D Exchange of Five-Membered Heteroarenes at

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

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Ag2CO3‑Catalyzed H/D Exchange of Five-Membered Heteroarenes at Ambient Temperature En-Ci Li,† Guang-Qi Hu,† Yu-Xing Zhu,† Hong-Hai Zhang,*,† Kang Shen,† Xiao-Chun Hang,† Cong Zhang,*,† and Wei Huang*,† †

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Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Jiangsu National Synergistic Innovation Center for Advanced Materials (SICAM), Nanjing Technical University (Nanjing Tech.), 30 Puzhu Road, Nanjing 211816, P.R. China S Supporting Information *

ABSTRACT: Ag2CO3-catalyzed hydrogen isotope exchange of five-membered heteroarenes is disclosed. The reaction can be conducted in the open air, at ambient temperature, and with D2O as deuterium source. Moreover, this protocol showed orthogonal site selectivity to existing technology, thereby greatly expanding the scope of substrates for HIE reaction. The mechanistic study indicated that the carbonate group plays a crucial role to achieve high levels of deuterium incorporation by lowering the activation energy of H/D exchange process.

D

Scheme 1. Transition-Metal-Catalyzed HIE

euterium labeling is increasingly attracting interest in the pharmaceutical industry because of its unique ability to alter the metabolic fate and pharmacokinetic properties of drugs while retaining the original biochemical potency and selectivity of drugs.1 Moreover, some of the drugs have been reported to obtain improved toxicity profiles by the introduction of deuterium at specific positions.2 Thus, selective deuterium labeling could be an efficient tool toward solving the metabolic and toxic issues of drugs. Indeed, a significant number of deuterated drug candidates have been forwarded to clinical trials, and the first deuterated drug has been approved by the US Food and Drug Administration in April 2017.3 Furthermore, deuterium-labeled compounds have also found widespread application in the study of reaction mechanisms and kinetics,4 the analysis of environmental pollutants and residual pesticides,5 as well as the production of innovative materials.6 Among the methods for deuterium labeling, direct hydrogen isotope exchange was found to be the most straightforward strategy.7 Advantages of HIE over other protocols8 include no need for prefunctionalization of the starting materials and the potential ability for late-stage deuterium labeling of pharmaceuticals. Consequently, vigorous efforts have been made to develop new methods for HIE.9 During the past decades, the iridium complexes, including Crabtree’s iridium catalyst and Kerr’s iridium−carbene catalyst, have been the prevalent catalysts for site-selective HIE at α-position of a variety of directing groups (Scheme 1A).10 Recently, several transition metal complexes other than iridium have been developed for HIE with distinct site-selectivity. In 2014, the Yu group reported a Pd(OAc)2-catalyzed HIE with the carboxylic acid moiety as directing group and deuterated acetic acid as solvent © XXXX American Chemical Society

(Scheme 1B).11 In 2016, Chirik and co-workers reported an iron complex catalyzed HIE reaction, affording deuterated arenes with special steric controlled site selectivity (Scheme 1C).12 In 2018, the same group reported a H/D exchange protocol with nickel complex as catalyst, occurring at αposition of nitrogen-containing heterocycles (Scheme 1D).13 Despite many efforts, the reported H/D exchange protocols still suffered from shortcomings including the use of commercially unavailable or expensive metal catalysts, the fussy operation under N2 protection, and narrow scope of substrates. Because the metabolic and related studies of pharmaceuticals require precise incorporation of deuterium at different positons for different purposes, development of an Received: July 9, 2019

