Recent work published by Rovis, Schoenebeck, and co-workers in Nature Chemistry describes a synergistic CO2 mediation and photocatalysis strategy for challenging α-alkylation of primary aliphatic amines by using quinuclidine as a hydrogen atom transfer (HAT) catalyst for γ-lactam synthesis. Electrostatic attraction between the in-situ-generated carbamate and quinuclidinium radical cation is critical for the selectivity. Recent work published by Rovis, Schoenebeck, and co-workers in Nature Chemistry describes a synergistic CO2 mediation and photocatalysis strategy for challenging α-alkylation of primary aliphatic amines by using quinuclidine as a hydrogen atom transfer (HAT) catalyst for γ-lactam synthesis. Electrostatic attraction between the in-situ-generated carbamate and quinuclidinium radical cation is critical for the selectivity. Selective functionalization of sp3 C−H bonds is one of the most challenging targets and has attracted decades of efforts from the synthetic chemistry community.1Hartwig J.F. Larsen M.A. Undirected, homogeneous C–H bond functionalization: Challenges and opportunities.ACS Cent. Sci. 2016; 2: 281-292Crossref PubMed Scopus (490) Google Scholar Transition-metal-catalyzed C−H activation has been established as a powerful platform for site-selective sp3 C−H functionalizations with the use of directing groups, which typically require pre-installation and removal.2He J. Wasa M. Chan K.S.L. Shao Q. Yu J.-Q. Palladium-catalyzed transformations of alkyl C–H bonds.Chem. Rev. 2017; 117: 8754-8786Crossref PubMed Scopus (1330) Google Scholar Photoredox-catalyzed hydrogen atom transfer (HAT) provides an alternative and sustainable method for sp3 C−H activation via radical intermediates.3Hu X.-Q. Chen J.-R. Xiao W.-J. Controllable remote C–H bond functionalization by visible-light photocatalysis.Angew. Chem. Int. Ed. 2017; 56: 1960-1962Crossref PubMed Scopus (196) Google Scholar However, controlling the site selectivity of the HAT process has proved to be difficult because of the multitude of C−H bonds and high reactivity of the radical species. In this context, the controllable functionalization of activated sp3 C−H bonds that are adjacent to functional groups such as ethers,4Le C. Liang Y. Evans R.W. Li X. MacMillan D.W.C. Selective sp3 C–H alkylation via polarity-match-based cross-coupling.Nature. 2017; 547: 79-83Crossref PubMed Scopus (316) Google Scholar alcohols,5Jeffrey J.L. Terrett J.A. MacMillan D.W. O-H hydrogen bonding promotes H-atom transfer from α C–H bonds for C-alkylation of alcohols.Science. 2015; 349: 1532-1536Crossref PubMed Scopus (314) Google Scholar amides,6Shaw M.H. Shurtleff V.W. Terrett J.A. Cuthbertson J.D. MacMillan D.W. Native functionality in triple catalytic cross-coupling: sp3 C–H bonds as latent nucleophiles.Science. 2016; 352: 1304-1308Crossref PubMed Scopus (401) Google Scholar and phenyl groups7Zhang J. Li Y. Zhang F. Hu C. Chen Y. Generation of alkoxyl radicals by photoredox catalysis enables selective C(sp3)–H functionalization under mild reaction conditions.Angew. Chem. Int. Ed. 2016; 55: 1872-1875Crossref PubMed Scopus (205) Google Scholar has been recently achieved via a selective HAT activation method. However, at the current stage, the regioselective α-C-functionalization of primary aliphatic amines is still largely unexplored and a long-standing challenging task for organic chemists. In recent years, visible-light photoredox catalysis has emerged as a mild and powerful technique for activating nitrogen-containing compounds to generate diverse reactive N-radical, N-radical ion, and α-C-radical species.8Chen J.-R. Hu X.-Q. Lu L.-Q. Xiao W.