Metal-Free Aerobic Oxidative Selective C–C Bond Cleavage in

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

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Metal-Free Aerobic Oxidative Selective C−C Bond Cleavage in Heteroaryl-Containing Primary and Secondary Alcohols Anjie Xia,†,§ Xueyu Qi,†,§ Xin Mao,†,§ Xiaoai Wu,† Xin Yang,† Rong Zhang,† Zhiyu Xiang,† Zhong Lian,† Yingchun Chen,‡ and Shengyong Yang*,† †

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State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China ‡ West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China S Supporting Information *

ABSTRACT: A transition-metal-free aerobic oxidative selective C−C bond-cleavage reaction in primary and secondary heteroaryl alcohols is reported. This reaction was highly efficient and tolerated various heteroaryl alcohols, generating a carboxylic acid derivative and a neutral heteroaromatic compound. Experimental studies combined with density functional theory calculations revealed the mechanism underlying the selective C−C bond cleavage. This strategy also provides an alternative simple approach to carboxylation reaction.

C

Scheme 1. Previous and Current C−C Bond Cleavage Reactions of Alcohols

leavage of carbon−carbon (C−C) bonds provides a direct approach to reorganizing molecular skeletons and generating new scaffolds, highlighting its significance in organic synthesis, biomass conversion, and medicinal chemistry.1 However, the inherent characters of C−C bonds (nonpolar, thermodynamically stable, and kinetically inert) render the C− C bond cleavage a great challenge.2 To overcome this challenge, tremendous efforts have been made in the past decade, and numerous unique C−C bond cleavage approaches have been established.3 A typical and widely studied example is the C−C bond cleavage in carbonyl compounds,4 for which a number of successful reactions have been developed, such as Baeyer−Villiger,5 haloform,6 and Haller−Bauer7 reactions. In comparison, fewer examples of C−C bond cleavage of alcohols have been reported. Direct dehydroxymethylation of primary alcohols has been realized with transition-metal catalysts that combine dehydrogenation and decarbonylation in one pot (Scheme 1, eq 1).8 Selective C−C bond cleavage of secondary and tertiary alcohols via β-carbon elimination, forming an organometallic intermediate and a carbonyl compound, has also been applied in organic synthesis (Scheme 1, eq 2). Shi9 and several other groups10 have made a great contribution to this area. Despite these achievements having made in the C−C bond cleavage of alcohols, most of the current methods often suffer from some limitations such as the use of expensive transition metals and strong oxidants, harsh conditions, and limited substrate scopes, which restrict its applications greatly. Herein, we report a new simple transition metal-free aerobic oxidative selective C−C bond cleavage strategy in primary and secondary heteroaryl alcohols, which leads to a carboxylic acid derivative and a neutral heteroaromatic compound in which © XXXX American Chemical Society

the (substituted) hydroxymethyl group is replaced by a hydrogen (Scheme 1, eq 3). The mechanism underlying this transition involves an aerobic alcohol oxidation in the presence of potassium tert-butoxide11 and a hydroxide-mediated cleavage of the C−C bond. In addition to the nonuse of transition metals, the advantages of this reaction also include mild conditions, a broad substrate scope, reaction scalability, and the use of cheaper and environmentally friendly oxygen other than traditional oxidants.12 Mechanisms underlying the selective C−C bond cleavage were also investigated. Received: February 13, 2019

A

DOI: 10.1021/acs.orglett.9b00563 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Scheme 3. Scope of Thiophene-Substituted Alcoholsa,b

Our research was inspired by a direct alkylation reaction of amines with (5-(4-methoxyphenyl)thiophene-2-yl)methanol (1a, Scheme 2) in the presence of KOH and toluene in air, Scheme 2. Model Reaction

