Letter Cite This: Org. Lett. 2019, 21, 448−452
pubs.acs.org/OrgLett
Trideuteromethylation Enabled by a Sulfoxonium Metathesis Reaction Zuyuan Shen,† Shilei Zhang,‡ Huihui Geng,† Jiarui Wang,† Xinyu Zhang,† Anqi Zhou,† Cheng Yao,† Xiaobei Chen,*,† and Wei Wang*,†,§
Org. Lett. 2019.21:448-452. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/18/19. For personal use only.
†
State Key Laboratory of Bioengineering Reactor, and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China ‡ Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China § Department of Pharmacology and Toxicology, and BIO5 Institute, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721-0207, United States S Supporting Information *
ABSTRACT: A conceptually novel sulfoxonium metathesis reaction between TMSOI and cost-effective DMSO-d6 is developed for the efficient generation of a new trideuteromethylation reagent TDMSOI. The new reagent TDMSOI is produced highly efficiently by simply heating a mixture of TMSOI and DMSO-d6 and directly used for subsequent trideuteromethylation in a “one-pot” operation. The preparative power of the new versatile reagent and the “one-pot” protocol is demonstrated by its use to install the −CD3 moiety into broad functionalities including phenols, thiophenols, acidic amines, and enolizable methylene units in high yield and at a useful level of deuteration (>87% D).
T
he potential for the use of deuterium across multiple applications is bolstered by its safety profile, its proven capacity to improve drugs, and the predictability of its effects on small molecule properties. 1 However, the limited availability of deuterated compounds is a major barrier that inhibits the use of deuterium in biomedical research and drug discovery.2 The methyl group, one of the most commonly occurring moieties in bioactive compounds, occupies an unrivaled position in medicinal chemistry because of the “magic methyl effect”.3 XCH3 (X = O, N, S, et al.) are also well-known groups that are easy to metabolize. Therefore, effort has been devoted to the development of trideuteromethylation analogues for these methyl-containing pharmaceuticals to improve their metabolic stability.4 Notably, the FDA has approved Austedo (deutetrabenazine) as the first deuterated product for the treatment of chorea associated with Huntington’s disease in 2017 (Figure 1).5 The other representative molecules, such as SD-254, CTP-518, AVP-786, deuterated glyburide, and deuterated urapidil, currently are in clinical trials. Despite its proved improved properties in drug discovery and structural simplicity, the methods for introducing −CD3 into the target molecules of interest remains elusive owing to the paucity of practically useful methods and reagents.6 CD3I and (CD3)2SO4 are widely used trideuteromethylation reagents but with the carcinogenic and cost concerns.7 The lower toxicity and/or more cost-effectiveness of CD3OD and DMSO-d6 make them appealing trideuteromethylation alternatives. Nonetheless, their application in drug discovery is hampered by a very limited number of available synthetic © 2019 American Chemical Society
Figure 1. Drugs containing trideuteromethyl group.
methods. The introduction of a CD3O− group into aromatics for the synthesis of ArOCD3 has been achieved by using the established palladium-catalyzed coupling of alcohols (e.g., CD3OD) with aryl halides (Scheme 1a).8 An interesting metalfree CF3CO2H- mediated radical process with aryl triazenes is also realized by Bräse and co-workers (Scheme 1b).9 The synthesis of the carbon−CD3 bond has been developed recently by Antonchick et al. via an elegant radical process using DMSO-d6 as deuterium source (Scheme 1c).10 No doubt, a broad applicable trideuteromethylation method for the alkylation of various functional groups such as OH, NH, SH, etc. will significantly facilitate drug discovery. Toward this end, herein we report a new, general trideuteromethylation strategy (Scheme 1d). A sulfoxonium metathesis11 is Received: November 14, 2018 Published: January 7, 2019 448
DOI: 10.1021/acs.orglett.8b03641 Org. Lett. 2019, 21, 448−452
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Organic Letters
0, 1, 2, 4, 8, and 16 h. The studies revealed that as time went on (Figure 2), (1) the content of DMSO and CD3SOCH3
Scheme 1. Methods for Introducing the CD3 Group
Figure 2. Monitoring the new sulfoxonium metathesis progress.
