Communication Cite This: J. Am. Chem. Soc. 2019, 141, 127−132
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A Mild and Direct Site-Selective sp2 C−H Silylation of (Poly)Azines Yiting Gu,†,¶,‡ Yangyang Shen,†,¶,‡ Cayetana Zarate,†,¶ and Ruben Martin*,†,§ †
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain ¶ Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, c/Marcel·lí Domingo, 1, 43007 Tarragona, Spain § ICREA, Passeig Lluís Companys, 23, 08010 Barcelona, Spain Downloaded via IOWA STATE UNIV on January 9, 2019 at 12:31:07 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
steric and electronic bias.11 If successful, we recognized that such a pathway would give access to elusive silylated advanced pharmaceutical ingredients (APIs) with predictable reactivity and site-selectivity. As part of our interest in catalytic C−Si bond-formations,12 we report herein the successful realization of this goal (Scheme 1, bottom). Our protocol is characterized by its simplicity, mild conditions and a predictable site-selectivity pattern, even in the context of late-stage silylation of azine drugs. Indeed, site-selectivity can be modulated by a judicious choice of the solvent employed while obviating the need for transition metal complexes or prefunctionalized substrates. Preliminary mechanistic studies suggest the intermediacy of silyl anions, offering orthogonal reactivity with existing silylation techniques. Our study began by evaluating the direct C4−silylation of pyridine (1a) with Et 3 SiBPin (Table 1). After some experimentation,13 we found that a transition metal-free protocol consisting of KHMDS in DME at rt afforded 2a in 74% isolated yield with excellent C4:C2 (10:1) ratio (entry 1). Interestingly, a strong solvent effect (entries 1−4) was noticed.
ABSTRACT: A base-mediated protocol that allows for the site-selective sp2 C−H silylation of azines is described. This method is distinguished by its mild conditions, simplicity and excellent site-selective modulation for a diverse set of azines, even in the context of late-stage functionalization, while exhibiting orthogonal reactivity with classical silylation reactions.
T
he prevalence of (poly)azines in pharmaceuticals and biologically active molecules has challenged chemists to design site-selective C−H functionalizations of these heterocycles.1,2 At present, these techniques typically rely on two-step procedures via preactivated (poly)azine intermediates (Scheme 1, path a).3 Despite the advances realized,2,3 a switchable and Scheme 1. Forging C−Heteroatom Bonds in (Poly)Azines
Table 1. Optimization of the Reaction Conditionsa
direct site-selective C−H functionalization capable of forging C−heteroatom bonds in (poly)azines still remains largely unexplored.4 For example, C4-selective functionalization is not as commonly practiced as one might initially anticipate, thus constituting a worthwhile endeavor.4−6 Driven by the versatility of (hetero)aryl silanes as synthons in organic synthesis and their interest in medicinal and materials science,7 the recent years have witnessed the design of metalcatalyzed sp2 C−H silylation reactions.8 While the coupling of electron-rich or electron-neutral (hetero)arenes has become routine,8,9 sp2 C−H silylation strategies of electron-deficient azines remain currently confined to C3-selective processes with noble Ir or Ru catalysts (Scheme 1, path b).10 Therefore, at the outset of our investigations it was unclear whether a switchable C2/C4−H silylation of pyridines could be developed without © 2018 American Chemical Society
entry
deviation standard conditions
yield (%)b
2a:3a
1 2 3 4 5 6 7 8 9 10 11
None diglyme as solvent 1a as solvent HMPA as solvent KOtBu instead of KHMDS Mg(HMDS)2 instead of KHMDS LiHMDS instead of KHMDS NaHMDS instead of KHMDS Et3SiH instead of Et3SiBPin no inert atmospheres (under air) from 1a N-oxide
80 (74)c 49 52 64 76 0 23 65 0 66 61
10:1 12:1 1.2:1 7:1 5:1 − 6:1 9:1 − 10:1 1:99
a 1a (0.40 mmol), Et3SiBPin (0.40 mmol), KHMDS (1 equiv), DME (2 mL) at rt. bGC yields using decane as internal standard. cIsolated yield, average of two independent runs.