from which an unpredicted dihydroxymethylated product, 2(4-methoxyphenyl)thiophene (2a, Scheme 2), could be isolated. We realized that there could be a new metal-free C−C bond-cleavage reaction of alcohols. To verify this point, the same reaction was repeated under the same conditions (KOH, toluene, air) but with only 1a as the substrate (for details, see Table S1). As expected, 2a was obtained, and the yield was 30% (Table S1, entry 1). Reaction conditions were then extensively screened. First, the same reaction was carried out in argon atmosphere instead of air, and no product was obtained (Table S1, entry 2), indicating the involvement of O2. We then replaced argon with oxygen. The reaction performed very well and afforded 2a in 90% yield (Table S1, entry 3), further demonstrating that O2 was indispensable in this transformation. Second, a range of commercially available bases were screened (Table S1, entries 4−10), and tBuOK was found to be the most efficient base for this reaction, which gave an excellent 99% yield (Table S1, entry 8). When the quantity of tBuOK was reduced to 2.0 equiv, the yield was decreased to 75% (Table S1, entry 11). In the absence of base, no product was detected (Table S1, entry 12). All of these results indicated that base was necessary and t BuOK was the best one. Third, a series of solvents were examined, and toluene was the best choice (Table S1, entries 8, 13−17). Finally, the influence of temperature was tested. Increasing the reaction temperature to 100 °C had no impact on the yield (Table S1, entry 21), while lower temperatures (60, 40 °C, and rt) led to decreased yields or no products (Table S1, entries 18−20). Therefore, tBuOK (3.0 equiv) in toluene under O2 at 80 °C were chosen as the optimized conditions. With the optimized reaction conditions in hand, the scope of substrates was then investigated. A series of substituted thiophene-2-ylmethanols were first examined in the case of primary alcohols. The reaction with 5-substituted thiophene-2ylmethanols proceeded with excellent yields (75−99%), tolerating a variety of functional groups (Scheme 3, 1a−m). 3-Substituted, 4-substituted, 4,5-disubstituted, and fully substituted thiophene-2-ylmethanols were also tolerated, affording the C−C bond-cleavage products in 80−97% yield (1n−w). Of note is that bulky substitution at the 3-position of the thiophene ring still gave an excellent yield (1v, 1w), indicating that steric hindrance did not affect this transformation. We then examined thiophene-3-ylmethanol derivatives as substrates. All of the thiophene-3-ylmethanol derivatives exhibited low reactivity with a poor yield (1x−z). Furthermore, secondary alcohols were examined to test the reactivity. It was found that all of the reactions proceeded smoothly in excellent yields for substituted phenyl(thiophene-2-yl)methanols, regardless of the substituents’ electronic nature (1aa−ar). We also noticed that substituted phenyl(thiophene3-yl)methanols 1as and 1at displayed excellent reactivity with yields of 94% and 85%, respectively, which are different from

a Reaction conditions: alcohols 1 (0.20 mmol, 1.0 equiv), tBuOK (0.6 mmol, 3.0 equiv), in toluene (1 mL) at 80 °C at 14 h under O2 balloon. bYield of isolated product. PMP: p-methoxyphenyl. c4 equiv of tBuOK was used.

the corresponding primary alcohols 1x−z. Secondary alcohols bearing aliphatic group 1au were also suitable for C−C bond cleavage. Most interestingly and importantly, both of the C−C bonds linking the thiophene ring and linking the phenyl ring were possible sites for C−C bond cleavage in these cases, but neutral substituted thiophenes dominated in the generated products, indicating a selective cleavage of the C−C bonds linking the thiophene ring. Subsequently, we evaluated the reactivity of other heteroaryl alcohols (Scheme 4). Primary heteroaryl alcohols bearing furan (1ba−bc) and thiazole (1bd−bh) skeletons successfully delivered the corresponding products in moderate to good yields, tolerating a variety of substitution groups (1ba−bh). Similarly, primary bicycloheteroaryl alcohols (1bi−bp) gave considerable yields, indicating suitable substrates. In addition, the other secondary heteroaryl alcohol also showed very good compatibility, and moderate to high yields using furan (1ca− cd), thiazole (1ce−cf), and pyridine (1cg−ck) containing substrates were observed. Interestingly, pyridin-3-yl-secondary alcohol (1cj,ck) showed higher reactivity than pyridin-2-yl secondary alcohol (1cg,ch) under the same conditions. Secondary dicycloheteroaryl alcohols bearing imidazo[2,1b]thiazole (1cl,cm), imidazo[1,2-a]pyridine (1cn−cp), and benzofuran (1cq) also underwent C−C bond cleavage smoothly. Here, it is necessary to mention again that the same selective C−C bond-cleavage pattern was found in the secondary alcohols with different heteroaryl rings. We then tried to explore the mechanism of the reaction system. Here, reactions of substrates 1a and 1ar were taken as the model reactions of primary and secondary heteroaryl alcohols, respectively. When the reaction process of 1a was monitored by TLC and MS, we detected the presence of oxidation intermediate aldehyde 3a, which was isolated after 10 min reaction (Scheme 5, eq 1-I). We subjected 3a to further reaction under the standard conditions, which resulted cleavage product 2a (eq 1-IV). In addition, both the oxidation B

DOI: 10.1021/acs.orglett.9b00563 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 4. Generality of Heteroaryl Groupsa,b

from, the reaction with tBuOK (10 equiv) in D2O (3 equiv) was conducted, which showed that the source was water (eq 3). Furthermore, the reaction of 1ar the presence of tBuOK (10 equiv) and H218O (3 equiv) indicated that the oxygen of carboxylic acid product 6 also came from the oxygen of water (eq 4). According to the above experimental data, we postulate a plausible mechanism of C−C bond cleavage of heteroaryl alcohols, which is summarized in Figure 1. Initially, the

