Skip to main content
NCBI home page
ACS Central Science logoLink to ACS Central Science
. 2025 Jul 1;11(7):1189–1198. doi: 10.1021/acscentsci.5c00797

Predictable C–H Functionalization of Complex beta-Fused Azines: A Mechanistically Bound Site-Specific Oxidation

Carla Obradors †,*, Christopher A Reiher ‡, Cristina Grosanu ‡, Mikko Muuronen §, Romain Tessier ∥, Egor M Larin †, Valentin Lehuédé †
PMCID: PMC12291144  PMID: 40726791

Abstract

Direct manipulation of C–H bonds enclosed in complex scaffolds persists today as an elusive disconnection when aiming for high and predictable site-selectivity. Its development toward the late-stage diversification of heterocycles remains of the upmost interest due to their ubiquitous presence in synthetic drugs and new methods consistently emerge to facilitate more versatile routes. The underlying challenge of activating a single C–H bond often leads to isomeric mixtures and a limited scope, which gets magnified in polycyclic frameworks, and the biased selectivity depending on the ring decoration recurrently hampers reliable retrosynthetic analyses. Here we report the straightforward C–H functionalization of multiple beta-fused azines toward a C–O bond formation with exclusive as well as predictable regiocontrol. Mild conditions enable the presence of a vast variety of motifs with orthogonal reactivity to transition-metals and highly sensitive moieties while also adding a divergent synthetic handle for further derivatizations in >10 distinct heterocyclic scaffolds.

graphic file with name oc5c00797_0008.jpg

graphic file with name oc5c00797_0007.jpg

Introduction

Drug discovery has long relied on the intricate assembly of heterocycles. − Engineered ring condensations along with derivatization of prefunctionalized building blocks constitute the most robust approaches for the preparation of N-based scaffolds. Nevertheless, constant development of novel methodologies is crucial to keep expanding the synthetic chemist’s toolkit toward a rapid diversification to new chemical space. − In the case of azines, a large variety of late-stage functionalization protocols has gradually arisen to unlock the direct manipulation of C–H bonds (Figure a); capitalizing on electrophilic substitutions, − radical transformations, − and transition-metal mediated C–H activation/deprotonation processes. − In spite of the tremendous progress, these often present recurrent pitfalls such as harsh conditions leading to a restricted scope, the necessity of directing groups, or limited selectivity. In parallel, preactivation strategies have also emerged to overcome some of these challenges. − An additional level of complexity that has usually been relegated to complementary examples of these methodologies, however, is the direct and efficient functionalization of polycyclic structures. Fused heterocycles are unequivocally cardinal pharmacophores in a vast array of biologically active products with further intrinsic synthetic hurdles. − Notably, complete regiocontrol is particularly challenging usually requiring either electronic or steric biases, plus a shift of selectivity can occur depending on each specific scaffold and/or the functional groups decorating the rings.

1.

1

Open in a new tab

State-of-the-art of C–H functionalization of azines. (a) Abundance in synthetic drugs and reactivity challenges when increasing structural complexity. (b) Specific examples of fused analogs. (c) This work: straightforward site-specific functionalization of multiple beta-fused azines with predictive regiocontrol.

For instance, one of the most common strategies utilized is electrophilic halogenation (Figure b). − Regioselectivity of this approach is strictly dictated by the electronics of the aromatic ring, changing with the substitution pattern, thus hampering its use as a reliable and selective late-stage retrosynthetic disconnection. Additionally, harsh conditions are often required for these electron deficient scaffolds that can lead to polyfunctionalization of the substrate, as in the isoquinoline pictured. These challenges are a general burden for direct C–H functionalization of multiple azines. − Namely, C–H amination enabled by photoredox catalysis required electron rich substrates, i.e., MeO-groups on the quinoline scaffold, where the regioselectivity is ring and substituent dependent. Similarly, predictability of radical additions is complex for many substrates. Regioselectivity tends to be favored in the α-position in the case of beta-fused azines, usually consuming superstoichiometric amounts of the coupling partner. In contrast, design of a directing template did enable distal C–H arylation with exclusive regioselectivity in isoquinolines. This method provided novel regiocontrol to the carbocyclic ring by using stoichiometric Pd. In analogy, Li/Mg/Zn-metalation of heterocycles facilitates a wide diversification of numerous scaffolds. − In this case, regioselectivity is also determined by the electronic bias of the substrate to favor deprotonation. Finally, effective preactivation strategies usually require superstoichiometric amounts of reagents as well generating significant waste, for example, in the phosphorus-mediated fluoroalkylation of azines. These precedents manifest the challenges in this area and the significant gap in providing general C–H functionalization strategies with a predictable selectivity independent of the heterocycle.

We disclose here the development of a broad, facile, and regiospecific C–H functionalization of distinct beta-fused azines that capitalizes on the intrinsic reactivity of the heterocyclic moiety (Figure c). The functionalization is characterized by the efficient and exclusive installation of sulfonates and chlorides at C4 that enable further derivatizations. The mild conditions permit its application to a wide chemical space, including densely functionalized drug-like scaffolds with sensitive functional groups and also to transition metals. It is worth pointing out that the protocol provides access to C–O bonds from the parent C–H, which has been a particularly demanding goal in the literature especially for electron poor rings. − Currently, the preparation of C4-oxidized beta-fused analogs involves multistep sequences initiated by deprotonation or electrophilic halogenation, wherein the regioselectivity is dictated by the substrate. In contrast, the reaction reported herein proceeds via a transient N-oxide that governs the regiocontrol of the transformation by completely migrating to C4. Thus, the method enables a predictable regioselectivity over >10 distinct heterocyclic scaffolds with diverse FG decoration through a mechanistically bound site-specificity, leading to a rare functionalization of beta-fused rings that has remained largely underexplored. Straightforward access to a versatile handle in such an elusive position streamlines targeted structure–activity relationship (SAR) explorations across multiple complex heterocycles. Furthermore, the method can be successfully transferred to an semi-automated platform for compound library synthesis. This capability is nowadays an essential feature in drug discovery to accelerate the medicinal chemistry’s design-test cycle; these ultimately enable the rapid generation of the key data to evolve a hit into a drug. −

