Transition-Metal-Catalyzed Annulations Involving the Activation of C(sp3)−H Bonds

Rúa Jenaro de la Fuente, s/n – Campus Vida – Universidade de Santiago de Compostela – 15782 Santiago de Compostela – www.usc.es/ciqus Transition-Metal-Catalyzed Annulations Involving the Activation of C(sp3)−H Bonds Marc Font, Moises Gulías, José L. Mascareñas Peer reviewed version This is the peer reviewed version of the following article: Font, M.; Gulías, M.; Mascareñas, J. L.; (2021), Transition-Metal-Catalyzed Annulations Involving the Activation of C(sp3)−H Bonds. Angew. Chem. Int. Ed., 61: e202112848, which has been published in final form at https://doi.org/10.1002/anie.202112848. This article may be used for noncommercial purposes in accordance with Wiley Terms and Conditions for Use of Self- Archived Versions. How to cite: Font, M.; Gulías, M.; Mascareñas, J. L.; (2021), Transition-Metal-Catalyzed Annulations Involving the Activation of C(sp3)−H Bonds. Angew. Chem. Int. Ed., 61: e202112848. doi: 10.1002/anie.202112848 Copyright information: © 2021 Wiley-VCH. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions C(sp3)-H Activation Transition-Metal-Catalyzed Annulations Involving the Activation of C(sp3)@HBonds Marc Font,* Mois8sGul&as,* and Jos8Luis MascareÇas* Angewandte Chemie A ngewandte Chemie Minireviews www.angewandte.org How to cite: Angew.Chem. Int. Ed. 2022,61,e202112848 International Edition: doi.org/10.1002/anie.202112848 German Edition: doi.org/10.1002/ange.202112848 Angew.Chem. Int.Ed. 2022,61,e202112848 (1 of 13) T2021 TheAuthors.AngewandteChemieInternational Editionpublished by Wiley-VCHGmbH 1. Introduction Synthetic technologies relying on C@Hactivation processes are among the most powerful tools in modern organic chemistry,inpart because they allow arapid and atomeconomical increase in molecular complexity from simple, unfunctionalized precursors.[1–5] Themost effective approaches to perform C@Hactivation/functionalization reactions rely on the use of transition-metal catalysts,which in many cases promote C@Hbond cleavage by concerted metalation-deprotonation (CMD) or oxidative addition processes.[4,5] Most of the metal-catalyzed C@Hfunctionalizations so far described involve the activation of C(sp2)@Hbonds.These reactions include oxidations,cross-couplings,cyclizations, and formal cycloadditions,among others.[3,6–10] Noticeably,analogous reactions involving the cleavage of C(sp3)@Hbonds are much less common and more challenging.This is in part due to the lower acidity of C(sp3)@Hbonds and the formation of less stable carbon–metal bonds.[11,12] Nonetheless,inthe last decade there has been an increasing number of reports dealing with the intermolecular functionalization of C(alkyl)@Hbonds.[13–17] Remarkably, similar reactions enabling annulation processes—both cyclizations and cycloadditions,which are very attractive from aconstructive standpoint—are much scarcer,[18,19] and only recently have they started to increase. This Minireview aims to highlight significant advances in the development of annulation reactions based on the activation and cleavage of C(sp3)@ Hbonds.Wedonot intend to be comprehensive,and thus we will only consider the most relevant approaches entailing cyclizations and formal cycloadditions that proceed through metalacyclicintermediates,such as those outlined in Scheme 1. Annulations involving the generation of carbenoid[20,21] and nitrenoid[22] intermediates,oradditions to p-allyl intermediates resulting from the activation of C@ Hbonds,[23] will not be discussed. Most of the schemes included in this Minireview follow acommon format:the general reaction highlighting (in bold) the bonds formed in the process,some key mechanistic intermediates (shown in parentheses), and afew selected products made using the method. 2. Transition-Metal-Catalyzed Cyclizations Promoted by the Activation of C(sp3)@HBonds 2.1. Lactonizations and Lactamizations Among the first examples of transition-metal-catalyzed C(sp3)@Hfunctionalizations,acetoxylation reactions occupy acentral role.In2004, the Sanford group reported the direct acetoxylation of C(alkyl)@Hbonds in substrates bearing oxime or pyridine directing groups,byusing Pd(OAc)2as acatalyst and PhI(OAc)2as an oxidant and acetyl source.