-J. Visible light photoredox-controlled reactions of N-radicals and radical ions.Chem. Soc. Rev. 2016; 45: 2044-2056Crossref PubMed Google Scholar In this respect, visible-light-induced α-C-functionalization of tertiary aliphatic amines has been well investigated via an in-situ-generated α-C-radical intermediate.9Shi L. Xia W. Photoredox functionalization of C–H bonds adjacent to a nitrogen atom.Chem. Soc. Rev. 2012; 41: 7687-7697Crossref PubMed Scopus (904) Google Scholar Among these reactions, tertiary amines are readily oxidized to N-radical cations, which subsequently undergo a facile deprotonation to deliver α-C-radical species for further radical transformations (Scheme 1A). In contrast, the formation of α-C-radicals from primary aliphatic amines has posed a long-standing challenge because of their high oxidation potential, strong N-nucleophilicity, and basicity and some competitive over-oxidation pathways. The recent success of α-C-functionalization of alcohols and amides by MacMillan and colleagues4Le C. Liang Y. Evans R.W. Li X. MacMillan D.W.C. Selective sp3 C–H alkylation via polarity-match-based cross-coupling.Nature. 2017; 547: 79-83Crossref PubMed Scopus (316) Google Scholar, 5Jeffrey J.L. Terrett J.A. MacMillan D.W. O-H hydrogen bonding promotes H-atom transfer from α C–H bonds for C-alkylation of alcohols.Science. 2015; 349: 1532-1536Crossref PubMed Scopus (314) Google Scholar, 6Shaw M.H. Shurtleff V.W. Terrett J.A. Cuthbertson J.D. MacMillan D.W. Native functionality in triple catalytic cross-coupling: sp3 C–H bonds as latent nucleophiles.Science. 2016; 352: 1304-1308Crossref PubMed Scopus (401) Google Scholar suggests that the visible-light-induced photoredox-catalyzed HAT strategy could provide a new potentially powerful platform for the α-C-functionalization of primary amines through selective generation of α-C-radical species. To address the aforementioned challenges, Rovis, Schoenebeck, and co-workers recently demonstrated a novel catalytic strategy by rationally combining CO2 mediation and a visible-light photoredox-catalyzed HAT process.10Ye J. Kalvet I. Schoenebeck F. Rovis T. Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics.Nat. Chem. 2018; https://doi.org/10.1038/s41557-018-0085-9Crossref PubMed Scopus (117) Google Scholar As depicted in Scheme 1A (bottom), they envisioned that the reversible reaction of the NH2 group of primary aliphatic amines with CO2 (1 atm) could significantly decrease the nucleophilicity of primary aliphatic amines and inhibit the undesired N-alkylation pathway, which could open up a new avenue for selective functionalization of the less reactive α-C(sp3)−H bonds. However, at the same time, the introduction of CO2 to the NH2 motif could decelerate the following HAT and functionalization process. The authors believe that the use of a cationic HAT reagent, such as the quinuclidinium radical cation, might overcome this problem via an electrostatically accelerated interaction between the in-situ-generated carbamate and quinuclidinium radical cation. The proposed mechanism is outlined in Scheme 1B. Upon irradiation of blue light-emitting diodes, the reaction commences with the generation of excited-state photocatalyst *IrIII (E1/2red [*IrIII/IrII] = +1.21 V versus saturated calomel electrode [SCE]), which is a strong-enough oxidant to oxidize quinuclidine 10 (E1/2ox = +1.1 V versus SCE) to a quinuclidinium radical cation 10-A. At the same time, the primary amine reacts with CO2 to give alkylammonium carbamate 5. Then, an H-atom abstraction of carbamate 5 by radical cation 10-A gives rise to the key α-C-radical intermediate 7. The high selectivity of this transformation is controlled by the intermolecular electrostatic interaction between 5 and 10-A. Subsequently, the addition of radical 7 to the electron-deficient acrylate 11-A generates the new alkyl radical 12 (which undergoes a sequential process involving single-electron transfer reduction, protonation, decarboxylation, and cyclization) to deliver the final product, γ-lactams 13. The current protocol shows broad scope with respect to primary aliphatic amines and electron-deficient acrylates (Scheme 1C). The amines bearing a linear, branched alkyl chain or α-substituent worked well in this transformation. Even some sterically demanding primary amines, such as myrtanylamine