Isoindolinone Synthesis via One‐Pot Type Transition Metal Catalyzed C−C Bond Forming Reactions

Abstract Isoindolinone structure is an important privileged scaffold found in a large variety of naturally occurring as well as synthetic, biologically and pharmaceutically active compounds. Owing to its crucial role in a number of applications, the synthetic methodologies for accessing this heterocyclic skeleton have received significant attention during the past decade. In general, the synthetic strategies can be divided into two categories: First, direct utilization of phthalimides or phthalimidines as starting materials for the synthesis of isoindolinones; and second, construction of the lactam and/or aromatic rings by different catalytic methods, including C−H activation, cross‐coupling, carbonylation, condensation, addition and formal cycloaddition reactions. Especially in the last mentioned, utilization of transition metal catalysts provides access to a broad range of substituted isoindolinones. Herein, the recent advances (2010–2020) in transition metal catalyzed synthetic methodologies via formation of new C−C bonds for isoindolinones are reviewed.


CÀHFunctionalization:A nnulation/Cyclization
In general, the covalentb ond between carbon and hydrogen (CÀH) is considered fairly inert and the activation of this bond for modificationh as remained as as ignificant challenge to synthetic chemists. Thus, the CÀHb ond catalytic activation can be considered as one of the most important areas of moderns ynthetic chemistry due to its wide potential in various applications in both industrial and academic settings. In recent years, significant improvements in the synthesis of N-heterocyclic compounds by CÀHb ondf unctionalization/activation have been made. [18] Ac ommon feature in most of the methods utilizing CÀHfunctionalization strategies for isoindolinone synthesis is the use of N-substituted benzamides as reactants bearing either activating or directing groups. Most commonly featured groups consist from: p-toluene sulfonate (Ts), methyl sulfonate (Ms), different alkoxides, 8-quinoline (Q), 2-pyridine or 2-pyridine oxide and acetate (OAc) or pivalate (OPiv) moieties. In the following discussion, the different reactions forming isoindoli-nones via CÀHf unctionalization are classified according to the transition metal used as the catalyst.

Palladiumcatalyzed CÀHf unctionalization
Pd-catalyzed olefination/alkylation-cyclization Both Zhu [19] and Youn [20] have described the oxidative synthesis of isoindolinones using tosylated benzamides with av ariety on alkene reactants and either palladium(II) acetate and palladium(II) trifluoracetate as catalysts (Scheme 1; Zhu: A and B; Youn: C). These methods utilize pure oxygen atmosphere or air as the oxidantb ut the methodp resented by Youn requires copper(II) acetate to oxidize the palladium catalyst as ap art of the catalytic cycle. In general, these methodologies provide moderate to high yields form ost reactant combinationsb ut significant steric hindrance close to the reaction site seems to lower the yield of the reaction.
An umber of isoindolinone derivativesw ere preparedf rom N-methoxy derivatized benzamides with alkenes by Li, [21] Wrigglesworth, [22] andH ii. [23] (Scheme 2A,Band C, respectively). Li and co-workersu tilized p-benzoquinone (BQ) as the oxidant and Wrigglesworth andc o-workers ac ombination of BQ and oxygen. The ortho-substituted benzamides and electron withdrawing substituents in general resulted in significant decrease in the isolated yields. Due to the genotoxic nature of p-benzoquinone, the group of Hii applied ac ombination of copper(II) acetate/O 2 as as uitable alternative, yielding 3-alkylidene isoindolinones in good yields. Here, only the use of trifluoromethyl substituents was reported to drastically decrease the yield. Later,L aha [24] described as imilarm ethodu sing underivatized benzamides with stoichiometric amount of copper(II) acetate as the oxidanta nd dioxane as solvent insteado fa cetic acid (Scheme 2D).
Carboxylic acid derivatives have also found utility as reactants in palladium catalyzed CÀHf unctionalization of derivat-ized benzamides. Wie [25] described ar edox-neutral CÀHf unctionalization strategy between 8-quinoline derivatized benza-Dr.S avelar eceived hisM Sc from the University of Turku,f ollowed by PhD from bo Akademi University, Laboratory of Organic Chemistry.D uring his PhD studies, he focused on applied Lewis acidc atalysis for synthetic organic chemistry.C urrently he is working as ap ostdoctoral researcher at bo AkademiU niversity,L aboratory Molecular Sciencea nd Technology.
Carolina MØndez-Gµlvez received her Ph.D. in 2013 from Universityo fS antiago, in the groupo fP rof. BruceC assels. In 2011s he was av isiting Ph.D. studenti nP rof. Julio Seijas groupa tt he University of Santiagod eC ompostela, Spain. From 2015 to 2017 she was a Postdoctoral Researcher at the University of Bristol, UK, under the supervision of Prof. RobinB edford. In 2018,s he moved to Finland with af ellowship from Otto A. Malm foundation to join the groupo fP rof. RekoL eino at bo Akademi University.H er researchi nterests include synthetic organic chemistry and homogeneous catalysis. mides and carboxylic acids or carboxylic acid anhydrides (Scheme 3). In this manner,abroad range of 3-alkylidene isoindolinones were synthesized in moderate to good yields.

Pd-catalyzed isocyanide insertion-cyclization
Dai and Yu [26] utilized Pd 2 (dba) 3 as ac atalyst to synthesize 3imino-isoindolinones in good yields from tert-butylisocyanides and N-methoxy benzamides using air as the oxidant. The methodology was able to overcome catalystd eactivation commonly associated with heterocyclesi nC ÀHa ctivation and produce 3-imino-isoindolinones with heterocyclic substituents (Scheme 4A). Interestingly,a nu nexpected reversal of the positions of the methoxy and tert-butyl groups takes place with this catalytic system.A lso, Wei and Qian [27] utilized isocyanide derivativesi nasimilarm anner but under oxygen atmosphere. Here, both methoxy and pentafluorobenzene based directing/ activating groups (R 3 in Scheme 4B)c ould be utilized with either tert-butyl-or isopropylisocyanides.