A

DOI: 10.1021/acs.orglett.9b02369 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters HIE reaction catalyzed by other metal catalysts for distinct siteselectivity to the existing method is highly desirable. Because silver salts are reported to play very important roles in C−H activation steps of direct arylation reactions,14 we envisioned that they could be good candidates to catalyze HIE. Use of a silver salt as catalyst for HIE may offer several advantages: First, silver salts are generally commercially available at relatively low cost. Second, silver salts are easily handled and not sensitive to air or water. Third, silver salts are compatible with a variety of functional groups, making them suitable for late-stage deuterium labeling of pharmaceuticals. Fourth, silver salts may offer orthogonal site selectivity to other metal catalysts, with H/D exchange occurring at the C−H bond with higher acidity. To the best of our knowledge, silver salt mediated H/D exchange reactions have never been employed for preparative purposes due to the challenge of sufficient deuterium incorporation, although it has been reported in the mechanism study of direct arylation reactions.14 Herein, we report our preliminary results on the Ag2CO3-catalyzed H/D exchange reaction with D2O as deuterium source at ambient temperature, affording fivemembered heteroarenes with high atom % deuterium incorporation. H/D exchange protocol was examined with thiophene derivatives as model substrates because thiophene is a common structure motif in drug molecules,15 existing in five of the 200 top-selling drugs in 2018.16 In addition, deuterium-labeled thiophene derivatives are usually prepared with highly reactive alkyllithium reagents which suffer from the poor tolerance of functional groups.17 With ethyl 2-thiophenecarboxylate as a model substrate, a number of catalysts, ligands, solvents, and additives were tested for the HIE process. Gratifyingly, Ag2CO3 and (2-biphenyl)di-tert-butylphosphine (“JohnPhos”) were found to be the optimal catalyst combination. When the reaction was carried out with Ag2CO3 (10 mol %) as silver salt, JohnPhos (10 mol %) as phosphine ligand, K2CO3 (1 equiv) as base, and D2O (20 equiv) as deuterium source in DMSO at 25 °C for 12 h, the product 2a with 91% deuterium incorporation could be isolated (see Schemes S1−S5 for detailed optimization studies). To understand the role of each reagent, a range of control experiments were subsequently conducted (Scheme 2). When no silver salt was used, H/D exchange did not occur, and only starting material without deuterium labeling (entry 2) was recovered. The use of silver salts other than Ag2CO3 resulted in lower levels of deuterium incorporation (entries 3−6). These results indicated that Ag2CO3 is the optimal catalyst for this HIE reaction. The effect of the phosphine ligand was next examined. In the absence of phosphine ligand, the product with a marginally 2% deuterium incorporation was observed (entry 7). While a number of phosphine ligands were effective for the reaction, the levels of deuterium incorporation were lower (entries 8 and 9). Product with a moderate level of deuterium incorporation of 72% was observed in the absence of K2CO3 as additive, which suggested that K2CO3 had a positive effect on the reaction. Interestingly, the level of deuterium incorporation was dramatically attenuated to around 10% by replacing potassium carbonate with potassium acetate, potassium pivalate, or potassium trifluoroacetate, which are common reagents for assisting C−H activation of thiophenes.18 The influence of D2O was then examined. Using a smaller amount of D2O led to a decreased level of deuterium incorporation, which is consistent with the H/D exchange

Scheme 2. Variation from Standard Conditions for H/D Exchange with 2-Thiophenecarboxylate as Substrate

mechanism. Lowering the Ag2CO3 and JohnPhos loading to 5 mol % still gave the desired product 2a, albeit in 67% deuterium incorporation. It is noteworthy that a high level of deuterium incorporation as (93%) was observed when the reaction was conducted in the absence of N2 protection. Therefore, subsequent reactions were all carried out in the open air without the N2 protection. With the optimized conditions in hand, the substrate scope for HIE was next explored (Scheme 3). The reaction performed smoothly with thiophenes substituted by electronwithdrawing groups at the α-position (2a−2f) as starting materials, providing the products with high levels of deuterium incorporation (84−98%). It is noteworthy that the standard conditions were compatible with bromide and chloride groups, which could be further transferred to a variety of other versatile functional groups. When compound 2d was employed as starting material, deuterium incorporation at the methyl group was also observed even without K2CO3. This result indicated that Ag2CO3 can also promote H/D exchange of C(sp3)−H bonds at the α-position of the carbonyl group. The deuterons on the methyl group of 2d can be exchanged back to protium with KOH as base in water without any decrease of deuteration at thiophene ring. Thiophenes substituted by an alkyl group at the α- or β-position were more sluggish substrates for Ag2CO3-catalyzed HIE, affording products with insufficient labeling. Encouragingly, increasing the temperature to 40 °C and use of 0.3 equiv of Ag2CO3 /JohnPhos as catalyst can provide high atom % deuterium incorporation (2h and 2n). The β-substituted thiophenes (2j−2n) were next examined as starting materials for H/D exchange, giving the B