Received: November 9, 2018 Published: December 18, 2018 127
DOI: 10.1021/jacs.8b12063 J. Am. Chem. Soc. 2019, 141, 127−132
Communication
Journal of the American Chemical Society
regioselectivity. As for Table 1 (entry 11), site-selectivity could be tuned and controlled by subtle modulation of the electronic properties of bipyridine cores via N-oxide derivatives (5y, 5z).18,19 The flexibility and generality of our site-selective silylation suggested that our protocol should be applicable within the context of late-stage silylation of azine drugs without requiring additional processing. As shown in Scheme 2, this turned out to
Specifically, C4 silylation was predominantly observed with bidentate solvents (entries 1−2) whereas the use of HMPA or 1a as solvent eroded both yield and selectivity (entries 3−4). Equally striking was the influence of the base and escorting counterion, thus revealing the noninnocent behavior of these variables on both reactivity and site-selectivity (entries 5−8).14 Moreover, Et3SiH as silyl source failed to provide 3a (entry 9)15,16 whereas good yields and selectivities were obtained under air (entry 10), thus constituting a bonus in practical terms.17 Interestingly, the utilization of N-oxide derivatives resulted in 3a as single regioisomer in 61% yield (entry 11).18,19 As evident from the results compiled in Table 2, systematic structural editing revealed that the C−H silylation can be
Scheme 2. Late-Stage Silylation of Azine Drugs
Table 2. Site-Selective Silylation of Azinesa,b
a
As Table 1 (entry 1). bIsolated yields, average of two independent runs. cKHMDS (2 equiv). d0 °C. e5 mmol scale. fFrom N-oxide derivative. gC4:C5 = 2.7:1.
be the case. C2- and C3-substituted pyridine drugs such as Doxylamine, Loratadine, Estrone and Nicotine exclusively delivered the corresponding C4-silylated pharmaceuticals (6, 8, 9 and 12) in good yields and site-selectivities.17 As evident from NMR spectroscopy,13 C2−Si bond-formation was solely obtained from Metyrapone (7) at the most electron-poor pyridyl backbone. A similar C2-selectivity pattern was observed with antiretroviral Nevirapine (10), an observation that could be confirmed by X-ray crystallography.21 Exhaustive C4-silylation could be applied to TmPyPB (11) whereas late-stage silylation was within reach for pyridimine-containing drugs such as Piribedil or Buspirone, affording 13 and 14 in good yields, the latter on a gram scale, as the only observable products. The non-negligible role exerted by both the solvent and escorting counterion suggested that C4-selectivity might be dictated by a solvent-separated ion pair, in which initial
applied to a wide number of azines. C4-silylated pyridines were invariably obtained in good yields and site-selectivities with azines possessing aliphatic or aromatic substituents at either C2 (5a, 5e−5h, 5k) or C3 (5b−5d, 5g−5j, 5l−5o), even with particularly sterically hindered combinations (5c, 5d).17 As anticipated, substituents at C4 gave rise to C2−silylated compounds (5p−5s). Notably, pyrazines (5u), pyridimines (5t), imidazo[1,2-b]pyridazines (5v), pyridimines (5w) or quinolines (5x) posed no problems. Equally interesting was the observation that ketones (5f), free amines (5k, 5l) or aryl chlorides (5m) do not interfere with C−Si bond-formation. The latter is particularly noteworthy, leaving ample room for further functionalization via cross-coupling reactions.20 Importantly, 5p could be scaled up without compromising neither yield nor 128
DOI: 10.1021/jacs.8b12063 J. Am. Chem. Soc. 2019, 141, 127−132
Communication
Journal of the American Chemical Society complexation of the nitrogen atom to K+ coordinated to DME confers a steric bias at C2 (Scheme 3, lef t).22,23 Exposure of 4p
Scheme 4. Intermediacy of Silyl Anion Species
Scheme 3. Regiodivergent Silylation of Pyridines
Scheme 5. Synthetic Application Profile