Pd-catalyzed cyclization using acyl radicals
Similarly to alkenes, aldehydes have also been found as useful substrates for isoindolinone synthesis. Zhao and Huang [28] successfully utilized av ariety of aldehydes together with N-derivatized benzamides fors ynthesis of 3-hydroxyisoindolinones using aqueous tert-butyl hydroperoxide( TBHP) as an oxidant (Scheme5A). The group of Zhang [29] described as imilar methodology,b ut in this context,t he aldehydes utilized in the reaction were generated by in situ oxidation of the toluene derivatives (Scheme 5B). This methodology wasf urther implemented to functionalization of 4H-Benzo[d][1,3]oxazin-4-onest of used tetracyclic compounds containing the isoindolinone moiety by Kumare tal. [30] (Scheme 5C).
Both Li [31] and Wang [32] utilized ad ecarboxylation based methodology for the synthesis of 3-hydroxy-isoindolinone and fused tricyclic isoindolinone derivatives, respectively (Scheme 6A and B). Both methodologies were applied for broad range of substrates and were able to proceed under air utilizing persulfates as oxidants. In general, substituents at meta-position (Scheme 6. R 1 ,R 2 or R 3 )r esulted in diminished yields.
Scheme5.Aldehydes as substrates for the synthesis of isoindolinones via palladium catalyzed CÀHa ctivation.
Qin [36] used an oxidative coupling strategy to provide access to ethane sulfonylfluoride derivatized isoindolinones from Nmethoxy substituted benzamides and ethenes ulfonylfluoride (Scheme 8A). The sulfonyl fluoride group can be readilyu tilized for example in as ulfur(VI) fluoridee xchange reaction, which is at ype of click reaction. Jeganmohan [37] conveyed their previous work with cobalt catalyzed isoindolinone synthesis (vide infra) to similar Rh III catalyzed method. Using maleimides as substrates with N-methoxy-benzamides, 3-spirosubstituted isoindolinones were produced in af acile manner (Scheme 8B).
To syl derivatized benzamides were successfully used in CÀH olefination [38a] providing ad irect route to 3,3-disubstituted-isoindolinones (Scheme9A). Initially,i na ddition to the N-tosyl benzamides, only 1,2-homodisubstituted activated alkenes were employed as reactants (Scheme 9B, C)b ut later [38b] it was furthero ptimized and expanded to terminal alkenes. The yield of these reactions was mainly dependent of electron withdrawing substituents on the alkene.
The combinationofC ÀHand CÀFbond functionalization utilizing redox neutralb imetallic Rh III /Ag I relay catalysis was described by Wang (Scheme 10 A). [39] Here, rhodium was used for CÀHf unctionalization and silver for the defluorinative cyclization to afford 3-alkylidene isoindolinones, which could further be derivatized for example to aristolactam BII. Similarly Feng and Loh [40] established ap urely rhodiumc atalyzed synthesis of 3-alkylidene isoindolinones from benzyl gem-difluoroacrylate and N-tosyl-benzamides at room temperature in the presence of an inorganic base andw ithoutt he need of protectiveg ases (Scheme 10 B). The combinationo fC ÀHa ctivation and CÀF cleavage was further expanded to gem-difluoromethylenea lkynes with N-methoxy-benzamide substrates. [41] It is noteworthy that ar eaction proceeded in the non-halogenated solvent under air and tolerated ab road range of substrates (Scheme 10 C).
Liu and Lu [42] described the coupling of a-allenols and N-methoxy-benzamide derivatives in the presence of ar hodiumc atalyst and silver acetate as the external oxidant, forming 3,3-disubtituted isoindolinones (Scheme 11 A). In their experiments,i t was found that the hydroxyl group, has as ignificant effect on the chemo-and regioselectivity.S imilarly,k etimines have been investigated as coupling partnersf or N-methoxy-benzamide derivatives. Lu andW ang [43] described CÀHb ond activation/an-nulation cascade forming 3-aminoisoindolinones and3 -diarylmethyleneisoindolinones depending on the substituents on the benzamide (Scheme 11 Ba nd C). For example, N-methoxy-1-naphthamides and benzamides bearing bulky substituents at ortho-position would lead to 3-diarylmethyleneisoindolinones. Later the diastereoselectivity of this cascade to 3-aminoisoindolinones was also investigated (Scheme 11 D). [44] Similarly to allene derivatives, enynes have been successfully coupled with benzohydroxamic acid or N-methoxy-benzamide derivatives forming 3,3-disubstituted isoindolinones. Chang [45] discovered that replacing two methyl groups from Cp* ligand for carboxylic acid ethyl ester would significantly tune the catalyst towards formal [4+ +1] annulation (Scheme 12 A). By treating N-pivaloyloxy benzamide with conjugatede nynones, an umber of isoindolinones could be synthesized with furan substituents on the position C3. An oxidative annulation between enynes and N-methoxybenzamides was described by Li (Scheme 12 B). [46] Here, combination of copper(II) acetate and air was employed as oxidants in methanola tr oom temperature forming av ariety of 3,3-disubstituted isoindolinones at good to excellent yields.
Propargyl alcohols and propargyl acetates have found utility as C 1 synthons in the preparation of isoindolinone derivatives. Liu [47] described the coupling of propargyl alcohol derivatives and N-ethoxy benzamides with cesium acetate in 1,2-dichloroethanea te levated temperatures under argon leadingt oa broad variety of isoindolinones (Scheme 13 A). The ethoxy group utilized as directing group was also removed during the courseo ft he reactionl imiting the need for subsequent synthetic operations. Li [48] was able to synthesize similar compounds under air at closet oa mbientc onditions in the presence of silver acetate ands ilver carbonate (Scheme 13 B). Ma [49] presented an approach to isoindolinone synthesis utilizing propargyl acetates as C 1 synthons in aqueous media in the presence of sodium acetate and acetic acid at reflux temperature. Based on experimental evidence,i tw as proposed that the reaction proceeds via allene intermediate formation followed by cyclization, whereas in the case of propargyl alcohol reactants the reactionw ould proceed via p-allylic intermediate.
Rh III -catalyzed three-component synthesis of isoindolinone frameworks was achieved by both Wang et al. [50] and Zhang et al. [51] Wang used ac ombination of benzoyl chloride derivative, 2-aminophenol and electron deficienta lkene derivatives to synthesize av ariety of substituted isoindolinones in as ingle step under air (Scheme 14 A). In comparison, Zhang utilized an aromatica ldehyde, 2-aminopyridines and similarly activated olefins under nitrogen atmosphere,a nd was able to synthesize pagoclone andp azinaclone in as ingle step, albeit in 15 %a nd 20 %i solated yields, respectively (Scheme 14 B). These reactions can be operated using commerciallya vailabler eactants without the need of significant prior synthetic work. In both cases the amine reactanti ss elected to function as ad irecting group for the oxidative rhodiumcatalyzed CÀHa ctivation reaction.
Yuan et al. [52] reported ar edox-neutral Rh III catalyzed double CÀHb ond functionalization cascade to produce 3-spiros ubstituted isoindolinones from 2,3-diarylcyclopropenones and benzamide derivatives (Scheme 15). In this manner, two new CÀC bonds and one new CÀNb ond were formed with the indene substituent at C3 positiono ft he isoindolinone skeleton. While this reactiond oes requiree levated temperature and halogenated solvent, it does not need protection from air.

Rh-catalyzed cyclization using carbene reagents
The coupling of diazo compounds to benzohydroxamic acid derivatives in Rh III -catalyzed formal [4+ +1] cycloaddition proceeding via CÀHb onda ctivation forming isoindolinones was demonstrated by both Rovis [54] and Yu. [55] Rovis utilized O-pivaloyl benzohydroxamica cids with methyl a-aryldiazoacetateso r 1-aryl-2,2,2-trifluoro diazoethanesa sc arbenoid coupling partners, whereas Yu focusedo nO-acetyl benzohydroxamic acids with diazomalonates (Scheme 17 Aa nd B, respectively). The methodr eported by Rovis proceeded in the presence of substoichiometric amount of base under air while Yu didn ot need additional base butu tilizedh ighert emperature under argon atmosphere.I na ddition of olefination of tosylated benzamides Zhu [38b] extended the their methodology to encompass diazoacetate reactantsi nsteado fa lkenes (Scheme 17 C). The yield of these reactions was mainly dependent of electron withdrawing substituents on the alkenes or of steric hindrances present in diazoacetate substrates.
Cui [56] reported the synthesis of isoindolinones from benzohydroxamic acids and diazo derivatives, generated in situ from ketones in presence of use of hydrazine and manganese oxide (Scheme 18). While in this mannert he need to handle and prepare possibly hazardousdiazo compounds is limited,the methodology still utilizeshighly toxic hydrazine as well as super stoichiometric amount of manganese oxide.

