Nitrogenation of Amides via C–C and C–N Bond Cleavage

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 May 2023Nitrogenation of Amides via C–C and C–N Bond Cleavage Ming-Hui Zhu, Zengrui Cheng, Jialiang Wei, Hui Tan and Ning Jiao Ming-Hui Zhu State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 , Zengrui Cheng State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 , Jialiang Wei State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 , Hui Tan State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 and Ning Jiao *Corresponding author: E-mail Address: [email protected] State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 State Key Laboratory of Organometallic Chemistry Sciences, Chinese Academy of Sciences, Shanghai 200032 https://doi.org/10.31635/ccschem.022.202202585 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Amides are among the fundamental chemicals in organic chemistry. Compared to other carbonyl functional groups, the transformation of amide is relatively difficult and remains a challenge. The traditional deconstruction transformations of amides to other functional products are usually limited to twisted or electronically activated amides. Herein, we describe a direct nitrogenation approach to convert amides into nitriles. This chemistry provides a novel amide transformation pathway via both C–C and C–N bond cleavage. Interestingly, the simple, readily available, and inexpensive inorganic salt NaNO2 is successfully employed as a nitrogen source in this organic N-incorporation process. Applications of this study are demonstrated through the late-stage modification of drug and natural product derivatives. Download figure Download PowerPoint Introduction Functional group transformations are fundamental synthetic methods in organic chemistry.1 In the past century, the direct transformation of active functional groups such as aldehydes, acetones, esters, carboxylic acid, alkenes and alkynes, and halides enables diversiform chemical synthesis.2,3 Theoretically, amide groups are relatively inert compared to the above active functional groups due to the n(N) to π*(C=O) conjugation leading to planar bonds containing double-bond characteristics (Scheme 1a).4–6 Generally, the direct conversion of amide groups is more difficult than that of aldehydes, ketones, or esters. To discover more organic transformation methodologies for synthesis and late-stage modification of complex chemicals, chemists have been interested in converting amides to other functional groups. Scheme 1 | Amide activation. Download figure Download PowerPoint Despite the significant development of addition, reduction, and substitution reactions with amides,7–41 the direct chemical bond functionalization strategy including C–C bond42–47 and C–N bond cleavage48–51 provides opportunities to discover new transformations of amides. In 1881, the Hofmann rearrangement reaction was reported, which enables the transformation of primary carboxamides to one-carbon-shorter amines through a key isocyanate intermediate (Scheme 1b).52,53 The degradation process occurs by the hydrolysis of the isocyanate group with the loss of CO2, which results in one carbon atom less than the starting amide but retention of the original N atom of the amide substrates.54–59 In 1981, the synthesis of ketones from N-methoxy-N-methylamides, known as the Weinreb ketone synthesis, was reported where the C–N bond of amides are cleaved by organometallic reagents (Scheme 1c).60–62 These two named reactions provide seminal amide transformation, although the substrates are limited to primary and N-methoxy substituted amides. Recently, several elegant strategies were disclosed to complete amide transformation through C–C or C–N bond activation. Charette and coworkers63 developed an interesting electrophilic activation approach to produce ketones (path I, Scheme 1d). Garg and coworkers64,65 