Sulfoxonium ylides for direct methylation of N-heterocycles in water

doi:10.21203/rs.3.rs-39962/v1

Download PDF

Article

Sulfoxonium ylides for direct methylation of N-heterocycles in water

https://doi.org/10.21203/rs.3.rs-39962/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

The direct methylation of N-heterocycles is an important transformation for the advancement of pharmaceuticals, agrochemicals, functional materials, and other chemical entities. Herein, the unprecedented C(sp2)–H methylation of iminoamido N-heterocycles as nucleoside base analogues is described. Notably, trimethylsulfoxonium salt was employed as a methylating agent under aqueous conditions. A wide substrate scope and excellent level of functional group tolerance were attained. Moreover, this method can be readily applied to the site-selective methylation of azauracil nucleosides. The feasibility of gram-scale reactions and various transformations of the products highlight the synthetic potential of the developed method. Combined deuterium-labeling experiments aided the elucidation of a plausible reaction mechanism.

Organic Chemistry

Physical Chemistry

Methylation is one of vital processes in biological systems because DNA and histone methylation is responsible for gene expression without affecting the gene sequence^1–2. For example, the C(sp²)–H methylation of uracil of deoxyuridine-5’-monophosphate (dUMP) by thymidylate synthase is a well-known metabolic process for DNA biosynthesis and RNA post-translational modification^3–4. In addition, methylation of cysteine can affect signaling pathways by disrupting ubiquitin-chain sensing in NF-κB activation⁵. Methylation is also an important modification in medicinal chemistry and drug discovery, as physical and pharmacological properties of lead candidates can be favorably or adversely affected with the mere addition of a methyl group⁶. To address this challenge, number of synthetic strategies have been explored to install methyl and alkyl groups on N-heterocyclic molecules^7–9. In particular, alkylation beyond monoazines, i.e., that of diazines and triazines, has emerged as a hot topic in this area due to the relevance of a number of bioactive molecules^10–14.

The conventional approach is the transition-metal-catyzed cross-coupling reactions between halogenated N-heterocycles and organometallic reagents (Fig. 1a)^15–16. Minisci-type alkylations using alkyl radicals^17–22 and metal-catalyzed C–H alkylations^23–30 of N-heterocycles constitute the current established protocols. Alternative routes including the metal-free C–H alkylations of preactivated N-heterocycles have been also developed^31–34. Recently, our group described the reductive C2-alkylation of heterocyclic N-oxides using phosphonium ylides (Fig. 1b)^35–36. In this reaction, a concerted [3+2] cycloaddition between a 1,3-dipolar fragment of pyridine N-oxides and zwitterionic phosphonium ylides provides aza-oxaphospholane intermediates, which subsequently undergo aromatization to afford C2-alkylated pyridines. A key driving force might be the formation of a strong P=O bond (bond dissociation energy of Ph₃P=O = 529 kJ/mol).

Since the landmark discovery by Johnson, Corey, and Chaykovsky in the 1960s^37–39, sulfoxonium ylides have been widely employed as methylene surrogates in epoxidations, cyclopropanations, and aziridinations via intermolecular nucleophilic addition into electron-deficient π-unsaturated compounds, such as carbonyls, α,β-unsaturated compounds, and imines^40–43. However, there are no reports on the direct alkylation of N-heterocyclic compounds using alkyl sulfoxonium ylides. Moreover, previous reports related to sulfoxonium ylides predominantly rely on the use of organic solvents, which preclude them as environmentally benign processes^44–48. Herein, we describe the unprecedented C(sp²)–H alkylation of iminoamido diazines and triazines as nucleoside base analogues with alkyl sulfoxonium salts. Of particular importance is the unconventional mechanistic pathway for the imino alkylation in aqueous media, which can provide novel insights into Corey-Chaykovsky reagents (Fig. 1c). Moreover, the amenability of this protocol to the pharmaceutical industry is attributed to the use of H₂O as the greenest solvent and KOH as an economical reagent.

