Silver-Mediated Indole (4 + 2) Dearomative Annulation with N

DOI: 10.1021/acscatal.8b04933. Publication Date (Web): January 17, 2019. Copyright © 2019 American Chemical Society. Cite this:ACS Catal. XXXX, XXX ...
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Silver-Mediated Indole (4 + 2) Dearomative Annulation with NRadicals: A Strategy to Construct Heterocycle-Fused Indolines Lin-Bao Zhang, Ming-Hui Zhu, Shao-Fei Ni, Li-Rong Wen, and Ming Li ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04933 • Publication Date (Web): 17 Jan 2019 Downloaded from http://pubs.acs.org on January 17, 2019

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Silver-Mediated Indole (4 + 2) Dearomative Annulation with NRadicals: A Strategy to Construct Heterocycle-Fused Indolines Lin-Bao Zhang,† Ming-Hui Zhu, † Shao-Fei Ni,‡,* Li-Rong Wen,†,* Ming Li†,* †State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao, 266042, (P. R. China). ‡Department of Chemistry, Southern University of Science and Technology, Shenzhen, 518055, (P. R. China). ABSTRACT: A regioselective AgI-mediated dearomative (4 + 2) annulation reaction of substituted indoles has been developed. The transformation provides rapid access to functionalized heterocycle fused indoline skeletons with broad functional groups, high atom economy and easy handle nature in one step. Moreover, the recovery experiment of silver catalysts could reduce the cost. Density functional theory (DFT) studies support a “radical-cation” pathway in which C-N bond formation determines the rate-limiting step. KEYWORDS: dearomative; N-centred radical; indoline; AgI-catalysis; radical-cation. INTRODUCTION Free radical reactions offer a straightforward synthetic route toward molecular fragments with high atom- and step-economy because of their unique reactivity and high efficiency.1 In particular, Ncentred radical (NCR) can serve as key intermediates for the synthesis of N-heterocycle compounds.2 Generally, the known approaches to access the NCRs are based on the homo-cleavage of a N–X bond (X = halogen, N, O, or S groups). However, hazardous initiators, high-energy UV irradiation and the tedious preparation procedure for the activation precursors have restricted their applications. In a few examples, the direct cleavage of acidified amidyl N–H bonds using photoredox catalysis also generates NCRs.3 The AgI-catalyzed reactions have been widely used for various organic synthesis,4 and commonly focused on the development of CC bond formation. Recently, the intramolecular amination of C–H bonds through the direct oxidation of N-H bonds to amidyl radicals has been developed by the use of the in-situ-generated AgIII catalysts, representing a new method for N-centred radicals formation.5 Such as, Li group found that the combination of Selectfluor and AgI salts could generate amidyl radicals, subsequently affording aminofluorination of alkenes (Scheme 1a).5a Shi group has developed direct amination of unactivated C-H bonds with the assist of AgOAc and PhI(OTFA)2.5b However, the methods relying solely on AgI-catalysis for generation of NCRs are still in its infancy, probably due to the weaker electronegativity of Ag(I) complexes compared to Ag(III) species.6 On the other hand, practical protocols have been made on the development of indole dearomatization, since such reactions provide efficient access to indoline skeletons, which could be utilized as N-heterocycle precursor in the synthesis of bioactive molecules and natural products.7 Among them, the transition-metal-catalyzed (3 + 2) cyclization represents a general strategy for the construction of dearomatization products.8 Recently, the groups of Jeffrey9a and Wu9b have independently described a metal-free (3 + 2) dearomative cycloaddition reaction of indoles with α-haloketone via aza-oxyallyl cationic intermediates (Scheme 1b). In the forward direction, the approach to develop (4 + 2) dearomative annulation reaction of indoles has been relatively unexplored compared to the (3 + 2) cycloaddition strategy described above.