continued to increase, while TMSOI kept decreasing and (2) a noticeable amount of CH3I was generated initially and then gradually disappeared. Therefore, the process involves the initial reversible decomposition of TMSOI to give DMSO and CH3I, and the latter reacts with DMSO-d6 to form a new deuterated sulfoxonium (2). The second decomposition of 2 releases CD3SOCH3 (3) and CD3I, and eventually the combination of CD3I and DMSO-d6 furnishes deuterated TDMSOI (1). Having proved the feasibility of the new sulfoxonium metathesis for the generation of 1 by simply heating the mixture of TMSOI and DMSO-d6, we next set out to optimize the metathesis and subsequent alkylation reaction conditions. A model trideuteromethylation with 4-nitrophenol 4a was probed (Table 1 and Tables S1−5). In the initial attempt, the formation of 1 was carried out using 30 equiv of DMSO-d6 (relative to TMSOI) at 80 °C for 4 h (Table 1, entry 1), and then 4a (0.9 equiv) and K2CO3 (1.0 equiv) were added. The mixture was stirred at 65 °C for 18 h to afford aryl ether in high yield, but the degree of deuterium incorporation was poor (36%). This may be attributed to incomplete exchange between TMSOI and DMSO-d6. Le Chatelier’s principle suggests that higher temperature and longer heating time drives the reaction forward to favor formation of the desired product.12 Indeed, enhancing these parameters could remarkably improve the deuterium incorporation, whereas it had an adverse effect on the reaction yield (entries 2−8). The best choice for further screening was the reaction conditions identified in entry 6 (120 °C, 2 h). When the loading of 1 was increased to 2 equiv, to our delight, a quantitative yield of 5a was furnished (entry 10). Next, adjusting the ratio of TMSOI/ DMSO-d6 from 30 to 40 times slightly enhanced the deuterium incorporation to 96% (entry 12). Eventually, a variety of bases were evaluated, all leading to inferior deuterium incorporations compared with K2CO3 (entries 14−18 vs 12). Nevertheless, it was found that the choice of a base for a specific substrate highly depended on the electronic nature of the substrate. Therefore, different bases were used in probing the substrate scope of the process. It is noteworthy that the role of TMSOI could be replaced by the same molar MeI in the metathesis reaction (entry 19). Owing to the absence of DMSO-h6, the desired deuterated product 5a was eventually generated with higher deuterium incorporation (98%) albeit in lower yield (89%).14
implemented between trimethyl sulfoxonium iodide (TMSOI) and readily accessible and less toxic DMSO-d6 and enables the efficient generation of trideuteromethyl sulfoxonium iodide (TDMSOI, 1) as a new, cost-effective trideuteromethylation reagent. The studies demonstrate that TDMSOI serves as a versatile trideuteromethylation reagent with a broad substrate scope and high efficiency in a “one-pot” operation. Structurally diverse phenols, carboxylic acids, thiophenols, anilines, and enolizable carbons can be trideuteromethylated with the reagent in high yield and at a useful level of deuteration (>87% D). Recently, we initiated a program aimed at developing practically applicable deuteration reagents and reactions for the synthesis of synthetically and medicinally valued deuterated building blocks and functional groups. To engineer the “magic methyl effect” deuterated version CD3 moiety into organic molecules, we harness the synthetic power of metathesis12 to create a new trideuteromethylation reagent. We envision that the sulfoxonium metathesis between trimethyl sulfoxonium iodide (TMSOI) and DMSO-d 6 might produce fully deuterated TDMSOI (1, Scheme 1d), which could be directly utilized for trideuteromethylation of various functionalities. The realization of the process can afford new safer and cheaper trideuteromethylation reagent than commonly used CD3I and (CD3)2SO4. However, implementing the metathesis strategy must overcome the challenge that the control of intrinsic reversibility enables to manipulate the equilibrium to achieve synthetically useful yields of the desired product. Inspired by Le Chatelier’s principle,13 we propose to explore the strategy of combining a thermodynamic approach with the use of one of the reaction components (e.g., DMSO-d6) in a large excess. The combined force drives the reaction forward to favor formation of the desired product (Scheme 1d). To test the hypothesis, a reaction of TMSOI (0.5 mmol) with DMSO-d6 (15 mmol) was heated at 80 °C. The metathesis reaction progress was monitored by 1H NMR at 449
DOI: 10.1021/acs.orglett.8b03641 Org. Lett. 2019, 21, 448−452
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Organic Letters Table 1. Optimization of Reaction Conditionsa
Scheme 2. Scope of Phenol as Substratesa−c
entry
temp (°C)
time (h)
1/4a
base
yieldb (%)
(% D)c
1 2 3 4 5 6 7 8 9 10 11 12d 13e 14d 15d 16d 17d 18d 19d,f
80 100 120 130 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120
4 4 4 4 3 2 1.5 1 2 2 2 2 2 2 2 2 2 2 2
1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.7 2.0 2.5 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Cs2CO3 KOH t-BuOK NaHCO3 K3PO4 K2CO3
94 87 49 45 56 58 62 66 74 99 99 99 99 91 90 88 99 91 89
36 75 94 93 94 94 91 89 94 94 94 96 96 91 71 84 93 85 98
a
Reaction conditions: unless otherwise specified, TMSOI (0.5 mmol) was dissolved in DMSO-d6 (15 mmol, 30 equiv) and stirred at 80− 130 °C in sealed tube for specified time. To the reaction mixture were added 4a (0.45−0.20 mmol) and base (1 mmol), and the resulting solution was stirred at 65 °C in sealed tube for 18 h. bIsolated yield. c Deuterium incorporation was determined by 1H NMR. d40 equiv of DMSO-d6 was used. e50 equiv of DMSO-d6 was used. fMeI (0.5 mmol) was used instead of TMSOI.