DOI: 10.1021/acs.orglett.9b02369 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Scope of Five-Membered Heteroarenesa

Scheme 4. Ag2CO3-Catalyzed HIE for Drug Moleculesa

a

The reaction was conducted on 0.3 mmol of 1, 6 mmol of D2O, 10 mol % of Ag2CO3, 10 mol % of JohnPhos, 1 mL of solvent at 25 °C; all yields are isolated yields; deuterium incorporation was determined by 1H NMR. bThe reaction was conducted with 30 mol % of Ag2CO3 and 30 mol % of JohnPhos at 40 °C. cThe reaction was conducted on 1.5 g of 3b.

labeled product with 91% deuterium incorporation and notably with excellent selectivity of for the thiophene ring versus the imidazole ring (4b). Application of Ag2CO3-catalyzed H/D exchange to methoxsalen resulted in deuterium labeling mainly at the α-position of the furan ring (4c), albeit with only a moderate level of deuterium incorporation. Finally, we were delighted to find that the H/D exchange reaction was amenable to scale up using 1.5 g of 3b without loss of efficiency. To fully understand the reason why this Ag2CO3-catalyzed HIE reaction can afford high atom % deuterium incorporation at ambient temperature, we turned our attention to investigate the mechanism. First, we observed a kinetic isotope effect of 1.9 by measuring the rate of reaction for both the installation and removal of deuterium (Scheme 5), which indicated a

a

The reaction was conducted on 0.3 mmol of 1a, 6 mmol of D2O, 10 mol % of Ag2CO3, and 10 mol % of JohnPhos in 1 mL of DMSO at 25 °C; all yields are isolated yields; deuterium incorporation was determined by 1H NMR bThe reaction was conducted with 30 mol % of Ag2CO3 and 30 mol % of JohnPhos at 40 °C.

Scheme 5. Kinetic Isotope Effect Study

products with deuterium incorporation of 84−95%, which indicated that steric effects have little influence on the H/D exchange process. Interestingly, 3-methoxythiophene (2k) showed obvious site selectivity at the α-position neighboring to methoxy group, suggesting it possibly has weak coordination between the methoxy group and silver(I) catalyst. The hydrogen at the 2-position of benzothiophene (2o) can also be selectively replaced by deuterium under the standard condition. Other S-containing heterocycles (2p−2r) are also demonstrated to be good substrates for Ag2CO3-catalyzed HIE. Interestingly, we further found that deuterium-labeling could occur at both the α- and β-positions of benzofuran derivatives (2s and 2t). Benzoxozole derivatives were found to be good substrates for HIE, affording the products with 93% and 94% deuterium incorporation (2u and 2v). Nevertheless, imidazole and indole derivatives completely shut down the HIE reaction and gave no deuterium-labeling products (2w and 2x). The successful and distinct H/D exchange of five-membered heterocycles under mild conditions prompted us to apply this method for direct deuterium-labeling of selected drug molecules (Scheme 4). Although it is difficult to introduce deuterium at the C(sp2)−H bond in the antiplatelet drug ticlopidine by traditional HIE protocols, the Ag2CO3-catalyzed H/D exchange can afford product labeled at the α-position of the thiophene ring with a high level of deuterium incorporation at 93% (4a). We next found that the antifungal drug tioconazole is a good substrate for HIE reaction, providing

silver-mediated C−H activation was involved in the ratedetermining step. Second, we confirmed the combination of Ag2CO3 and phosphine ligand act as catalyst in the exchange process through the control experiments (entries 1, 2, and 7, Scheme 2). Third, a mechanism involving free radicals should be ruled out because the radical inhibitor TEMPO has no negative effect to the reaction (see the SI for details). We then designed a series of experiments to investigate the effect of additives. The HIE reaction was first conducted with Ag2O as catalyst. In the absence of K2CO3 as additive, the product 2a with dramatically decreased level of deuterium incorporation as 11% was observed (Scheme 6a). In addition, the similar result was found with Ag2CO3 as catalyst (Scheme 6b). Then a number of carbonate bases were employed for H/ D exchange, and most of them provided a positive effect toward HIE (Scheme S8). These results suggested that the carbonate group may serve as the key motif to promote H/D exchange process. C

