Generation of Endocyclic Vinyl Carbene Complexes via Gold

N-oxide 4b in 1,2-dichloroethane (DCE) as solvent under the standard conditions, the formation of chlorinated naphthalen-. 1-ol 2ae was observed in 18...
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Generation of Endocyclic Vinyl Carbene Complexes via Gold-Catalyzed Oxidative Cyclization of Terminal Diynes: Towards Naphthoquinones and Carbazolequinones Chao Shu, Chong-Yang Shi, Qing Sun, Bo Zhou, TianYou Li, Qiao He, Xin Lu, Rai-Shung Liu, and Long-Wu Ye ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04455 • Publication Date (Web): 24 Dec 2018 Downloaded from http://pubs.acs.org on December 24, 2018

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Generation of Endocyclic Vinyl Carbene Complexes via Gold-Catalyzed Oxidative Cyclization of Terminal Diynes: Towards Naphthoquinones and Carbazolequinones Chao Shu,†,# Chong-Yang Shi,†,# Qing Sun,† Bo Zhou,† Tian-You Li,† Qiao He,† Xin Lu,*,† Rai-Shung Liu,‡ and Long-Wu Ye*,†,§ †

iChEM, State Key Laboratory of Physical Chemistry of Solid Surfaces, and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China. ‡ Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan. § State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China. ABSTRACT: Carbene cascade reactions involving carbene/alkyne metathesis have attracted much attention over the past decades because this chemistry offers great potential to build complicated cyclic molecules. However, the formed vinyl metal carbenoids in these reactions are limited to exocyclic carbenes, and the generation of endocyclic vinyl carbene complexes remains unexplored. Here we report an unprecedented gold-catalyzed oxidative cyclization of terminal diynes. Importantly, the generation of endocyclic vinyl carbene complexes was involved in this oxidative cyclization, which is distinctively different from previous protocols. This method allows the facile synthesis of various valuable naphthoquinones and carbazolequinones from readily available diynes under exceptionally mild reaction conditions and features a broad substrate scope and wide functional group tolerance. Moreover, theoretical calculations provide further evidence on the divergent selectivity of this cyclization reaction. KEYWORDS : gold, oxidation, cyclization, carbenes, diynes

INTRODUCTION Catalytic transformations via a metal carbenoid pathway are considered to be one of the most important aspects of homogeneous transition-metal catalysis.1 Among those, carbene cascade reactions involving carbene/alkyne metathesis have attracted much attention because this chemistry offers great potential to build complicated cyclic molecules, and metal-catalyzed decompositions of diazo carbonyls are the principal and most reliable strategy.2 Unfortunately, this strategy is hindered by the nature of these diazo substrates, which are hazardous, not easily accessible, and potentially explosive. Recently, several non-diazo approaches to such a carbene cascade reaction have been established.3-5 In 2013, Gevorgyan and co-workers reported an elegant protocol for the rhodium-catalyzed transannulation reaction of alkynyl Nsulfonyl-1,2,3-triazoles, leading to various 5,5-fused pyrroles (Scheme 1a).3 In addition, the gold-catalyzed cycloisomerization of 1,6-diyne esters via carbene/alkyne metathesis was also nicely exploited by the research groups of Chan, Hashmi, and Liu (Scheme 1b).4 In particular, recent studies on the transition metal-catalyzed diyne oxidations by an N–O bond oxidant provided an attractive alternative method for such a carbene/alkyne metathesis, and various synthetic methods involving a 1,6-carbene transfer were disclosed (Scheme 1c).5 For example, Hashmi et al. demonstrated that the α-oxo gold carbenoids generated by gold-catalyzed alkyne oxidation could be transferred across the second alkyne via a

Scheme 1. Non-Diazo Approaches for Carbene Cascade Reactions Involving Carbene/Alkyne Metathesis

