Oxidation-Induced β-Selective C–H Bond Functionalization: Thiolation

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Oxidation-Induced #-Selective C-H Bond Functionalization: Thiolation and Selenation of N-Heterocycles Huamin Wang, Yongli Li, Qingquan Lu, Mingming Yu, Xudong Bai, Shengchun Wang, Hengjiang Cong, Heng Zhang, and Aiwen Lei ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b05054 • Publication Date (Web): 25 Jan 2019 Downloaded from http://pubs.acs.org on January 26, 2019

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ACS Catalysis

Oxidation-Induced β-Selective C-H Bond Functionalization: Thiolation and Selenation of N-Heterocycles Huamin Wang,† Yongli Li,† Qingquan Lu,† Mingming Yu,† Xudong Bai,† Shengchun Wang,† Hengjiang Cong,† Heng Zhang,† and Aiwen Lei*,†‡⊥ †

Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China ‡ State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. China ⊥ National Research Center for Carbohydrate Synthesis Jiangxi Normal University, Nanchang 330022, Jiangxi, P. R. China

ABSTRACT: Site-selective intermolecular C-H bond functionalization is of central importance to synthetic chemistry. Particularly, direct β-functionalization of N-heterocycles still remains a great challenge. Herein, we develop a strategy for oxidation-induced thiolation and selenation at β position of piperidine derivatives and 1,2,3,4-tetrahydroisoquinoline (THIQs) via C-H bond functionalization. Various 4-sulfenylisoquinolines, 3-sulfenylpyridines, and 4-selenylisoquinolines can be obtained by using O2 as only oxidant. Notably, neither directing group nor a metal catalyst is necessary in this transformation. The preliminary mechanistic studies revealed the oxidation and rearrangement pathway were key steps in this transformation, which provides a meaningful strategy for controlling site selectivity in β-functionalization of N-heterocycles. KEYWORDS: β-C-H functionalization, site selectivity, dioxygen, rearrangement, gram-scale synthesis

Site-selective C-H bond functionalization has been a challenging issue in synthetic chemistry.1 In this field, introduction of directing group has proven to be an available approach to controlling the site-selective C-H bond functionalization.2 Nevertheless, introduction and remove of the directing group limits the applications of these methods in industry and results in the waste of the materials when the directing group is not part of the target molecular. Thus, seeking an alternative strategy beyond directing group to access site-selective intermolecular CH bond functionalization directly is an appealing but longstanding challenge.3 Isoquinoline derivatives especially 4-sulfenylisoquinolines exist in many natural products, pharmaceuticals, and biologically active compounds.4 Consequently, the approaches to generation of 4-sulfenylisoquinolines have attracted much attention.5 Up to date, most of the methods having been reported need multiple steps for the preparation of starting materials, resulting in labor-intensive multistep operations and unexpected side products (Scheme 1).5 On the base of our interest in oxidative cross-coupling,6 we wonder whether cross coupling using THIQs and S-H as reaction partners directly access 4-sulfenylisoquinolines, which might offer a more simple and straightforward synthetic strategy without the need of prefunctionalization of substrates. In the past decade, α C-H bond functionalization of THIQs and piperidines have made great progress owing to the generation of reactive iminium or iminium ion intermediate in the process, and both of which can be easily transformed to target molecular through further reaction.7 Nevertheless, because of the higher activation barrier than α C-H bond, rare example of β C-H bond functionalization of piperidines and THIQs have been disclosed.8 Hence, direct accessibility to 4sulfenylisoquinolines from simple THIQs and S-H remains great challenging. Compared to transition metal catalyst, iodine has become an increasingly popular catalyst for C-S/N-S bond formation owing to its special properties.9 In addition, oxidant is necessary for this oxidative cross coupling. Considering the advantage of

environmental friendliness and cleanliness, O2 is a good alternative to peroxides in oxidative reaction.10 Therefore, we envisioned that the combination of iodine and O2 is a worthwhile method to achieve thiolation and selenation at β position of Nheterocycles. Herein, we disclose an unprecedented oxidationinduced C-S bond and C-Se bond formation at β position of Nheterocycles through C-H bond functionalization, providing various 4-sulfenylisoquinolines, 3-sulfenylpyridines, and 4selenylisoquinolines in good efficiency, and some corresponding products that we described in this work are difficult to be synthesized by the existing methods (Scheme 1).6 Experiment results demonstrated that I might be the intermediate in this transformation. Oxidation of I and rearrangement of II might be the key steps for the site selectivity (Scheme 1).