Scheme 1. New Design for Synthesis of Heterocycle-Fused Indoline via N-Radical Consistent with our continuing interest in metal-catalyzed C-H bond functionalizations,10 we have disclosed a method that the alkoxylation of C(sp2)–H bond could be promoted by cobalt catalyst combined silver salts, in which an intermolecular singleelectron-transfer (SET) mechanism was involved with the aid of bidentate N-O auxiliary. We postulated that N-centred radical generated from CONHOMe directing group11 could be resonantly stabilised by the electron donating effect of neighbouring O atom,12 thus may react with indoles to achieve (4 + 2) dearomative annulation reaction (Scheme 1c). Furthermore, given the redox potential potential of 1a [anodic peak potential= +0.43 vs SCE; see the Supporting Information], we theorized that 1a could smoothly be oxidized by AgI salts [standard reduction potential (Ag+/Ag) = + 0.80 vs SCE] to generate amidyl radicals. We report herein the first AgI-promoted dearomative (4 + 2) annulation reactions between indoles and NCRs, providing a novel means to prepare heterocycle fused indoline skeletons. RESULTS AND DISCUSSION To probe the feasibility of this strategy, we commenced the study on the reaction of 1a with indole 2a. To our delight, the desired product 3aa was obtained in 36% yield when 1a was treated with both AgOAc and NaOAc in HFIP under an air atmosphere at 100 o C. The structure of 3aa (CCDC 1854400) was further confirmed by X-ray diffraction analysis. Various silver salts were tested and

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AgOPiv proved to be most effective, while other Ag(I) salts resulted in the decreased yield (Table 1, entries 1-4). Increasing or decreasing reaction temperature resulted slightly inferior results (see the Supporting Information). Further exploration of solvents revealed that HFIP was optimal (Table 1, entries 5-7). It was found that concentration played an important role in the formation of 3aa. A lower concentration was beneficial to the reaction, probably due to the inhibition of the byproduct (Table 1, entry 8).11d Bases could have some effect on the reactivity of radicals (Table 1, entries 9-14), DIPEA gave a substantially increased yield, although the selectivity was still unsatisfactory, while sodium formate was effective for promoting the reaction with a satisfactory yield and regioselectivity (see the Supporting Information). Moreover, only trace of 3aa was afforded along with the majority of starting material 1a was decomposed at the reaction conditions of 20 mol% AgOPiv combined PhI(OAc)2, indicating AgIII-catalysis was not suitable for the reaction (Table 1, entry 15). 3aa was obtained in 47% yield at 100 oC even within 10 minutes (Table 1, entry 16), however, only 11% yield of 3aa was got when the reaction system was placed at room temperature, along with a part of 1a was decomposed (Table 1, entry 17), indicating that the transformation was sensitive to reaction temperature. Moreover, the Nmethoxyamide moiety was critical since other amides (A, B and C) did not work under the optimized reaction conditions. Notably, D and E enable the reaction without improving the yield.

Table 2. Scope of N-Alkoxyamides 1.a,b

Table 1. Optimization of Reaction Conditions a a

Reaction Conditions: 0.1 mmol of 1, 0.2 mmol of 2a, AgOPiv (0.2 mmol, 2.0 equiv), HCO2Na (0.4 mmol, 4.0 equiv), air, 100 o C, HFIP, 1 h, isolated yields. bThe ratio is determined by 1H NMR analysis.

a

Entry

[Ag]

Solvent

Base

Yield [%]

1 2 3 4 5 6 7 8b 9b 10b 11b 12b 13b 14b 15b,c 16b,d 17b,e

AgOAc AgOPiv AgTFA AgNO3 AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv

HFIP HFIP HFIP HFIP TFE MeOH DCE HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP

NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc KOAc Na2CO3 DABCO TEA DIPEA HCOONa HCOONa HCOONa HCOONa

36 58 29 32 39 trace trace 72 65 52 60 73 83 97 trace 47 11

Reaction Conditions: 0.1 mmol 1a, 0.2 mmol 2a, [Ag] (0.2 mmol, 2.0 equiv), Base (0.4 mmol, 4.0 equiv), air, 100 oC, HFIP (1.0 mL), 1 h, isolated yields. bHFIP (4.0 mL). cConditions: AgOPiv (20 mol%), PhI(OAc)2 (2.0 equiv). dreaction time: 10 minute. eroom temperature, 1 h. OPiv = pivaloyloxy, TFA = trifluoroacetic acid, TFE = trifluoroethanol, TEA = triethylamine, HFIP = hexafluoroisopropanol, DIPEA = N,N-diisopropylethylamine, DABCO = 1,4-diazabicyclo[2.2.2]octane.