Investigation of reaction conditions. Optimization of reaction conditions commenced with the coupling between pyrazinone 1a and trimethylsulfoxonium iodide (2a), as shown in Table 1. The formation of C3-methylated pyrazinone 3a was achieved with the use of KO^tBu in THF at 100 ^oC (entry 1). This reaction could likewise be performed in protic solvents, such as MeOH (entry 3). Surprisingly, aqueous media accelerated the coupling reaction between 1a and 2a to afford 3a in 84% yield within 2 h (entry 4). It should be noted that the aziridine compound generated from the imine functionality by the Corey-Chaykovsky aziridination was not observed in all cases, suggesting that the reaction pathways of the Corey-Chaykovsky reaction and the C(sp²)–H methylation reported herein are distinct. More importantly, this reaction was successful with the use of KOH, a cost-efficient base, to provide 3a in 91% yield (entry 5). Screening of other bases yielded inferior results (entries 6 and 7). Control experiments revealed that the loading amount of KOH and reaction temperature were crucial for increasing the yield of 3a (entries 8 and 9) (see Table 1 in the Supplementary Files).

Substrate scope with respect to pyrazinones. With the optimized reaction conditions in hand, the substrate scope of pyrazinones was examined (Table 2). A wide range of N-alkylated and N-benzylated pyrazinones 1b–1f were found to be suitable substrates for this transformation, providing the corresponding C3-methylated pyrazinones 3b–3f in high yields. Substrates 1c–1f produced the corresponding products in low yields in H₂O, presumably due to the presence of hydrophobic substituents. After careful screening of reaction conditions, it was established that protic solvents, such as EtOH and i-PrOH, resulted in higher levels of conversion. Notably, N-tetrahydropyranyl and N-benzyl groups are readily removable via conventional protocols for further elaboration of the free-(NH)-amido group. In addition, we observed the successful methylation of N-arylated pyrazinones 1g–1l. Halogen-substituted and electron-rich N-aryl groups (1g and 1j) displayed good reactivity, whereas electron-deficient N-aryl groups (1h, 1i, 1k and 1l) were relatively less reactive. The electronic effect on this transformation was likewise observed for the C4-arylated pyrazinones 1m–1p. The tolerance of cyano and bromo groups presents valuable opportunities for further versatile synthetic transformation. Moreover, tri-substituted pyrazinone adduct 3q was formed smoothly in 73% yield. Furthermore, the site-selective methylation of 1r–1t was successfully achieved under the standard reaction conditions, affording the corresponding products 3r–3t in high yields. (see Table 2 in the Supplementary Files)

Substrate scope with respect to sulfoxonium salts. Having established the broad scope of pyrazinones, the scope of sulfoxonium salts 2b–2e was then evaluated. In the case of ethylation and propylation, trialkyl sulfoxonium chlorides were employed as alkylating agents to afford the corresponding products 3u (70%) and 3v (77%). The current protocol could be implemented using Johnson’s sulfoxonium salts⁴⁹ 2d and 2e to furnish cyclopropylated pyrazinone 3w (45%) and methylated pyrazinone 3a (35%), respectively.

Substrate scope with respect to quinoxalinones. Meanwhile, the scope of quinoxalinones 4a–4l was explored (Table 3). N-Alkylated quinoxalinones 4a–4c and N-benzylated quinoxalinone 4d were successfully reacted with 2a to provide C3-methylated quinoxalinone adducts 5a–5d in excellent yields. Additionally, quinoxalinones 4e and 4f were coupled with 2a to afford 5e (94%) and 5f (32%), respectively. The reaction also readily proceeded with N-arylated quinoxalinones 4g–4k, furnishing the corresponding products 5g–5k. Notably, the electronic property of the quinoxalinone or N-aryl rings had a profound effect on this transformation. For example, the methylation of highly electron-deficient quinoxalinone derivatives 4f, 4h and 4k was less efficient. Finally, pyrido-pyrazinone 4l also participated in the methylation reaction to provide 5l in 78% yield. (see Table 3 in the Supplementary Files)

