Iminyl Radical-Triggered Intermolecular Distal C(sp3)–H

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Iminyl Radical-Triggered Intermolecular Distal C(sp3)−H Heteroarylation via 1,5-Hydrogen-Atom Transfer (HAT) Cascade Yu-Rui Gu, Xin-Hua Duan, Li Chen, Zhi-Yong Ma, Pin Gao, and Li-Na Guo* Department of Chemistry, School of Science, Xi’an Key Laboratory of Sustainable Energy Material Chemistry, and MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong University, Xi’an 710049, China

Org. Lett. Downloaded from pubs.acs.org by UNIV OF GOTHENBURG on 01/28/19. For personal use only.

S Supporting Information *

ABSTRACT: An efficient iron-catalyzed intermolecular remote C(sp3)−H heteroarylation of alkyl ketones has been developed via an iminyl radical-triggered 1,5-hydrogen-atom transfer (HAT) cascade. This protocol was amenable to a wide variety of alkyl ketones and heteroaryls, thus providing a straightforward method for the late-stage functionalization of alkylketones and heteroaryls.

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irect functionalization of unactivated C(sp3)−H bonds in hydrocarbons constitutes a promising, atom- and stepeconomic strategy for rapid assembly of complex molecules.1 However, due to their inherently low reactivity and ubiquity, it is really a great challenge to activate such inert C(sp3)−H bonds efficiently and selectively. In recent years, the radical mediated hydrogen-atom transfer (HAT) strategy has emerged as an attractive alternative to traditional transition-metal-catalysis, which enabled not only activating a remote C(sp3)−H bond selectively but also facilitating the coupling of C−C and C−Y bonds (Y = O, N, X, Si, etc.).2,3 Over the past few years, significant achievements have been made in distal C(sp3)−H functionalization through a radical 1,5-HAT.3 For instance, carbon-,4 oxygen-,5 and nitrogen-centered6 radicals-initiated remote C(sp3)−H (hetero)arylation reactions have been developed successfully. However, these reports mainly focused on the intramolecular transformations, which delivered an array of carbocyclic and heterocyclic compounds. The intermolecular 1,5-HAT/(hetero)arylations are relatively rare and challenging.5b,c Iminyl radicals are highly important intermediates in radical chemistry. In recent years, iminyl radical-mediated transformations such as cyclization,7 C−C bond cleavage,8 and C(sp3)−H bond activation6a,b,9 have attracted much attention from chemists and have provided a powerful tool for the construction of chemical bonds. In relation to the C(sp3)−H bond activation aspect, the groups of Forrester and Nevado demonstrated independently iminyl radical-mediated intramolecular remote C(sp3)−H arylation, producing a variety of cyclic ketones (Figure 1, above).6a,b Our group recently demonstrated a visible-light mediated γ-hydroxyalkylation of remote C(sp3)−H bonds via a 1,5-HAT and difunctionalization of alkenes cascade.9e Although some remarkable achievements have been made, the intermolecular remote C(sp3)−H arylation via iminyl radical-mediated 1,5-HAT has never been reported. Heteroaryls such as quinoxalin-2(1H)-ones are well-known, highly valuable, and prevalent skeletons, which are found in many natural products, pharmaceuticals, and materials.10 © XXXX American Chemical Society

Figure 1. Iminyl radical-triggered distal C(sp3)−H (hetero)arylation via 1,5-HAT cascade.

Recently, many research groups have devoted themselves to modifying those scaffolds via direct C(sp2)−H functionalization.11 Herein, we disclose the first iron-catalyzed intermolecular heteroarylation of distal C(sp3)−H bonds through an iminyl radical-triggered 1,5-HAT cascade, providing a new route to γcarbonylalkylated heterocycles via dual C−H bond functionalization (Figure 1, below). In this reaction, a commercially available and environmentally benign iron complex was used as a single catalyst in aqueous media.12 This protocol provides a new strategy for the late-stage functionalization of alkyl ketones as well as heteroaryls. Initially, the quinoxalin-2(1H)-one 1a and oxime ester 2a were chosen as model substrates to optimize the reaction conditions under iron catalysis (for details, see the Supporting Information (SI)). To our delight, the reaction afforded the desired γ-heteroarylated ketone 3a in 84% yield by using 5 mol % Fe(OAc)2 as the catalyst, 1.0 equiv of HOAc as the additive in DMSO/H2O (9:1, v/v) at 100 °C for 12 h (Table 1). Other iron(II) and iron(III) catalysts such as FeCl2, Fe(OTf)2, and Fe(OTf)3 all showed lower catalytic activities, affording the Received: December 4, 2018

