Photocatalyzed Metal-Free Alkylheteroarylation of Unactivated Olefins

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Photocatalyzed Metal-Free Alkylheteroarylation of Unactivated Olefins via Direct Acidic C(sp3)−H Bond Activation Jie Fang, Wan-Li Dong, Guo-Qiang Xu, and Peng-Fei Xu* State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China

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S Supporting Information *

ABSTRACT: A visible-light-promoted metal-free alkylheteroarylation of unactivated olefins was developed by using readily available ketones/esters as the alkyl radical source. With this strategy, both linear and cyclic ketones/esters could be conveniently converted to corresponding α-carbonyl alkyl radical species by using commonly found diacylperoxide (LPO) as the hydrogen atom transfer reagent, and heteroaryl-containing 1,7carbonyl compounds were synthesized via distal heteroaryl ipsomigration in good to excellent yields with high functional group tolerance and a broad substrate scope. In addition, this approach was also amenable to C−H functionalization of acetonitrile, dichloromethane, 1,2-dichloroethane, and chloroform.

C

the utilization of simple ones are more fascinating in synthetic chemistry since they are stable, inexpensive, and easily available. A variety of methods have been described for value-added product constructions by using simple ketone/ ester as nucleophilic reagents.2 On the other hand, an impressive range of reactions involving carbonyl α-C−H functionalization via radical pathway has been developed in the past few decades.3 However, there are still several challenges associated with the formation of the α-carbonly radicals from ketones/esters under common conditions, such as UV light irradiation, direct hydrogen atom transfer (HAT) at high temperature (80−130 °C), and single-electron oxidation mediated by transition metals (Scheme 1b). Therefore, developing a mild and efficient method for activating the carbonyl-containing chemical feedstocks is still desired. Photoredox catalysis has recently emerged as a powerful strategy for the discovery and invention of numerous unique and valuable transformations through open shell pathways.4VaVarious C−H functionalization transformations have recently been realized through a polarity-governed HAT pathway under mild reaction conditions.5 Most of the HAT transformations involve the weak, hydridic C−H bonds6 (adjacent to a heteroatom; when adjacent to an oxygen atom, the bond dissociation energy (BDE) ≈ 92 kcal/mol) and the strong, unactivated, aliphatic C−H bonds7 (for cyclohexane, BDE ≈ 100 kcal/mol).8 Despite these advances, a mild and general strategy for the direct hydrogen atom abstraction from acidic

arbonyl-containing compounds are useful building blocks because of their versatile reactive sites such as the electrophilic carbonyl group and the nucleophilic α-carbon. The addition of nucleophilic carbon anion intermediates to polarized double bonds, which are the most commonly utilized strategies known as Michael, aldol, and Mannich reaction and so on, is one of most important transformations with broad applications in modern organic synthesis (Scheme 1a).1 Compared with using complicated carbonyl-containing molecules for constructing challenging natural product skeletons, Scheme 1. General Approach to Functionalization of the Acidic C(sp3)−H Bond

Received: April 16, 2019

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.9b01329 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters C−H bonds (adjacent to an electron-withdrawing group) remains elusive. Difunctionalization of alkenes is one of the most intriguing transformations to increase the level of saturation of C−C double bonds in small molecules, in which the distal heteroaryl migration strategy is an efficient synthetic approach to construct C−C bonds. For examples: Zhu and co-workers reported the alkylheteroarylation of alkenes induced by CF3 and other alkyl radicals.9 Herein, we describe a successful approach combining the distal heteroaryl migration with direct activation of the α-carbonyl C(sp3)−H bond via hydrogen atom abstraction to construct heteroaryl-containing 1,7dicarbonyl compounds (Scheme 1c). To the best of our knowledge, this work represents the first example of the visiblelight induced functionalization of the acidic C(sp3)−H bond by direct hydrogen atom abstraction under mild conditions. Our study was initiated by using benzothiazole-substituted tertiary alcohol 1a as the model alkene and peroxides as the oxidants in acetone under blue LED irradiation at ambient temperature (Table 1). After extensive investigation of the

used instead of BPO (entry 8). We next examined the influence of different photocatalysts such as Ru(bpy)3·6H2O, Ir(ppy)3, [Ir(dF(CF3)ppy)2dtbbpy]PF6, Acr+−Mes·ClO4−, and 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene). All the catalysts could afford the desired migration product 2aa in moderate to excellent yields (56%−87%), and Acr+− Mes·ClO4− proved to be the best catalyst (entries 6−11). The yield of the product increased smoothly to 90% when the reaction was performed in 1.5 mL of acetone (entry 13), while the product yield decreased to 57% when the solvent was reduced (entry 12). A series of control experiments demonstrated the necessity of the catalyst and oxidant (LPO), and no product was observed when either one was individually omitted from the reaction mixture (entries 14− 15). With the conditions optimized, the substrate scope of the visible-light induced alkene alkylheteroarylation protocol was then investigated. The benzothiazolyl group migrated chemoselectively in preference to the aryl group regardless of its functional group substitutions (Scheme 2, 2aa−2aj). The