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presumable 1,6-carbene transfer, which could undergo subsequent transformations such as Wagner−Meerwein chemistry, CH insertions and double oxidation. 5a Tang et al. also reported rhodium-catalyzed such a diyne oxidation, leading to various substituted 2-oxopyrrolidines.5b Very recently, our group realized the copper-catalyzed oxidation of azido-diynes, where the generated vinyl copper carbenoid was eventually trapped by the azido group.5c Moreover, the relevant gold-catalyzed oxidative cyclization of 1,6-diynes was further developed by the groups of Zhang5d and Ji,5e respectively. Despite these findings, the formed vinyl metal carbenoids in all these carbene cascade reactions are limited to exocyclic carbenes, and the generation of endocyclic vinyl carbene complexes has not yet been reported.6 Inspired by these findings and our study of catalytic alkyne oxidations,7,8 we envisioned that the gold-catalyzed oxidative cyclization of terminal diynes might generate endocyclic vinyl gold carbenoids, which would undergo a subsequent second oxidation to produce the corresponding 1,4-naphthoquinones. Herein, we wish to report the realization of such a carbene/alkyne metathesis involving the generation of endocyclic vinyl carbene complexes, which is distinctively different from the above protocols (Scheme 1d). This method allowed the facile synthesis of a range of valuable substituted naphthoquinones9 and carbazolequinones,10 structural motifs that can be observed frequently in various natural products and bioactive molecules (Figure 1). Moreover, our proposed mechanistic rationale for this unique oxidative cyclization, especially for the distinct selectivity, is well supported by theoretical calculations. In this paper, we wish to report the results of our detailed investigations of this gold-catalyzed oxidative cyclization of terminal diynes involving the generation of endocyclic vinyl carbene complexes, including substrate scope, synthetic applications and mechanistic studies.

entries 1–7). Using 2-bromopyridine N-oxide 3a (3.0 equiv) as oxidant, trifluoroacetic acid (2.0 equiv) as additive, and the bulky BrettPhosAuNTf2 (10 mol %) as gold catalyst, we were pleased to find the corresponding 1,4-naphthoquinone 2a could be formed in 64% yield (Table 1, entry 6). Of note, other metal catalysts such as AgNTf2, PtCl2, and Zn(OTf)2 failed to provide even a trace of the desired 2a (Table 1, entries 8– 10). Further investigation of the oxidants (Table 1, entries 11– 14) revealed that 70% yield was obtained by the use of 8ethylquinoline N-oxide 4b as an oxidant (Table 1, entry 13). In addition, it was found that the reaction efficiency was significantly improved by changing the counteranion of the gold catalyst from Tf2N– to F6Sb–, under which conditions 2a was furnished in 81% yield (Table 1, entry 15).12 Finally, it should be mentioned that the reaction gave a slightly decreased yield in the absence of acid additive.11,7e Table 1. Optimization of Reaction Conditionsa

a

Reaction conditions: [1a] = 0.05 M, oxidant (3.0 equiv). Measured by 1H NMR using diethyl phthalate as internal standard. cAr = 2,4-di-tert–butylphenyl. d60 oC, 24 h. b

Figure 1. Representative natural products and bioactive molecules with naphthoquinone and carbazolequinone motifs.

RESULTS AND DISCUSSION 1. Catalyst Evaluation. At the outset, dialkyne 1a was employed as the model substrate to examine the oxidative cyclization, and some of the results are listed in Table 1. 11 The influence of various gold catalysts was first screened (Table 1,

2. Substrate Scope. With the optimized reaction conditions in hand (Table 1, entry 15), we then investigated the scope of this oxidative diyne cyclization reaction. As shown in Table 2, the reaction proceeded smoothly with various diyne substrates 1, and the corresponding 1,4-naphthoquinones 2 were formed in moderate to good yields. Diynes with electron-donating groups were first screened, and the reaction furnished the desired products 2a–2k in 59–83% yields (Table 2, entries 1– 11). It is notable that a range of functional groups such as the protected hydroxy and amino were well tolerated in this transformation (Table 2, entries 6–11). In particular, the reaction could be extended to sterically hindered diyne 1g,

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leading to the desired 2g in 60% yield (Table 2, entry 7). Electron-deficient aryl substrates were also suitable substrates for this oxidative cyclization to produce the corresponding naphthoquinones 2m–2o in serviceable yields, and similar decreased efficiency was also observed in Zhang’s13a and Gagosz’s13b protocols on the oxidative cyclization (Table 2, entries 13–15). Moreover, it was found that the naphthalenelinked diyne 1p also proceeded well (Table 2, entry 16). Notably, attempts to extend the reaction to the cyclohexene-linked diyne 1q and internal diynes such as 1r and 1s gave only a complex mixture of products, and the oxidative cyclization of unsymmetrical diyne 1t only led to the formation of the exocyclic product 2t as the main product.11,14 A gram-scale reaction of 1a (1.08 g) was carried out in the presence of 5 mol % of gold catalyst, and the desired 2a was formed in 75% yield, highlighting the synthetic utility of this chemistry (Table 2, entry 1). Table 2. Reaction Scope for the Formation of 1,4Naphthoquinones 2a