reported a significant Ni-catalyst for the direct coupling reaction of amides with nucleophiles via C–N bond activation (path I, Scheme 1d). Interestingly, the Ni- or Pd-catalyzed relay of C–N bond activation, decarbonylation, and coupling reaction of amides was developed by the groups of Matasubara and Kurahashi,66,67 Szostak,68,69 Tobisu,70 and Zhou,71 respectively (path II, Scheme 1d). Despite the significance of these approaches, so far, aromatic amides and sensitive transition-metal catalysts are required in this relay strategy. A novel amide transformation discovery is still desired to enable more synthetic strategies and the direct late-stage modification of bioactive compounds. Inspired by the Hofmann rearrangement52,53 and our previous C–C bond nitrogenation reactions,72–75 we envisioned that preactivation of the amide would provide an opportunity for a N-nucleophile or N-radical addition and subsequent rearrangement process, which would enable a new conversion of amides. Herein, we report a powerful transition-metal-free nitrogenation of tertiary amides with both C–C and C–N bond cleavage for direct synthesis of nitriles (Scheme 1e). With readily available and inexpensive inorganic salt NaNO2 as nitrogen source, this chemistry provides a novel amide transformation and demonstrates an efficient protocol for late-stage modification of drug and natural product derivatives. Results and Discussion Initially, 3-(4-bromophenyl)-N,N-diethylpropanamide S1 was selected as the model substrate for condition optimization (see Supporting Information Tables S1−S5 for details). Through the initial investigation, the experimental results indicated that the substrate was interestingly converted into 2-(4-bromophenyl)acetonitrile 1 in 75% NMR yield in the presence of NaNO2, 2-OMe-Py and Tf2O reagents with trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) as the additives in MeCN (entry 1, Table 1). Poor yields were obtained with other bases such as 2-F-Py and 2-Cl-Py (entries 2 and 3). Further experiments showed that the ratios of NaNO2, 2-OMe-Py, and Tf2O had a big influence on the efficiency of this transformation (entries 4–6). Replacement of MeCN with EtOAc slightly increased the yield to 82% (entry 7). In contrast, the reaction in dichloromethane (DCM) absolutely suppressed this transformation (entry 8). Then, we evaluated the necessity of every component. The reaction was completely inhibited by the absence of 2-OMe-Py, Tf2O, or NaNO2 (entries 9–11). Fortunately, 1 was obtained in 79% in the absence of TFA and TFAA (entry 10). After the screening of different parameters (see Supporting Information), the optimal conditions (bold values) were identified: 2-OMe-Py (4 equiv) as base, Tf2O (3 equiv) as activation reagent, NaNO2 (2.5 equiv) as nitrogen source, and EtOAc as the solvent to perform the reaction under atmosphere (entry 12, Table 1). Table 1 | Selected Results of Reaction Optimizationa Entry Base (equiv) Tf2O (equiv) NaNO2 (equiv) Additive Solvent Yield (%)b 1 2-OMe-Py (4.0) 3.0 2.5 TFA and TFAA MeCN 75 2 2-F-Py (4.0) 3.0 2.5 TFA and TFAA MeCN 35 3 2-Cl-Py (4.0) 3.0 2.5 TFA and TFAA MeCN 47 4 2-OMe-Py (4.0) 3.0 2.0 TFA and TFAA MeCN 70 5 2-OMe-Py (3.5) 2.5 2.5 TFA and TFAA MeCN 66 6 2-OMe-Py (3.0) 2.0 2.5 TFA and TFAA MeCN 54 7 2-OMe-Py (4.0) 3.0 2.5 TFA and TFAA EtOAc 82 8 2-OMe-Py (4.0) 3.0 2.5 TFA and TFAA CH2Cl2 n.d. 9 — 3.0 2.5 TFA and TFAA EtOAc n.d. 10 2-OMe-Py (4.0) — 2.5 TFA and TFAA EtOAc n.d. 11 2-OMe-Py (4.0) 3.0 — TFA and TFAA EtOAc n.d. 12 2-OMe-Py (4.0) 3.0 2.5 — EtOAc 82 (79)c aReactions conducted on a 0.2 mmol scale. bYield was determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. n.d. = not detected. cIsolated yield. With the optimized conditions in hand, we investigated the substrate scope. Variant carbon chains (R1) were examined (Table 2). The β-aryl amides substituted by electron-rich, electron-deficient, and