Results and Discussion

Reaction Development

Typical conditions to functionalize isoquinolines at position 1 toward C–X bonds rely on the preparation of the N-oxide to facilitate nucleophilic addition and subsequent rearomatization of the azine (Figure a). During the derivatization of substrate 1a with TsCl, we observed that assembling compound 2 competes with heterocycle tosylation. Reaction in the presence of a base and a nucleophile such as tert-butyl amine, saccharine or para-hydroxyanisole undergoes both the expected nucleophilic addition in position 1 along with tosyl addition toward an isomeric mixture. Particularly, this competition becomes more pronounced when decreasing the nucleophilicity of NuH, leading to traces of bromination when tetrabutylammonium bromide (TBABr) is used along with hydration and dimerization. Thus, reaction of the N-oxide with TsCl forms the ion pair Int I where the nucleophiles add to C1 leading to Int II and product 2 after deprotonation (Figure b). However, instead of compound 2, 1H NMR analysis suggested the formation of another regioisomer as the major product of tosyl addition. Indeed, in the absence of a nucleophile and base, a distinct selectivity to C4 is obtained, affording isoquinoline 3a as a single isomer. We envisioned that this unusual disconnection could be a straightforward solution to a long-standing challenge in the direct C–H functionalization of complex polyaromatic scaffolds. Albeit the transformation is rather slow when utilizing TsCl, we were able to optimize the formation of 3a in excellent yield using Ts2O instead. Moreover, the reaction proceeds at multigram scale without significant erosion of its efficiency.

2.

2

Open in a new tab

Reaction development. (a) Nucleophilic addition to N-oxides and unusual TsO-regioselectivity. (b) Mechanistic hypothesis of conventional reactivity. (c) Direct transformation to C4 from the azine via mild oxidation in situ. Ratios measured by UPLC-UV. Yields measured by quantitative NMR, isolated yields in parentheses or in green.

To overcome the limited commercial availability of N-oxides, we reasoned that it would be key to develop a protocol that was practical and generated the N-oxide in situ from any fused azine, while remaining compatible with the subsequent activation/addition steps (Figure c). Complete oxidation proceeds under mild conditions with urea-hydrogen peroxide (UHP) and 5 mol % of methyltrioxorhenium (MTO). , Then, the immediate addition of Ts2O leads to the formation of isoquinoline 3a in 78% yield. This design effectively enables a simple one pot approach toward the straightforward and facile C–H functionalization of a beta-fused azine such as 4a with complete regiocontrol to C4. The one-pot procedure is similarly scalable.

Semi-Automated Scope Evaluation

We next examined the generality of the transformation by leveraging our high throughput experimentation (HTE) and purification (HTP) platforms. In drug discovery, these technologies use automation and miniaturization to enable rapid data generation from large compound libraries in parallel (10–103 substrates). − Here, we first identified readily available azine-containing fused building blocks, clustered them computationally by structural similarity, and then selected substrates to cover a wide range of medicinal chemistry relevant scaffolds and diverse functional groups (96- compounds library, 0.1 mmol scale). UPLC-MS analysis upon reaction completion demonstrated that a varied subset successfully underwent single tosylation, as depicted in Figure , as well as the feasibility of executing the protocol in a parallel mode (over 30% success; see SI for complete details). Besides multiple substitution patterns, the transformation tolerates esters, ketones, carboxylic acids, alkyl, alkoxy, polyfluoromethyl, bromide, chloride, nitro, and nitrile moieties as well as amine and hydroxyl groups. Notably, the reactivity observed for isoquinolines can efficiently be extended to multiple beta-fused N-heterocyclic scaffolds including naphthyridines and pyrido-isoxazoles, -thiophenes, -thiazoles, -isothiazoles, -triazoles, and -pyrazoles. In contrast, quinolines, quinazolines, monocyclic pyridines and 4-susbtituted isoquinolines do not undergo tosylation under these conditions, which establishes orthogonality between heterocycles. In addition, compounds with readily oxidizable functionalitiesfor example, aldehydes or boronic estersare not tolerated. More importantly, subsequent HTP enabled the confirmation of a predictable regioselectivity regardless of the scaffold used (>95% purity).

3.

3

Open in a new tab

Assessment of the generality of the transformation, selected examples from the HTE evaluation (over 30% success). Compounds detected by UPLC-MS were isolated by reverse phase HTP to >95% purity for characterization. a94% purity. b83% purity.