With the established conditions in hand (Table 1, entry 14), the scope of indoles 1 for the (4 + 2) dearomative annulation reaction was explored (Table 2), furnishing the corresponding annulation products 3aa−3Da in 41%−99% yields. The different functional groups including methyl, methoxy, phenyl, ester, halogen and protected amine were tolerated in the reaction conditions. High yields were obtained in 3aa-ma, 3sa and 3za. To our delighted, when the C3 and C5 position of indole substrates (1b-j) were substituted with electron-donating or electron-withdrawing groups, the reaction proceeded smoothly in good yield (77%-99%). Noteworthy, natural product derivatives such as 1k and 1l were also applicable in the reaction, affording the target products 3ka and 3la in 96% and 81% yield respectively, whereas D-tryptophan derivative 1m gave two unseparated isomer 3ma/3ma' in a 1:0.6 ratio with 97% overall yield. Various electron-donating and withdrawing substituents including methyl (3oa, 3ta and 3Aa), methoxyl (3na, 3sa,and 3za), fluoro (3ua), chloro (3pa, 3va and 3Ba) and ester (3ra and 3ya) at 4-, 5and 6- positions on indole could be tolerated in the reaction, giving the desired products in moderate to good yields (41%-94%). The relatively reactive bromo and iodo groups were also well tolerated in the reaction (3qa, 3wa and 3xa), which could serve as a handle for further transformation. Worthnotingly, 4-pyrrazole 1D gave the corresponding product 3Da in 67% yield under the reaction conditions, demonstrating the compatibility of the heterocyclic substituent. Table 3. Scope of 3-Substituted Indoles 2.a,b

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a

Reaction Conditions: 1a (0.1 mmol), 2 (0.2 mmol), AgOPiv (0.2 mmol, 2.0 equiv), HCO2Na (0.4 mmol, 4.0 equiv), air, 100 o C, HFIP, 1 h, isolated yields. bThe ratio is determined by 1H NMR analysis. Next, we explored various indole substrates 2 in the cyclization reaction and found that a variety of 3-substituted indoles 2 could be efficiently coupled with 1a to give products 3aa-3am (Table 3). The successful formation of products 3ab and 3ac showed that cyclohexyl- and isopropyl- substituted indoles at C3 position were well tolerated. The sterically hindered tryptophol derivative 2d led to the generation of two regioisomers 3ad/3ad' in a 1:0.5 ratio with 68% overall yield. It should be mentioned that electron-withdrawing groups somewhat retarded the cyclization, such as, 5-bromo-1,3dimethyl-1H-indole 2e only gave a 38% yield of 3ae. Furthermore, a mixture of products 3af/3af' was generated in moderate yield with a ratio of 1:0.8 when 2f was used. Good results (3ag-3aj, 75%-82%) were observed for 3, 5 bis-substitued N-methylindoles 2g-2i. The substrate scope was then extend to N-benzyl-, N-ethyl-, Nisopropyl-substituted indoles, which furnished their respective products in reasonable yields (3ak, 69%; 3al, 41% and 3am, 34%).

radical quencher, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 2,6-diisopropyl-4-methylphenol (BHT), or benzoquinone (BQ) obviously inhibited the reaction (Scheme 2a), suggesting that the cascade reaction might proceed via a radical process. The kinetic isotope effect (KIE) experiments were conducted, and an intermolecular KIE (KH/KD = 0.84) was observed for the competition reaction of 1a and deuteriumlabeled 1a-D with 2a (Scheme 2b). A similar KIE value of 0.82 was obtained from two parallel reactions (Scheme 2c). These results suggest that C-H bond cleavage was unlikely involved in the rate-limiting step. Moreover, to better understand how the radical reacts with indoles, 3-cyclopropyl-indole 1E was employed as a radical probe. Unexpectedly, ring-unopening product 3Ea was delivered in 92% yield, suggesting that the radical species may not exist at C3 position of indoles.13 To investigate the further reaction mechanism, we compared the cyclic voltammograms of 1a and 2a, respectively. The redox potential of 1a (0.43 vs SCE) was found to be 580 mV lower than the redox potential of 2a (1.01 vs SCE), thus provides a support for 1a was first oxidated by Ag(I) to generate an amidyl radical (see the Supporting Information). Moreover, the increased current with the addition of AgOPiv and HCO2Na indicated that the oxidation process could be promoted by a base with a quick electron transfer (Figure 1).14

Figure 1. Cyclic voltammograms at 100 mV/s: background (a); MeCN containing 0.1 M n-Bu4NPF6, 5 mM 1a (b); MeCN containing 0.1 M n-Bu4NPF6, 5 mM 1a and 10 mM AgOPiv (c); MeCN containing 0.1 M n-Bu4NPF6, 5 mM 1a, 10 mM AgOPiv and 20 mM HCO2Na (d).