Substrate scope with respect to azauracils and azauracil nucleosides. Azauracil, an azapyrimidinone analogue of uracil, is of interest in medicinal chemistry due to its potential to inhibit various species of microorganisms. The ribonucleosides of 6-azauracil have been shown to display diverse biological profiles such as antiviral, antitumor, and antifungal activities^50–53. Based on the methylation of uracil in nature, we envisioned the direct alkylation of 6-azauracils and 6-azauracil nucleosides (Scheme 4). N-Substituted azauracil 6a was smoothly alkylated with 2a–2c to afford the corresponding products 7a–7c in satisfactory yields. In addition, triazinones 6b–6e were compatible with this process. It is noteworthy that hydroxyl and 2-pyranosyl groups in 7e and 7g were also tolerable. Direct C(sp²)–H methylation of 2’-deoxy-6-azauridine nucleoside 6f was successfully achieved by using K₃PO₄ as a base, providing 7h in 94% yield. Moreover, azauracil ribonucleoside 6g was also methylated with 2a to afford 7i in 91% yield.

Mechanistic investigation and proposed reaction mechanism. To garner mechanistic insights into this process, a series of deuterium-labeling experiments were performed (Fig. 2a). Treatment of 1a with KOH in the presence of D₂O resulted in 45% and 94% deuterium incorporation at the C3 and C6 positions, respectively. Partial deuteration (20%) on the N–Me group was also observed. These results indicate that a hydroxide anion possibly undergo nucleophilic addition onto imino functionality of pyrazinone 1a to generate a nitrogen anion intermediate, which can undergo a deuteration/deprotonation equilibrium reaction at the C3 and C6 positions (see the Supporting Information for the proposed mechanism). The reaction of 1a with 2a in the presence of D₂O under otherwise identical reaction conditions provided 93% deuteration at the benzylic CH₃ moiety as well as 73% deuteration at the C6 position, suggesting C3-methylation by sulfoxonium ylide on 1a followed by subsequent deproto-deuteration at the benzylic position. Benzylic deuteration was further confirmed by the reaction of 3a in aqueous KOH solution. To evaluate the unique reactivity of pyrazinones as cyclic iminoamides, control experiments were performed with N-aryl 2-pyridone and 2H-benzo[b][1,4]oxazin-2-one. No formation of methylated adducts under the standard reaction conditions was observed, revealing that the cyclic iminoamide backbone is crucial for the C(sp²)–H methylation (see the Supporting Information for the details). Based on the deuterium-labeling experiment results and previous literature related to sulfoxonium ylides,⁸ we propose a plausible reaction mechanism (Fig. 2b). Sulfoxonium ylide A, derived from 2a and KOH, undergoes nucleophilic addition onto the imine moiety of 1a, generating intermediate B. Under basic aqueous conditions, protonation of the nitrogen anion and E2 elimination of intermediate B spontaneously occur to deliver intermediate C and DMSO. The release of DMSO was detected by GC-MS analysis of the crude reaction mixture. Finally, protonation of the exo-olefin in C occurs to afford the C3-methylated pyrazinone 3a.

Synthetic applications. To illustrate the synthetic potential of the developed protocol, gram-scale experiments were first performed (Fig. 3a). The reaction of pyrazinone 1a (2 g, 10.8 mmol) with 2a afforded 3a in 90% yield. In addition, a gram-scale reaction of quinoxalinone 4d was also successfully performed, providing 5d in 95% yield. It is noteworthy that both products 3a and 5d were isolated by simple filtration instead of column chromatography, indicating the capability of the developed method in process chemistry. Next, various transformations of the synthesized C3-methylated products were performed (Fig 3b). The Ni(II)-catalyzed cross-coupling reaction between 3a and benzyl alcohol gave 8a in 82% yield. Benzylic oxidation of 3a with SeO₂ followed by reductive amination with 1-adamantylamine provided 8b in 40% yield. In addition, benzylic bromination of 5a and subsequent O-nucleophilic substitution with estrone furnished 8c in 50% yield. To demonstrate the utility of the N-protecting group, the tetrahydropyranoyl group on 3d was removed under acidic conditions to provide the free-(NH)-pyrazinone adduct in 90% yield, which further reacted with arylsulfonyl chloride to deliver 8d in 60% yield.