Scheme 1. β-selective C-H bond functionalization of N-heterocycles Table 1. Effect of reaction parametersa

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reaction partner in the presence of O2 (Table 1, entry 14). However, only trace amount of desired product (3a) was detected under N2 atmosphere (Table 1, entry 15). Table 2. Cross Coupling between 1,2,3,4-Tetrahydroisoquinoline and Different Thiophenolsa

a

Standard conditions: 1a (1.2 mmol), 2a (0.3 mmol), I2 (25 mol%), O2, 120 oC, 12 h in DMAc (2.0 mL). b The yield of 3a was determined by HPLC analysis with biphenyl as the internal standard. c yield in parentheses refers to isolated product.d 2aa (p-tolyl disulfide, 0.15 mmol).

Initially, 1,2,3,4-tetrahydroisoquinoline (1a) and p-toluenethiol (2a) were selected as model substrates with the use of iodine as a catalyst and dioxygen as single oxidant to optimize the reaction conditions (Table 1). In principle, Cross coupling between THIQs and p-toluenethiol has the possibility of affording four products (Table 1, 3ab, 3ac, 3ad, and 3ae). Firstly, no 3a was

observed when the reaction was carried out at room temperature (Table 1, entry 2). Surprisingly, a trace amount of 3a could be detected at 100 oC (Table 1, entry 3). At the same time, 3ac was detected in this reaction, which was analyzed and confirmed by GC-MS and NMR.11 On the contrary, 3ab, 3ad, and 3ae have not been observed in the reaction. Then, more 4-sulfenylisoquinoline 3a was generated along with the increase of temperature (Table 1, entry 4). To our delight, a single isomer 3a from β-H bond thiolation of 1,2,3,4-Tetrahydroisoquinoline was obtained in 80% yield at 120 oC (Table 1, entry 1). Encouraged by the result, further screenings were carried out. It was found that solvents had a big influence on the efficiency of this transformation. DMAc was shown as an ideal solvent (Table 1, entries 5-6). Moreover, the decreased catalyst loading led to the decrease of the reaction yield (Table 1, entries 7 and 8). Simply changing the amount of 1a led to a decrease in the reaction yield (Table 1, entry 9). Extension of time was unsuccessful to improve the yield of the reaction (Table 1, entry 10). By comparison, the use of other catalysts such as NIS and KI in the reaction proved unfavorable, demonstrating iodine was an optimal catalyst for this C-S bond formation reaction (Table 1, entries 11-12). Notably, there was no further conversion when the reaction was carried out under N2 atmosphere, suggesting that O2 played an important role in the transformation (Table 1, entry 13). In addition, 75% yield was obtained when 2aa was used as

a

Reaction conditions (unless otherwise stated): 1 (1.2 mmol), 2 (0.3 mmol), I2 (25 mol%), 120 oC, O2, 12 h in DMAc (2.0 mL), isolated yields. b 24 h. c 110 oC, 17 h. d 36 h. With the optimal conditions in hand, we investigated the substrate scope of the C-S bond formation reaction. As shown in Table 2, electron-donating group, such as methyl, tert-butyl, and methoxyl could be amenable to this transformation, giving the corresponding products in moderate to good yields (3a-3c). Gratifyingly, benzenethiols containing halogen groups which can further transform to other useful molecules via chemical reaction afforded the desired products (3d-3f) in good efficiency. Moreover, benzenethiol bearing nitro group was a suitable partner in this C-S bond formation protocol, and 70% yield of the corresponding product (3g) could be observed. CF3 group was also compatible with this protocol (3h). In addition, meta-position substituted benzenethiols were investigated, providing the desired products in 78%, 75% and 82% yield (3i-3k). Ortho-

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ACS Catalysis substituents, having steric hindrance, reacted smoothly with THIQs to generate the expected products in good yield (3l-3n). Pleasingly, this protocol was compatible with bis-substituted benzenethiol, delivering desired product in good yield (3o). When 2-naphthalenethiol was used as reaction partner, 3p was successfully generated in 73% yield. Furthermore, heterocyclic substrates were also investigated. Reaction between 2-thiophenethiol and THIQs was able to afford the corresponding product (3q) in 66% yield. Most importantly, 1-mercaptooctane was a valid coupling partner, delivering the 3r in 36% yield.