We next considered the possibility of extending the reaction to other heterocycle-tethered diynes. Gratifyingly, this oxidative cyclization of indole-linked diynes 5 also occurred readily, leading to the desired carbazole-1,4-quinones 6 in moderate yields (Table 3). Diynes bearing different Nprotecting groups, even the labile N-Ac group (Table 3, entry 5), were suitable substrates for such an oxidative cyclization to afford the corresponding products 6a–6e in 59–65% yields (Table 3, entries 1–5). Substrates with both electron-donating and electron-withdrawing substituents on the indole ring also worked (Table 3, entries 6–9), but the reaction proceeded less efficiently in the latter case (Table 3, entries 8 and 9). The molecular structure of 6a was further confirmed by X-ray diffraction (Figure 2).15 Thus, this protocol provides a facile and general way for the synthesis of valuable carbazolequinones, which are not readily accessible by known methods.16 Table 3. Reaction Scope for the Formation of Carbazole1,4-quinones 6a

a

Reactions run in vials; [5] = 0.05 M; isolated yields are reported.

Figure 2. Structure of compound 6a in its crystal. a

Reactions run in vials; [1] = 0.05 M; isolated yields are reported. 7.0 mmol scale with 5 mol % of BrettPhosAuCl/AgSbF6.

b

In addition, this oxidative cyclization also proceeded efficiently with pyrrole-linked diynes 7, and the desired indolequinones 8a–8b were formed in good yields (eq. 1).

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Notably, this heterocyclic motif is found in a variety of bioactive molecules.17

3. Synthetic Applications. The substituted naphthoquinones, which are not readily prepared by typical ways for naphthoquinone synthesis, are potentially useful in organic synthesis and medicinal chemistry. Moreover, these naphthoquinones could be converted to an array of valuable naphthoquinone derivatives.18 For example, naphthoquinone 2a underwent selective bromination to deliver the desired 2aa and 2ab in 85 and 80% yield,18a respectively, and both could be further converted to bioactive molecules.19 In addition, 2a could be transformed into the desired epoxide compound 2ac in 75% yield.18b In particular, the direct arylation of 2a with phenyl boronic acid via palladium-catalyzed C–C coupling led to the formation of aryl-substituted naphthoquinone 2ad in 79% yield,18c which is a beneficial supplement to the reaction scope of this protocol. Furthermore, naphthoquinone 2g, a BoNT/A inhibitor,20 could be readily transformed into juglone 2ga9e by removal of the Me group. Of note, selective palladium-catalyzed arylation of 2ga by the addition of boronic acids afforded the corresponding BACE1 inhibitors9g 2gb and 2gc, respectively, according to the known procedures.18c Scheme 2. Synthetic Applications

4. Mechanistic Study. To gain further mechanistic insights into this process, several control experiments were performed. It was found that when diyne 1a was treated with 2 equiv of N-oxide 4b in 1,2-dichloroethane (DCE) as solvent under the standard conditions, the formation of chlorinated naphthalen1-ol 2ae was observed in 18% yield, and the yield could be further improved to 35% by employing (ArO)3PAuNTf2 as a catalyst (eq. 2). Moreover, the oxidative cyclization of 1a in 1,2-dibromoethane (EDB) also led to the significant formation of the corresponding brominated naphthalen-1-ol 2af. These results are consistent with the involvement of a highly reactive gold carbene intermediate in this tandem sequence.21