Reaction Scope

Consecutively, we contrasted these exploratory results to bench scale synthesis further assessing the procedure’s potential (Figure ). Under the optimized conditions, the purification of the N-containing products endured as the main challenge. Nevertheless, isoquinoline 3b bearing a nitrile (HTE-7) is obtained in 70% isolated yield. Investigation of the peripheral functional groups led analogously to distinct decorations in good yields (3c, 3e, 3f, 3g, 3i, and 3j), also incorporating fluoride groups and 8-substitution. Albeit with lower yield, the presence of electron-donating groups is also tolerated (3d). Moreover, the reaction allows fine-tuning of the conditions to increase the yield, such as higher temperatures during the oxidation step, as exemplified by the electron poor substrate 3h (see SI for details). Notably, reaction with 1-methylisoquinoline builds compound 3 as a minor product, instead favoring the Boekelheide transformation (5). Functionalization of more complex azines bearing multiple heteroatoms highlights further the prospects of the method. Preparation of naphthyridines 3k and 3l with bromide and chloride handles, respectively, validates the orthogonality of the protocol to transition-metal catalyzed reactions. In addition, this leads to polyfunctionalized scaffolds set for concurrent SAR diversifications. Similarly, as detected in the HTE, highly decorated [6,5]-fused heterocycles build the analogous products also with exclusive regiocontrol. Thus, substrates 3m, 3n, 3o, and 3p could be efficiently obtained and isolated here.

4.

4

Open in a new tab

Site-specific functionalization of a wide variety of N-heterocycles (isolated yields). aCross-checked examples from HTE. bOxidation under reflux. cCompound 3 observed as byproduct (19% LCAP). dSlightly unstable on silica gel. eOxidation with meta-chloroperbenzoic acid.

Tosylation of several densely functionalized compounds was also carried out, demonstrating its potential toward additionally complex drug-like scaffolds. A fluoxetine derivative underwent C–H functionalization to forge compound 3q, which introduced amides to the scope. Beyond discrimination from position 1, the reaction solely occurs on the heterocyclic ring, in contrast to alternative methods based on steric biases. The mild conditions of the protocol also permit the presence of highly sensitive moieties such as acetals, carbamates or epimerizable stereocenters as exemplified by the excellent yields for both glucoside and amino acid scaffolds 3r and 3t, respectively. The transformation shows orthogonal reactivity with monocyclic azines, such as pyridine, enabling the simultaneous presence of several N-heterocycles (3s). Finally, the more complex pyrido-isothiazole-sulfonamide of Celecoxib leads exclusively to C4 tosylation after major oxidation of the beta-fused azine with meta-chloroperbenzoic acid (3u). Beyond the various heterocyclic scaffolds, other activating agents were also interrogated (Figure a). Alkyl anhydrides such as Ms2O leads also to the corresponding product 3v. In parallel to TsCl, other arylsulfonyl chlorides consistently react with the azine, as shown by the para-nosyl group in 3w. No C–H functionalization was observed with Tf2O, Ac2O, bis­(trimethylsilyl) sulfate, tris­(trimethylsilyl) phosphate, or a sulfonyl fluoride. Finally, chlorination also occurs when using SO2Cl2 forming a mixture of 3x and 2.

5.

5

Open in a new tab

Access to product derivatives. (a) Alternative functionalization via migration of other activating groups. (b) Utility of tosylate as a synthetic handle. aCompound 2 was observed as the main product. bReaction conditions for the deprotection of 3a: KOH (5 equiv) and t BuOH (10 equiv) in PhMe at 100 °C. cFor the Kumada coupling: butylmagnesium chloride (2 equiv), 10 mol % (dme)­NiCl2 and 20 mol % PPh3 in 1,4-dioxane at 25 °C. dFor the C–P coupling: diisopropyl phosphonate (3 equiv), 10 mol % rac-BINAP Pd G4 and K2HPO4 (3equiv) in DMA at 120 °C. eFor the Buchwald–Hartwig coupling: p-toluidine (2 equiv), 10 mol % GPhos Pd G4 and Cs2CO4 (3 equiv) in 4:1 DMA/H2O at 90 °C. fFor the Sonogashira coupling: 1-ethynyl-4-methoxybenzene (2 equiv), 10 mol % XPhos Pd G4 and K3PO4 (3 eqiuv) in t BuOH at 90 °C. gFor the Suzuki coupling: p-tolyl boronic acid (2 equiv), 10 mol % PEPPSI-IPr and K3PO4 (3 equiv) in 4:1 1,4-dioxane/H2O at 90 °C.

Further Derivatizations

The C–OTs functionality presents many opportunities as a derivatization handle for unique molecular construction. − Besides deprotection to the hydroxylated product 6, multiple cross-coupling reactions that unlock diverse SAR explorations are accessible leading to compounds that would be difficult to obtain from simple isoquinoline (Figure b). For example, nickel-catalyzed Kumada builds compound 7 via C­(sp 2)–C­(sp 3) formation. Palladium catalysis enables forging C–X bonds, such as in phosphonates (8) as well as to anilines via a Buchwald–Hartwig reaction (9). Finally, we also prepared C­(sp 2)–C­(sp) and C­(sp 2)–C­(sp 2) analogs in excellent yields via Sonogashira and Suzuki couplings, products 10 and 11 respectively.

Mechanistic Insights

Finally, we conducted a kinetic analysis of the transformation via UPLC-UV that revealed that the reaction with the N-oxide generated in situ was faster than its isolated form (Figure a). Reaction of 1a and Ts2O led to 70% of 3a in 1 h, whereas TsCl consistently reached 40% (bold blue and gray lines, respectively). In contrast, in situ generation of the N-oxide from 4a with MTO/UHP increased the yield to 85% within 15 min but rapidly evolved to 12 (yellow line), presumably via overoxidation pathways. Such degradation could be prevented by using an excess of Ts2O (bold green line), which corresponds to the optimized conditions of the methodology. We reasoned the main difference between both procedures relies on the presence of H2O. Indeed, addition of 3 equiv of H2O to 1a remarkably increased the yield to 80% within 30 min with no degradation (red line). We hypothesize this behavior is due to a phase transfer effect between DCM and H2O. , Moreover, we also examined a potential kinetic isotope effect via an intermolecular competition experiment (Figure b). Reaction up to 54% conversion of a 1:1 mixture of 4a and d 7 -4a under standard conditions afforded a mixture of 3a and d 6 -3a with 48% of D incorporation, suggesting no significant KIE and thus a fast C–H bond cleavage.