Rh-catalyzed asymmetric synthesis of isoindolinones
Since the seminalw ork on asymmetric arylation of N-tosylaryliminesb yX ua nd Lin in 2007, [57] only af ew examples of asymmetric synthesis of isoindolinones by transitionmetal catalyzed transformations have been reported. In case of asymmetric rhodiumc atalyzed CÀHf unctionalization reactions, all of the catalysts described share ac ommon feature of bulky axially chiral substituent, such as 1,1'-binaphtyl or 1,1'-spirobiindane derivative, at the Cp ring. Cramer [58] was the first to utilize these types of ligands for rhodiumc atalyzed asymmetric synthesis of isoindolinone via CÀHf unctionalization reaction. The reactions proceeded under mild conditions and allowed to achieve high enantioselectivities without the need of superstoichiometric amounto fa dditives (Scheme 19 A). This methodology was based on previous work of Rovis [54] utilizing donor/acceptor diazo compounds with O-pivaloyl benzhydroxamic acids. Based on the work of Loh, [41] Wang [59] reported as olvent-dependent asymmetrics ynthesis of alkynyl and monofluoroalkenyli soindolinones (Scheme 19 Ba nd C). In isobutyronitrile, the monofluoroalkenyl isoindolinones were formed in moderate to good enantioselectivity with predomi-nance of the Z isomer,w hereas in methanol the alkynyl derivatives were formed withv ery high enantioselectivity.Y ou [60] described the first enantioselective [4+ +1] annulation reaction between N-(tert-butoxycarbonyl)benzamides and alkenes via rhodium catalyzedC ÀHa ctivation using chiral dimericr hodium precatalysts (Scheme 19 D). The reactionp roceeds under mild conditions and is fully atom economic, requiringo nly minimal amountso fa dditives, although the reaction was performed under argon atmosphere andt rifluoroethanol ast he solvent. The methodology was appliedt oabroad range of benzamide and styrene derivatives with the only major limitations arising from ortho-substituted styrene derivatives.
N-Sulfonated benzamides have been successfully utilized as substrates in the ruthenium catalyzed CÀHfunctionalization reactions for the synthesis of 3-substitutedi soindolinones. Ackermann [62] described an oxidative CÀHc oupling with subsequent aza-Michael reactionb etween ortho-substituted N-tosyl-benzamides and av ariety of acrylates (Scheme 21 A). Miura et al. [63] utilized as imilar approach to CÀHf unctionalization applied to internal alkynes and N-sulfonated aromatic amides, followed by base catalyzed intramolecular cyclization (Scheme21B). Later the methodology was extended to aldimines [64] as well (Scheme 21 Ca nd D). Jeganmohan [65] described the use of allylic alcohols and Nalkyl/aryl benzamides in oxidative CÀHc oupling/cyclization cascade. N-Benzylated benzamides proved to be the best substrates under the conditions utilized, providing ab road range of 3-subtituted isoindolinones (Scheme 22 A). Based on experimental investigations, it was proposed that the allylic alcohols would most likely dehydrogenatively convert into a,b-unsaturated enones prior to the CÀHf unctionalization and cyclization cascade. Few years later the methodology was expanded to coupling of N-alkylated benzamides with phenylv inyl sulfone or acrylate derivatives, producing 3-alkylidenei soindolinones (Scheme 22 Ba nd C). [66] Furthermore, it was demonstratedt hat the 3-(phenylsulfonyl)methylene derivatized isoindolinones could be converted into aristolactams in as ingle step in good, isolated yields.
Similarly to their work with rhodium, [47] Liu [67] reported a ruthenium catalyzed formal [4+ +1] annulation of propargyl alcohol derivativesw ith N-ethoxy benzamides by means of CÀH functionalization reaction (Scheme 23). In comparison to the rhodiumc atalyzed method the overall isolated yields are very close to each other and the reaction with the ruthenium catalyst is operated at slightly lower temperature, not to mention the price difference between rhodiuma nd rutheniumc omplexes. Similar to the work on rhodium,i tw as proposed that the reaction proceeds via p-allylic ruthenacycle intermediate.
Jeganmohan [68] demonstrated the utility of dichloro(p-cymene)ruthenium(II) dimer as precatalyst for the cyclization of benzonitriles with phenyl vinyl sulfone or acrylate derivatives producing 3-alkylidene isoindolinones with very high Z selectivity (Scheme24A and B). In these reactions, the benzonitrile is oxidized in situ to benzamide by the copper(II) acetate followed by the CÀHf unctionalization and subsequentc yclization. Liu [69] described the use of imidates and electron deficient terminal olefins in the synthesis of various 3-methyleneisoindolin-1-ones (Scheme 24 C). The NÀHi midates functioned as ad irecting group for the oxidative alkenylation/annulation cascade, yieldingexclusively the Z-isomer of the 3-methyleneisoindolin-1-one derivatives.

Ru-catalyzed spiroannulation via CÀHfunctionalization
The use of 3-aryl-N-sulfonyl ketimines and aryl-isocyanate in spiroannulation to form spiro-isoindolinone-benzosultams was established by SubbaR eddy (Scheme 25). [70] The methodology produced av ariety of spiro-isoindolinone-benzosultamsi n good yields without the excessive need of additives. Based on previousp ublications, the reactionw as proposed to proceed via initial formationo fb enzamide derivative by CÀHf unctionalizationfollowed by the cyclization.

Ni-catalyzed olefination-cyclization
Both Zheng et al. [71] and Zhang [72] described an ickel catalyzed oxidative CÀHa lkynylation/annulation cascade with terminal alkynes under oxygen atmosphere yielding 3-alkylidene isoindolinones in mostly Z-selective manner (Scheme 26 Aand B, respectively). The Z/E selectivity wasm ainly attributedt ot he steric hindrance formed by the substituent in both substrates. In both cases, the reaction mechanism is proposed to proceed in identical manner,b yi nitial CÀHa lkynylation of the aromatic ring, followed by intramolecular annulation to form the isoindolinone.
Chen [73] used 8-quinoline as ad irecting group for nickel(II)/ silver(I)-catalyzed CÀHa ctivation and intramoleculara nnulation cascade (Scheme 27). Geminald ibromoalkenes were utilized to from bromoalkynes in situ with the help of sodium carbonate followed by alkynylation via nickel catalyst. Subsequent cyclization was mediated by silver carbonate and tert-butylammoni-Scheme23. Coupling of propargyl alcohol derivatives with N-ethoxy benzamides.
Scheme24. Reagents with unsaturated carbon nitrogen bonds utilized in isoindolinone synthesis.
Scheme26. Nickel catalyzedalkenylation/annulation cascade terminal alkenesa nd benzamides with pendant directing groups. um iodide forming an umber of 3-alkylidene isoindolinones in moderate to good yields.
Yu [76] establishedacopper(I) catalyzed radical benzylation and cyclization of tertiarye namides generating av ariety 3,3disubstituted isoindolinone derivatives in moderate to good yields.I nt his manner, two new CÀCb onds are generated in successive fashion (Scheme 30). While the detailed reaction mechanism is not yet fully clarified, it was postulated that the catalyst, copper(I) chloride, in combination with an oxidant, ditert-butyl peroxide, generates ab enzylr adical which will initiate the CÀCb ond formingc ascade together with the utilized tertiaryenamides.
Ackermann [80] demonstrated the use cobalt(II) acetate in a CÀHo lefination/annulation cascade with N-(quinolin-8-yl) benzamides and acrylates as substrates (Scheme 33 A). Later,J eganmohan [81] applied somewhat similarr eaction conditions for N-(quinolin-8-yl) benzamides andm aleimides as substrates generating 3-spirosubstituted isoindolinones (Scheme 33 B). Where Ackermann applied am ixture of PEG 400 and trifluoroethanol as the solventa nd silver pivalate as the oxidant, Jeganmohan utilized 1,2-dichloroethanea st he solventw ith silver carbonate as the oxidant and as mall amount of pivalic acid as additive to improve the reactiony ields. Both proposed very similar reaction mechanisms for the initial CÀHa lkenylation, followed by cyclization either as separate reaction( Ackermann) or as ap art of the same catalytic cycle (Jeganmohan). Zhao [82] described the use of Co II and Cu II as catalysts for oxidative CÀH/NÀHf unctionalization of benzamides with ketones (Scheme 34). Here, the copper(II) catalysti su tilized in dehydrogenationo ft he ketone with the help of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)a nd Ag 2 CO 3 to form an a,b-unsaturated ketone,w hich the is utilized in the cobalt catalyzed CÀH functionalization followed by annulation. The methodology was applied to ab road range of N-(quinolin-8-yl) benzamide derivatives and av ariety of ethyl aryl ketones.