Figure 1. Proposed mechanism

oxidation of heteroaryl alcohol 1 was promoted by O2 and t BuOK, which afforded the aldehyde or ketone intermediate 3. A hydroxide ion (generated by tBuOK and H2O) attacked the positive carbon center of intermediate 3. The resulting tetrahedral oxyanion I underwent deprotonation to form dioxyanion II. Then the cleavage of the C−C bond linking the heteroaryl fragment occurred to form intermediates III and IV. Protonation of III produced the desired heteroaryl compound 2, and post treatment of IV gave the carboxylic acid derivatives. To understand the intrinsic reason for the selective C−C bond cleavage in secondary heteroaryl alcohols, density functional theory (DFT) calculations were performed for the C−C bond-cleavage reaction of 3aa. All of the calculations were conducted using Gaussian 0913 (see the Supporting Information for details). The free energy profile calculated by the DFT B3LYP-GD3BJ method is shown in Figure 2. The ketone intermediate 3aa afforded 2b and IVaa (the cleavage

a

Reaction conditions: alcohols 1 (0.20 mmol, 1.0 equiv), tBuOK (0.6 mmol, 3.0 equiv), in toluene (1 mL) at 80 °C at 14 h under O2 balloon. bYield of isolated product. PMP: p-methoxyphenyl.

Scheme 5. Experimental Mechanistic Studies

intermediate 3a and the final product 2a were not detected when carried out under standard conditions without O2 or base (eq 1-II, III). The control experiment of intermediate 3a under the standard conditions without base could not give 2a (eq 1-VI), but still performed without O2 (eq 1-V). Similarly, we detected the oxidative intermediate ketone 3ar in the 10 min reaction of 1ar, and 3ar under standard conditions delivered product 2a (eq 2). In the reaction of 1ar under standard conditions, 1-naphthoic acid (4ar) instead of thiophene-2-carboxylic acid dominated in the generated products, indicating a selective C−C bond-cleavage mechanism. To determine where the installed hydrogen atom came

Figure 2. DFT calculations for the complete energy profile for the C− C bond cleavage of 3aa at the level of (SMD)B3LYP-GD3BJ/def2TZVP//(SMD)B3LYP-GD3BJ/6-311G*. C

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Organic Letters

In summary, we have reported a highly efficient, metal-free, and site-selective C−C bond cleavage reaction of primary and secondary heteroaryl alcohols with oxygen as the oxidant. This general method has been proven to tolerate a wide variety of functional groups and is not impeded by heteroaromatic scaffolds. This reaction also provides a convenient method to prepare carboxyl compounds, which may have potential use in the synthesis of biologically important materials. Further applications of this protocol are currently underway in our laboratory.

products of C−C bond linking the heteroaryl fragment) via the transition state TS-A, which has an overall free energy barrier of 20.1 kcal/mol. Furthermore, our calculation data revealed that transformation traversing the transition state TS-B, which generates the products of C−C bond cleavage linking the phenyl fragment, demands a much higher free energy barrier of 5.1 kcal/mol than TS-A. On the basis of these results, a selective cleavage of C−C bond linking the heteroaryl fragment can be expected, which is consistent with our experimental observations. Finally, we explored the possible applications of this newly discovered C−C bond-cleavage reaction in heteroaryl alcohols. Before investigating application examples, we conducted a gram-scale reaction of 1a (5 mmol, 1.1 g) in toluene (20 mL) with 3 equiv of tBuOK under O2 balloon, and the desired product 2a was isolated in 85% yield (Scheme 6a), indicating a

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00563. Detailed information on experimental procedures, characterization data, photophysical data, computational calculations, and crystallographic and spectroscopic data (PDF)

Scheme 6. Gram-Scale Reaction and Synthetic Application

Accession Codes

CCDC 1885769 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +86-28-85164063. Fax: +8628-85164060. ORCID

Yingchun Chen: 0000-0003-1902-0979 Shengyong Yang: 0000-0001-5147-3746 Author Contributions §

A.X., X.Q., and X.M. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (81573349, 81773633, and 21772130), National Science and Technology Major Project (2018ZX09711002-014-002, 2018ZX09711002-011-019, and 2018ZX09711003-003-006), and 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University.

good reaction scalability. An obvious application of this selective C−C bond cleavage is the carboxylation reaction. For instance, selective ring-opening reaction of five-membered cyclitol 8H-indeno[2,1-b]thiophene-8-ol 7 could afford the corresponding carboxylic acid in 87% yield (Scheme 6b). Furthermore, the transition-metal-catalyzed direct nucleophilic C−H addition to aldehydes is desirable for alcohol synthesis,14 and the alcohol products 9 could be easily converted to carboxyl products 10 by selective C−C bond cleavage (Scheme 6c). As is well-known, steroids can modulate a variety of biological processes and have been widely used in medicine; therefore, structural modifications of steroid compounds often provide potential new bioactive compounds.15 We also performed carboxylation of 3,17-dimethoxy-β-estradiol 11 to the corresponding acid 13 in 71% yield and confirmed the structure of 13 by X-ray crystal structure analysis (Scheme 6d).

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REFERENCES

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