Table 1. Reaction Condition Optimizationsa

Scheme 2. Substrate Scope of the Heteroaryl-Substituted Tertiary Alcohola

entry

photocatalyst

oxidant

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12c 13d 14e 15f

[Ir(ppy)2(dtbbpy)PF6 [Ir(ppy)2(dtbbpy)]PF6 [Ir(ppy)2(dtbbpy)]PF6 [Ir(ppy)2(dtbbpy)]PF6 [Ir(ppy)2(dtbbpy)]PF6 [Ir(ppy)2(dtbbpy)]PF6 Ru(bpy)3·6H2O Ir(ppy)3 [Ir(dF(CF3)ppy)2dtbbpy]PF6 4CzIPN Acr+−Mes·ClO4− Acr+−Mes·ClO4− Acr+−Mes·ClO4− Acr+−Mes·ClO4− −

TBHP DTBP TBPB K2S2O8 BPO LPO LPO LPO LPO LPO LPO LPO LPO LPO LPO

NR NR 30 NR 76 80 70 56 85 81 87 57 90 NR NR

a

Reaction conditions: 1a (0.1 mmol), photocatalyst (1 mol %), oxidant (2 equiv), in 1 mL acetone at 25 °C under nitrogen with blue LED irradiation for 20 h. bIsolated yield. c0.5 mL acetone. d1.5 mL acetone. eWithout visible light irradiation. fNo photocatalyst.

oxidants, it was found that the desired product 2aa could be isolated in 30% yield in the presence of tert-butylperoxybenzoate (TBPB) (entry 3). Compared with other peroxides (TBHP, DTBP, K2S2O8), the benzoyloxy radical was found to be to be more active than general alkoxyl radicals for α-carbonyl C(sp3)−H abstraction (entries 1−2, entry 4). The previous studies indicated that the rate of hydrogen abstraction of the C(sp3)−H bond by the benzoyloxy radical was very quick.10 Inspired by these conditions, we wondered whether the benzoyloxy radical could be used for the hydrogen atom abstraction process. Surprisingly, the desired migration product 2aa was obtained in 76% yield by using benzoyl peroxide (BPO) as the oxidant (entry 5). The yield of the product increased slightly to 80% when diacylperoxide (LPO) 4 was

Reaction conditions: 1a (0.1 mmol), Acr+−Mes·ClO4− (1 mol %), LPO (2 equiv), in 1.5 mL of acetone at 25 °C under nitrogen with blue LED irradiation for 20 h. a

benzothiazole-substituted tertiary alcohols bearing electronrich aryl groups, such as Me−, Ph−, and MeO− substituted aryl groups, delivered the expected products in good to excellent yields (2ab−2af, 79%−96% yield). Aryls with an electron-withdrawing substituent at the para position, such as F, Cl, Br, and CF3, were also well-tolerated in the reaction, B

DOI: 10.1021/acs.orglett.9b01329 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

pentanone, and cyclohexanone could also deliver the target products in moderate to good yields with similar diastereomer ratios (3ah−3aj, 65%−84% yield). Remarkably, this visiblelight mediated system could also be used to enable α-carbonyl C(sp3)−H alkylation of γ-butyrolactone (3ak, 73% yield, d.r. = 1.1:1). In comparison to the reported protocol for the selective activation in the α-position of the oxygen atom (a hydridic C− H), our method enabled specific activation in the α-position of the carbonyl group (an acidic C−H).11 Further efforts were devoted to apply this alkene alkylheteroarylation protocol to other substrates (also as solvents). Satisfactorily, the expected migration products were obtained when acetonitrile, dichloromethane, 1,2-dichloroethane, and chloroform were used under the optimized conditions (3al−3ao, 65%−84% yield). These results further proved the hydrogen atom abstraction ability of carboxylate oxygen radicals.12 To further demonstrate the synthetic value of this methodology, a gram-scale reaction was conducted with 1i (3.25 mmol) in acetone to give the corresponding product 3ai (1.03 g) in a yield of 75% (Scheme 4a).

obtaining the alkylheteroarylation products in good yields (2ag−2aj, 78%−89% yield). Replacing the aryl group with a naphthyl group led to a decreased yield (2ak, 50% yield), presumably because of the large steric hindrance. The aryl group was dispensable for this reaction, which could be replaced by either a linear or cyclic alkyl group (2al and 2am, 79% and 86% yield, respectively). The reaction of substrate 1a bearing a thiophene or furanyl moiety also proceeded and produced the migration product in moderate yield (2an and 2ao, 41% and 68% yield, respectively). To further explore the potential of this methodology, substituted benzothiazoles and thiazole groups were also found to migrate smoothly, affording the difunctionalization products in moderate yields (2ap−2at, 64%−78% yield). Next, the generality of the alkene alkylheteroarylation reaction was examined using esters and other ketones as substrates. To our delight, the visible-light induced alkene alkylheteroarylation could proceed smoothly under standard reaction conditions (Scheme 3). Common esters such as ethyl Scheme 3. Substrate Scope of the Electrophilic Alkyl Radical Precursorsa