Co-catalyzedc yclization using carbene reagents
Li [83] applied a-diazoketones as substrates for cobalt catalyzed oxidative CÀHf unctionalization cyclization cascade.D epending on the choice of cobalt catalyst and oxidants, the reaction could be directed to form either 3-mono-o r3,3-disubtituted isoindolinones in moderate to excellent yields (Scheme 35 A and B).

Co-catalyzed isocyanide insertion-cyclization
Av ariety of cobalt catalyzed methodologies for synthesis of 3iminoisosindolinones have been published during the past ten years,w ith ac ommonf eature in the use of 8-quinolinyl (Q) directingg roup. Gu et al. [84] described the use of oxidative CÀH functionalization/annulation cascade with cobalt(II) acetate as the catalyst and tert-butyl peroxybenzoate as the oxidant (Scheme 36 A), followed by Hao [85] and Sundararaju [86] using cobalt(II) acetyl acetonate and silver salt as the oxidant (Scheme 36 Ba nd C, respectively). Later,S undararaju [87] reported ag eneral site-selective cobalt-catalyzed insertion of isocya-nides to form aryl amides through CÀHb onda ctivation and alcohol assisted intramolecular trans-amidation with as ignificantly broad substrate scope( Scheme 36 D). Chen et al. [88] presented am ild cobalt catalyzed CÀHf unctionalization/annulations cascadeu sing electrochemical oxidation in an undivided cell equippedw ith ar eticulated vitreous carbon (RVC) anode and nickel cathode( Scheme 36 E). In their work, electricity was utilized as the oxidantr emovingt he need for stoichiometric oxidants but still stoichiometric amounts of pivalate salts were required as additives. In generalization for all above-mentioned reactions, benzamides bearing steric bulk near the CÀHf unctionalization site or benzamides with nitro-substituentsa re more likelyt oresult in poor yields.

Cross-Coupling:Annulation/Cyclization
Transition metal catalyzed coupling reactions are among the most efficient methods available for forming carbonÀcarbon bonds. [91] To date, av ariety of effective coupling processes, such as intramolecular Heck or Sonogashira reactions, have allowed the preparation of isoinolinone scaffolds and this field is dominated by palladium-and copper-catalyzed reactions. In this section we discuss the developments in this area, focusing on reactions involving CÀCb ond formation in cyclization/annulation processes. The followings ection is categorized by the metal used and subcategorized by the type of isoindolinone derivativeobtained as product.
In 2018, Mendoza-Perez and Vazquez described am icrowave assisted domino reactions tarting from N-protected iodoaminoacrylates and boronic acids via 5-exo-trig process, followed by Suzuki coupling, to yield isoindolinones bearing quaternary carbon centers (Scheme40). [94] Gevorgyan described the synthesis of 3-substitutedisoindolinones involving av isible light inducedp alladium catalyzedi ntramolecular CÀHa rylationo fb enzamides via fragmentation of C(sp 2 )ÀOb onds of aryl triflates. [95] The reactionw as reportedt o proceeds via formation of hybrid aryl Pd-radical intermediates. By using benzamides bearing alkyl, methoxy,h alo-, trifluoromethyl and naphthyl groups, this reaction provides the corresponding isoindolinones in moderate to good yields. Cyclization of cyclohexyl-and isobutyl-derivatized amides was also successful leadingt ot he formation of the products in moderate to good yields (Scheme 41).
In 2011, aQ -Phos ligatedp alladium catalyzed domino carbohalogenation reaction formingi ndoline-fused isoindolinones containing multiple stereogenic centers was reported by Lautens and co-workers. [96] Under the reported reactionc onditions, the polyunsaturated aryl iodide provides the domino cyclization product in high yield and diastereoselectivity with no formationo fm onocyclization product. In addition, aryl bromides can be used to form the polycyclica lkyl iodide derivativev ia halogen exchange dominor eaction(Scheme 42).
withdrawing and electron-donating substituents on the substrates were compatible with these reactionconditions.
In 2015, Pal and co-workersr eported ad ouble Heck reaction to yield indolone-fused isoindolinone rings starting from dihalo N-allyl substituted N-arylbenzamide derivatives. [99] This methodology is based on the reactivity differences of the aromatic halideso ft he startinga mides towardst he Pd-catalyst (Scheme 45 A). The authors proposed that substrates with more reactive halideso nt he aniline ring (X in Scheme45A) than on the aroyl moiety (Y in Scheme 45) is essential for this reaction. Oney ear later,K im reported as equential Heck reaction of benzamidoacrylatesw ith Pd(OAc) 2 and NaHCO 3 to render an indolizine-fused isoindolinone ring as part of the strategyf or the total synthesis of decumbenine B (Scheme 45 B). [100] Polycyclic isoindolinones can be efficientlys ynthesized by palladium catalyzed dearomativet ransformations. Dearomative Heck reactions of indoles have been reporteda sa ne fficient methodf or the construction of indoline-fused isoindolinone skeleton containing quaternary stereocenters. In 2012, Yaoa nd Wu set ap recedence [101] fori ndole dearomatization methods involving ac arbopalladation mechanism, via catalytic intramolecular Heck-type dearomatization reaction startingf rom 2,3disubstituted indoles (Scheme 46 A). It was shownt hat steric hindrance at the C2 positiono ft he alkyl substituted indole resulted in lower reaction yields. Jia employed aP d(OAc) 2 /(R)-BINAP based catalyst system to achieve the first asymmetric indole dearomatization reaction to yield chiral polycyclic isoin-dolinones with excellent enantioselectivities via reductive Heck reactionu sing C2-substituted indoles (Scheme46B). [102] Steric effect from aromatic groups at C2-position in the indole resulted in significantly lower yields. One year later,K itamuraa nd Fukuyama reported an asymmetricd earomative Heck type cyclization of an N-acyl indole using ap alladium catalyst with Feringa's phosphoramide ligand to obtain polycyclic compound bearing the isoindolinone moiety at multigram scale as part of as ynthetic strategy fort he synthesis of hinckdentine A (Scheme 46 C). [103] Wang, Shang and co-workers [104] described the first dearomative palladium catalyzed isocyanide insertion reactionf or synthesis of indoline-fused isoindolinones via dearomativearyl/cycloimidoylation of N-(2-bromobenzoyl)indoles. This methodology was reported to have aw ide functional group tolerance (Scheme 47).
In addition to indoled earomatization transformations, ap alladium catalyzed dominoL arock annulation/Heck dearomatization reaction to render tetracyclic indoline-isoindolinones derivatives was investigated. [105] The reaction proceeds via Larock annulation of N-bromobenzoyl o-iodoanilines with alkynes and as ubsequenti ntramolecular dearomativeH eck reactiont o form three chemical bonds in as ingle step (Scheme 48). A broad scopeo fs ubstrates was employed to afford the products in moderate to good yields.
Palladium catalyzed asymmetric intramolecular dearomatizations of pyrroles to yield pyrroline-fused isoindolinones were described by both Jia [106] and You [107] in 2018 (Scheme49). Jia reported the use of Pd(dba) 2 and (S)-SEGPHOS ligand and extended the methodology to the dearomatization of disubstituted indoles using aryl triflate derivativest oo btain the indoline-isoindolinone products in moderate to high yields and good enantioselectivities.Y ou utilized aP d(OAc) 2 as catalysts in collaboration of Feringa's phosphoramide ligand,o btaining similar yields and enantioselectivities as Jia.