Synthesis of tetra-substituted pyrazine. To further demonstrate the utility of the developed methodology, the sequential transformation of N-benzylated pyrazinone 9a was performed (Fig. 4). Pyrazinone 9a was smoothly methylated with 2a to provide 9b in 82% yield. Removal of the benzyl group of 9b followed by treatment with PhPOCl₂ afforded chloropyrazine 9c in 79% yield. Finally, Suzuki cross-coupling reaction between 9c and 2-thiophene boronic acid under Pd(II) catalysis provided tetra-substituted pyrazine 9d in 70% yield.

In conclusion, we presented an unprecedented protocol for the direct C–H alkylation of N-heterocycles, including pyrazinones, quinoxalinones, and azauracils, using sulfoxonium salts as the alkylating agents. The use of aqueous solvent in the coupling reaction and the selective methylation of azauracil nucleosides under the developed reaction conditions are noteworthy. The synthetic applicability of this method was demonstrated by successful gram-scale reactions and valuable synthetic transformations of the methylated products, as well as by the synthesis of a tetra-substituted pyrazine via sequential transformations. The findings of this study are expected to be of significant interest to organic and medicinal chemists because of the synthetic simplicity, broad substrate scope, high efficiency, excellent chemoselectivity, and environmentally benign nature of the developed methodology.

General methods. For the synthetic procedure and ¹H, ¹³C and ¹⁹F NMR specta of all compounds in this manuscript, see Supplementary Informations.

General procedure for the methylation of 3a. To an oven-dried sealed tube charged with 1-methyl-5-phenylpyrazinone (1a) (37.6 mg, 0.2 mmol, 1.0 equiv.), KOH (33.6 mg, 0.6 mmol, 3.0 equiv.), and trimethylsufoxonium iodide (2a) (132.0 mg, 0.6 mmol, 3.0 equiv.) was added H₂O (1 mL) at room temperature under air. The reaction mixture was allowed to stir at 100 ^oC for 2 h. The reaction mixture was cooled to room temperature and filtered through a bed of Na₂SO₄. The solid bed was washed with a mixture of CH₂Cl₂ and MeOH (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (CH₂Cl₂/acetone = 97:3) to afford 36.0 mg of 3a in 90% yield.

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (Nos. 2019R1A4A2001451, 2020R1A2C3005357 and 2020M3A9I2081693).

Author Contributions

I.S.K. conceived and designed the experiments. I.S.K. and P.G. wrote the manuscript. P.G., N.Y.K., S.K. and S.H. performed experiments and prepared the Supplementary Information. S.H.L., W.A., N.K.M. and S.B.H. helped collecting some starting materials. P.G. and N.Y.K. contributed equally on this work. All authors discussed the results and commented on the manuscript.

Competing Interests

The authors declare no competing interests.

Additional Information

Supplementary Information is available for this paer at https://

Correspondence and requests for materials should be addressed to I.S.K.