halogenated (F, Cl, and I) phenyl groups provided the corresponding compounds in good efficiency ( 2– 8). Decreasing ( 9 and 10) or increasing ( 11 and 12) the carbon-chain length of amides produced the one carbon shorter nitriles in moderate to good yields. Other aryl groups like naphthyl ( 13) and thienyl ( 14) substituted amides were also tolerated, resulting in moderate yields of the desired nitriles. It is noteworthy that the very simple aliphatic amides ( 19 and 20) as well as aliphatic amides with various functional groups like alkynyl ( 15), alkenyl ( 16), ester ( 17), and bromide ( 18) were compatible under the standard conditions. Moreover, the tetraethyladipamide with two amide groups successfully produced the succinonitrile ( 21) in 76% yield. Table 2 | Scope of Amidesa aReactions were conducted with 0.3 mmol of S (amide), 1.2 mmol of 2-OMe-Py, 0.9 mmol of Tf2O, and 0.75 mmol of NaNO2 in 4 mL of EtOAc for 12 h at 0 °C to rt. Isolated yields. bReactions were conducted with 0.3 mmol of S, 2.4 mmol of 2-OMe-Py, 1.8 mmol of Tf2O, and 1.5 mmol of NaNO2 in 4 mL of EtOAc for 12 h at 0 °C to rt. Next, amides ( S) with a range of N-substituents ( R 2 and R 3) on the nitrogen atom were explored (Table 3a). Dimethyl ( S22), dibenzyl ( S23), and ethyl, n-butyl ( S24) substituted β-aryl amides were converted into 2-(4-bromophenyl)acetonitrile with moderate yields. An array of cyclic alkyl substituents was also investigated, such as pyrrolidine ( S25), piperidine ( S26), and morpholine ( S27) substituents, delivering the products in 73% to 89% yields. As for N-alkyl-N-phenylamides ( S28 and S29), the transformation was accomplished with diminished yields, albeit without the observation of by-product formation. Remarkably, when six- to nine-membered lactams were employed in this reaction, the ring opened and liner products containing the N-nitrosamine and cyano groups were accessed in 34% to 68% yields ( 30– 33) (Table 3b). Unfortunately, primary and secondary amides were not suitable for this transformation under the standard conditions. Table 3 | Scope of N-substituted Amidesa aReactions were conducted with 0.3 mmol of S (amide), 1.2 mmol of 2-OMe-Py, 0.9 mmol of Tf2O, and 0.75 mmol of NaNO2 in 4 mL of EtOAc for 12 h at 0 °C to rt. Isolated yields. bReactions were conducted with 0.3 mmol of S, 2.4 mmol of 2-OMe-Py, 1,8 mmol of Tf2O and 1.5 mmol of NaNO2 in 4 mL of EtOAc for 12 h at 0 °C to rt. cReactions were conducted in MeCN. Furthermore, we anticipated our methodology could be applied to late-stage modification of drugs and natural product derivatives possessing the amide groups. The utility of this protocol was showcased by conversion of 34 to 41 (Table 4). The pharmaceutical amide derivatives delivered the corresponding nitrile structures in good yields, for example, 34 (from isoxepac), 35 (from mycophenolic acid), and 38 (from mupirocin). With the chlorambucil derivative 39, the reaction resulted in the formation of the desired nitrile with a further nitration process at the 2-position of the phenyl group under the standard conditions. Notably, the indometacin derivative containing two amide groups S40 was chemoselectively converted into target molecule 40, in which the amide group without α-methylene selectively survived. These results demonstrated the compatibility of complex structure of drugs and natural product derivatives in the present transformation. Table 4 | Late-Stage Modificationa aReactions were conducted with 0.3 mmol of S (amide), 1.2 mmol of 2-OMe-Py, 0.9 mmol of Tf2O, and 0.75 mmol of NaNO2 in 4 mL of EtOAc for 12 h at 0 °C to rt. Isolated yields. A series of experiments were carried out to obtain insights into the mechanism of this destruction reaction of amides. The labelling experiment with 15N-NaNO2 indicated that the nitrogen of nitrile product originated from NaNO2 (Scheme 2a), which is completely different from the