Pd-catalyzed isocyanide insertion-cyclization
Khan and Pardasani reported ao ne-potP d-catalyzed isocyanide insertion, imine hydration and 5-exo-dig cycloisomerization sequence reaction by using an isocyanide as amide surrogate. In this reaction, an alkylbenzamide is generated in situ followed by cyclization to give the isoindolinone derivative (Scheme 51). [116] The nature of the substituent on the triple bond had am ajor impact on the reaction. Aromatic groups containing an electron-withdrawing substituent increased the efficiency of the reaction to produce the isoindolinone by decreasingt he electron density at the proximal end of the triple bond. Alkyl and alkenyl substituents failed to produce the cyclized product and, instead, furnished an amide intermediate as the only product. Thea uthorsp roposed that, in this reaction, the electrophilicity of the alkyne is the driving force of the tandem process andt he presence of the Pd catalysti sc rucial only in the carboxamidation step.
In 2013, Chauhan described am icrowavea ssisted highly stereoselectivel igand free reaction protocol using amides and isocyanides as coupling partnerst or ender substituted isoindolinonesw ith high stereoselectivity via isocyanide insertion (Scheme 52). In this reaction al arge variety of amides are well tolerated, except for 2-chloro or 2-bromo-substituted amide substrates resulting in lower yields. [117] Nickel-catalyzed coupling reactions

Ni-catalyzed cyclization via alkylation
In 2011S hacklady-McAtee [118] and co-workers described an intramolecular cyclization of N-benzoyl aminalsm ediated by Ni 0 in the presence of aL ewis acid to render av ariety of isoindolinones C3-substituted in moderate to good yields (Scheme 53). The reaction proceeds in three steps from benzoyl chloride, primary amines and aldehydes via initial formationo fi minium ion intermediate with the help of the Lewis acid followed by an a-amidoalkyl nickel (II) intermediate. An electron-rich Ni 0 catalysti sr equired for the formation of this in intermediate, which is then followed by the cyclization to final product.

Ni-catalyzed cyclization via dearomatization/Heck reaction
In 2017, aN i-catalyzed asymmetric Heck type dearomatization reactions tartingf rom C2-substituted indoles to afford fused isoindolinone-indolines with high enantioselectivity was reported by Zhou (Scheme 54 A). [119] The authorsp roposed that this mechanism is distinct from the analogousp alladium catalyzed methods. [101][102] In this process, an ickelÀcarbon bond is converted into aC ÀHb ond to release the product via protonation. This investigation constitutes the first example of an ickel-catalyzed asymmetric reductiveH eck cyclization.R ecently,L autens [120] reported ad earomative carboiodination reactiont oi nstall reactives econdary benzylic iodides (Scheme54B). The authors proposed that this reaction proceeds by the meanso fa syn intramolecular carbonickelation across a2 -substituted indole with subsequentd iastereoretentive reductive elimination of the carbon-iodine bond to afford fused isoindolinoneindoline rings. Aw ide variety of functional groups were well tolerated affording the products in moderate to good yields with excellent diastereoselectivities.

Cu-catalyzed cyclization via olefination/alkylation
The use of copper catalyzed coupling reactions for synthesis of isoindolinones from products obtained from Ugi-4CRr eaction was described by Chauhan. [121] The diamides obtained from the Ugi-4CRr eaction were cyclized to isoindolinones via Cucatalyzed deamidative CÀCc oupling. This two-step sequence allows the synthesis of isoindolinone derivatives using ab road range of 2-halobenzoic acids, isocyanides,a mines anda ldehydes (Scheme 55).
Sen [122] reported ao ne-pot palladium-free copper-mediated dominoS onogashira-5-exo-dig-cyclization of o-iodo-N-phenylbenzamides with phenylacetylenef ollowedb yr egioselective nucleophilic addition of indole using CuI as the catalysta nd a salen-type ligand to obtain al ibrary of indolyl isoindolinones in high yield and in short reactiont imei na queous micellar medium( Scheme 56). Using o-bromo-N-phenylbenzamides, a lower reaction yield was observed and using the corresponding aryl chlorides the reaction was found to be inefficient.
In 2020, Yaor eportedaone-pot two-step sequential carbon degradation/ringc ontraction reaction fort he synthesis of 3-hydroxyisoindolinones from iodo-benzamides and various substi-tuted benzyl cyanides as benzoyl synthons in the presence of CuCl and l-proline as the ligand under nitrogen atmosphere (Scheme 57). [123] The authors described the initial formation of the corresponding substituted aminoisoquinolinone, which showedt ob estable after 12 h. Without isolating the isoquinoline derivative, the reactionv essel waso penedt oa ir allowing the ring contraction to take place. Ab road reaction scope of various3 -hydroxyisoindolinones wasp resented in moderate to good yields. The reactions performed using 2-bromobenzyl cyanide substrates did not requiret he use of l-prolinea sa ligand.
In 2016, ad omino amidation/arylation reactiono fq uaternary and tertiary aminoboronates with 2-halobenzoyl chlorides in the presence of 2,2'-bipyrydine/copper(II) catalyst was reported by Dumas and co-workers( Scheme58A). [124] Av ariety of acid chlorides were examined by the authors, aryl chlorides at any positiono ft he ring were well tolerated (X in Scheme 58 A), as well as fluoride ande lectron-donating methoxide were found compatible with the reactionc onditions. Also, aryl bromides underwent cyclization exclusively at the 2-Br group without the formationo fi ntermolecular coupling products. The reaction performed well startingf rom aminoboronates containing an adjacent aromatic ring and bearing halogen and electrondonating groups.T his reactioni st he first reported example of arylation of fully substituted aminoboronates or Cu-catalyzed couplings of quaternary boronates. The authors proposed that the reaction proceed via configurationally unstableC u I -inter-Scheme55. Ugi-4CRreaction followed by Cu-catalyzed deamidative CÀCcoupling by Chahuan.
Scheme56. Synthesis of isoindolinones in an aqueous micellar medium byS en.