6.

6

Open in a new tab

Mechanistic experiments. (a) Monitoring of the reaction under the conditions pictured in the scheme (bold blue line), reaction using TsCl instead of Ts2O (gray), reaction with the N-oxide generated in situ using MTO/UPH (yellow), reaction with the N-oxide generated in situ and with an excess of Ts2O (bold green), and reaction as pictured but in the presence of 3 equiv of H2O (red). (b) Intermolecular KIE experiment. (c) Hypothesis supported by NMR analysis and DFT calculations.

Combined with previous studies, − these experiments led us to postulate the mechanistic scenario depicted in Figure c. Initially, the N-oxide reacts with Ts2O forming the ion pair Int III. 1H NMR monitoring revealed an intermediate with a downfield shift of H1 in 1a, comparable to its protonation with TsOH (see SI for details). At this point, the TsO- attached to the nitrogen undergoes an unusual migration to C4 upon nucleophilic attack of the TsO– counterion to position 1. We performed DFT calculations to understand this step further, which suggested that the nucleophilic attack and the migration forming trans -Int IV occur here in a concerted fashion (TS‡). Dynamic reaction coordinate calculations revealed that simple addition of TsO– at C1 did not lead to a stable intermediate but triggers the elongation of the N–O bond while approaching the sulfonate to C4 in a [3,3]-sigmatropic rearrangement. Analysis of TS‡’s bond lengths shows these are formed/broken asynchronously (O–C1 1.48 Å, N–O 1.79 Å, and O–C4 3.6 Å). Subsequently, rearomatization of the heterocycle is achieved via a preferred deprotonation of the α-position of the iminium in trans -Int V (deprotonation from trans -Int IV cannot be excluded), which results in the regioselectivity observed in 3a. Overall, intramolecular migration of the activating group in the fused azine instills a mechanistically bound regiocontrol and, therefore, the predictable C–H functionalization. Favored deprotonation of H4 in the dearomatized intermediatebeing at the α-position of an iminiumtranslates to the exclusive C4 regiospecificity observed.

Conclusions

In summary, we have developed a novel method for the straightforward C–H functionalization of multiple beta-fused azines transpiring with exclusive site-selectivity. Once synthetically elusive, this reaction now enables consistently the introduction of sulfonate or chloride handles at C4, unlocking multiple diversifications toward SAR exploration. The transformation proceeds under mild conditions tolerating a wide variety of functional groups including those sensitive to transition-metals and with drug-like complex scaffolds. Moreover, the method efficiently translates in an semi-automated platform toward compound libraries, which is nowadays an essential feature in drug discovery to accelerate the medicinal chemistry’s design-test cycle. Of critical importance, the protocol enables this challenging C–O bond formation with predictable selectivity in an array of >10 fused heterocycles and independent of a diverse FG decoration. The proposed intramolecular migration of the activated N-oxide formed in situ drives the complete regiocontrol achieved.

Supplementary Material

oc5c00797_si_001.pdf (10.9MB, pdf)

Acknowledgments

We thank Thomas De Vijlder, Guido Verniest, Kiran Matcha, Hilmar Weinmann, Jaume Balsells, Scott Wolkenberg, and Kuanchang Chen for support and helpful discussions.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscentsci.5c00797.

  • Experimental procedures, spectroscopic and computational data. (PDF)

The authors declare no competing financial interest.