On the basis of the above experimental observations and density functional theory (DFT) computations, plausible mechanisms to rationalize the formation of naphthoquinone 2l using bulky model ligand L = BrettPhos and simplified model ligand L= PH3, respectively, are illustrated (Scheme 3).11,22,23 Initially, nucleophilic attack by N-oxide on the Au(I)-ligated diyne A forms a vinyl gold intermediate B. Notably, cleavage of the N-O bond in intermediate B gives directly the cyclopropenic intermediate C1, by -oxo goldcarbene intermediate C. This step follows the so-called twostep no-intermediate mechanism.24 The absence of the presumed gold-carbene intermediate C accounts for the absence of 1,2-diketone byproduct which otherwise can be readily formed by nucleophilic attack of a second N-oxide to the goldcarbene intermediate. The intermediate C1 readily isomerizes into another cyclopropenic intermediate D with Au(I)L coordinated to the C=C bond, which further transforms into the endocyclic vinyl gold carbenoid intermediate E. Nucleophilic attack by another N-oxide on the carbenoid carbon atom of E is barrierless and exothermic, forming intermediate F. Cleavage of the N-O bond in F affords the Au(I)-ligated naphthoquinone G, which releases the final product 2l upon migration of Au(I)L to diyne 1l. The whole process is highly exothermic with free energy release amounting to 152.1 kcal/mol. Note that the use of bulky ligand has little effect on the activation free energies of the rate limiting step (the first O-transfer step around the transition state TSC by N-O bond cleavage), 13.4 kcal/mol for L=PH3 vs. for 12.1 kcal/mol for L=BrettPhos. This justifies the use of the simplified model ligand instead of the large BrettPhos for efficient computational exploration of the reaction mechanism. Furthermore, a more detailed mechanistic research and the mechanistic difference between terminal diynes and internal diynes using the simplified model ligand PH3 are provided in the supporting materials.11 Thus, based on these results and previous studies, 6 exo vs endo selec-

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tivity might be dependent on the nature of the substituent attached to the alkyne tether, and the generation of stable vinyl cation is the key for the regioselectivity of cyclization. Scheme 3. Plausible Reaction Mechanism. Relative Free Energies (ΔGDCM) of Key Intermediates and Transition States Were Computed at the SMD-M06/6-31+G(d)/SDD Level for Model Reaction in DCM at 298 K. Data for the Case of L=PH3 Were Given in Parentheses.

CONCLUSIONS In summary, we have developed a novel gold-catalyzed oxidative cyclization of terminal diynes. Importantly, the generation of endocyclic vinyl carbene complexes was involved in this oxidative cyclization, which is distinctively different from previous protocols. The new method leads to the facile and straightforward synthesis of various valuable naphthoquinones, carbazolequinones and indolequinones from readily available diynes under exceptionally mild reaction conditions and features a broad substrate scope and wide functional group tolerance. Furthermore, a computational study provides further evidence for the feasibility of the proposed mechanism, especially for the distinct selectivity.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge via the Internet at http://pubs.acs.org. Experimental procedures, compound characterization data, computational details, and copies of 1H and 13C NMR spectra (PDF) Crystallographic data of 6a (CIF)

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] *E-mail: [email protected]

Author Contributions C.S. and C.-Y.S. contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

We are grateful for the financial support from the National Natural Science Foundation of China (21572186, 21622204, 21772161 and 91545105), PCSIRT, NFFTBS (J1310024) and Science & Technology Cooperation Program of Xiamen (3502Z20183015).