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DOI: 10.1021/acs.orglett.8b03865 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

Scheme 1. Scope of the Quinoxalin-2(1H)-ones and Othersa

entry

deviation from standard conditions

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12

5 mol % of FeCl2 as the catalyst 5 mol % of Fe(OTf)2 as the catalyst 5 mol % of Fe(OTf)3 as the catalyst DMSO as the solvent without HOAc 1.0 equiv of TFA was added 1.0 equiv of Et3N was added 5 mol % of Pd(OAc)2 as the catalyst 5 mol % of Co(OAc)2·4H2O as the catalyst 5 mol % of Ni(OAc)2·7H2O as the catalyst 5 mol % of Cu(OAc)2 as the catalyst without catalyst

22 45 48 47 74 68 71 8 trace trace n.r.c n.r.c

a Reaction conditions A: 5 mol % of Fe(OAc)2, 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), additives (0.2 mmol, 1.0 equiv), DMSO/H2O (9:1, 2.0 mL), 100 °C, 12 h, under N2. bIsolated yields. c n.r. = no reaction.

a

Standard conditions A: 5 mol % of Fe(OAc)2, 1 (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), HOAc (0.2 mmol, 1.0 equiv), DMSO/H2O (9:1, 2.0 mL), 100 °C, 12 h, under N2. Isolated yields. b An inseparable mixture of 6- and 7-substituted quinoxalin-2(1H)ones was used. cStandard conditions B: 10 mol % of Fe(OTf)3, 1 (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), HOAc (0.2 mmol, 1.0 equiv), MeOH/H2O (4:1, 2.0 mL), 100 °C, 12−18 h, under N2. Isolated yields.

product 3a in 22−48% yields (entries 1−3). Solvent screening revealed that the use of water as cosolvent had a positive impact on the yield of 3a (entry 4). Without the addition of HOAc, a slightly diminished yield was observed (entry 5). The role of HOAc might increase the electrophilic nature of heteroarenes to enable easier trapping by the nucleophilic alkyl radical.4a,b Then, several additives such as TFA and Et3N were tested. But none of them led to a better yield than HOAc (entries 6 and 7). Other metal catalysts such as Pd(OAc)2, Co(OAc)2·4H2O, Ni(OAc)2· 7H2O, and Cu(OAc)2 proved to be less or ineffective for this reaction (entries 8−11). Finally, the control experiment revealed that the iron catalyst was essential for this transformation (entry 12). Subsequently, the generality and limitations of this distal C(sp3)−H heteroarylation reaction were evaluated. A variety of substituted quinoxalin-2(1H)-ones underwent this transformation efficiently to afford the targeted γ-heteroarylated ketones 3b−n in good to excellent yields (Scheme 1). Quinoxalin2(1H)-ones bearing strong electron-withdrawing groups such as CO2Et and NO2 on the aromatic rings furnished products in relatively low yields (3g and 3h). Satisfactorily, functional groups such as MeO, Br, CO2Et, and NO2 were intact in this reaction, providing opportunities for further synthetic transformations. Besides the methyl group, substrates with n-Pr, Bn, and CH2CO2Et protecting groups were also efficient, delivering the corresponding products 3k−m in good yields. The unprotected quinoxalin-2(1H)-one 1n also converted into the desired product 3n in 91% yield. Remarkably, this low-cost iron catalytic system was applicable to other electron-deficient heterocycles. Quinolin-2(1H)-one 1o, 2H-chromen-2-one 1p, and quinoxaline 1q were amenable substrates, albeit giving somewhat low yields. The quinoline N-oxide 1r and quinoxaline N-oxides 1s−u also reacted smoothly to deliver the anticipated product in moderate yields. Additionally, the benzo[d]thiazole also furnished the desired product 3v in 51% yield under the modified reaction conditions. However, other heteroarenes such as pyridine, pyrazine, and quinoline were inefficient under the standard conditions (not shown).