(4e-4g). Trifluoromethoxy group were well tolerated, delivering 4h in 62%. It is noteworthy that heteroaromatic group was found to be suitable for this protocol (4i). More importantly, piperidine derivatives were compatible with this transformation. β-Selective products were obtained with the increase of temperature. The reaction between p-toluenethiol (2a) and piperidine afforded desired product in 72% yield (4j). 4k and 4l were successfully generated when 4-phenylpiperidine and 4-methylpiperidine were used as substrates, respectively. In addition, 3methylpiperidine was also tolerated (4m).

Table 3. Cross Coupling between p-Toluenethiol and Different 1,2,3,4-Tetrahydroisoquinolinesa

Subsequently, we evaluated the tolerance of various 1,2,3,4Tetrahydroisoquinolines in this oxidation-induced C-Se bond formation by using diphenyl selenide (2') as coupling partner, as shown in Table 4. THIQs (1a) could react smoothly with diphenyl selenide, affording 5a in 52% yield. When using 7bromo-1,2,3,4-tetrahydroisoquinoline as reaction partner, 5b was successfully synthesized in 67% yield, which could further transfer to other chemical compounds via the activation of CBr bond. Additionally, F and Cl group were compatible with this reaction (5c and 5d). Trifluoromethoxy group was tolerated in this transformation (5e). Furthermore, 5f could be obtained in 25% yield. Table 4. Cross Coupling between Diphenyl Selenide and Different 1,2,3,4-Tetrahydroisoquinolinesa

a

Reaction conditions (unless otherwise stated): 1 (1.2 mmol), 2' (0.15 mmol), I2 (0.075 mmol), 120 oC, O2, 20 h in DMAc (2.0 mL), isolated yields. a

Reaction conditions (unless otherwise stated): 1 (1.2 mmol), 2a (0.3 mmol), I2 (25 mol%), 120 oC, O2, 12 h in DMAc (2.0 mL), isolated yields. b 13 h.c 1 (1.5 mmol), 2a (0.3 mmol), I2 (25 mol%), 130 oC, 48 h, isolated yields. Next, the substrate scope with regard to tetrahydroisoquinolines were investigated, as shown in Table 3. 6-Br-1,2,3,4-tetrahydroisoquinoline could react smoothly with p-toluenethiol to afford 4a in 50%. THIQs bearing methyl group was amenable with this protocol (4b). When we used 7-Br-1,2,3,4-tetrahydroisoquinoline and 8-Cl-1,2,3,4-tetrahydroisoquinoline as coupling partner, 4c and 4d could be obtained in 72% and 81%, respectively. Moreover, a series of aromatic groups were compatible with this process, suggesting the wide group tolerance

In this C-S bond formation protocol, p-tolyl disulfide (2aa), isoquinoline (1'), and 6d could be detected by GC-MS (for details, see Supporting Information). p-Tolyl disulfide (2aa) could react smoothly with THIQs to give the desired product 3a in 75% yield (Table 1, entry 14), suggesting 2aa might be the intermediate in this reaction. On the contrary, no conversion between 1' and 2a occurred under the standard condition, which excludes the possibility of isoquinoline as the intermediate in the transformation (Scheme 2a). Moreover, 6d was successfully transformed into 3d under the standard conditions, suggesting that 6d might be intermediate (Scheme 2b). The yield of 3d was increased to 73% when we added 1a to this system, demonstrating that 1a could promote the transformation from 6d to 3d (Scheme 2c).