References

  1. Vitaku E., Smith D. T., Njardarson J. T.. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 2014;57:10257. doi: 10.1021/jm501100b. [DOI] [PubMed] [Google Scholar]
  2. Brown D. G., Bostrom J.. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 2016;59:4443. doi: 10.1021/acs.jmedchem.5b01409. [DOI] [PubMed] [Google Scholar]
  3. Blakemore D. C., Castro L., Churcher I., Rees D. C., Thomas A. W., Wilson D. M., Wood A.. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 2018;10:383. doi: 10.1038/s41557-018-0021-z. [DOI] [PubMed] [Google Scholar]
  4. Ishihara, Y. ; Montero, A. ; Baran, P. S. . The Portable Chemist’s Consultant; Apple Publishing Group, 2016. [Google Scholar]
  5. Cernak T., Dykstra K. D., Tyagarajan S., Vachal P., Krska S. W.. The medicinal chemist’s toolbox for late-stage functionalization of drug-like molecules. Chem. Soc. Rev. 2016;45:546. doi: 10.1039/C5CS00628G. [DOI] [PubMed] [Google Scholar]
  6. Murakami K., Yamada S., Kaneda T., Itami K.. C-H functionalization of azines. Chem. Rev. 2017;117:9302. doi: 10.1021/acs.chemrev.7b00021. [DOI] [PubMed] [Google Scholar]
  7. Zhang L., Ritter T.. A perspective on late-stage aromatic C-H bond functionalization. J. Am. Chem. Soc. 2022;144:2399. doi: 10.1021/jacs.1c10783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bellotti P., Huang H. M., Faber T., Glorius F.. Photocatalytic late-stage C-H functionalization. Chem. Rev. 2023;123:4237. doi: 10.1021/acs.chemrev.2c00478. [DOI] [PubMed] [Google Scholar]
  9. Josephitis C. M., Nguyen H. M. H., McNally A.. Late-stage C-H Functionalization of Azines. Chem. Rev. 2023;123:7655. doi: 10.1021/acs.chemrev.2c00881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bakke J. M., Svensen H., Ranes E.. The reaction mechanism of the nitration of pyridine compounds by N2O5-NaHSO4 . J. Chem. Soc., Perkin Trans. 1998;2:2477. doi: 10.1039/a804259d. [DOI] [Google Scholar]
  11. Bakke J. M., Ranes E., Riha J., Svensen H.. The synthesis of b-nitropyridine compounds. Acta Chem. Scand. 1999;53:141. [Google Scholar]
  12. Adams D. R., Bentley J. M., Benwell K. R., Bickerdike M. J., Bodkin C. D., Cliffe I. A., Dourish C. T., George A. R., Kennett G. A., Knight A. R., Malcolm C. S., Mansell H. L., Misra A., Quirk K., Roffey J. R.A., Vickers S. P.. Pyrrolo­(iso)­quinoline derivatives as 5-HT2C receptor agonists. Bioorg. Med. Chem. Lett. 2006;16:677. doi: 10.1016/j.bmcl.2005.10.029. [DOI] [PubMed] [Google Scholar]
  13. Smith, M. B. ; March, J. . Advanced Organic Chemistry: Reactions, Mechanisms, and Structure; Wiley-Interscience, 2007. [Google Scholar]
  14. Gao M., Nie C., Li J., Song B., Cheng X., Sun E., Yan L., Qian H.. Design, synthesis and biological evaluation of N 1 -(isoquinolin-5-yl)-N 2 -phenylpyrrolidine-1,2-dicaboxamide derivatives as potent TRPV1. Bioorg. Chem. 2019;82:100. doi: 10.1016/j.bioorg.2018.09.033. [DOI] [PubMed] [Google Scholar]
  15. Wang Y., Bi C., Kawamata Y., Grant L. N., Samp L., Richardson P. F., Zhang S., Harper K. C., Palkowitz M. D., Vasilopoulos A., Collins M. R., Oderinde M. S., Tyrol C. C., Chen D., LaChapelle E. A., Bailey J. B., Qiao J. X., Baran P. S.. Discovery of N-X anomeric amides as electrophilic halogenation reagents. Nat. Chem. 2024;16:1539. doi: 10.1038/s41557-024-01539-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nagao Y., Hirota K., Tokumaru M., Kozawa K.. Synthesis of 7-substituted derivatives of 5,8-dimethylisoquinoline. Heterocycles. 2007;73:593. doi: 10.3987/COM-07-S(U)38. [DOI] [Google Scholar]
  17. Astrazeneca A. B. Novel gram-negative anti-bacterial agents. WO 2010/100475 A1, 2010.
  18. Instituto di ricerche di biologia molecolare P. Angeletti S.P.A. Pyrrolopyridine therapeutic compounds. WO 2010/115901 A1, 2010.
  19. Koseoglu A., Gul T., Acar A. E.. A systematic study on the synthesis of n-butyl substituted 8-aminoquinolines. J. Hetero. Chem. 2016;53:263. doi: 10.1002/jhet.2399. [DOI] [Google Scholar]
  20. Takeda Pharmaceutical Company. Heterocyclic compounds as EP4 receptor antagonists. WO 2016/021742 A1, 2016.
  21. Fosu S. C., Hambira C. M., Chen A. D., Fuchs J. R., Nagib D. A.. Site-selective C-H functionalization of (hetero)­arenes via transient, non-symmetric iodanes. Chem. 2019;5:417. doi: 10.1016/j.chempr.2018.11.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Vivace therapeutics INC. Bicyclic compounds. WO 2020/214734 A1, 2020.
  23. Gupta S. S., Manisha, Kumar R., Dhiman A. K., Sharma U.. Predictable site-selective functionalization: promoter group assisted para-halogenation of N-substituted (hetero)­aromatics under metal-free conditions. Org. Biomol. Chem. 2021;19:9675. doi: 10.1039/D1OB02000E. [DOI] [PubMed] [Google Scholar]
