Electrophilic Aminating Agents in Total Synthesis

Abstract Classical amination methods involve the reaction of a nitrogen nucleophile with an electrophilic carbon center; however, in recent years, umpoled strategies have gained traction where the nitrogen source acts as an electrophile. A wide range of electrophilic aminating agents are now available, and these underpin a range of powerful C−N bond‐forming processes. In this Review, we highlight the strategic use of electrophilic aminating agents in total synthesis.


Introduction
Thea mine functionality is ubiquitous in nature,p harmaceuticals,a grochemicals and materials. [1] Thei mportance of nitrogen-containing molecules is demonstrated by their large representation within FDA-approved, small-molecule drug compounds. [2] As ar esult, the development of new synthetic methodologies for the construction of CÀNb onds is of paramount importance. [3,4] In recent years,significant advances in this area have been made in the fields of photoredox catalysis, [5][6][7] organocatalysis [8][9][10] and transition-metal cataly-sis. [11,12] Nevertheless,the most commonly utilized methods in total synthesis remain substitution reactions,r eductive amination, [13,14] and transition-metal-catalyzed C-N cross-coupling reactions. [15,16] These approaches all involve nucleophilic sources of nitrogen, and this can present issues in the synthesis of complex molecules.F or example,the common problem of overalkylation of amine nucleophiles is often circumvented by use of protecting groups,which, in turn, means that several synthetic steps can be required to introduce one new C À N bond. More recently,e fforts have been directed towards the development of umpoled strategies that employ electrophilic sources of nitrogen (i.e.e quivalents to the R 2 N + synthon). This approach addresses problems associated with nucleophilic nitrogen-based strategies and has several advantages, notably the ability to functionalize typically unreactive bonds. Al arge proportion of electrophilic amination reactions are carried out with ap reformed electrophilic aminating agent, and due to the topical interest in this strategy,aplethora of variants are now readily available (Scheme 1). Electrophilic aminating agents can be split into two distinct classes:t hose that undergo substitution reactions,a nd those that undergo addition reactions.C ertain reagents can participate in both mechanistic regimes.F or substitution reactions,t he general structure of the aminating reagent is R 2 N-X, where Xi san electron-withdrawing group,w hich is displaced by nucleophilic attack or bond cleavage.T he most commonly used Nbased electrophiles for substitutions are N-chloroamines, [17,18] oxaziridines [19,20] and hydroxylamines. [21,22] Examples of electrophilic aminating agents that tend to undergo addition processes include azo compounds [23,24] and iminomalonates, [25] whilst azides [26,27] and oximes [28] are able to engage in both.
Until the last decade,t he use of electrophilic aminating agents had received little attention;h owever, there are now several excellent reviews outlining the multitude of transformations that can be achieved. [29][30][31][32][33][34][35] This review aims to give an overview of the burgeoning field of electrophilic amination by presenting the most relevant examples of total syntheses involving preformed electrophilic aminating agents.F or the purposes of this review,e lectrophilic amination with nitrene species will not be discussed;the reader is instead directed to several comprehensive reviews for further information on this topic. [36][37][38][39][40][41][42][43]

a-Amination of Carbonyl Compounds
Thed evelopment of methods for electrophilic amination adjacent to acarbonyl group has been of significant interest as it allows the synthesis of a-amino acid derivatives,acommon feature of many bioactive molecules.T he asymmetric synthesis of quaternary amino acids is relatively challenging and is commonly carried out by chiral-auxiliary-controlled Strecker syntheses,o rb yd iastereoselective alkylation of chiral enolates. [44][45][46][47][48][49][50] However,t hese methods usually require ap rotecting group strategy when applied to the synthesis of acomplex molecule.The use of electrophilic aminating agents can avoid this,a nd such transformations can be carried out asymmetrically,u sing either ac hiral auxiliary or chiral catalyst (Scheme 2). Thef ormation of aC ÀNb ond in this manner constitutes one of the simplest methods to establish astereogenic carbon center of this type,and anumber of total syntheses have incorporated this methodology as ak ey step.
The a-amination of carbonyl compounds can be achieved either via apreformed enolate or via direct a-amination using an organocatalyst or metal catalyst. [17,26,[51][52][53][54][55][56][57] Awide range of electrophilic aminating agents have been used in these processes to generate ap lethora of products with new CÀN bonds (Scheme 2). Fort his type of transformation, an amine is rarely installed directly;h owever,t here are several reported methods that allow the one-or two-step conversion of the initial adduct into either the corresponding amine or another synthetically useful N-based functionality.T he most commonly utilized electrophiles in total syntheses are azides and azo compounds.T hese reagents are often commercially available,a nd the resulting azide or hydrazine products are readily manipulated.