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methylthiophenol (2a) under the standard condition (Scheme 4a). Nevertheless, only a trace amount of 2aa was detected in the absence of iodine (Scheme 4b). Moreover, no desired product was detected without iodine (Scheme 4c). 6d could not react with 1a to provide the 3d in the absence of iodine (Scheme 4d). These above results demonstrate that iodine is necessary for the formation of 2aa and desired product (3d). To understand the oxidative aromatization of THIQs (1a) to isoquinoline (1'), electron paramagnetic resonance (EPR) experiments were carried out (Figure 1, for details, see SI). A signal was detected when 5,5-dimethyl-1-pyrroline N-oxide (DMPO), a free radical spin trapping agent, was added to reaction mixture of I2 and 1,2,3,4-tetrahydroisoquinoline (1a) under O2 atmosphere (Figure 1a). The same signal was also observed under the standard condition (Figure 1b). Based on the previous work,12 we speculated that the signal signifies superoxide radical anion. No signal of superoxide radical anion was monitored in the absence of THIQs 1a (Figure 1c). It is noteworthy that a different signal of the trapping radical was observed without O2. The parameters observed for the spin adduct are g=2.0065, ɑN1=13.90 G, ɑN2=1.80 G, ɑH=17.00 G. We proposed this radical signal belongs to N radical (Figure 1d). In accordance with the above result, we conjectured that HI could be generated from I2 in oxidative aromatization of 1a to 1'. Subsequently, HI is oxidized to I2 by oxygen with the release of superoxide radical anion and H2O, thus closing the catalytic cycle of I2.13 Similarly, we assumed that oxidation of intermediate I involved the same catalytic cycle process (Scheme 1).

Scheme 2. Intermediate experiments

Scheme 3. Radical trapping experiments Additionally, this transformation was found to be strongly inhibited when radical scavengers, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), was added to this system (Scheme 3a). Notably, 2aa could react smoothly with 2ab to provide 2ac in 75% yield (Scheme 3b), suggesting the existence of sulfur radical under the standard condition.

Figure 1. EPR experiments for oxidative aromatization of THIQs

Scheme 4. Effect of I2 in this transformation To know more details about the mechanism, the role of the iodine was investigated (Scheme 4). p-Tolyl disulfide (2aa) could be easily obtained via oxidation of the 4-

On the base of the above result, we proposed a tentative mechanism for this C-S bond formation protocol (Scheme 5). Firstly, p-toluenethiol (2a) is oxidized by I2, affording the ptolyl disulfide (2aa). Secondary, the reaction of 2aa with I2 provides an electrophilic species 4-Me-PhSI.13 This electrophilic species can couple with 1a to form N-S bond (6a) and this process is reversible. Thereafter, intermediate III is obtained via the oxidation of 6a in the presence of I2. Subsequently, III is quickly transformed into IV via rearrangement. Finally, desired product 4-sulfenylisoquinoline (3a) is formed through abstraction of a proton. In this transformation, HI is generated. Then,

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ACS Catalysis HI is oxidized to I2 by oxygen with the release of superoxide radical anion, thus closing the catalytic cycle.13a

ASSOCIATED CONTENT Supporting Information.

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

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (21390402, 21520102003), the 973 Program (2012CB725302), the CAS Interdisciplinary Innovation Team. XAS study was performed at National Synchrotron Radiation Research Center. The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also appreciated. This paper is dedicated to Professor Xiyan Lu on the occasion of his 90th birthday.

Scheme 5. Proposed mechanism To further verify the synthetic utility of this protocol, the reaction was performed on 8 mmol scale. Pleasingly, 72% yield of the corresponding product (3a) was observed. Moreover, 3e and 4c were smoothly synthesized on gram scale, which shows the usefulness and potential application of this method (Scheme 6). 4-sulfenylisoquinolines are versatile building blocks in chemical synthesis.5 For instance, 3a could be further transformed into various valuable compounds. 7 and 8 were successfully generated in 82% and 78%, respectively (Scheme 7).14,15

Scheme 6. Reaction scale-up

Scheme 7. Transformation of 3a In summary, we have developed an unprecedented method for oxidation-induced direct β-selective C-H bond functionalization of N-heterocycles, affording a series of 4-sulfenylisoquinolines, 3-sulfenylpyridines, and 4-selenylisoquinolines. Furthermore, gram-scale synthesis under metal-free condition demonstrates the utility of this protocol. A series of control experiments were conducted to investigate the mechanism of this protocol, revealing the oxidation and rearrangement process were key steps in this transformation. More importantly, single β-selective C-H bond functionalization was achieved without protecting group and directing group, providing a meaningful strategy for controlling site selectivity in C-H bond functionalization field.

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