traditional Hofmann rearrangement process. When 3,3-diphenylpropanamide ( S42) was subjected to this transformation, the indole derivative 42 (CCDC 2173734) was obtained (Scheme 2b), which indicated that an α-nitrogenation intermediate might be generated for the subsequent Friedel–Crafts type reaction captured by the phenyl group in the substrate S42. To further investigate the nitrogenation intermediate, the α-oxime substituted amide S43, which is a tautomer of α-nitroso substituted amide S43′ was synthesized. With the S43 as substrate, the corresponding nitrile product 43 was produced in 66% yield (Scheme 2c). These results suggested that the α-nitroso species might be the key intermediate involved in this transformation. Notably, under the standard conditions, the ketenimine salt int-1, int-4+H+, and int5+H+ were detected through the electrospray ionization high-resolution mass spectrometry (ESI-HRMS) analysis upon the reaction of S1, demonstrating the generation of ketenimine and α-nitroso species in situ (Scheme 2d). Scheme 2 | Mechanism studies. Download figure Download PowerPoint Based on the above preliminary results and previous reports,30–41,76–80 a possible mechanism is proposed in Scheme 3. Initially, amide is activated by Tf2O and 2-OMe-Py to afford the keteniminium salt int-1 (detected by HRMS, I, Scheme 2d). Subsequently, int-2 is formed by the oxygen atom of the nitrite nucleophile attacking the α-C of keteniminium salt. Then the relay of cyclization and fragmentation via four-membered ring int-3 occurs producing the key intermediate int-4 and its tautomer int-5 (detected by HRMS, II, Scheme 2d). Finally, with the assistance of Tf2O, oxonium int-6 is likely favorable to leave the TfOH leading to nitrile products through C–C cleavage. Meanwhile, int-7 is liberated, which undergoes the hydrolysis and decarbonation to give the diethylamine. Under the standard conditions, it easily further reacts with NaNO2 to deliver the by-product N,N-diethylnitrous amide. Alternatively, another pathway involving the direct reaction between enol intermediate of amide and nitrosonium to generate the int-4 could not be excluded at this stage. Scheme 3 | Proposed mechanism. Download figure Download PowerPoint Conclusion We developed a novel amide activation transformation to nitriles through inert C–C and C–N cleavage in good selectivity and yields. Utilizing simple and readily available NaNO2 as the nitrogen source, the shift from inorganic salt to organic nitrile compounds was accomplished by this protocol. Mechanism studies indicated the involvement of the formation of high-activity four-membered ring and α-nitroso species as the crucial intermediates. The application of the methodology was demonstrated by late-stage modification of natural and pharmaceuticals derivatives. We anticipate that the present chemistry will provide chemists new insights into amide transformation. Supporting Information Supporting Information is available and includes general information, substrate synthesis, experimental procedures, optimization details, control experiments, synthesis transformations, X-ray crystallographic data, product characterization data, NMR spectra, and HRMS. Conflict of Interest There is no conflict of interest to report. Acknowledgments We acknowledge the National Key R&D Program of China (grant no. 2021YFA1501700), the NSFC (grant nos. 22131002, 22161142019, and 81821004), and the Tencent Foundation for financial support. We thank Xi Wang in this group for reproducing the reactions of 19 and 26. References 1. Corey E. J.; Cheng X.