Encouraged by these results, the scope of oxime esters 2 was examined with the quinoxalin-2(1H)-one 1a. Both tertiary and secondary γ-C(sp3)−H bonds in the oxime esters were compatible with this iron catalytic system, giving the γfunctionalized ketones 4a−r in reasonable yields (Scheme 2). The completely regioselective formation of 4a indicated that the 1,5-HAT process favors tertiary C−H bonds over the secondary and primary ones. Substrates bearing cyclic tertiary γ-C(sp3)−H bonds also gave the desired products 4g and 4h in 77% and 38% yields, respectively. Notably, the oxime ester having a phenyl substituent at the α-position (R1 = Ph) led to the desired product 4i in only 14% yield along with a 22% yield of cycloketone 4i′ as the byproduct, which was formed through the intramolecular radical cyclization.6a The oxime esters with secondary γ-C(sp3)−H bonds reacted with 1a smoothly to afford the target products 4j−r in 34−96% yields. As expected, the benzylic secondary C−H bonds exhibited higher reaction reactivity, furnishing the products 4m−o in 77−83% yields. The Br and OMe groups on the aromatic ring were tolerant. Satisfactorily, the substrate bearing a benzo[d]thiazole substituent was also efficient, furnishing the desired product 4p in moderate yield. It is noteworthy that oxime ester with secondary γ-C−H bonds and benzylic secondary C−H bonds reacted regioselectively to deliver the 4q as the sole product, which was due to the stabilization of the radical by the aromatic ring. Unfortunately, oxime esters with primary C−H bonds, even benzylic C−H bonds, were totally ineffective for this reaction. To our delight, the reaction could be easily scaled up to a gram level. For example, the reaction of 1a (6 mmol) and 2a proceeded efficiently to afford the desired product 3a in 79% B

DOI: 10.1021/acs.orglett.8b03865 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Scope of the Oxime Esters

Scheme 3. Radical-Trapping Experiments

Scheme 4. Proposed Mechanism

radical I, which triggers a 1,5-HAT process to form the carboncentered radical II.12 The radical II is subsequently trapped by substrate 2a to deliver the radical species III, which is oxidized by Fe(III) followed by deprotonation to afford the precursor of product 3a′. Finally, hydrolysis of compound 3a′ yields the desired product 3a.11 However, a radical chain propagation mechanism cannot be ruled out completely, wherein oxidation of radical intermediate III by 1a affords the desired product 3a. In summary, we have developed an iron-catalyzed intermolecular distal C(sp3)−H heteroarylation of alkyl ketones via iminyl radical-triggered 1,5-HAT cascade in aqueous media. A wide variety of alkyl ketones and heteroaryls were compatible with this tandem 1,5-HAT/C−H bond heteroarylation reaction, wherein a C(sp3)−C(sp2) bond was constructed rapidly and regioselectively via dual C−H bond functionalization. This protocol provided an efficient method for the late-stage functionalization of alkyl ketones and heteroaryls.

a

Standard conditions A: 5 mol % of Fe(OAc)2, 1a (0.2 mmol, 1.0 equiv), 2 (0.3 mmol, 1.5 equiv), HOAc (0.2 mmol, 1.0 equiv), DMSO/H2O (9:1, 2.0 mL), 100 °C, 12 h, under N2. Isolated yields. b Standard conditions B: 10 mol % of Fe(OTf)3, 1a (0.2 mmol, 1.0 equiv), 2 (0.3 mmol, 1.5 equiv), HOAc (0.2 mmol, 1.0 equiv), MeOH/H2O (4:1, 2.0 mL), 100 °C, 12 h, under N2. Isolated yields. c 3.0 equiv of 2 were used. dYield of cycloketone 4i′ is given in parentheses.

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isolated yield (eq 1), thus offering reliable and practical access to γ-carbonylalkylated quinoxalin-2(1H)-ones, which are difficult to obtain by other means.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03865.

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Furthermore, the radical trapping experiments were performed to elucidate the reaction mechanism. As shown in Scheme 3, the addition of TEMPO suppressed this reaction obviously and the alkyl-TEMPO adduct 5a was isolated in this case. Consistently, the addition of BHT also inhibited this transformation significantly. Both results suggest a radical pathway for this transformation. Based on the above results and previous literature, we proposed the following reaction pathway (Scheme 4). Initially, single-electron reduction of oxime ester 1a by Fe(II) generates the corresponding iminyl

Experimental procedures and spectroscopic data of new compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xin-Hua Duan: 0000-0002-1527-5934 Li-Na Guo: 0000-0002-9789-6952 Notes

The authors declare no competing financial interest. C

DOI: 10.1021/acs.orglett.8b03865 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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ACKNOWLEDGMENTS Financial support from the Natural Science Basic Research Plan in Shaanxi Province of China (No. 2016JZ002), the National Natural Science Foundation of China (No. 21602168), Key Laboratory Construction Program of Xi’an Municipal Bureau of Science and Technology (No. 201805056ZD7CG40), and the Fundamental Research Funds of the Central Universities (No. zrzd2017001, xjj2016056) is greatly appreciated. We also thank Miss Lu at Instrument Analysis Center of Xi’an Jiaotong University for her assistance with HRMS analysis.

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DOI: 10.1021/acs.orglett.8b03865 Org. Lett. XXXX, XXX, XXX−XXX