[24] Since this report, the number of methods for the direct conversion of hydrocarbon precursors into valuable acetylated products has grown significantly.[15,17] Related intramolecular processes were first reported in 1991 by Kao and Sen, who observed the formation of small amounts of b-and g-lactones upon reacting aliphatic carbox- The selective functionalization of C(sp3)@Hbonds using transitionmetal catalysis is among the more attractive transformations of modern synthetic chemistry.Inaddition to its inherent atom economy, such reactions open unconventional retrosynthetic pathways that can streamline synthetic processes.However,the activation of intrinsically inert C(sp3)@Hbonds,and the selection among very similar C@H bonds,represent highly challenging goals.Inrecent years there has been notable progress tackling these issues,especially with regardto the development of intermolecular reactions entailing the formation of C@Cand C@heteroatom bonds.Conversely,the assembly of cyclic products from simple acyclic precursors using metal-catalyzed C- (sp3)@Hbond activations has been less explored. Only recently has the number of reports on suchannulations started to grow.Herein we give an overview of some of the more relevant advances in this exciting topic. Scheme 1. Mechanistic outline of a) transition-metal-catalyzed cyclizations and b) formal cycloadditions involving the activation of C(sp3)@H bonds. [*] Dr.M.Font, Prof. M. Gul&as, Prof. J. L. MascareÇas Centro Singular de InvestigaciknenQu&mica Biolkxica eMateriais Moleculares (CIQUS) Departamento de Qu&mica Org#nica Universidade de Santiago de Compostela 15782, Santiago de Compostela (Spain) E-mail:m[email protected] [email protected] [email protected] The ORCID identification number for one of the authors of this article can be found under:https://doi.org/10.1002/anie.202112848. T2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercialand no modifications or adaptations are made. A ngewandte Chemie Minireviews Angew.Chem. Int.Ed. 2022,61,e202112848 (2 of 13) T2021 TheAuthors.AngewandteChemieInternational Editionpublished by Wiley-VCHGmbH ylic acids with sub-stoichiometric amounts of K2PtCl4and K2PtCl6.[25] Despite this early observation, progress in the lactonization of carboxylic acids enabled by C(sp3)@H activations has been very slow,and essentially limited to ortho-methylbenzoic acids[26–28] or precursors equipped with abidentate directing group.[29] Selective b-lactonization processes remained elusive until very recently,when Zhuang and Yu developed an effective strategy for promoting this reaction from alkyl carboxylic acids that relies on PdII/PdIV catalytic cycles (Scheme 2).[30] Theuse of b-amino acid ligand L1,which chelates the metal into asix-membered cycle with alarge bite angle,seems to be key to facilitate the C@Hactivation, as well as to trigger the reductive elimination in the ensuing alkyl-PdIV intermediate (II,Scheme 2). Theauthors also demonstrated that the resulting b-lactones represent versatile platforms for the selective installation of diverse functionalities at the b position of the carboxylic acid. Later on, the same research group reported the cyclization of aliphatic diacids into five- to seven-membered lactone rings.[31] Alkyl amides can also cyclize to form g-orb-lactams, provided they are equipped with N,N-bidentate directing groups,which not only favor the C@Hactivation but also stabilize high-valent PdIV intermediates.[3,4,32] Chen and coworkers described in 2013 the g-lactamization of secondary carboxamides containing 8-aminoquinoline (AQ) auxiliaries to give pyrrolidinones (Scheme 3a). Mechanistically,ithas been postulated that the reaction entails the formation of six-membered palladacycle intermediates,and involves PdII/PdIV redox cycles.[33] In arelated transformation, the Shi group demonstrated that 2-(pyridine- 2-yl)isopropylamine (PIP) auxiliaries are particularly efficient at promoting the activation of benzylic methylene C@H bonds in b-aryl alanines to afford b-lactams (Scheme 3b).[34] Thesame group subsequently reported an updated version of the cyclization using 5-methoxyquinolin-8-amineauxiliaries, which are easier to remove than the PIP pendants.