Scheme57. Synthesis of 3-hydroxyisoindolinones by Yao.
Scheme58. Copper catalyzedcross-coupling alkylborons for synthesis of isoindolinones. mediate as ar acemic isoindolinone was observed when enantioenriched aminoboronates were utilized as startingm aterials. Based on the amidation/arylations equence reported by Dumas,astereospecific intramolecular Suzuki-Miyaura type cross-coupling reactiono fe asily accessible enantioenriched a-[(o-bromobenzoyl)amino]benzylboronates using bipyridinecopperc atalystw as described by Yamamoto and Suginome (Scheme 58 B). [125] This reaction proceeds with stereochemical inversion relyingo nt he stereoretentivet ransmetalation step, which is favored by using aBrønsted acid additive. The highest enantiospecificities were achieved using substrates with electron-donating substituents in the para-position of the pendant benzylm oiety (R 1 at Scheme 58 B). Notably,s terically hindered groups at the stereogenic carbon afforded high enantiospecificities. In case of fully substituted stereogenic boron-bound carbon atom centers (R 3 = Me at Scheme 58 B), less sterically demanding bipyridine ligands resulted in highere nantioselectivities.
While the majority of the reported procedures for the preparation of 3-methyleneisoindolinones describe the use of 2-halobenzamides, aC u-catalyzed one-pot synthesis of targeted compounds via decarboxylative coupling of arylakynylcarboxylic acid with iodo-or bromobenzoic acid was reported by Lee in 2014. [126] This ligand free structurally divergentr eaction methodology affords isoindolinone or isoquinolinone derivatives selectively from the same substrates by switching from one-pot reaction to sequential addition ammonium acetate (NH 4 OAc) (Scheme59A). Ab road range of arylalkynylcarboxylic acid were well tolerated, however,i nt he presenceo fa liphatic analogues no isoindolinone derivatives were observed. The methodology was further extended to the chloro-benzoic acid substrates by the same authors (Scheme 59 B). [127] As eries of Cu-catalyzed domino synthetic protocols for the synthesis of 3-methyleneisoindolinones startingf rom 2-halobenzamides and alkynes have been reported (Scheme 60). [128][129][130][131][132] In 2013, Zhang and co-workers reporteda stereoselective microwave assisted synthesis of (Z)-3-methyleneisoindolinone derivativesf rom N-substituted-2-bromobenz-amides and arylacetylenes using aC u(OAc) 2 ·H 2 O/DBU catalyst. [128] Later,aCu-catalyzedd ecarboxylative cross-couplingo f N-substituted-2-halobenzamidesw ith aryl alkynyl carboxylic acids, followedb y5 -exo-dig heteroannulation, was reported by the Patel. [129] The use of acid derivativesa sa lkyne surrogates has advantages,s uch as higherr eactivity or lower susceptibility to homocoupling reaction. For 2-bromo benzamides, aC uI/1,10-phenantroline catalysts ystem is needed, however, when more reactive 2-iodo benzamides were used as substrates the reaction proceededs moothly in the absence of ligand without affectingt he yield. In 2016, Yao [130] reported the reactiono fa lkynylanilines with 2-iodo-N-methylbenzamides in the presence of ac opperc atalyst to form 3-(2-aminobenzylidene)-2-substituted isoindolinone derivatives via C-terminal attack of the 2-alkynylaniline to 2-iodobenzamide. The isoindolinone products were converted to spiro fused isoindolinoneindolines utilizingh alonium ion mediated strategy using NBS/ TCC in the presence of acetic anhydride. In the same year,t he Prakash [131] described at riple domino desilylation, cross-coupling and hydroamidation sequence under aqueous phasetransfer conditions. Use of (silyl)alkynes as coupling partners affordedt he products with exclusive Z-configuration, with the exception of (silyl)alkynes containing strong electron-withdrawing substituents. The scope of the (silyl)alkyned erivatives was found to be broad and alloweda ccess to the target molecules with av aried range of functionalities in good yields. N-Unprotected iodobenzamides were wellt olerated, affording the substitutedi soindolinones in high yield. In 2018, Phukandescribed ad omino reactiono fu nprotected2 -halobenzamide andt erminal alkynes using as quare pyramidal [Cu(DMAP) 4 I]I complex as ac atalyst to yield the corresponding( Z)-3-methyleneisoindolinones with free NH group via cross-coupling reaction followed by 5-exo-dig cycloisomerization. [132] This methodology allows the use of ab road range of terminala lkynes. The authors also described the extension of this methodology to phenyl propiolic acid derivatives and silylated alkynes with N-protectedbromobenzamides to afford the products in good yield.

Pd/Cu-catalyzed cyclization via olefination
Based on the advantages of utilizing alkynylsilanes as coupling partnerst oa fford 3-methylene-isoindolinones reported by Prakash in 2016, am ulticomponent one-pot reaction using TMSA, 2-iodo-N-methylbenzamidea nd aryl halides (bromides or iodides) under Pd/Cu catalysis was investigated and reported by the same author. [131] This protocol affords the corresponding isoindolinones in high yields (Scheme 61) and emphasizes the importance of using alkylsilanes to facilitate consecutive crosscoupling processes in one-pot procedures from aryl electrophiles and TMSA as acetylene surrogate.

Carbonylation:A nnulation/Cyclization
Transition metal-catalyzed carbonylation reactions, are widely used in synthetic chemistry. The simplicity and low cost of carbon monoxide (CO) as C-1 unit as well as its application in green chemistry and wide use in industry settings are among the most significant advantages of carbonylation reactions. A number of reviews [136] on the use of this type of transformations in heterocycle synthesis have appeared. Here, we intend to report ab rief update on transition metal catalyzed carbonylation reactions appliedi nto isoindolinone synthesis.
Jiang [138] reported ap alladium-catalyzed carbonylation of aromatic oximes via ortho-C(sp 2 )ÀHb ond functionalization (Scheme 65). While the reaction does take place under atmospheric carbon monoxide pressure,asignificant amount of palladium catalyst is required. Nevertheless, in this manner av ariety of N-underivatized 3-alkylidene isoindolinones can be generated in good yields.
Wang et al. [139] presented an oxalyl amide assisted palladiumcatalyzed carbonylation via CÀHf unctionalization fors ynthesis of pyrrolidones whichw as applied to as mall scope of isoindolinones( Scheme 66 A). The combinationo fs ilver salt as an oxidant and meta-(trifuoromethyl)benzoica cid (m-CF 3 PhCO 2 H) as an additive was found to be vital to achieveh igh yields. Later, Zhang et al. [140] applied av ery similarc arbonylation approach to unprotectedb enzyl amines utilizing copper(II) trifuoroacetate as the oxidanti nstead of silver (Scheme 66 B). As with many ortho-CÀHf unctionalization methods, substrates with ortho-substituents resulted in significantly lower yields. Carbonylation of sterically hindered N-alkyl or N-aryl benzylamines using TEMPO as as toichiometric oxidantw as reported by Cheng et al. (Scheme 66 C). [141] The method provided good to high yields for N-methyl/ethyl derivatized substrates and lower yields for N-aryl derivatized. Finally,t he methodology was successfully applied to the synthesis of spiropachysin-20-one.
Guo et al. [142] In the case of the cyclocarbonylation, aw ide range of substrates were tolerated with only drasticd rop in the yield observed with ortho-substituents( R 3 )i nt he pendant arene group. The arenes utilized in the cyclocarbonylation are commonlyp repared via rhodium catalyzed annulation of suitable benzamide and aryl alkyne, and thus combinedi nto onepot two-step synthesis to achieve similar structures in facile manner. Instead of carbon monoxide, Wang [143] utilized carbon dioxide in the synthesis of isoindolo[2,1-b]isoquinoline-5,7diones via cyclocarbonylationi nm oderate to good yields (Scheme 67 C). Similarly as with method described by Guo the ortho-substituent (R 3 )i nt he pendant arene group did not allow the carbonylation to take place. It was proposed thatt he activation of carbon dioxide proceeds via formation of hemicarbonate ion with lithium tert-butoxide followed by ligand exchange with palladium(II) acetate forming the startinga ctive catalytic complex.