  24. Keueper A. C., Fengler K., Ostler F., Danelzik T., Piekarski D. G., Garcia Mancheno O.. Fine tuning substrate-catalyst halogen-halogen interactions for boosting enantioselectivity in halogen bonding catalysis. Angew. Chem., Int. Ed. 2023;62:e202304781. doi: 10.1002/anie.202304781. [DOI] [PubMed] [Google Scholar]
  25. Margrey K. A., McManus J. B., Bonazzi S., Zecri F., Nicewicz D. A.. Predictive model for site-selective aryl and heteroaryl C-H functionalization via organic photoredox catalysis. J. Am. Chem. Soc. 2017;139:11288. doi: 10.1021/jacs.7b06715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Proctor R. S. J., Phipps R. J.. Recent advances in Minisci-type reactions. Angew. Chem., Int. Ed. 2019;58:13666. doi: 10.1002/anie.201900977. [DOI] [PubMed] [Google Scholar]
  27. Berger F., Plutschack M. B., Riegger J., Yu W., Speicher S., Ho M., Frank N., Ritter T.. Site-selective and versatile aromatic C-H functionalization by thianthrenation. Nature. 2019;567:223. doi: 10.1038/s41586-019-0982-0. [DOI] [PubMed] [Google Scholar]
  28. Cai C. Y., Chen S. J., Merchant R. R., Kanda Y., Qin T.. C3 selective hydroxylation of pyridines via photochemical valence isomerization of pyridine N-oxides. J. Am. Chem. Soc. 2024;146:24257. doi: 10.1021/jacs.4c10057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lyons T. W., Sanford M. S.. Palladium-catalyzed ligand directed C-H functionalization reactions. Chem. Rev. 2010;110:1147. doi: 10.1021/cr900184e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nakao Y., Yamada Y., Kashihara N., Hiyama T.. Selective C4 alkylation of pyridine by nickel/Lewis acid catalysis. J. Am. Chem. Soc. 2010;132:13666. doi: 10.1021/ja106514b. [DOI] [PubMed] [Google Scholar]
  31. Larsen M. A., Hartwig J. F.. Iridium-catalyzed C-H borylation of heteroarenes: scope, regioselectivity, application to late-stage functionalization, and mechanism. J. Am. Chem. Soc. 2014;136:4287. doi: 10.1021/ja412563e. [DOI] [PubMed] [Google Scholar]
  32. Shi H., Lu Y., Weng J., Bay K. L., Chen X., Tanaka K., Verma P., Houk K. N., Yu J. Q.. Differentiation and functionalization of remote C-H bonds in adjacent positions. Nat. Chem. 2020;12:399. doi: 10.1038/s41557-020-0424-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Gribble M. W., Liu R. Y., Buchwald S. L.. Evidence for simultaneous dearomatization of two aromatic rings under mild conditions in Cu­(I)-catalyzed direct asymmetric dearomatization of pyridine. J. Am. Chem. Soc. 2020;142:11252. doi: 10.1021/jacs.0c04486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Zhang T., Luan Y. X., Lam N. Y. S., Li J. F., Li Y., Ye M., Yu J. Q.. A directive Ni catalyst overrides conventional site selectivity in pyridine C-H alkenylation. Nat. Chem. 2021;13:1207. doi: 10.1038/s41557-021-00792-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Docherty J. H., Lister T. M., Mcarthur G., Findlay M. T., Domingo-Legarda P., Kenyon J., Choudhary S., Larrosa I.. Transition metal catalyzed C-H bond activation for the formation of C-C bonds in complex molecules. Chem. Rev. 2023;123:7692. doi: 10.1021/acs.chemrev.2c00888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Snieckus V.. Directed ortho-metalation, tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics. Chem. Rev. 1990;90:879. doi: 10.1021/cr00104a001. [DOI] [Google Scholar]
  37. Schlosser M.. The 2 × 3 toolbox of organometallic methods for regiochemically exhaustive functionalization. Angew. Chem., Int. Ed. 2005;44:376. doi: 10.1002/anie.200300645. [DOI] [PubMed] [Google Scholar]
  38. Chevallier, F. ; Mongin, F. . Lithiations and magnesiations on quinoline and isoquinoline. In Metallation of Azines and Diazines; Topics in Heterocyclic Chemistry; Springer, 2012. [Google Scholar]
  39. Balkenhohl M., Greiner R., Makarov I. S., Heinz B., Karaghiosoff K., Zipse H., Knochel P.. Zn-, Mg-, and Li-TMP bases for the successive regioselective metalations of the 1,5-naphthyridine scaffold (TMP = 2,2,6,6-tetramethylpiperidyl) Chem.Eur. J. 2017;23:13046. doi: 10.1002/chem.201703638. [DOI] [PubMed] [Google Scholar]
  40. Balkenhohl M., Jangra H., Makarov I. S., Yang S. M., Zipse H., Knochel P.. A predictive model towards site-selective metalations of functionalized heterocycles, arenes, olefins, and alkanes using TMPZnCl·LiCl. Angew. Chem., Int. Ed. 2020;59:14992. doi: 10.1002/anie.202005372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Kremsmair A., Hess A., Heinz B., Knochel P.. Regioselective magnesiation and zincation reactions of aromatics and heterocycles triggered by Lewis acids. Chem.Eur. J. 2022;28:e202103269. doi: 10.1002/chem.202103269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Bull J. A., Mousseau J. J., Pelletier G., Charette A. B.. Synthesis of pyridine and dihydropyridine derivatives by regio- and stereoselective addition to N-activated pyridines. Chem. Rev. 2012;112:2642. doi: 10.1021/cr200251d. [DOI] [PubMed] [Google Scholar]