[35] Marc Font studied chemistry at the University of Girona, where he was awarded his PhD in 2015 under the supervision of Prof. X. Ribas and Prof. M. Costas. His PhD studies included research at the University of California, Berkeley with Prof. J. F. Hartwig. Subsequently, he was awarded aMarie Curie postdoctoral fellowshipfor research with Prof. I. Larrosa at the University of Manchester, UK. In 2017, he joined the University of Santiago de Compostela, where he is currently Juan de la Cierva fellow.His research focuses on transitionmetal-catalyzed C@Hfunctionalization reactions and their mechanisms. Mois8sGul&as obtained his PhD in 2006 at the University of Santiago de Compostela. In 2007–2009 he was aMarie-Curie postdoctoral fellow in the research group of Prof. M. J. Gaunt at the University of Cambridge, UK. In 2015, he received the Spanish Society of Chemistry Young Investigator Award and, in 2016, he became permanent professor at the University of Santiago de Compostelaand principal investigator at the CIQUS. His current research focuses on metal-catalyzed C@Hfunctionalization and asymmetric synthesis. Jos8Luis MascareÇascompleted his PhD at the University of Santiago in 1988. After postdoctoral work at Stanford University (USA) under the supervision of Prof. P. Wender (1989–1990), he moved to the University of Santiago (permanent professor: 1993 and full professor: 2005). He has been scientific director of CIQUS since 2014. In 2015 he received the gold medal of the Spanish Society of Chemistry,and in 2016 was appointed amember of the European Academy of Sciences. His research combines discovering novel methods based on metal catalysis and chemical biology to develop synthetic tools for biological intervention. Scheme 2. PdII-catalyzed b-lactonization of alkyl carboxylic acids. Scheme 3. a) PdII-catalyzed g-lactamization of alkyl amides bearing 8- aminoquinoline (AQ) directing groups. b) PdII-catalyzed b-lactamiza- tion of alkyl amides bearing the 2-pyridylmethyl (PIP) directing group. A ngewandte Chemie Minireviews Angew.Chem. Int.Ed. 2022,61,e202112848 (3 of 13) T2021 TheAuthors.AngewandteChemieInternational Editionpublished by Wiley-VCHGmbH Several additional examples of related lactamizations to build five- and six-membered lactams,also based on palladium catalysis,have been described.[19,36–38] Interestingly,firstrow transition-metal (Co,Ni, and Cu) catalysts can also catalyze the lactamization of amides equipped with bidentate directing groups.These reactions proceed through similar mechanistic pathways to those proposed for Pd.[19] Despite all these advances,there are still many challenges ahead, such as the development of lactamizations of substrates lacking auxiliary directing groups,the controlled formation of different ring sizes,and the implementation of enantioselective variants. 2.2. Oxa- and Azacyclizations Theformation of oxacycles by the direct oxacyclization of aliphatic alcohols has proven more challenging than the homologous lactonizations.This is mainly associated with the inability of hydroxy groups to work as directing groups in the C@Hactivation step.However,some strategies based on introducing designed directing groups in the substrates have been successfully implemented. In 2015, the Dong group reported aPd-catalyzed synthesis of cyclic ethers from the corresponding aliphatic alcohols by using an oxime auxiliary (Scheme 4a).[39] Theauthors proposed that, after the C@H activation of the terminal methyl group of the substrate,there is an oxidation of Pd to form an alkyl-PdIV intermediate, which undergoes an SN2-type reductive elimination with the pendant alcohol to give the oxacyclic product (usually in modest yields). Aparallel strategy,relying on the use of the PIP auxiliary as adirecting group,has enabled the activation of secondary C@Hgroups for the assembly of tetrahydrofuran and tetrahydropyran derivatives.[40] Using different types of substrates equipped with an amide containing achiral bidentate directing group,Hong, Baik, and co-workers developed adiastereoselective oxacyclization of aliphatic alcohols (Scheme 4b).[41] In contrast to alcohols,free aliphatic amines can be directly cyclized using C(sp3)@Hactivation reactions.Gaunt and co-workers have demonstrated extensively that appropriately designed a-methylated secondary amines,such as those shown in Scheme 5, can be readily converted into aziridines.