Control experiments were performed to obtain some mechanism insight into the reaction. As shown in scheme 2, the presence of a

Based on the control experiments, we speculate that the reaction pathway may differ from classic radical cascade addition.15 In order to find additional support for an alternative possible pathway, Density Functional Theory (DFT) calculations were carried out with the ωB97X-D functional based on our experimental studies. Moreover, they could also be used to explain the regioselectivity observed in our reaction system. The details of the calculations and the full picture of the potential energy surface can be found in Supporting Information. A “radical-cation” mechanism as shown in Figure 2 is established here according to our experimental and computational investigations. The reaction starts with the rapid deprotonation of substrate 1a, followed by AgI oxidation to generate a N-centred radical 4. And then the subsequent radical transfer process leads to the formation of carbon-centred radical 5, where a free energy bar

rier of 18.8 kcal/mol via TS2 is needed for the process. Our calculations also support that the radical addition at the C2 position

of indole is slightly preferred than that at C3 position via transition state TS2', which agrees with the experimental observation of

Scheme 2. Control Experiments

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Figure 2. DFT-computed free-energy profile for the most favorable pathway regioisomers in some cases. For intermediate 5, the further oxidation by AgI leads to a C-centred cation 6. Next, cation 6 undergoes intramolecular nuclephilic attack pathway to produce 7,16 which agrees well with our radical clock results. The nuclephilic attack pathway is calculated to be more favorable compared with the radical addition route via TS3'. Another rapid deprotonation process of 7 yields the final product 3aa. The whole process is calculated to be exothermic and C-N bond formation process determines the rate-limiting step. The products could be efficiently deprotected by cleavage of the N-O bond. For example, heterocycle fused indoline 3aa was treated with SmI2 in THF, readily providing 8 in 90% yield (Scheme 3).17

nature. The recovery silver catalysts could reduce the cost. Preliminary mechanism studies reveal that a “radical-cation” pathway is involved in the reaction through the oxidation of Ag(I) salts. Further applications of the protocol for the synthesis of other heterocycles are currently underway in our laboratory.

AUTHOR INFORMATION Corresponding Author †*E-mail: [email protected]. †*E-mail: [email protected]. ‡*E-mail: [email protected]. ORCID Ming Li: 0000-0003-4906-936X Li-Rong Wen: 0000-0001-7976-0878

Notes The authors declare no competing financial interest.

ASSOCIATED CONTENT Scheme 3. Transformation of Annulation Product 3aa Recovering silver catalysts from reaction residue and silver mirror has also been performed to reduce the cost.18 Actually, the silver salts could be regenerated by filtration and treating with nitric acid and NaOPiv. The recycled AgOPiv promoted the (4 + 2) dearomative annulation reaction in a comparable yield (Scheme 4).

Experimental details, spectroscopic data and chemical compound information (PDF), X-ray data of 3aa (CIF). The Supporting Information is available free of charge on the ACS Publications website.

ACKNOWLEDGMENT This work was financially supported by the National Natural Science Foundation of China (21572110, 21372137 and 21801152).

REFERENCES

Scheme 4. Recovery Experiment of Ag Salts CONCLUSIONS In summary, we have developed an efficient protocol for (4 + 2) dearomative annulation reaction between indoles and NCRs, leading to the formation of heterocycle fused indoline skeleton. This method is featured with good selectivity, broad substrate scope, high atom economy, relatively mild reaction conditions and easy handle