Jones, P. A. & Takai, D. The role of DNA methylation in mammalian epigenetics. Science 293, 1068–1070 (2001).
Sasaki, H. & Matsui, Y. Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat. Rev. Genet. 9, 129–140 (2008).
Finer-Moore, J. S., Santi, D. V. & Stroud, R. M. Lessons and conclusions from dissecting the mechanism of a bisubstrate enzyme: thymidylate synthase mutagenesis, function, and structure. Biochemistry 42, 248–256 (2003).
Mishanina, T. V., Koehn, E. M. & Kohen, A. Mechanisms and inhibition of uracil methylating enzymes. Bioorg. Chem. 43, 37–43 (2012).
Zhang, L., Ding, X., Cui, J., Xu, H., Chen, J., Gong, Y.-N., Hu, L., Zhou, Y., Ge, J., Lu, Q., Liu, L., Chen, S. & Shao, F. Cysteine methylation disrupts ubiquitin-chain sensing in NF-κB activation. Nature 481, 204–208 (2012).
Leung, C. S., Leung, S. S. F., Tirado-Rives, J. & Jorgensen, W. L. Methyl effects on protein–ligand binding. J. Med. Chem. 55, 4489–4500 (2012).
Lewis, J. C., Bergman, R. G. & Ellman, J. A. Direct functionalization of nitrogen heterocycles via Rh-catalyzed C−H bond activation. Acc. Chem. Res. 41, 1013–1025 (2008).
Nakao, Y. Transition-metal-catalyzed C–H functionalization for the synthesis of substituted pyridines. Synthesis 20, 3209–3219 (2011).
Pan, S. & Shibata, T. Recent advances in iridium-catalyzed alkylation of C–H and N–H bonds. ACS Catal. 3, 704–712 (2013).
Azuaje, J., Carbajales, C., González-Gómez, M., Coelho, A., Caamaño, O., Gutiérrez-de-Terán, H. & Sotelo, E. Pyrazin-2(1H)-ones as a novel class of selective A3 adenosine receptor antagonists. Future Med. Chem. 38, 1373–1380 (2015).
Ramesh, R., Bovino, M. T., Zeng, Y. & Aubé, J. Synthesis of the nonribosomal peptide phevalin and analogs. J. Org. Chem. 84, 3647−3651 (2019).
Motohashi, K., Inaba, K., Fuse, S., Doi, T., Izumikawa, M., Khan, S. T., Takagi, M., Takahashi, T. & Shin-ya, K. JBIR-56 and JBIR-57, 2(1H)-Pyrazinones from a marine sponge-derived Streptomyces sp. SpD081030SC-03. J. Nat. Prod. 74, 1630–1635 (2011).
Abbas, H. S., Al-Marhabi, A. R., Eissa, S. I. & Ammare, Y. A. Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anticancer activity as inhibitors of c-Met kinase. Bioorg. Med. Chem. 23, 6560–6572 (2015).
Yuan, H., Li, X., Qu, X., Sun, L., Xu, W. & Tang, W. Synthesis and primary evaluation of quinoxalinone derivatives as potent modulators of multidrug resistance. Med. Chem. Res. 18, 671–682 (2009).
Molander, G. A. & Gormisky, P. E. Cross-coupling of cyclopropyl- and cyclobutyltrifluoroborates with aryl and heteroaryl chlorides. J. Org. Chem. 73, 7481−7485 (2008).
Price, G. A., Hassan, A., Chandrasoma, N., Bogdan, A. R., Djuric, S. W. & Organ, M. G. Pd-PEPPSI-IPent-SiO₂: a supported catalyst for challenging Negishi coupling reactions in flow. Angew. Chem., Int. Ed. 56, 13347−13350 (2017).
Antonchick, A. P. & Burgmann, L. Direct selective oxidative cross-coupling of simple alkanes with heteroarenes. Angew. Chem., Int. Ed. 52, 3267–3271 (2013).
McCallum, T. & Barriault, L. Direct alkylation of heteroarenes with unactivated bromoalkanes using photoredox gold catalysis. Chem. Sci. 7, 4754–4758 (2016).
Nuhant, P., Oderinde, M. S., Genovino, J., Juneau, A., Gagné, Y., Allais, C., Chinigo, G. M., Choi, C., Sach, N. W., Bernier, L., Fobian, Y. M., Bundesmann, M. W., Khunte, B., Frenette, M. & Fadeyi, O. O. Visible-light-initiated manganese catalysis for C–H alkylation of heteroarenes: applications and mechanistic studies. Angew. Chem., Int. Ed. 56, 15309–15313 (2017).