and bicyclo[2.2.1]heptan-2-amine, were efficiently coupled. Some sensitive functionalities in radical reactions, such as alkene, alkyne, F, and CF3 groups, are all well tolerated. The obvious differentiation of in-situ-generated alkylammonium carbamate and N-Boc carbamate suggested that the higher reactivity of the α-C-radical intermediate was derived from anionic carbamate and further demonstrated the high selectivity of this reaction variant (13-D). In addition, some heteroaryl groups, such as pyridinyl, thiazolyl, isoxazolyl, and imidazolyl, could all be efficiently incorporated into the final products. Interestingly, methacrylonitrile also proved suitable for this transformation by giving the corresponding cyclic amidine 13-F in 54% yield. This reaction featured mild conditions, broad scope, high selectivity, and excellent functional-group tolerance. Despite these advantages, however, some limitations still remain, such as the requirement of relatively high loading of quinuclidine (50 mol %) and low yields in some cases. The authors conducted a series of control experiments to investigate the reaction mechanism. They found that visible light, photocatalyst, CO2, and quinuclidine are all critical to this transformation. When they employed the pre-synthesized alkylammonium carbamate intermediate 5 under standard conditions, the reaction also proceeded smoothly to afford the expected γ-lactam in 75% yield, indicative of the intermediacy of an alkylammonium carbamate in this reaction. Stern-Volmer analysis indicated that the excited state of photocatalyst *IrIII can be quenched by quinuclidine 10. To further evaluate the role of CO2 in this reaction, Rovis, Schoenebeck, and co-workers carefully monitored the conversion of primary amine and acrylate, as well as the yield of product γ-lactam, during the reaction process in the presence or absence of CO2. The results showed that acrylate consumption and γ-lactam formation are much faster in the presence of CO2, suggesting that the reversible generation of carbamate between the NH2 group and CO2 might accelerate the subsequent HAT and alkylation process. All of these results are in good agreement with the proposed mechanism depicted in Scheme 1B. The authors also conducted density functional theory (DFT) calculations to understand the origins of reaction selectivity and the role of CO2. They found that the commonly used guidelines, such as the bond dissociation energy (BDE) of C−H bonds and the stabilities of newly generated radicals, cannot be utilized to rationally explain the observed reaction selectivity and the reactivity enhancement promoted by CO2. In fact, there are no significant difference in BDEs of C−H bonds among primary amine, carbamic acid, and the in-situ-generated alkylammonium carbamate. Further DFT calculations on the HAT process with the assistance of a quinuclidinium radical cation indicated that the abstraction of a H atom at the α-C−H site has a −8.2 kcal/mol (ΔΔG‡) lower activation energy barrier than the γ-C−H site. Other HAT reagents, such as a neutral N-radical, C-radical, and N-centered radical with a distant positive charge, were also used for calculating the corresponding free energy of the HAT process. However, in these cases, the data suggested that γ-C−H bonds are more reactive and that γ-selectivity is the favorable reaction pathway. The results of computational studies further demonstrated that the exclusive α-site selectivity of this reaction mainly relies on the electrostatic interaction between the in-situ-generated carbamate and the positive charge of quinuclidinium. By synergistically combining CO2 mediation and visible-light-driven photoredox-catalyzed HAT, Rovis, Schoenebeck, and co-workers have achieved an elegant and highly selective α-alkylation of primary aliphatic amines, providing access to various biologically important γ-lactams with high efficiency. This protocol opens a new pathway for the selective functionalization of sp3 C−H bonds.