to KHMDS in THF-d8 corroborated this notion, showing a significant deshielding of the pyridine H atoms by 1H NMR spectroscopy.13 Although preactivated N-oxide azines offered a solution to enable a C2-silylation (Table 1, entry 11),19 we wondered whether a site-selectivity switch could be effected with unfunctionalized azines by a subtle modulation of the solvent denticity and aggregation.24 Interestingly, solvents lacking a proximal bidentate coordination mode such as dioxane predominantly resulted in a C2-silylation (3a−3e),25−27 suggesting the involvement of contacted ion pairs (Scheme 3, right).22,23 This interpretation gains credence by the erosion in C2-selectivity found with dioxane in the presence of DME or 18crown-6, with the latter providing exclusive access to 2a.13 The data summarized above suggest a scenario based on an initial complexation of the azine to K+ and the intermediacy of silyl anion species.28,29 This notion is supported by the reactivity found with 15 with Et3SiBPin (Scheme 4, right pathways). As shown, dearomatization was observed upon quenching with D2O or Me3SiCl (18−19), whereas their aromatized congeners (20−21) were cleanly obtained upon subsequent oxidation. To put these results into perspective, 16 and 17 were exclusively observed from 15 via KOtBu/Et3SiH-mediated silylation15a or Ni-catalyzed C−O cleavage (lef t pathways),12b thus showing the complementarity and orthogonal reactivity with other silylation events.30,31 The results shown in Scheme 5 further illustrates the prospective potential of our protocol, either triggering unusual defluorinative C−H silylations via nucleophilic attack followed by two consecutive [1,3]-H shifts (22)32 or as handles for subsequent functionalization via C−Si bond-cleavage (23− 24).33 In summary, we have developed a mild and site-selective C2/ C4-silylation of (poly)azines that obviates the need for transition metals, thus complementing existing sp2 C−H silylation events. The method can be applied for late-stage silylation of azine drugs, with a site-selectivity that can be
modulated by the nature of the solvent utilized. Further studies into the mechanism and related processes are currently ongoing.34
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b12063. Data for C21H28N4OSi (CIF) Data for C27H45N5O2Si (CIF) Experimental procedures, crystallographic data and spectral data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Yangyang Shen: 0000-0003-4607-9722 Cayetana Zarate: 0000-0002-4002-6147 Ruben Martin: 0000-0002-2543-0221 Author Contributions ‡
Y. Gu and Y. Shen contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank ICIQ and MINECO (CTQ2015-65496-R) for support and the ICIQ X-ray Diffraction Unit for the crystallo129
DOI: 10.1021/jacs.8b12063 J. Am. Chem. Soc. 2019, 141, 127−132
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Journal of the American Chemical Society
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graphic data. Y.S. and Y.G. thank China Scholarship Council (CSC) and MINECO for predoctoral fellowships.
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(12) (a) Somerville, R.; Hale, L.; Gomez-Bengoa, E.; Burés, J.; Martin, R. Intermediacy of Ni-Ni Species in sp2 C−O Bond Cleavage of Aryl Esters: Relevance in Catalytic C−Si Bond Formation. J. Am. Chem. Soc. 2018, 140, 8771. (b) Zarate, C.; Nakajima, M.; Martin, R. A Mild and Ligand-Free Ni-Catalyzed Silylation via C−OMe Cleavage. J. Am. Chem. Soc. 2017, 139, 1191. (c) Zarate, C.; Martin, R. A Mild Ni/CuCatalyzed Silylation via C−O Cleavage. J. Am. Chem. Soc. 2014, 136, 2236. (13) See Supporting Information for details. (14) For selected examples in which the escorting counterion plays a non-negligible role on reactivity, see: (a) Tobisu, M.; Takahira, T.; Morioka, T.; Chatani, N. Nickel-Catalyzed Alkylative Cross-Coupling of Anisoles with Grignard Reagents via C−O Bond Activation. J. Am. Chem. Soc. 2016, 138, 6711. (b) Cornella, J.; Martin, R. Ni-Catalyzed Stereoselective Arylation of Inert C-O bonds at Low Temperatures. Org. Lett. 2013, 15, 6298. (c) see ref 12b. (d) Casado, F.; Pisano, L.; Farriol, M.; Gallardo, I.; Marquet, J.; Melloni, G. J. Org. Chem. 2000, 65, 322. and citations therein. (15) The combination of Et3SiH/KOtBu has shown to promote the silylation of electron-rich heteroarenes via radical chain or pentacoordinated species: (a) Toutov, A. A.; Liu, W.