a Reaction conditions: unless otherwise specified, TMSOI (0.5 mmol) was dissolved in DMSO-d6 (20 mmol) and stirred at 120 °C in sealed tube for 2 h. To the reaction mixture were added 4 (0.25 mmol) and base (1 mmol), and the resulting solution was stirred at 65 °C in a sealed tube for 18 h. bIsolated yield. cDeuterium incorporation was determined by 1H NMR. dTMSOI (1 mmol) and DMSO-d6 (40 mmol) were used. eTMSOI (1.5 mmol) and DMSO-d6 (60 mmol) were used.
With the optimal reaction conditions in hand, the scope of the reactions was probed with a wide range of phenol substrates (Scheme 2). The results showed that the protocol served as a general strategy for the synthesis of structurally diverse aryl trideuteromethyl ethers. A variety of phenols, containing electron-withdrawing (4a−p) or -donating substituents (4q−v), could efficiently participate in the process to give products 5 with good to excellent yields and good deuterium incorporations. Furthermore, a similar trend was observed for naphthol 4w and heterocyclic phenols 4x−ac. The reaction was also applicable to double and triple trideuteromethylations of polyphenols (4ad−af), albeit with slightly decreased deuterium incorporations. Notably, the broad applicability of this methodology enabled the convenient access to trideuteromethyl versions of valuable drug and natural product targets (agomelatine 5ag, Ts-protected melatonin 5ah, and xanthotoxin 5ai) from their phenol precursors with satisfactory results. Encouraged by the successful trideuteromethylation of phenols, we then turned our attention to other types of substrates (Scheme 3). Remarkably, when the optimized protocol was applied to carboxylic acids, whether they were connected with aromatic or alkyl moieties, they could be readily converted into the corresponding trideuteromethyl esters 7a−k in 62−99% yields with uniformly high deuterium incorporations (96%). Significantly, when hydroxyl and carboxylic groups presented in the same molecule, both of them were well trideuteromethylated (7l). Thiophenols, the
analogues of phenols, were also proved to be effective substrates, providing the desired products 7m−r even without affecting the NH2 group in 7r. The methylation of nitrogen-containing moieties is a highly useful method. It was demonstrated that phthalimide, indole, and indoline all could be transformed into their corresponding trideuteromethylated products (7s−u). Finally, when active methylene compounds were treated with 1, one or two trideuteromethyl groups were efficiently introduced as illustrated in the formations of 7v−aa (see the optimization reaction conditions in Tables S6 and S7). Thus, the strategy serves as a versatile approach to the construction of O-CD3, SCD3, N-CD3, and C-CD3. In conclusion, in the study described here we developed a new, versatile trideuteromethylation reagent TDMSOI and a “one-pot” method for facile installation of the pharmaceutically relevant CD3 moiety into various functionalities in high yields and with a useful level of deuteration. Notably, a sulfoxonium metathesis reaction between TMSOI and DMSO-d6 is implemented for the synthesis of deuteration reagents by taking advantage of ready availability and cost effectiveness of 450
DOI: 10.1021/acs.orglett.8b03641 Org. Lett. 2019, 21, 448−452
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ACKNOWLEDGMENTS Financial support of this research from the program of the National Natural Science Foundation of China (21572055 and 21738002, W.W., and 21702058, X.C.) and the National Institutes of Health (1R01GM125920-01, W.W.) is gratefully acknowledged.
Scheme 3. Scope of Carboxylic Acid, Thiol, Amine and Active Methylene as Substratesa−c
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Reaction conditions: see the Supporting Information for experimental details. bIsolated yield. cDeuterium incorporation was determined by 1H NMR.
widely deuterated reagents/solvents. This new reagent and the protocol serve as alternatives to expensive and harmful CD3I and (CD3)2SO4, the regularly used trideuteromethylated reagents. It is expected that versatility of the new trideuteromethylation reagent and the simplicity and efficiency of the protocol will make it useful in approaches for the practical production of highly valued trideuteromethyl structures, an emerging tool in contemporary drug discovery.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03641. Experimental procedures, analytical data, and NMR spectra (PDF)
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REFERENCES
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AUTHOR INFORMATION
Corresponding Authors
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[email protected]. *E-mail:
[email protected]. ORCID
Shilei Zhang: 0000-0001-8169-0098 Wei Wang: 0000-0001-6043-0860 Notes
The authors declare no competing financial interest. 451
DOI: 10.1021/acs.orglett.8b03641 Org. Lett. 2019, 21, 448−452
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