-M.The Logic of Chemical Synthesis; Wiley & Sons, Inc.: New York, 1995. Google Scholar 2. Larock R. C.Comprehensive Organic Transformations: A Guide to Functional Group Preparations; Wiley & Sons, Inc.: New York, 1999. Google Scholar 3. Katritzky A. R.; Taylor R. J. K.Comprehensive Organic Functional Group Transformations II; Elsevier Science Ltd.: Oxford, 2004. Google Scholar 4. Kemnitz C. R.; Loewen M. J."Amide Resonance" Correlates with a Breadth of C−N Rotation Barriers.J. Am. Chem. Soc.2007, 129, 2521–2528. Google Scholar 5. Greenberg A., Breneman C. M., Liebman J. F., Eds.; The Amide Linkage: Structural Significance in Chemistry, Biochemistry and Materials Science; Wiley & Sons, Inc.: New York, 2003. Google Scholar 6. Szostak M.; Meng G.; Shi S.Cross-Coupling of Amides by N–C Bond Activation.Synlett2016, 27, 2530–2540. Google Scholar 7. Bower S.; Kreutzer K. A.; Buchwald S. L.A Mild General Procedure for the One-Pot Conversion of Amides to Aldehydes.Angew. Chem. Int. Ed.1996, 35, 1515–1516. Google Scholar 8. White J. M.; Tunoori A. R.; Georg G. I.A Novel and Expeditious Reduction of Tertiary Amides to Aldehydes Using Cp2Zr(H)Cl.J. Am. Chem. Soc.2000, 122, 11995–11996. Google Scholar 9. Motoyama Y.; Mitsui K.; Ishida T.; Nagashima H.Self-Encapsulation of Homogeneous Catalyst Species into Polymer Gel Leading to a Facile and Efficient Separation System of Amine Products in the Ru-Catalyzed Reduction of Carboxamides with Polymethylhydrosiloxane (PMHS).J. Am. Chem. Soc.2005, 127, 13150–13151. Google Scholar 10. Das S.; Addis D.; Zhou S.; Junge K.; Beller M.Zinc-Catalyzed Reduction of Amides: Unprecedented Selectivity and Functional Group Tolerance.J. Am. Chem. Soc.2010, 132, 1770–1771. Google Scholar 11. Cheng C.; Brookhart M.Iridium-Catalyzed Reduction of Secondary Amides to Secondary Amines and Imines by Diethylsilane.J. Am. Chem. Soc.2012, 134, 11304–11307. Google Scholar 12. Das S.; Li Y.; Bornschein C.; Pisiewicz S.; Kiersch K.; Michalik D.; Gallou F.; Junge K.; Beller M.Selective Rhodium-Catalyzed Reduction of Tertiary Amides in Amino Acid Esters and Peptides.Angew. Chem. Int. Ed.2015, 54, 12389–12393. Google Scholar 13. Donnelly L. J.; Berthet J. C.; Cantat T.Selective Reduction of Secondary Amides to Imines Catalysed by Schwartz's Reagent.Angew. Chem. Int. Ed.2022, 61, e202206170. Google Scholar 14. Shirokane K.; Kurosaki Y.; Sato T.; Chida N.A Direct Entry to Substituted N-Methoxyamines from N-Methoxyamides via N-Oxyiminium Ions.Angew. Chem. Int. Ed.2010, 49, 6369–6372. Google Scholar 15. Fuentes de Arriba A. L.; Lenci E.; Sonawane M.; Formery O.; Dixon D. J.Iridium-Catalyzed Reductive Strecker Reaction for Late-Stage Amide and Lactam Cyanation.Angew. Chem. Int. Ed.2017, 56, 3655–3659. Google Scholar 16. Ou W.; Han F.; Hu X. N.; Chen H.; Huang P. Q.Iridium-Catalyzed Reductive Alkylations of Secondary Amides.Angew. Chem. Int. Ed.2018, 57, 11354–11358. Google Scholar 17. Ong D. Y.; Fan D.; Dixon D. J.; Chiba S.Transition-Metal-Free Reductive Functionalization of Tertiary Carboxamides and Lactams for α-Branched Amine Synthesis.Angew. Chem. Int. Ed.2020, 59, 11903–11907. Google Scholar 18. Li Z.; Zhao F.; Ou W.; Huang P. Q.; Wang X.Asymmetric Deoxygenative Alkynylation of Tertiary Amides Enabled by Iridium/Copper Bimetallic Relay Catalysis.Angew. Chem. Int. Ed.2021, 60, 26604–26609. Google Scholar 19. Hoerter J. M.; Otte K. M.; Gellman S. H.; Cui Q.; Stahl S. S.Discovery and Mechanistic Study of AlIII-Catalyzed Transamidation of Tertiary Amides.J. Am. Chem. Soc.2008, 130, 647–654. Google Scholar 20. Stephenson N. A.; Zhu J.; Gellman S. H.; Stahl S. S.Catalytic Transamidation Reactions Compatible with Tertiary Amide Metathesis under Ambient Conditions.J. Am. Chem. Soc.2009, 131, 10003–10008. Google Scholar 21. Kobayashi S.; Kiyohara H.; Yamaguchi M.Catalytic Silicon-Mediated Carbon−Carbon Bond-Forming Reactions of Unactivated Amides.J. Am. Chem. Soc.2011, 133, 708–711. Google Scholar Li G.; Szostak Transamidation of Amides and of Esters at Google Scholar Li G.; Szostak Transamidation of Unactivated Amides and Direct of Esters by Am. Chem. Google Scholar D.; Wang Q.; L.; Huang T.; Szostak M.; Chen Transamidation of Unactivated Tertiary Amides by by Chem. Int. Ed.2022, 