Matsui, J. K., Primer, D. N. & Molander, G. A. Metal-free C–H alkylation of heteroarenes with alkyltrifluoroborates: a general protocol for 1°, 2° and 3° alkylation. Chem. Sci. 8, 3512–3522 (2017).
Dong, J., Lyu, X., Wang, Z., Wang, X., Song, H., Liu, Y. & Wang, Q. Visible-light-mediated Minisci C–H alkylation of heteroarenes with unactivated alkyl halides using O₂ as an oxidant. Chem. Sci. 10, 976–982 (2019).
Proctor, R. S. J. & Phipps, R. J. Recent advances in Minisci-type reactions. Angew. Chem., Int. Ed. 58, 13666–13699 (2019).
Lewis, J. C., Bergman, R. G. & Ellman, J. A. Rh(I)-catalyzed alkylation of quinolines and pyridines via C–H bond activation. J. Am. Chem. Soc. 129, 5332–5333 (2007).
Ryu, J., Cho, S. H. & Chang, S. A versatile rhodium(I) catalyst system for the addition of heteroarenes to both alkenes and alkynes by a C–H bond activation. Angew. Chem., Int. Ed. 51, 3677–3681 (2012).
Nakao, Y., Yamada, Y., Kashihara, N. & Hiyama, T. Selective C–4 alkylation of pyridine by nickel/Lewis acid catalysis. J. Am. Chem. Soc. 132, 13666–13668 (2010).
Xiao, B., Liu, Z.-J., Liu, L. & Fu, Y. Palladium-catalyzed C–H activation/cross-coupling of pyridine N-oxides with nonactivated secondary alkyl bromides. J. Am. Chem. Soc. 135, 616–619 (2013).
Andou, T., Saga, Y., Komai, H., Matsunaga, S. & Kanai, M. Cobalt‐catalyzed C4‐selective direct alkylation of pyridines. Angew. Chem., Int. Ed. 52, 3213–3216 (2013).
Wu, X., See, J. W. T., Xu, K., Hirao, H., Roger, J., Hierso, J. C. & Zhou, J. S. A general palladium-catalyzed method for alkylation of heteroarenes using secondary and tertiary alkyl halides. Angew. Chem., Int. Ed. 53, 13573–13577 (2014).
Uemura, T., Yamaguchi, M. & Naoto, C. Phenyltrimethylammonium salts as methylation reagents in the nickel-catalyzed methylation of C–H bonds. Angew. Chem., Int. Ed. 55, 3162–3165 (2016).
Zell, D., Bu, Q., Feldt, M. & Ackermann, L. Mild C–H/C–C activation by Z-selective cobalt catalysis. Angew. Chem., Int. Ed. 55, 7408–7412 (2016).
Jo, W., Kim, J., Choi, S. & Cho, S. H. Transition-metal-free regioselective alkylation of pyridine N-oxides using 1,1-diborylalkanes as alkylating reagents. Angew. Chem., Int. Ed. 55, 9690–9694 (2016).
Zhou, W., Miura, T. & Murakami, M. Photocatalyzed ortho-alkylation of pyridine N-oxides through alkene cleavage. Angew. Chem., Int. Ed. 57, 5139–5142 (2018).
Moon, Y., Park, B., Kim, I., Kang, G., Shin, S., Kang, D., Baik, M.-H. & Hong, S. Visible light induced alkene aminopyridylation using N-aminopyridinium salts as bifunctional reagents. Nat. Commun. 10, 4117 (2019).
Mathi, G. R., Jeong, Y., Moon, Y. & Hong, S. Photochemical carbopyridylation of alkenes using N-alkenoxypyridinium salts as bifunctional reagents. Angew. Chem., Int. Ed. 59, 2049–2054 (2020).
Han, S., Chakrasali, P., Park, J., Oh, H., Kim, S., Kim, K., Pandey, A. K., Han, S. H., Han, S. B. & Kim, I. S. Reductive C2-alkylation of pyridine- and quinoline-N-oxides using Wittig reagents. Angew. Chem., Int. Ed. 57, 12737–12740 (2018).
Ghosh, P., Kwon, N. Y., Han, S., Kim, S., Han, S. H., Mishra, N. K., Jung, Y. H., Chung, S. J. & Kim, I. S. Site-selective C−H alkylation of diazine-N-oxides enabled by phosphonium ylides. Org. Lett. 21, 6488–6493 (2019).
Corey, E. J. & Chaykovsky, M. Dimethylsulfonium methylide, a reagent for selective oxirane synthesis from aldehydes and ketones. J. Am. Chem. Soc. 84, 3782–3783 (1962).