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(11) a) Zheng, J.; Zhang, Y.; Cui, S. Rh(III)-catalyzed Selective Coupling of N-Methoxy-1H-indole-1-carboxamides and Aryl Boronic Acids. Org. Lett. 2014, 16, 3560-3563; b) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. Pd(II)catalyzed Cross-coupling of sp3 C−H Bonds with sp2 and sp3 Boronic Acids Using Air as the Oxidant. J. Am. Chem. Soc. 2008, 130, 7190-7191; c) Liu, Y.-J.; Xu, H.; Kong, W.-J.; Shang, M.; Dai, H.-X.; Yu, J.-Q. Overcoming the Limitations of Directed C–H Functionalizations of Heterocycles. Nature 2014, 515, 389-393; d) Zhu, R.-Y.; Farmer, M. E.; Chen, Y.-Q.; Yu, J.-Q. A Simple and Versatile Amide Directing Group for C−H Functionalizations. Angew. Chem. Int. Ed. 2016, 55, 10578-10599; e) Kong, W.-J.; Chen, X.; Wang, M.; Dai, H.-X.; Yu, J.-Q. Rapid Syntheses of Heteroaryl-substituted Imidazo[1,5-a]indole and Pyrrolo[1,2-c]imidazole via Aerobic C2–H Functionalizations. Org. Lett. 2018, 20, 284-287. (12) Kikugawa, Y.; Shimada, M.; Matsumoto, K. Cyclization with Nitrenium Ions Generated from N-Methoxy- or N-allyloxy-N-chloroamides with Anhydrous Zinc Acetate. Synthesis of N-Hydroxy- and N-Methoxynitrogen Heterocyclic Compounds. Heterocycles 1994, 37, 293-301. (13) Liu, W.-B.; Schuman, D. P.; Yang, Y.-F.; Toutov, A. A.; Liang, Y.; Klare, H. F. T.; Nesnas, N.; Oestreich, M.; Blackmond, D. G.; Virgil, S. C.; Banerjee, S.; Zare, R. N.; Grubbs, R. H.; Houk, K. N.; Stoltz, B. M. Potassium tertButoxide-catalyzed Dehydrogenative C–H Silylation of Heteroaromatics: A Combined Experimental and Computational Mechanistic Study. J. Am. Chem. Soc. 2017, 139, 6867-6879. (14) a) Tian, C.; Massignan, L.; Meyer, T. H.; Ackermann, L. Electrochemical C−H/N−H Activation by Water-tolerant Cobalt Catalysis at Room Temperature. Angew. Chem. Int. Ed. 2018, 57, 2383-2387; b) Wu, Z.-J.; Xu, H.-C. Synthesis of C3-Fluorinated Oxindoles through Reagent-Free Crossdehydrogenative Coupling. Angew. Chem. Int. Ed. 2017, 56, 4734-4738. (15) Xuan, J.; Studer, A. Radical Cascade Cyclization of 1, n-Enynes and Diynes for the Synthesis of Carbocycles and Heterocycles Chem. Soc. Rev. 2017, 46, 4329-4346. (16) a) Bandini, M.; Eichholzer, A. Catalytic Functionalization of Indoles in a New Dimension. Angew. Chem. Int. Ed. 2009, 48, 9608-9644; b) Lakhdar, S.; Westermaier, M.; Terrier, F.; R.; Goumont, Boubaker, T.; Ofial, A. R.; Mayr, H. Nucleophilic Reactivities of Indoles. J. Org. Chem. 2006, 71, 90889095. (17) Shen, K.; Wang, Q. Copper-catalyzed Aminoalkynylation of Alkenes with Hypervalent Iodine Reagents. Chem. Sci. 2017, 8, 8265-8270. (18) He, C.; Guo, S.; Ke, J.; Hao, J.; Xu, H.; Chen, H.; Lei, A. Silver-mediated Oxidative C–H/C–H Functionalization: A Strategy to Construct Polysubstituted Furans. J. Am. Chem. Soc. 2012, 134, 5766-5769.

(8) For selected reviews of transition-metal-catalyzed [3+2] cyclizations, see: a) Dauban, P.; Malik, G. A Masked 1,3-Dipole Revealed from Aziridines. Angew. Chem. Int. Ed. 2009, 48, 9026-9029; b) Otero-Fraga, J.; MontesinosMagraner, M.; Mendoza, A. Perspectives on Intermolecular Azomethine Ylide [3+2] Cycloadditions with Non-Electrophilic Olefins. Synthesis 2017, 49, 802-809.

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