61, Google Scholar M.; M. of Substituted via the of Am. Chem. Google Scholar 26. G.; Charette A. Reduction of Tertiary Amides.J. Am. Chem. Soc.2008, 130, Google Scholar N. J.; E.; D. S.; Reaction of Google Scholar G.; S.; Charette A. and Reduction of Secondary Amides.J. Am. Chem. Soc.2010, 132, Google Scholar K. J.; J. M.; K. Y.; Wang Y.; Huang P. One-Pot Reductive of with and Through Chem. Int. Ed.2010, 49, Google Scholar M.; M. of Am. Chem. Google Scholar K. J.; Wang A. E.; Huang P. of Secondary Amides into Secondary Reductive Chem. Int. Google Scholar D.; C.; of Amides.Angew. Chem. Int. Google Scholar de A.; M.; S.; L.; and of Amides with Am. Chem. Google Scholar M.; M. D.; of Am. Chem. Soc.2007, 129, Google Scholar de A.; D.; and of Amides to Amides and Amides.J. Am. Chem. Google Scholar D.; de A.; S.; by In of an Chem. Int. Ed.2017, 56, Google Scholar Li L. H.; J.; Li of Amides by C–C Bond A New to 54, Google Scholar M.; M. Reaction for the of and Google Scholar C. R.; M.; C. J.; D.; L.; to the of Amides with Am. Chem. Google Scholar C. J.; D.; M.; H.; of with Google Scholar J. W.; and for the and of Chem. Int. Google Scholar S. Bond A for Chem. Int. Google Scholar Wang M. A.; C–C Bond the in Synthesis.Angew. Chem. Int. Ed.2020, 59, Google Scholar Y.; or of C–C Google Scholar Shi S. H.; Y.; Jiao C–C Bond Google Scholar X. Y.; Chen J. R.; C–C Bond in Organic Google Scholar H.; Y.; P. F.; Wei via Bond Google Scholar N. of and C–N Using Google Scholar Wang Q.; Y.; Li L.; Huang Catalysed C–N Bond Google Scholar K.; W.; Xi Cleavage of C–N Google Scholar R.; K.; Yamaguchi of Esters and Google Scholar Hofmann A. of on Amides in Google Scholar C. H.; L. E.; R. A.; R. D.; R.; P. of in The Species in the Hofmann Am. Chem. Google Scholar of Substituted to with a Google Scholar Y.; T.; Hofmann Google Scholar D. S.; S.; K. H.; K. and of Carboxamides to Google Scholar C. J.; G. M.; J. C.; S.; K. G.; J.; R.; of and Google Scholar K. G. M.; S.; C. J.; J. C.; N. A.; Li G. M.; to the and Am. Chem. Google Scholar C. M.; J. N.A and of Amines by a One-Pot Chem. Int. Google Scholar S.; Weinreb S. as Google Scholar M.; A. Relay Weinreb Amide for the One-Pot of and Chem. Int. Google Scholar S.; T.; K.; Sato T.; Chida to Substituted from and to the of Chem. Int. Google Scholar S.; G.; Charette A. of and by of Organometallic to Secondary Google Scholar L.; N. F.; K.; E. L.; F.; K. N.; Garg N. of Amides to Esters by the of Amide C–N Google Scholar N. A.; E. L.; Garg N. of Google Scholar Y.; S.; of to Am. Chem. Soc.2008, 130, Google Scholar T.; T.; of with Am. Chem. Google Scholar Shi S.; Meng G.; Szostak of Through of Amides by Bond Chem. Int. Google Scholar C.; Szostak of Amides by and The of Amide Chem. Int. Ed.2017, 56, Google Scholar Y.; S.; R.; T.; of C–C of Amides to The Am. Chem. Google Scholar Y.; Y.; Y.; L.; Y.; H.; Zhou of an via between an Amide and a 12, Google Scholar Wang T.; Jiao and of via Am. Chem. Google Scholar T.; Wang T.; C.; Jiao of A Direct to Through Bond Chem. Int. Google Scholar Y.; H.; X. Z.; Wang Y.; Cheng Z.; Wang Tan H.; S.; G.; K. N.; Jiao for Google Scholar Wang to via Efficient Through or C–C Bond Chem. Google Scholar R.; M.; J. of Am. Chem. Google Scholar J.; S.; and by Reaction of Tertiary Amides with Chem. Int. Google Scholar Reactions of and with Google Scholar Charette A. of the of Amides with and J. Google Scholar D.; A.; M.; An for Google Scholar by S, and S of alkenes using 2 and , Organic & Chemistry, Cheng Li S and Jiao N from Secondary Amides by C–C Bond S, Wang and Szostak coupling of amines with amides and pathway to and Chemical Information & Chinese Chemical acknowledge the National Key R&D Program of China (grant no. 2021YFA1501700), the NSFC (grant nos. 22131002, 22161142019, and 81821004), and the Tencent Foundation for financial support. We thank Xi Wang in this group for reproducing the reactions of 19 and 26.