[42] Thereaction involves aPd-catalyzed activation of the pendant methyl groups to give four-membered cyclopalladated intermediates.The ensuing oxidation of the palladacycle to aPd IV species followed by reductive elimination yields the aziridine core.Importantly,the introduction of steric bulk around the NH moiety is needed to avoid the formation of off-cycle bis(amine)–palladium complexes.The authors further demonstrated the synthetic potential of this method by opening the aziridine rings with different types of nucleophiles.They also reported afollow-up enantioselective version.[43] Introducing asuitable protecting/auxiliary group in the amine seems to facilitate the azacyclization.[19] Therefore,in 2009, Glorius and co-workers demonstrated that acetylprotected ortho-alkylanilides can be cyclized into the corresponding indolines under PdII catalysis,although all the reported examples consist of anilides with ortho-tert-butyl (or very similar) substituents.[44] In arelated approach, Nadres and Daugulis reported in 2012 aPd II-catalyzed activation of d- C@Hbonds in selected alkylamides and ortho-methylanilides bearing picolinamide bidentate auxiliaries to afford pyrrolidines and isoindolines.[45] Chen and co-workers extended this approach to the preparation of azetidines and pyrrolidines.[46] An alternative entry to pyrrolidines was reported by Shi and co-workers,and involves the use of alkyl triflamides as precursors and silver salts as catalysts.The authors postulate that PhI(OTFA)2induces the oxidation of the silver precursor to aAg III species,which promotes aCMD-like cleavage of primary or secondary benzylic C(sp3)@Hbonds of the substrates.Finally,aC-N reductive elimination generates the pyrrolidine core (Scheme 6).[47] Scheme 4. a) PdII-catalyzed cyclization of alcohols bearing oxime directing groups to yield cyclic ethers. b) PdII-catalyzed cyclization of alcohols bearing achiral amide directing group. Scheme 5. PdII-catalyzed aziridination of designed secondary amines. A ngewandte Chemie Minireviews Angew.Chem. Int.Ed. 2022,61,e202112848 (4 of 13) T2021 TheAuthors.AngewandteChemieInternational Editionpublished by Wiley-VCHGmbH 2.3. Carbocyclizations In addition to metal-catalyzed heterocyclizations,anumber of carbocyclization strategies have also been developed for reactions involving the activation of C(sp3)@Hbonds.One of the earliest and most prolific approaches is based on the use of aryl halide or pseudohalide precursors (Ar-X) and Pd0 catalysts.This approach, pioneered by the group of Dyker,[48] relies on an initial oxidative addition of Pd0to Ar@Xbonds to generate aryl-PdII species,which promote selective C(sp3)@H activations in nearby alkyl chains.Afinal reductive elimination from the resulting palladacycles produces the desired carbocycles. TheBaudoin group has been particularly active in exploring the potential of this strategy.Their first studies focused on the construction of benzocyclobutanes from orthoalkyl bromoarenes,asillustrated in Scheme 7a.[49,50] Similar approaches have since been used for the assembly of awide range of fused carbocycles and heterocycles of different sizes,[18,51,52] even in an asymmetric manner.For example, Kgndig and co-workers developed aPd 0-catalyzed enantioselective carbocyclization of aryl halides for the synthesis of enantioenriched fused indolines by using achiral NHC ligand (L2,Scheme 7b).[53] Thecatalytic carbocyclization sequence can also be triggered by an initial C@Hactivation through aCMD mechanism, followed by an oxidative addition to an internal aryl halide,togive aPd IV intermediate (Scheme 8a).[54] This strategy,which requires substrates bearing 8-aminoquinoline (AQ) auxiliaries,was later used in the macrocyclization of peptide-like architectures,thereby enabling the obtention of macrocycles with up to 37 members (Scheme 8b).[55] More recently,related carbocyclization approaches that exploit transient directing groups instead of semipermanent auxiliaries have started to emerge.