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For pioneering work, see: (e) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. Alkynes as equivalents of α-diazo ketones in generating α-oxo metal carbenes: a gold-catalyzed expedient synthesis of dihydrofuran-3-ones. J. Am. Chem. Soc. 2010, 132, 3258−3259. (8) For selected examples, see: (a) Wang, C.-M.; Qi, L.-J.; Sun, Q.; Zhou, B.; Zhang, Z.-X.; Shi, Z.-F.; Lin, S.-C.; Lu, X.; Gong, L.; Ye, L.-W. Transition-metal-free oxidative cyclization of N-propargyl ynamides: stereospecific construction of linear polycyclic N-heterocycles. Green Chem. 2018, 20, 3271–3278. (b) Pan, F.; Li, X.-L.; Chen, X.-M.; Shu, C.; Ruan, P.-P.; Shen, C.-H.; Lu, X.; Ye, L.-W. Catalytic ynamide oxidation strategy for the preparation of α-functionalized amides. ACS Catal. 2016, 6, 6055–6062. (c) Li, L.; Zhou, B.; Wang, Y.-H.; Shu, C.; Pan, Y.-F.; Lu, X.; Ye, L.-W. Zinc-catalyzed alkyne oxidation/C-H functionalization: highly site-selective synthesis of versatile isoquinolones and β-carbolines. Angew. Chem., Int. Ed. 2015, 54, 8245-8249. (d) Li, L.; Shu, C.; Zhou, B.; Yu, Y.-F.; Xiao, X.-Y.; Ye, L.-W. Generation of gold carbenes in water: efficient intermolecular trapping of the α-oxo gold carbenoids by indoles and anilines. Chem. Sci. 2014, 5, 4057–4064. (9) For selected examples, see: (a) Zhang, Y.; Guo, D.; Ye, S.; Liu, Z.; Zhu, G. Synthesis of trifluoromethylated naphthoquinones via copper-catalyzed cascade trifluoromethylation/cyclization of 2-(3-arylpropioloyl)benzaldehydes. Org. Lett. 2017, 19, 1302–1305. (b) Cheng, D.; Wu, L.; Lv, H.; Xu, X.; Yan, J. CDC reaction and subsequent cyclization for the synthesis of 2-hydroxy-3-alkyl-1,4-naphthoquinones and pyranonaphthoquinones. J. Org. Chem. 2017, 82, 1610–1617. (c) Fujii, S.; Shimizu, A.; Takeda, N.; Oguchi, K.; Katsurai, T.; Shirakawa, H.; Komai, M.; Kagechika, H. Systematic synthesis and antiinflammatory activity of ω-carboxylated menaquinone derivatives-Investigations on identified and putative vitamin K2 metabolites. Bioorg. Med. Chem. 2015, 23, 2344–2352. (d) Molleti, N.; Singh, V. K. Highly enantioselective synthesis of naphthoquinones and pyranonaphthoquinones catalyzed by bifunctional chiral bis-squaramides. Org. Biomol. Chem. 2015, 13, 5243– 5254. (e) Bhasin, D.; Chettiar, S. N.; Etter, J. P.; Mok, M.; Li, P.-K. Anticancer activity and SAR studies of substituted 1,4naphthoquinones. Bioorg. Med. Chem. 2013, 21, 4662–4669. (f) Teiten, M. H.; Mack, F.; Debbab, A.; Aly, A. H.; Dicato, M.; Proksch, P.; Diederich, M. Anticancer effect of altersolanol A, a metabolite produced by the endophytic fungus Stemphylium globuliferum, mediated by its pro-apoptotic and anti-invasive potential via the inhibition of NF-κB activity. Bioorg. Med. Chem. 2013, 21, 3850–3858. (g) Ortega, A.; Rincón, Á.; JiménezAliaga, K. L.; Bermejo-Bescós, P.; Martín-Aragón, S.; Molina, M. T.; Csákÿ, A. G. Synthesis and evaluation of arylquinones as BACE1 inhibitors, β-amyloid peptide aggregation inhibitors, and destabilizers of preformed β-amyloid fibrils. Bioorg. Med. Chem. Lett. 2011, 21, 2183–2187. (10) For selected examples, see: (a) Bedford, R. B.; Bowen, J. G.; Weeks, A. L. Synthesis of murrayaquinone A and analogues via ring-closing C-H arylation. Tetrahedron 2013, 69, 4389– 4394. (b) Itoigawa, M.; Kashiwada, Y.; Ito, C.; Furukawa, H.; Tachibana, Y.; Bastow, K. F.; Lee, K. H. Antitumor agents. 203. carbazole alkaloid murrayaquinone A and related synthetic carbazolequinones as cytotoxic agents. J. Nat. Prod. 2000, 63, 893–897. (c) Saha, C.; Chowdhury, B. K. Carbazoloquinones from Murraya koenigii. Phytochemistry 1998, 48, 363–366. (11) For details, please see the Supporting Information (SI). (12) Schießl, J.; Schulmeister, J.; Doppiu, A.; Wörner, E.; Rudolph, M.; Karch, R.; Hashmi, A. S. K. An industrial perspective on counter anions in gold catalysis: underestimated with respect to “ligand effects”. Adv. Synth. Catal. 2018, 360, 2493– 2502. (13) (a) Wang, Y.; Ji, K.; Lan, S.; Zhang, L. Rapid access to chroman-3-ones through gold-catalyzed oxidation of propargyl aryl ethers. Angew. Chem., Int. Ed. 2012, 51, 1915–1918. (b)

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Henrion, G.; Chava, T. E. J.; Le Goff, X.; Gagosz, F. Biarylphosphonite gold(I) complexes as superior catalysts for oxidative cyclization of propynyl arenes into indan-2-ones. Angew. Chem., Int. Ed. 2013, 52, 6277–6282. (14) For the structures of compounds 1q–t and 2t, see below:

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(15) CCDC-1852462 (6a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (16) (a) Guo, J.; Kiran, I. N. C.; Reddy, R.; Gao, J.; Tang, M.; Liu, Y.; He, Y. Synthesis of carbazolequinones by formal [3 + 2] cycloaddition of arynes and 2-aminoquinones. Org. Lett. 2016, 18, 2499– 2502. (b) Roy, J.; Pal, R.; Mal, D. Hauser annulation of furoindolones in the synthesis of carbazole-1,4-quinones and benzo[b]carbazoloquinones. Tetrahedron Lett. 2015, 56, 6210–6213. (17) Eastabrook, A. S.; Wang, C.; Davison, E. K.; Sperry, J. A procedure for transforming indoles into indolequinones. J. Org. Chem. 2015, 80, 1006–1017. (18) (a) Anuratha, M.; Jawahar, A.; Umadevi, M.; Sathe, V. G.; Vanelle, P.; Terme, T.; Meenakumari, V.; Benial, A. M. F. SERS investigations of 2,3-dibromo-1,4-naphthoquinone on silver nanoparticles. Spectrochim. Acta, Part A 2013, 105, 218–222. (b) Jakka, K.; Liu, J.; Zhao, C.-G. Facile epoxidation of α,β-unsaturated ketones with cyclohexylidenebishydroperoxide. Tetrahedron Lett. 2007, 48, 1395–1398. (c) Molina, M. T.; Navarro, C.; Moreno, A.; Csákÿ,A. G. Arylation of benzo-fused 1,4-quinones by the qddition of boronic acids under dicationic Pd(II)-catalysis. Org. Lett. 2009, 11, 4938. (d) Wang, D.; Ge, B.; Du, L.; Miao, H.; Ding, Y. Synthesis of aryl- and alkylquinones through rhodium-catalyzed C-C coupling under mild conditions. Synlett, 2014, 25, 2895–2898. (e) Josey, B. J.; Inks, E. S.; Wen, X.; Chou, C. J. Structure-activity relationship study of vitamin K derivatives yields highly potent neuroprotective agents. J. Med. Chem. 2013, 56, 1007–1022. (f) Macharla, A. K; Nappunni, R. C.; Nama, N. Regio- and stereoselective hydroxybromination and dibromination of olefins using ammonium bromide and oxone. Tetrahedron Lett. 2012, 53, 1401–1405. (g) Commandeur, C.; Chalumeau, C.; Dessolin, J.; Laguerre, M. Study of radical decarboxylation toward functionalization of naphthoquinones. Eur. J. Org. Chem. 2007, 3045–3052. (h) Thapliyal, P. C. Iodine catalyzed chlorination of naphthoquinones using metal (II) chlorides. Syn. Commun. 1998, 28, 1123–1126. (19) (a) Buckle, D. R.; Cantello, B. C. C.; Smith, H.; Spicer, B. A. 2-Cyano-l,3-dicarbonyl compounds with antiallergic activity. J. Med. Chem. 1977, 20, 265–269. (b) Buckle, D. R.; Smith, H.; Spicer, B. A.; Tedder, J. M. Studies on v-triazoles. 9.1 Antiallergic 4,9-dihydro-4,9dioxo-lH-naphtho[2,3-d]-v-triazoles. J. Med. Chem. 1983, 26, 714– 719. (20) Bremer, P. T.; Hixon, M. S.; Janda, K. D. Benzoquinones as inhibitors of botulinum neurotoxin serotype A. Bioorg. Med. Chem. 2014, 22, 3971–3981. (21) (a) He, W.; Xie, L.; Xu, Y.; Xiang, J.; Zhang, L. Electrophilicity of α-oxo gold carbene intermediates: halogen abstractions from halogenated solvents leading to the formation of chloro/bromomethyl ketones. Org. Biomol. Chem. 2012, 10, 3168–3171. (b) dos Santos Comprido, L. N.; Klein, J. E. M. N.; Knizia, G.; Kästner, J.; Hashmi, A. S. K. The stabilizing effects in gold carbene complexes. Angew. Chem., Int. Ed. 2015, 54, 10336–10340. For the recent study of aurated vinylcarbene intermediates, see: (c) Mulks, F. F.; Antoni, P. W.; Rominger, F.; Hashmi, A. S. K. Cyclopropenylgold(I) complexes as aurated carbenoids or quasi-carbenes. Adv. Synth. Catal. 2018, 360, 1810–1821. (22) The DFT studies on substituent effects were given in the SI.

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