  43. Ying B., Xu J., Zhu X., Shen C., Zhang P.. Catalyst-controlled selectivity in the synthesis of C2 and C3 sulfonate esters from quinoline N-oxides and aryl sulfonyl chlorides. ChemCatChem. 2016;8:2604. doi: 10.1002/cctc.201600555. [DOI] [Google Scholar]
  44. Fier P. S.. A bifunctional reagent designed for the mild, nucleophilic functionalization of pyridines. J. Am. Chem. Soc. 2017;139:9499. doi: 10.1021/jacs.7b05414. [DOI] [PubMed] [Google Scholar]
  45. Mathi G. R., Kweon B., Moon Y., Jeong Y., Hong S.. Regioselective C-H functionalization of heteroarene N-oxides enabled by a tracesless nucleophile. Angew. Chem., Int. Ed. 2020;59:22675. doi: 10.1002/anie.202010597. [DOI] [PubMed] [Google Scholar]
  46. Zhang X., Nottingham K. G., Patel C., Alegre-Requena J. V., Levy J. N., Paton R. S., McNally A.. Phosphorous-mediated sp 2 -sp 3 couplings for C-H fluoroalkylation of azines. Nature. 2021;594:217. doi: 10.1038/s41586-021-03567-3. [DOI] [PubMed] [Google Scholar]
  47. Obradors C., List B.. Azine activation via silylium catalysis. J. Am. Chem. Soc. 2021;143:6817. doi: 10.1021/jacs.1c03257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Cao H., Cheng Q., Studer A.. Radical and ionic meta-C-H functionalization of pyridines, quinolines, and isoquinolines. Science. 2022;378:779. doi: 10.1126/science.ade6029. [DOI] [PubMed] [Google Scholar]
  49. Day A. J., Jenkins T. C., Kischkewitz M., Christensen K. E., Poole D. L., Donohoe T. J.. Metal and activating group free C4-alkylation of isoquinolines via a temporary dearomatization strategy. Org. Lett. 2023;25:614. doi: 10.1021/acs.orglett.2c04149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Zhang M., Zhou Q., Luo H., Tang Z. L., Xu X., Wang X. C.. C3-Cyanation of pyridines: constrains on electrophiles and determinants of regioselectivity. Angew. Chem., Int. Ed. 2023;62:e202216894. doi: 10.1002/anie.202216894. [DOI] [PubMed] [Google Scholar]
  51. Bhattacharya D., Studer A.. meta-Hydroxylation of Pyridines, Quinolines, and Isoquinolines Using Dearomatized Intermediates. Angew. Chem., Int. Ed. 2025;137:e202423512. doi: 10.1002/ange.202423512. [DOI] [PubMed] [Google Scholar]
  52. Dick A. R., Hull K. L., Sanford M. S.. A highly selective catalytic method for the oxidative functionalization of C-H bonds. J. Am. Chem. Soc. 2004;126:2300. doi: 10.1021/ja031543m. [DOI] [PubMed] [Google Scholar]
  53. Borgel J., Tanwar L., Berger F., Ritter T.. Late-stage aromatic C-H oxygenation. J. Am. Chem. Soc. 2018;140:16026. doi: 10.1021/jacs.8b09208. [DOI] [PubMed] [Google Scholar]
  54. Li Z., Wang Z., Chekshin N., Qian S., Qiao J., Cheng P. T., Yeung K. S., Ewing W. R., Yu J. Q.. A tautomeric ligand enables directed C-H hydroxylation with molecular oxygen. Science. 2021;372:1452. doi: 10.1126/science.abg2362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Chopard C., Bertho G., Prange T.. Naphthalene-dioxygenase catalyzed cis-dihydroxylation of bicyclic azaarenes. RSC Adv. 2012;2:605. doi: 10.1039/C1RA00706H. [DOI] [Google Scholar]
  56. Roy S., Pradhan S., Punniyamurthy T.. Copper-mediated regioselective C-H etherification of naphthyridine with arylboronic acids using water as an oxygen source. Chem. Commun. 2018;54:3899. doi: 10.1039/C8CC02158A. [DOI] [PubMed] [Google Scholar]
  57. Hughes J. P., Rees S., Kalindjian S. B., Philpott K. L.. Principles of early discovery. Br. J. Pharmacol. 2011;162:1239. doi: 10.1111/j.1476-5381.2010.01127.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Hoffer L., Voitovich Y. V., Raux B., Carrasco K., Muller C., Fedorov A. Y., Derviaux C., Amouric A., Betzi S., Horvath D., Varnek A., Collette Y., Combes S., Roche P., Morelli X.. Integrated strategy for lead optimization based on fragment growing: the diversity oriented target focused synthesis approach. J. Med. Chem. 2018;61:5719. doi: 10.1021/acs.jmedchem.8b00653. [DOI] [PubMed] [Google Scholar]
  59. Schneider G.. Automating drug discovery. Nat. Rev. Drug Discovery. 2018;17:97. doi: 10.1038/nrd.2017.232. [DOI] [PubMed] [Google Scholar]
  60. Mahjour B., Zhang R., Shen Y., McGrath A., Zhao R., Mohamed O. G., Lin Y., Zhang Z., Douthwaite J. L., Tripathi A., Cernak T.. Rapid planning and analysis of high-throughput experiment arrays for reaction discovery. Nat. Commun. 2023;14:3924. doi: 10.1038/s41467-023-39531-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Brocklehurst C. E., Altmann E., Bon C., Davis H., Dunstan D., Ertl P., Ginsburg-Moraff C., Grob J., Gosling D. J., Lapointe G., Marziale A. N., Mues H., Palmieri M., Racine S., Robinson R. I., Springer C., Tan K., Ulmer W., Wyler R.. MicroCycle: an integrated and automated platform to accelerate drug discovery. J. Med. Chem. 2024;67:2118. doi: 10.1021/acs.jmedchem.3c02029. [DOI] [PubMed] [Google Scholar]
  62. Londregan A. T., Jennings S., Wei L.. Mild addition of nucleophiles to pyridine N-oxides. Org. Lett. 2011;13:1840. doi: 10.1021/ol200352g. [DOI] [PubMed] [Google Scholar]