[56,57] In the last few years there has been an upsurge in carbocyclization methods based on twofold C@Hactivations. Taking as reference the seminal work by Dyker on the Pdcatalyzed dimerization/carbocyclization of iodoanisoles through double C@Hactivation processes,[58] Baudoin and co-workers developed aversatile method to build cyclo- Scheme 6. AgI-catalyzed cyclization of alkyl triflimidestopyrrolidines. Scheme 7. a) Pd0-catalyzed cyclization of aryl bromides to afford benzocyclobutanes through C(sp3)@Hactivation. b) Pd0-catalyzed enantioselective cyclization of aryl bromides to afford fused indoline cores. Scheme 8. a) PdII-catalyzed intramolecular arylation of 8-aminoquino- line-containing alkyl chains by chelation-assisted C(sp3)@Hactivation. Ring sizes are listed in the scheme. b) PdII-catalyzed macrocyclization of peptide-like structures exemplified with atripeptide derivative. A ngewandte Chemie Minireviews Angew.Chem. Int.Ed. 2022,61,e202112848 (5 of 13) T2021 TheAuthors.AngewandteChemieInternational Editionpublished by Wiley-VCHGmbH propanes from acyclicprecursors using aPd 0-promoted C(sp3)@Hactivation cascade.[59] Thereaction involves an initial oxidative addition of the aryl halide to generate palladacyclopentane I,which evolves by proto-depalladation to give species II in aformal 1,4-Pd shift (Scheme 9). This intermediate promotes the cleavage of aC(sp3)@Hbond in an alkyl group of the substrate to afford palladacyclobutane III,which yields the final cyclopropane by reductive elimination. In substrates containing alkyl chains with b-hydrogen atoms, b-hydride elimination pathways compete with the cyclopropanation. Theauthors found that the use of pivalates instead of carbonates is key to favor the desired cyclopropanation pathway. Other carbocylizations relying on double C@Hactivation processes have also been reported by Yu and co-workers. Their reactions,however,are not initiated by oxidative addition of Pd0to haloarenes,but by acarboxylate-directed C(sp3)@Hactivation process (Scheme 10).[60] Asubsequent oxidation of the intermediate generates an alkyl-PdIV complex that promotes the C(sp2)@Hactivation of the arene prior to aring-forming C@Creductive elimination. Thereaction, which is only effective for the activation of methyl groups,was used in afour-step synthesis of indane-containing sesquiterpene (:)-russujaponol D. In the above reactions,the C(sp3)@Hactivation step occurs through aCMD-type mechanism and requires electrophilic metal catalysts,inmost cases based on PdII.An alternative for performing the C@Hactivation step relies on oxidative addition to low-valent transition-metal centers. Indeed, synthetic methods based on C(sp3)@Hoxidative additions that lead to metal-hydride intermediates are finding increasing synthetic applications.This is the case for wellknown RuII-, RhI-, and IrI-catalyzed borylation and silylation reactions,[61,62] as well as in intermolecular hydrocarbonation processes.[63] Conversely,intramolecular hydrocarbonations to build cyclic products are much less common. An early contribution was published by Jones et al. in 1986, which demonstrated the viability of assembling indoles from 2,6- dialkylphenylisocyanides[64,65] using low-valent ruthenium catalysts.Another relevant contribution relying on an iridium-catalyzed hydrocarbonation of alkenes was reported by Sames and co-workers in 2004.[66] TheSuginome group has recently described elegant examples of carbocyclization reactions to build indolines through the Ir-catalyzed C(sp3)@Hactivation of methylaniline precursors.The reaction can even be performed in an enantioselective fashion by using chiral BINAP derivatives as ligands (L4,Scheme 11).[67] This concept has been further exploited by the authors to build benzofuran skeletons.[68] To conclude this section, we can state that cyclization reactions triggered by metal-promoted C(sp3)@Hactivations can be ranked among the more promising strategies to build cyclic products from simple acyclic precursors.The progress in this topic has been slow but steady,and, very likely,many new methods will see the light in the years to come. Scheme 9. Pd0-catalyzed cyclization of gem-dialkyl (pseudo)haloarenes by double C(sp3)@Hactivation. Scheme 10. PdII-catalyzed cyclization of aryl alkyl carboxylic acids by twofold C@Hactivation. The oxidized intermediates are indicated. Scheme 11. IrI-catalyzed enantioselective cyclization of 2-alkenyl-N- methylanilines to afford indolines. A ngewandte Chemie Minireviews Angew.Chem. Int.Ed. 2022,61,e202112848 (6 of 13) T2021 TheAuthors.AngewandteChemieInternational Editionpublished by Wiley-VCHGmbH 3. Transition-Metal-Catalyzed Formal Cycloadditions by C(sp3)@HActivation From aconstructive point of view,cycloadditions are even more appealing than cyclizations,owing to their inherent complexity-increasing characteristics.Transition-metal catalysis has demonstrated an enormous potential in the development of formal cycloadditions of unsaturated precursors.