-B.; Betz, K. N.; Fedorov, A.; Stoltz, B. M.; Grubbs, R. H. Silylation of C−H bonds in aromatic heterocycles by an Earth-abundant metal catalyst. Nature 2015, 518, 80. (b) Liu, W.-B.; Schuman, D. P.; Yang, Y.-F.; Toutov, A. A.; Liang, Y.; Klare, H. F. T.; Nesnas, N.; Oestreich, M.; Blackmond, D. G.; Virgil, S. C.; Banerjee, S.; Zare, R. N.; Grubbs, R. H.; Houk, K. N.; Stoltz, B. M. Potassium tert-Butoxide-Catalyzed Dehydrogenative C−H Silylation of Heteroaromatics: A Combined Experimental and Computational Mechanistic Study. J. Am. Chem. Soc. 2017, 139, 6867. (c) Banerjee, S.; Yang, Y.-F.; Jenkins, I. D.; Liang, Y.; Toutov, A. A.; Liu, W.-B.; Schuman, D. P.; Grubbs, R. H.; Stoltz, B. M.; Krenske, E. H.; Houk, K. N.; Zare, R. N. Ionic and Neutral Mechanisms for C−H Bond Silylation of Aromatic Heterocycles Catalyzed by Potassium tert-Butoxide. J. Am. Chem. Soc. 2017, 139, 6880. (16) It is worth noting that not even traces of 2a/3a were observed by exposing electron-poor azines to either KOtBu /Et3SiH (see ref 15) or KHMDS/Et3SiH, indicating that our silylation follows a different mechanistic rationale. (17) The addition of extra KHMDS/Et3SiBPin does not improve yields. The mass balance accounts for unreacted azine. (18) For a mechanistic rationale, see ref 13. (19) Albini, A.; Pietra, S. Heterocyclic N-Oxides; CRC Press: Boca Raton, FL, 1991. (20) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: Weinheim, 2004. (21) At present, we do not have a rationale behind the role exerted by the ketone backbone on site-selectivity en route to 7 and 10. (22) For the importance of coordination on the functionalization of azines, see: (a) Nagase, M.; Kuninobu, Y.; Kanai, M. 4-PositionSelective C−H Perfluoroalkylation and Perfluoroarylation of SixMembered Heteroaromatic Compounds. J. Am. Chem. Soc. 2016, 138, 6103. (b) Andou, T.; Saga, Y.; Komai, H.; Matsunaga, S.; Kanai, M. Cobalt-Catalyzed C4-Selective Direct Alylation of Pyridines. Angew. Chem., Int. Ed. 2013, 52, 3213. (c) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition of N-Activated Pyridines. Chem. Rev. 2012, 112, 2642. (d) Tsai, C. − C.; Shih, W. − C.; Fang, C. − H.; Li, C. − Y.; Ong, T. − G.; Yap, G. P. A. Bimetallic Nickel Aluminum Mediated Para-Selective Alkenylation of Pyridine: Direct Observation of η2,η1-Pyridine Ni(0)−Al(III) Intermediates Prior to C−H Bond Activation. J. Am. Chem. Soc. 2010, 132, 11887. (e) Nakao, Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. Selective C−4 Alkylation of Pyridine by Nickel/Lewis Acid Catalysis. J. Am. Chem. Soc. 2010, 132, 13666. (f) See ref 5a. (23) For selected references dealing with the complexation of K+ in DME, see: (a) Binda, P. I.; Delbridge, E. E.; Dugah, D. T.; Skelton, B. W.; White, A. H. Synthesis and Structural Characterization of Some Potassium Complexes of Some Bis(phenolate) Ligands and Some Novel Heterobimetallic Binuclear Arrays Formed with Trivalent 131
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Journal of the American Chemical Society 140, 163. (e) Chen, K.; Berg, N.; Gschwind, R.; König, B. Selective Single C(sp3)−F Bond Cleavage in Trifluoromethylarenes: Merging Visible-Light Catalysis with Lewis Acid Activation. J. Am. Chem. Soc. 2017, 139, 18444. (33) (a) von Wolff, N.; Char, J.; Frogneux, X.; Cantat, T. Synthesis of Aromatic Sulfones from SO2 and Organosilanes Under Metal-free Conditions. Angew. Chem., Int. Ed. 2017, 56, 5616. (b) Komiyama, T.; Minami, Y.; Hiyama, T. Aryl(triethyl)silanes for Biaryl and Teraryl Synthesis by Copper(II)-Catalyzed Cross-Coupling Reaction. Angew. Chem., Int. Ed. 2016, 55, 15787. For an ipso-iodination event, see ref 13. (34) It is worth noting that even unactivated benzene can be silylated in moderate yield. See ref 13.
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