Corey, E. J. & Chaykovsky, M. Dimethyloxosulfonium methylide ((CH₃)₂SOCH₂) and dimethylsulfonium methylide ((CH₃)₂SCH₂). formation and application to organic synthesis. J. Am. Chem. Soc. 87, 1353–1364 (1965).
Johnson, C. R. The utilization of sulfoximines and derivatives as reagents for organic synthesis. Acc. Chem. Res. 6, 341–347 (1973).
Li, A.-H., Dai, L.-X. & Aggarwal, V. K. Asymmetric ylide reactions: epoxidation, cyclopropanation, aziridination, olefination, and rearrangement. Chem. Rev. 97, 2341–2372 (1997).
McGarrigle, E. M., Myers, E. L., Illa, O., Shaw, M. A., Riches, S. L. & Aggarwal, V. K. Chalcogenides as organocatalysts. Chem. Rev. 107, 5841–5883 (2007).
Sun, X.-L. & Tang, Y. Ylide-initiated Michael addition-cyclization reactions beyond cyclopropanes. Acc. Chem. Res. 41, 937–948 (2008).
Zhu, C., Ding, Y. & Ye, L.-W. Ylide formal [4 + 1] annulations. Org. Biomol. Chem. 13, 2530–2536 (2015).
Paxton, R. J. & Taylor, R. J. K. Improved dimethylsulfoxonium methylide rich cycalopropanatiron procedures, including a tandem oxidation variant. Synlett 4, 633–637 (2007).
Edwards, M. G., Paxton, R. J., Pugh, D. S., Whitwood, A. C. & Taylor, R. J. K. gem-Dimethylcyclopropanation using triisopropylsulfoxonium tetrafluoroborate: scope and limitations. Synthesis 20, 3279–3288 (2008).
Sone, T., Yamaguchi, A., Matsunaga, S. & Shibasaki, M. Catalytic asymmetric synthesis of 2,2-disubstituted terminal epoxides via dimethyloxosulfonium methylide addition to ketones. J. Am. Chem. Soc. 130, 10078–10079 (2008).
Marsini, M. A., Reeves, J. T., Desrosiers, J.-N., Herbage, M. A., Savoie, J., Li, Z., Fandrick, K. R., Sader, C. A., McKibben, B., Gao, D. A., Cui, J., Gonnella, N. C., Lee, H., Wei, X., Roschangar, F., Lu, B. Z. & Senanayake, C. H. Diastereoselective synthesis of α-quaternary aziridine-2-carboxylates via Aza-Corey–Chaykovsky aziridination of N-tert-butanesulfinyl ketimino esters. Org. Lett. 17, 5614−5617 (2015).
Lee, J., Ko, D., Park, H. & Yoo, E. J. Direct cyclopropanation of activated N-heteroarenes via site- and stereoselective dearomative reactions. Chem. Sci. 11, 1672–1676 (2020).
Johnson, C. R., Haake, M. & Schroeck, C. W. Preparation and synthetic applications of (dimethylamino)phenyloxosulfonium methylide. J. Am. Chem. Soc. 92, 6594–6598 (1970).
Lacramoe, J. F. A., Freyne, E. J. E., Deroose, F. D., Fortin, J. M. C. & Coesemans, E. Interlukin-5 inhibiting 6-azauracil derivatives. Intl. Pub. No. WO 2001/010866, (2001).
Crance, J. M., Scaramozzino, N., Jouan, A. & Garin, D. Interferon, Ribavirin, 6-azauridine and glycyrrhizin: antiviral compounds active against pathogenic flaviviruses. Antiviral Res. 58, 73–79 (2003).
Brown. J. M. & Rudel, L. L. Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery. Curr. Opin. Lipidol. 21, 192–197 (2010).
Park, J.-G., Ávila-Pérez, G., Nogales, A., Blanco-Lobo, P., de la Torre, J. C. & Martínez-Sobrido, L. Identification and characterization of novel compounds with broad-spectrum antiviral activity against influenza A and B viruses. J. Virol. 94, 1–20 (2020).

Due to technical limitations the Tables are available as a download in the Supplementary Files.

There is NO Competing Interest.

NatCommunSupportingInformationInSuKim.pdf
Sulfoxonium ylides for direct methylation of N-heterocycles in water
Tables.pdf

Download PDF

Version 1

posted

You are reading this latest preprint version

Sulfoxonium ylides for direct methylation of N-heterocycles in water

Status:

Version 1

Abstract

Figures

Introduction

Results

Discussion

Methods

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1