[69–71] In recent years there has been asubstantial increase in cycloadditions involving transition-metal-catalyzed C@Hactivation, with most of the examples so far reported involving the cleavage of C(sp2)@Hbonds.[7] Analogous formal cycloadditions entailing the activation of C(sp3)@Hbonds is more challenging,and has been much less developed. In most cases, these reactions follow the general pathways outlined in Scheme 12:Ametal-promoted C(sp3)@Hactivation followed by amigratory insertion of an unsaturated partner, and afinal reductive elimination that yields the cycloaddition product. In addition to the intrinsic difficulties of the C@Hactivation step, the other steps can also be problematic,inpart because they present competing b-hydride elimination pathways (Scheme 12).[72] Despite these hurdles,methods formally involving such cycloadditions are starting to emerge. 3.1. Formal Cycloadditions with Carbon Monoxide Among the first examples describing formal cycloadditions involving the activation of C(sp3)@Hbonds,those based on the use of carbon monoxide as an annulation partner occupy aprominent position. Awide variety of methods for the construction of succinimides and lactams,usually operating through the mechanistic profile outlined in Scheme 12, have been reported. Thefirst reports based on this approach appeared more than ten years ago,when Yu and co-workers described aPdcatalyzed formal (4+1) cycloaddition of electron-deficient alkyl amides and CO (Scheme 13a).[73] Theelectron-poor nature of the aromatic amide is essential for the C@H activation step. Related annulations to give succinimides have also been developed using other transition metals,such as ruthenium,[74] copper,[75] cobalt,[76] and nickel.[77] In some cases,these methods use CO surrogates,such as nitromethane or DMF, as annulation partners.Inall these examples,the presence of coordinating groups appended to the amide nitrogen atom seems crucial for the C(sp3)@Hactivation step. Other than amides,aliphatic carboxylic acids have also been reported to participate in PdII-catalyzed carbonylations. Indeed, Yu and co-workers developed aformal (4+1) cycloaddition using Mo(CO)6as the CO source and baminothioether L5 as the ligand (Scheme 13b). Thereaction products were isolated as acyclicdiester derivatives because of the high sensitivity of anhydrides toward hydrolysis.[78] Moreover,preliminary results of an enantioselective version using the b-aminothioether ligand L6 have been reported. Analogous carbonylations of amine precursors containing auxiliary directing groups (oxalyl- or picolinamides) have recently been reported.[79,80] Carretero and co-workers have exploited pyridylsulfonyl auxiliaries in alkyl amines to promote their conversion into pyrrolidinones under Pd- (OAc)2catalysis,using Mo(CO)6as aCOsurrogate (Scheme 14).[81] Gaunt and co-workers delineated alternative carbonylative annulations directly from hindered unprotected amines. They described apractical entry to avariety of b-lactams by PdII-catalyzed carbonylation of amines under aCO/air Scheme 12. General mechanistic scenario for transition-metal-cata- lyzed formal cycloadditionthrough C(sp3)@Hactivation processes. Scheme 13. a) PdII-catalyzed formal (4+1) cycloaddition of alkyl amides. b) PdII-catalyzed formal (4+1) cycloaddition of alkyl carboxylic acids. Scheme 14. PdII-catalyzed formal (4+1) cycloaddition of pyridylsulfonyl-protected alkyl amides. A ngewandte Chemie Minireviews Angew.Chem. Int.Ed. 2022,61,e202112848 (7 of 13) T2021 TheAuthors.AngewandteChemieInternational Editionpublished by Wiley-VCHGmbH atmosphere (Scheme 15).