Pd-catalyzed carbonylationvia CÀXf unctionalization
Am ulti-component palladium catalyzed carbonylation reaction was presentedb yK ollµr [144] andH an et al. [145] Kollar used 2-iodobenzyl bromide in the presence of primary amines under carbon monoxide atmosphere to successfully synthesize a small scope of N-derivatizedi soindolinones (Scheme 68 A). Han et al. described an in situ condensationo f2 -bromobenzaldehydes and phenylhydrazines followed by palladium catalyzed carbonylation to generated2 -amino isoindolinones (Scheme 68 B). Here, both 2-bromo and 2-iodobenzladehydes resultedi ng ood to excellent yields but 2-triflate bearing analogs yielded in significantly inferior outcome.A lso, strongly electronw ithdrawing substituents on the benzene ring of the hydrazine reactants resulted in lower yields.
Cyclocarbonylative coupling of ortho-chloro arylketimines with carbon monoxide was described by Hua [146] using phosphine ligated palladiumc atalyst at elevated temperatures (Scheme 69). In this manner,anumber of 3-methylidenei soindolinones werep roduced in good yields but switching to synthesis of 3-ethylidene analog has proved challenging for the methodology.
Am ulti-component cascade reaction utilizing either carbonylationo rd ouble-carbonylation process of 2-bromoanilines with 2-formylbenzoic acid or 2-halobenzaldehydes generating functionalized isoindolinones was reported by Wu (Scheme 71). [148] In the case of 2-formylbenzoic acids, the use of 3-amino-2-chloropyridine insteado f2 -bromoanilines resulted in significant drop in the yield but otherwise halide,m ethyl and acetyl substituents were well tolerated. In the case of 2halobenzaldehydes,2 -iodobenzaldehyde substrates resulted in the highest yields, but still lower than what was obtained with 2-formylbenzoic acids.
Asymmetric synthesis of fluorinated isoindolinones by palladium-catalyzed intramolecular aminocarbonylation of the chiral-a-fluoroalkyl-2-iodobenzylaminesw as described by Bario et al. (Scheme 75 A). [154] In general, the best yields were achieved with tert-butoxycarbonyl or benzyloxycarbonyl derivatized amines and "free" secondarya mines resulted in slightly lower yields. Especially fluoride and trifluoromethyl substituents (R 1 )r esulted in significant erosiono ft he opticalp urity, probablyd ue to ab ase-mediated anti b-hydridee limination process as suggested by the authors. The degradation of the opticalp urity was correlated with pK a of the base and it was demonstrated that the racemization process could be minimized with weakerb ases. Instead of 2-halobenzylamines, Zhou [155] utilized 2-(aminomethyl)aryl tosylatesa ss ubstrates for intramolecular aminocarbonylation. Palladium(II) acetate and DPPP were used as catalyst/ligandc ombination in the presence of potassium carbonate as ab ase at 10 atm of carbon monoxide and significantly elevated temperatures were required for ther eactiont op roceed (Scheme 75 B). In general, the halogenateda nd ester bearings ubstrates resulted in moderate yields, whereas other tested substrates resulted in good to high yields.
As an example, TAK-071 is an M 1 positive allosteric modulator pharmacophore developed by Ta keda Pharmaceutical Com-pany Limited, bearing an isoindolin-1-one ring system. In the scale-up of the synthesis, al ate stage carbocyclization was utilized. The benzyl amine derivative was carbonylated under 5 atm of carbon dioxide utilizing1 ,1'-ferrocenediyl-bis(diphenylphosphine) (DPPF)l igated palladium(II)c hloride as ac atalyst in the presence of an organic base (Scheme 78). [158] Pd-catalyzed dearomative carbonylation Wu [159] described the first example of palladium-catalyzed dearomative carbonylation of N-(2-bromobenzoyl)indoles leading to av ariety of polycyclic spiro compounds containing the isoindolinone skeleton. Here, palladium(II)a cetate and DPPP as the catalyst/ligand combination with sodium tungstate as a base yieldedt he best results.T he optimized conditions were successfully appliedt oavarietyo fa nilines anda lcohols as nucleophiles (Scheme 79).

Pd-catalyzed carbonylationwith CO-surrogates
Carbon monoxide is one of the cheapest C 1 sourcesa vailable, but due to its hazardousp roperties,s uch as high toxicitya nd flammability,aconstant use of CO detector is required for Scheme73. Synthesis of 6H-isoindolo[2,1-a]indol-6-ones by means of intramolecular carbonylation or by intermolecular carbonylation/intramolecular dehydrogenative-coupling.
Benzene-1,3,5-triyl triformate (TFBen) was applied as aC Osurrogate by both Fu et al. [162] and Wu [163] to palladium catalyzed carbonylation of benzyla mines via oxidative CÀHf unctionalization.Fue tal. applied the methodology to broad range of benzyl aminesy ielding the respective 3a nd N-substituted isoindolinones in moderate to good yields (Scheme 81 A). From the tested substrates, only cyano and bromo substituents resulted in lower yields and 3,4-disubtituted benzyla mines lead into mixtures of isomeric structures. Wu described ar oute to N-derivatized isoindolinones with ap endant 2-methyl thiophene as ap art of site-selective carbonylative methodology (Scheme 81 B).

Pd-catalyzed asymmetric carbonylation
Enantioselective preparation of chiral isoindolines via palladium-catalyzed carbamoylation by means of CÀHf unctionalization was reported by Ta ng (Scheme 83 A). [166] Ac hiral mono-phosphorus ligand (R)-AntPhos was utilized as the ligand under 9a tm of carbonm onoxidey ielding av ariety of chiral isoindolines in high enantiomeric excess and moderate to high yields. Long alkyl chains and bulky substituentsi nt he amine as well as trifuoromethyl substituentsi nt he aryl groups resulted in lower yields. An enantioselectiveo xidative carbonylation processo fa ctivated benzylic amines was described by Wu (Scheme83B). [167] Ab imetallic Pd/Cu-based catalyst systemi n the presence of mono-N-protecteda mino acid ligandsc atalyzed aC ÀHc arbonylation of prochiral arylsulfonamides via desymmetrization process. The reaction providesafacile stereoselectivec onstruction of isoindoline-1-ones in good yields and enantioselectivities under atmospheric pressure of CO/O 2 in the ratio of 1:5.
Q. Huang et al. [169] presented ar hodium-catalyzed synthesis of 6H-isoindolo[2,1-a]indol-6-one derivatives via oxidative NÀ H/CÀHc arbonylation of 2-arylindoles under atmosphericC Opressure (Scheme 85). The optimized conditions were applied to ab road substrates cope generating the titlec ompounds in moderate to very high yields. Substrates with cyano or nitro groups at the indole (R 1 )o ri odo substituent at the pendant aryl (R 2 )g roup resulted in lowest yields.
Scheme82. Synthesis of isoindolinones using N-monosubstituted oxamic acids or CO generated from mixture of sulfuric and glyoxylic acid.

Rh-catalyzed carbonylation via CÀXfunctionalization
Morimoto [170] reported aC O-surrogate based Rh I -catalyzed asymmetrics ynthesis of 3-substitutedi soindolinones via aminocarbonylation reactioni nm oderate to good yield andv ery high ee (Scheme 86). First the rhodium catalyzed carbonylation of chiral N-tosylated-2-halobenzylamines utilizing either pentafluorobenzaldehyde or formaldehyde as CO-surrogate was optimized. In most cases the yield of the product was dependent on the CO-surrogate utilized, with pentafluorobenzaldehyde achieving higher isolatedy ields in comparison to formaldehyde. Subsequently,a na symmetric one-pot two-step reaction with Rh I -catalyst was described, starting from coupling of prochiral aldimines and arylboronic acids followed by subsequent carbonylation reaction, yielding the title compoundsc lose to similar yields and enantiomeric excesses when compared to those of the single step carbonylation.
Cyano-substituted aryl iodides as well as with bulky N-substituents (R 3 )i nt he aldimines were found to result in lower yields.

Cobalt catalyzed carbonylation reactions
Co-catalyzed carbonylationwith CO-surrogates Zhong [174] and Grigorjeva [175] both appliedd iethyl azodicarboxylate (DEAD) and diisopropyl azodicarboxylate (DIAD) as COsurrogates in the cobalt-catalyzed oxidative CÀHc arbonylation of benzyl amines, using picolinamide as at racelessd irecting group (Scheme 90 Aa nd B, respectively). In both cases, av ariety of N-underivatized isoindolinones were prepared in moderate to high yields, with marginal differences between electron withdrawing and donating substituents at the arene (R 1 ). When chiral benzylic amines were used as substrates, the enantiopurity of the chiral centerw as maintained and Zhong demonstrated how the developed method could be appliedt o the synthesis of (+ +)-garenoxacin.

Lactamization via Transition Metal Catalyzed Condensation or Addition Reactions
Zinc, scandium and indium catalyzed reactions Zn, Sc and In-catalyzedM annich reaction-lactamization Multicomponent Lewis acid catalyzed Mannich/lactamization cascade for synthesis of various isoindolinones was described by both Singh [176] and Cai [177] (Scheme91A and B, respectively). Singh applied o-formylm ethylbenzoates, trimethylsilyl enol ethers and aniline derivatives in the presence of zinc(II) or scandium(III) triflate catalysts to generate ab road scopeo fi soindolinones in moderate to high yields. Here the main difficulties arose from ortho-substituted anilines anda nilinesb earing multiple electron donating groups.C ai applied indium(III) triflate as ac atalystf or 2-formylbenzoic acids, primary amines and difluoroenoxysilanes to afford N-substituted 3-oxoisoindoline-1-difluoroalkyl derivatives in good yields with exception of ortho-substituted anilines.