  63. Soldaini G., Cardona F., Goti A.. Catalytic oxidation of imines based on methyltrioxorhenium/urea hydroperoxide: a mild and easy chemo- and regioselective entry to nitrones. Org. Lett. 2007;9:473. doi: 10.1021/ol062862w. [DOI] [PubMed] [Google Scholar]
  64. Wengryniuk S. E., Weickgenannt A., Reiher C., Strotman N. A., Chen K., Eastgate M. D., Baran P. S.. Regioselective bromination of fused heterocyclic N-oxides. Org. Lett. 2013;15:792. doi: 10.1021/ol3034675. [DOI] [PubMed] [Google Scholar]
  65. Jones M., Goodyear R. L.. High throughput purification in drug discovery: scaling new heights of productivity. ACS Med. Chem. Lett. 2023;14:916. doi: 10.1021/acsmedchemlett.3c00073. HTP uses mass-directed, reverse phase semi-preparative HPLC in a highly industrialized process to purify compounds to >95% for biological assays: [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Gelman D., Buchwald S. L.. Efficient palladium-catalyzed coupling of aryl chlorides and tosylates with terminal alkynes: use of a copper cocatalyst inhibits the reaction. Angew. Chem., Int. Ed. 2003;42:5993. doi: 10.1002/anie.200353015. [DOI] [PubMed] [Google Scholar]
  67. So C. M., Lau C. P., Chan A. S. C., Kwong F. Y.. Suzuki-Miyaura coupling of aryl tosylates catalyzed by an array of indolyl phosphine-palladium catalysts. J. Org. Chem. 2008;73:7731. doi: 10.1021/jo8014819. [DOI] [PubMed] [Google Scholar]
  68. Zhang Y., Lavigne G., Cesar V.. Buchwald-Hartwig amination of (hetero)­aryl tosylates using a well-defined N-heterocyclic carbene-palladium­(II) precatalyst. J. Org. Chem. 2015;80:7666. doi: 10.1021/acs.joc.5b01272. [DOI] [PubMed] [Google Scholar]
  69. Fu W. C., So C. M., Kwong F. W.. Palladium-catalyzed phosphorylation of aryl mesylates and tosylates. Org. Lett. 2015;17:5906. doi: 10.1021/acs.orglett.5b03104. [DOI] [PubMed] [Google Scholar]
  70. Piontek A., Ochedzan-Siodlak W., Bisz E., Szostak M.. Nickel-catalyzed C­(sp 2 )-C­(sp 3 ) Kumada cross-coupling of aryl tosylates with alkyl Grignard reagents. Adv. Synth. Catal. 2019;361:2329. doi: 10.1002/adsc.201801586. [DOI] [Google Scholar]
  71. Kang K., Huang L., Weix D. J.. Sulfonate versus sulfonate: nickel and palladium catalyzed multimetallic cross-electrophile coupling of aryl triflates with aryl tosylates. J. Am. Chem. Soc. 2020;142:10634. doi: 10.1021/jacs.0c04670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Wang Y., Gao Q., Liu Z., Bai S., Tang X., Yin H., Meng Q.. Enantioselective a-benzoyloxylation of b-keto esters by N-oxide phase transfer catalysis. J. Org. Chem. 2018;83:2263. doi: 10.1021/acs.joc.7b03150. [DOI] [PubMed] [Google Scholar]
  73. Anishchenko V. M., Redko A. M., Dykun O. M., Rybachenko V. I.. Efficient synthesis of mixed aliphatic benzoic anhydrides in a two-phase system. J. Mol. Struct. 2023;1281:135051. doi: 10.1016/j.molstruc.2023.135051. [DOI] [Google Scholar]
  74. Simmons E. M., Hartwig J. F.. On the interpretation of deuterium kinetic isotope effects in C-H bond functionalizations by transition metal complexes. Angew. Chem., Int. Ed. 2012;51:3066. doi: 10.1002/anie.201107334. [DOI] [PubMed] [Google Scholar]
  75. Ochiai E., Ikehara M.. Polarisation der heterozyklischen Ringe mit aromatischem Charakter: über eine Umlagerung von Isochinolin N-oxyd mittels Tosylchlorids. Pharm. Bull. Tokyo. 1955;3:454. doi: 10.1248/cpb1953.3.454. [DOI] [PubMed] [Google Scholar]
  76. Oae S., Kitao T., Kitaoka Y.. The mechanisms of the reactions of para-toluenesulfonyl chloride with isoquinoline and pyridine N-oxides. Tetrahedron. 1963;19:827. doi: 10.1016/S0040-4020(01)99334-2. [DOI] [Google Scholar]
  77. Oae S., Ogino K., Tamagaki S., Kozuka S.. Rearrangement of tertiary amine N-oxides: mechanism of the reaction of isoquinoline N-oxide with substituted benzenesulfonyl chlorides. Tetrahedron. 1969;25:5761. doi: 10.1016/S0040-4020(01)83084-2. [DOI] [Google Scholar]
  78. Ogino K., Oae S.. Mechanisms of the reactions of substituted isoquinoline and quinoline N-oxides with arenesulfonyl chlorides. Tetrahedron. 1971;27:6037. doi: 10.1016/S0040-4020(01)91768-5. [DOI] [Google Scholar]
  79. Maryanoff B. E., Zhang H. C., Reitz A. B., Leo G. C., Jones W. J.. Heteroaromatic N-oxide rearrangements: reinvestigation of 1,3-tosyloxy migration in the reaction of isoquinoline N-oxide with tosyl chloride. Tetrahedron Lett. 1993;34:7247. doi: 10.1016/S0040-4039(00)79299-9. [DOI] [Google Scholar]
  80. Lewis R. S., Wisthoff M. F., Grissmerson J., Chain W. J.. Metal-free functionalization of N,N-dialkylanilines via temporary oxidation to N,N-dialkylaniline N-oxides and groups transfer. Org. Lett. 2014;16:3832. doi: 10.1021/ol501813s. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

oc5c00797_si_001.pdf (10.9MB, pdf)

Articles from ACS Central Science are provided here courtesy of American Chemical Society

RESOURCES