[43] Theauthors were even able to isolate key azapalladacycle intermediates resulting from the C@Hactivation. Less-hindered amines containing tertiary,secondary,and even primary carbon atoms can also engage in this type of annulation, although such reactions follow different mechanistic pathways.Computational and experimental studies suggested that the reaction entails the carbonylation of the amine to give an acyl palladium intermediate,which undergoes aC(sp3)@Hactivation to generate species I(Scheme 16a). After optimization of the reaction parameters,t he Gaunt group applied the method to the preparation of awide range of b-lactams with good to excellent yields (Scheme 16a).[82] This method can also be used for the late-stage carbonylation of pharmaceuticals and other biologically active products. These formal (3 +1) cycloadditions can also be extended to other secondary amines[83] or a-tertiary amines[84] that require the activation of b-methylene [email protected] tuning of the reaction conditions allowed the regioselectivity of these processes to be shifted to activate g-methyl groups of secondary amines and deliver g-lactams in aformal (4 +1) cycloaddition (Scheme 16b). To achieve this selectivity it is key to use areaction atmosphere with alow content of CO (6.25%CO/air mixture), and thus prevent the formation of carbamoyl-Pd species,asthese reactions proceed through five-membered palladacycles (species I,Scheme 16b).[85] It can be concluded that the carbonylation of C(sp3)@H bonds in formal cycloaddition processes has proven very fruitful for building succinimides,succinic anhydrides,and lactams of different sizes.However,most of these transformations require careful engineering of the substrate to prevent undesired side reactions,which represents aserious limitation in terms of scope and generality.Noticeably,related cycloadditions with CO,involving the formation of two C@C bonds,have not yet been reported. 3.2. Formal Cycloadditions with Alkenes, Dienes, and Allenes Formal cycloadditions involving the activation of C(sp3)@ Hbonds but using olefinic partners instead of CO are very attractive (Scheme 11), although they represent asignificant challenge.The palladacyclic intermediates resulting from the migratory insertion of the alkene tend to undergo b-hydride elimination processes,which halts the canonical cycloaddition. However,the resulting olefinated adducts can still be converted into cyclic products through an intramolecular Michael-type addition. This was indeed demonstrated by Yu and co-workers in 2010 with the reaction between alkyl amides and acrylates using PdII catalysts and oxidizing additives.The reaction is initiated by activation of aC(sp3)@ Hbond in the bposition to an amide to give apalladacyclic intermediate,which evolves to the final g-lactam by the aforementioned Heck-type coupling/Michael addition mechanism (Scheme 17a).[86] This transformation could be extended to build six-membered rings using amide substrates bearing b-quaternary carbon atoms.[87] More recently,Shi and co-workers reported aPd II-cata- lyzed alkenylation/cyclization process to build g-lactams using alkyl amides bearing apyridyl-isopropylamine directing group (PIP) and alkenyl iodide coupling partners (Scheme 17b). In this case,the Pd catalyst promotes aC(sp3)@H alkenylation of the alkyl amide,followed by a syn-amino- palladation (II!III). Finally,ab-hydride elimination step delivers the aza-Wacker cyclized product. Theauthors also demonstrated that using BINOL derivatives as chiral ligands for Pd enables the reaction to occur with excellent levels of enantioselectivity.[88,89] Compared to amides,related alkenylation/cyclizations of alkyl carboxylic acids have proven more challenging.As indicated in Section 2.1, the C@Hactivation of these precursors is favored by using alkali metal bases,which exhibit k2-coordination with the acid substrate and prevent poisoning of the catalyst.[90] Scheme 15. PdII-catalyzed C(sp3)@Hcarbonylation of hindered secondary free amines. Scheme 16. a) PdII-catalyzed b-carbonylation of secondary bulky amines via carbamoyl-PdII species. The reaction intermediate Iwas characterized by X-ray diffraction. b) PdII-catalyzed g-carbonylation of hindered secondary amines. A ngewandte Chemie Minireviews Angew.Chem. Int.Ed. 2022,61,e202112848 (8 of 13) T2021 TheAuthors.AngewandteChemieInternational Editionpublished by Wiley-VCHGmbH