DOI: 10.1021/acs.orglett.9b02369 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 6. Study of the Effect of K2CO3

Figure 1. Computed energy profile for the HIE assisted by carbonate or carboxylate groups.

second step, indicating that the first step is the ratedetermining step, which is consistent with the kinetic isotope experiment result. Importantly, the reaction energy profile showed the carbonate group can dramatically decrease the energy barrier of the first step to 16.43 kcal/mol and the second step to 13.55 kcal/mol, which is likely the reason why the reaction can be conducted at room temperature. Compared with the pathway involving the carboxylic group, the one involving the carbonate group is more energy favorable. Therefore, the products generated from the two pathways showed a substantial difference in the level of deuterium incorporation. In summary, we have developed an Ag2CO3-catalyzed H/D exchange reaction, which is an economic and convenient approach for the direct and selective introduction of deuterium to five-membered heteroarenes. The reaction was conducted in the open air, at ambient temperature, and with D2O as the deuterium source, which made it a very practical method. Furthermore, this protocol can be applied in the late-stage deuterium labeling of selected pharmaceuticals due to its compatibility with a variety of functional groups under mild conditions. The mechanism study demonstrated that the adoption of the carbonate group is the key to lowering the activation energy of the H/D-exchange process, which leads to high levels of deuterium incorporation at ambient temperature. This finding not only may be applied in the Ag(I)-catalyzed HIE reaction but also can provide clues for cross-coupling reactions via C−H activation under mild conditions. Further extension of the substrate scope beyond five-membered heterocycles is now under investigation.

In contrast, carboxylate salts with different substituents showed a negative effect on the reaction, affording products with low levels of deuterium incorporation (Scheme S9). Furthermore, by varying the amount of KOAc, we found 0.1 equiv or more of KOAc can dramatically decrease the level of deuterium incorporation (Scheme 7), suggesting that the Scheme 7. Exploring the Effect of KOAc in the Ag2CO3Catalyzed HIE Reactiona

a

The reaction was conducted on 0.3 mmol of 1a, 6 mmol of D2O, 10 mol % of Ag2CO3, 10 mol % of JohnPhos, and additives in 1 mL of DMSO at 25 °C. bDetermined by GC−MS.

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carboxylate group possibly replaced the carbonate group to coordinate with silver cation and retarded the H/D exchange process (Scheme S10). This result is interesting because carboxylate salts are commonly employed to accelerate the C− H activation process. In an attempt to gain more insight into the reaction mechanism, density functional theory (DFT) calculations were conducted at the PCM-B3LYP/SDD/6-31G(d,p) level with DMSO as solvent. All of the intermediates and transition states were examined with frequency analysis. As shown in Figure 1, the reaction pathway involving a carbonate or carboxylic group was calculated separately. The H/D exchange process is mainly carried out via two steps. The first step is abstraction of hydrogen from thiophene by the Ag(I) salt. The second step is transfer of deuterium from heavy water to thiophene and release of the Ag(I) salt. According to the reaction energy profile, the first step has a higher energy barrier than the

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02369. Experimental procedures and spectral data (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hong-Hai Zhang: 0000-0003-1413-8847 D

DOI: 10.1021/acs.orglett.9b02369 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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Xiao-Chun Hang: 0000-0002-3097-1268 Wei Huang: 0000-0001-7004-6408 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Grant No. 21704041), Major Program of Natural Science Research of Jiangsu Higher Education Institutions of China (No.18KJA150005), and Natural Science Foundation of Jiangsu Province (No.BK20181373) for support. We thank Peter V. Bonnesen and Kunlun Hong (Oak Ridge National Laboratory) for assistance with the preparation of the manuscript.

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