Zn, Sc and In-catalyzed Strecker reaction-lactamization
Singh [178] appliedZ n II and In III triflates( Scheme 92 A) and Cai [179] Sc III triflate (Scheme 92 B) to Strecker reaction/lactamization cascade, producing 3-cyano derivatized isoindolinones in good to excellent yields. In the method reported by Singh, only very bulky ortho-substituted anilinesw ere reported to result in low isolated yields, whereas in the case of scandium(III) triflatec atalyst only para-nitro aniline and tert-butyl amine were not tolerated.

Zn and In-catalyzed allylation-lactamization
Lewis acid catalyzed one-pot cascade was optimizedf or In III and Zn II triflate catalysts utilizing tin based allylationr eagent (Scheme 93). [180] In accordance with the Lewis acid catalyzed Mannicha nd Strecker reaction based methodologies (vida supra), the substituents at o-formyl benzoates had minimal effect on the yield of the reactionw hile bulky O-substituted anilineshad as ignificantly detrimental effect on the yield.
Cu-catalyzed in situ imine formation/alkynylation/lactamization cascade Sun et al. [185] reportedac opper catalyzed multicomponent reaction for the synthesis of 2,3-disubstituted isoindolinones utilizing in situ imine formation/alkynylation/lactamization cascade with methyl2 -formylbenzoates,a nilinesa nd alkynes as the reactants (Scheme 98 A). While an umber of isoindolinones can be formed in this manner in low to good yields, the isolated yields are highly dependento nt he alkynes utilized ass ubstrates. In addition, similarly above-mentioned metal triflate catalyzed methods the ortho-substituted anilinesr esulted at best in trace amounts of product. In 2014, Singh [186] reported for the first time ah ighly enantioselective Cu-catalyzed alkynylation/lactamizationc ascade of o-formyl methyl benzoates with aromatic amines and terminal alkynes using a iPr-pybox ligand (Scheme 98 B). In the presence of aromatic amines bearing an ortho substituent and less nucleophilic amines, such as CbzNH 2 ,t he reactionf urnished the product in low yield. Alkynes bearing aromatic rings or aliphatic side chains were successfully used. Methyl 2-formyl benzoates containing electronwithdrawing groups at the para position with respect to the aldehyde functional group did not afford the desired isoindolinone products. In general,l ower reaction yields were observed using methyl 2-formyl benzoates bearing electron withdrawing substituents by decreasing the nucleophilicity of the aromatic secondary amines. The absolute configuration of the products was assigneda sS and the authors showed that steric hindrance adjacent to the aldehyde resultedi ns ignificant drop in enantiomeric purity.L ater,t he same group used the alkynylation/lactamization protocol as ak ey step in the synthesis of medicinally important isoindolinones. [187] Maiti [188] applied a copper(II) based heterogeneousn anocatalyst for similar transformation in good yields but only af ew examples towards the synthesis of isoindolinones were explored (Scheme 98 C).

Cycloaddition, Cyclotrimerization and Annulation Reactions
Gold catalyzed reactions

Au-catalyzed cycloaromatization
Ag old-catalyzed cascade cycloaromatization to ab road range of enantioenriched isoindolinones from unconjugated (E)-ene-diynes was described by Zamanie tal. (Scheme99). [189] It was shown that substituents at the enyne (R 2 )h ad most effect on the yield of the reactionb ut significant trends cannot be drawn based on the limited substrates cope. Based on experimental and computational evidence, the reactionw as shown to proceed via ad ual-gold s,p-activation mode, involvinga key gold-vinylidene-anda llenyl-gold-containing intermediate.

Ruthenium and cobalt catalyzed reactions
Ru or Co-catalyzed formal[2+ +2+ +2] cycloaddition Sheppard [190] reported ar uthenium catalyzed formal [2+ +2+ +2] cycloaddition between amide tethered diynes and alkynes, generating ab road scope aryl substituted isoindolinones in highly regioselective manner (Scheme 100 A). While in most cases the isolated yields were from moderate to excellent, depending on the diyne/alkyne combinationa pplied, as ignificant amount of homocoupling of the diynes was observed. This could however be mitigated by dropwise addition of the diyne to the reactionm ixture. MØndez-Gµlvez et al. [191] also utilized as imilara pproach with cobalt catalyst to afford N-unsubstitutedi soindolinones, albeit only af ew isoindolinone examples were reported (Scheme 100 B).

Palladiumand nickel catalyzed reactions
Pd-catalyzed [4+ +2] cross-benzannulation Ma [192] reported an oxidative palladium and copper co-catalyzed [4+ +2] cross-benzannulation leadingt od iversely substituted isoindolinones from enediynes and alkynes (Scheme 101). For the reactiont otake place, aromatic substituents at R 1 were required, whereas aromatic substituents at R 2 would improveo utcomeo ft he reactions. Both diaryl and dialkyl alkynes were well toleratedw ith few exceptions, but the regioselectivity with unsymmetrical alkynes was highly dependent on the substrate. Based on experimental observations the reaction was suggested to proceed by initial 5-endo cyclization followed by a syn carbopalladation. Subsequent nucleophilic attack of H 2 Oa nd Cu II mediated one-electron oxidation followed by oxidation with O 2 would then provide the target compounds.

Ni-catalyzed annulation
Kalyani [193] described ab is(cyclooctadiene)nickel(0) catalyzed arylation of ortho-halo benzamidesw iths odium tert-butoxide forming av ariety of isoindolinones in moderate to high yields (Scheme 102). In general secondary andp referable tertiary carbon centerw as required adjacent to the amide as methyl substituted amides resulted in very low yields. It was shown that the reaction most likely proceed via radical intermediates which is align with observations on the increased efficiency of the arylation with more substituted alkyl CÀHb onds adjacent to amide.

Ir-catalyzed annulation
As imilar to methodp resented Kalyani, [193] al ight mediated quaternary annulation protocol was reported by Dai et al. [194] Here, strongly reducing iridium species based on tris[2-phenylpyridinato-C 2 ,N]iridium(III) (fac-Ir(ppy) 3 )w as used as catalyst and potassium tert-butoxide as the terminal reductant (Scheme 103). Even at 50 ppm catalyst loadingst he quaternary annulation was ablet oc ompete with the uncatalyzed nucleophilic aromatic substitution, leadingi nto full retention of the enantiomeric information. Reactions using ortho-fluorinated, chlorinated or brominated benzamides provided good to excellent yields with the exception of substrates containingm ultiple halogens in the aryl ring.

Summary and Outlook
Duringt he past ten years as ignificant amount of transitionmetal catalyzed methods applied to the synthesis of isoindolinones have been reported. By the methods presented above a vast number of isoindolinone derivatives can be accessed, without even taking into account the multitude of methods not employing transition metal catalysts. One of the most prominentf ields of research relating to isoindolinone synthesis has been CÀHfunctionalization reactions. While these methods often allow convenient routes from mostly commercially available compounds to isoindolinones, they are commonly prepared with super stoichiometrica mountso ft he oxidant or the additives.I nb oth CÀHf unctionalization and carbonylation based methodologies the use of temporary and sometimespermanent directing groups are ac ommonf eature. To date only af ew examples of reactions with truly transient/traceless directingg roups or methods with minimal need for additional reagents are presented.
In the future, increasei nt he amount of reports concerning enantioselective and multicomponent, directing group free methodologies can be expected. Interestingly,w hile the iron catalyzed methods have gained significant attention,t oo ur knowledge,a pplicationst owards isoindolinone synthesis via CÀCb ond formation have not been described during the last decade. Similarly,t he heterogeneoust ransition metal catalyzed methodsf or synthetic organic chemistry applications are limited when preparative approaches towards isoindolinones are considered.