center radical A. 18 Then, the intermolecular a,b-conjugated addition of the resulting C-center radical A onto N-tethered 1,7enynes 1, followed by 6-exo-dig cyclization and H-abstraction affords alkyl radical intermediate D. 15 The intramolecular 5endo-trig cyclization (the addition of C-center radical onto the double bond of intermediate D) occurs to generate radical intermediate E, which undergoes a single electron transfer (SET) and deprotonation to give the desired products 3 and 5.

Conclusions
In conclusion, we have developed a C-center radical-triggered bicyclization of N-tethered 1,7-enynes with a large variety of functional groups that provides efficient construction of richly decorated ploycyclic cyclopenta [c]quinolines with two allcarbon quaternary stereocenters via a sequential silvercatalyzed decarboxylation/C-center radical-induced a,b-conjugated addition/6-exo-dig cyclization/H-abstraction/5-endo-trig cyclization/SET process. This transformation offers a valuable replenishment for constructing a series of spirocyclic cyclopenta [c]quinolones with high diastereoselectivity through siteselective decarboxylative C(sp 3 )-H functionalization. The bond-forming/annulation efficiency, accessibility of starting materials, and functional group tolerance make this reaction a powerful synthetic tool with a great substrate scope. Further study on the scope extension of this reaction is currently underway in our laboratories.

General information
All one-pot reactions were carried out in a 10 mL Schlenk tube equipped with a magnetic stir bar under air conditions. All  melting points are uncorrected. The NMR spectra were recorded in CDCl 3 or DMSO-d 6 on a 400 MHz instrument with TMS as internal standard. Chemical shis (d) were reported in ppm with respect to TMS. Data are represented as follows: chemical shi, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, m ¼ multiples), coupling constant (J, Hz) and integration. HRMS analyses were carried out using a TOF-MS instrument with an ESI source. X-ray crystallographic analysis was performed with a SMART CCD and a P4 diffractometer.