Scheme 4. Applications of Alkylheteroarylation of Olefins and Mechanistic Studies

Reaction conditions: 1a (0.1 mmol), Acr+−Mes·ClO4− (1 mol %), LPO (2 equiv), in solvent (1.5 mL) at 25 °C under nitrogen with blue LED irradiation for 20 h. a

acetate and tert-butyl acetate were all suitable for this transformation despite decreased yields (3aa and 3ab, 55% and 36% yields, respectively). Compared with the unsubstituted ester (3aa), ethyl fluoroacetate showed better efficiency affording the product in 76% yield albeit with low diastereoselectivity (d.r. = 1.1:1) (3ac). However, the transformation was suppressed when ethyl difluoroacetate was used (3ad, 38% yield), perhaps due to the low efficiency of the HAT process. Asymmetrical ketones such as cyclopropyl methyl ketone and pinacolone could also react to afford the corresponding products in 66% and 45% yields, reapectively (3ae, 3af). Diethyl ketone afforded product 3ag in 52% yield (d.r. = 1:1). Cyclic ketones such as cyclobutanone, cyclo-

Then several experiments were performed to gain insight into the mechanistic details for this reaction system (Scheme 4). First, radical trapping experiments were conducted with TEMPO to capture the radical intermediates in the system. Under the standard conditions, both the acetonyl radical from acetone and the alkyl radical from the oxidant LPO were trapped by TEMPO with no product 2aa detected (see Supporting Information (SI) for details); LPO was generally used as an alkyl radical precursor as reported previously.13 Notably, only the acetonyl radical was trapped by TEMPO with no product 2aa obtained while the radical from BPO was not trapped (Scheme 4b; see SI for details). This result indicated that the carboxylate oxygen radical played a decisive C

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Organic Letters role in the hydrogen abstraction process. The reaction of d6acetone with substrate 1a produced a deuterium product 3ap in 36% yield, which further confirmed that this reaction was a free radical process (Scheme 4c). The control experiments without photocatalyst at higher reaction temperature were also tested. We found that the product 2aa could be obtained in moderate to good yields when the reaction was performed at 60, 80, and 100 °C (68−79% yield), whereas it is nonreactive at 40 °C (Scheme 4d). Stern−Volmer quenching studies showed that the light-activated photocatalyst was quenched by benzothiazole-substituted tertiary alcohol 1a rather than by the oxidant LPO (see the SI, Figures S1, S2). In addition, the quantum yield of the reaction revealed that the reaction contained a radical chain propagation process (see the SI). To understand the migration manner of this reaction, several benzothiazole-substituted tertiary alcohols were examined under the standard reaction conditions (Scheme 5). Only

Scheme 6. Plausible Mechanism for the Alkene Alkylheteroarylation

carbonyl C(sp3)−H bond through a radical pathway. Based on this strategy, we completed the direct alkylheteroarylation of unactivated alkenes via distal heteroaryl ipso-migration. This mild protocol has a broad substrate scope and does not generate toxic byproducts using environmental benign oxidants. In addition, mechanism studies revealed that the reaction involved a radical chain propagation process.

Scheme 5. Transition States of Radical-Induced Heteroaryl Migration

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01329. Experimental procedures and spectroscopic data for all new compounds and fluorescence studies (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Peng-Fei Xu: 0000-0002-5746-758X

the allylic (5a, n = 0), bishomoallylic (1a, n = 2), and trishomoallylic alcohol (5c, n = 3) afforded the corresponding heteroaryl-migrated products 5aa, 2aa, and 5ac, respectively. These results indicated that this radical-induced heteroaryl migration process might involve cyclic transition states, and the three-, five-, and six-membered cyclic transition states are thermodynamically favored, while four- and seven-membered cyclic transition states are disfavored (5ab and 5ad).9a According to the analysis above, a plausible mechanism is illustrated in Scheme 6. The reductive quenching of photoactivated catalyst Acr+−Mes·ClO4− by substrate 1a leads to the reduced Acr+−Mes·ClO4−, which further reduces the oxidant LPO to produce the carboxylate anion A and carboxylate oxygen radical B.14 The radical B then delivers an alkyl radical C via the release of carbonate dioxide (pathway a). Furthermore, the radical B can also promote a hydrogen atom abstraction from acetone to deliver the electrophilic acetonyl radical D (pathway b). The electrophilic C-centered radical D undergoes addition to the alkene to produce the C− C bond formation intermediate; subsequent heteroaryl group migration followed by deprotonation and chain propagation affords the product 2aa. In summary, we have developed a novel metal-free photocatalytic approach to achieve the activation of the α-

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the NSFC (21632003, 21871116, and 21572087), the Key Program of Gansu Province (17ZD2GC011), and the “111” Program from the MOE of P. R. China for financial support.

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REFERENCES

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