Azide Electrophiles
Al arge range of azide electrophiles are commercially available or readily prepared. [58] a-Amination using these reagents produces anew azide (Scheme 2A), which can serve as av ersatile handle for further manipulation. Fore xample, the azide group can be readily converted to the corresponding amine by reduction. [59] Thee lectrophilic azidation process usually requires the preformation of an enolate nucleophile, and the aminating agent is typically equipped with an electron-withdrawing sulfonyl unit, which activates it and is removed at the end of the reaction. Asymmetric versions of this process typically employ achiral auxiliary on the enolate partner. [26] Although the use of ac hiral auxiliary is suboptimal, the versatility of the resulting azide group and the ability to construct af unctionalized stereocenter offers significant benefits.A dditionally,t his approach can provide complementary access to diazo compounds via judicious choice of enolate precursor,e lectrophilic azide source and workup procedure. [60] In 2006, Akita reported the first synthesis of the peptidyl nucleoside antibiotic polyoxin M ( 9), where as ubstratecontrolled diastereoselective electrophilic azidation was employed as ak ey step (Scheme 3). [61] Substituted lactone 1 was synthesized in three steps from commercially available d-glutamic acid. It was postulated that the bulky TBDPS protecting group of 1 could be used to direct the azidation of the enolate from the opposite face.Anelectrophilic azidation reaction was chosen in preference to other electrophilic C À N bond formations because earlier work on as imilar substrate found that high diastereoselectivities could be achieved with this approach. [26,62] In the event, treatment of the lithium enolate of 1 with trisyl azide 2 provided azide product 3 in 53 %y ield, but with modest diastereoselectivity (2:1 d.r.). Subsequent Staudinger reduction of azide 3 gave free amine 4 in excellent yield. This was advanced to 5 via at hree-step sequence involving hydrolysis of the lactone,a cid-mediated formation of the 1,3-oxazinane (HCl, HCHO) and methyl esterification. Af urther five steps gave active ester 6,w hich was coupled via amide bond formation with uracil polyoxin C (7), previously synthesized in thirteen steps from dribose. [63,64] Tr eatment of the resulting amide 8 with TFA effected removal of the N-Boc and N,O-acetal protecting groups to give polyoxin M( 9)i n4 7% yield. Although the electrophilic azidation step (1 ! 3)s uffered from poor diastereoselectivity,i td id enable the establishment of ak ey stereocenter in ad irect and simple manner,a nd it provides an otable example of the use of as ubstrate-controlled azidation reaction in total synthesis.
Thed iastereoselectivity of the azidation reaction in Akitass ynthesis is under substrate control;h owever,a uxiliary-controlled processes have also been exploited. In 2018, Thomson reported the synthesis of the tetrapeptide tambromycin (20), where one of the peptide units was installed by ac hiral-auxiliary-controlled diastereoselective electrophilic azidation reaction (Scheme 4). [65] Retrosynthetically,i tw as postulated that fragments 17 and 18 could be combined by amide coupling, and therefore efforts centered on their synthesis.T he indole fragment 18 was synthesized in ten steps from commercially available 4methoxyindole.T he synthesis of fragment 17 began with the installation of the chiral auxiliary,w hich was necessary to achieve good diastereoselectivity in the electrophilic azidation reaction. Acylation of 10 with oxazolidinone 11 gave 12 in excellent yield. After extensive optimization, it was found that reaction of 12 with KHMDS and electrophilic aminating agent 2 gave the desired azide product 13 in good yield and, importantly,a sasingle stereoisomer.R emoval of the chiral auxiliary with lithium hydrogen peroxide gave acid 14 in good yield, and epimerization of the potentially labile C(5) stereocenter was not observed. Amide coupling of 14 with a-l-methyl-serine methyl ester 15 gave amide 16,a nd the azide was subsequently reduced by hydrogenation to give 17 in excellent yield. Following coupling of 17 and 18, 19 was advanced to tambromycin (20)i nt wo further steps,w ith the synthesis completed in thirteen steps (longest linear sequence) and ac ombined yield of 1.3 %.
Although auxiliary-based, the conversion of 12 to 13 by electrophilic azidation provided asingle diastereomer,which would have been challenging to achieve by other methods. From as trategic viewpoint, it is also important to recognize that conventional methods for accessing peptides often require the installation and removal of ap rotecting group on nitrogen. An electrophilic azidation strategy can help minimize protecting group manipulations.Recently,catalystcontrolled electrophilic a-azidation protocols have been developed, and these remove the need for ac hiral auxiliary. Fore xample,i th as been shown that chiral iron or copper catalysts can promote highly enantioselective electrophilic azide transfers. [27,66] In these processes,t he electrophilic aminating agent is an azide-containing hypervalent iodine-(III) species.T hese species are often highly unstable; however, it has been shown that safer variants can be developed. [67] At the current stage,t hese catalyst-controlled a-azidation processes are relatively substrate specific, although their development bodes well for future applications in total synthesis.Advances in this area will be important for enhancing electrophilic amination as as ynthetic design strategy and maintaining its competitiveness versus other contemporary approaches.F or example,i nt he case of tambromycin (20), Renata subsequently disclosed ac ompetitive synthetic route that exploits advances in biocatalytic C-Hf unctionalization. [68] Theu se of enzymes in this case, removed the need for achiral auxiliary during the assembly of the right-hand fragment, 17.

Azodicarboxylate Electrophiles
In the context of total synthesis,azodicarboxylate aminating agents are by far the most popular electrophiles for the aamination of carbonyl compounds. [69][70][71][72][73][74][75][76][77] This is because they are commercially available,relatively bench stable,and highly electrophilic.C hiral organocatalysts and chiral auxiliarybased methods have been developed that provide high enantioselectivities.F or the former,t he high efficiency of proline-based catalysts can be rationalized by the transition state indicated in Scheme 5; here,a pproach of the azodicarboxylate is directed by hydrogen bonding between one of its nitrogen centers and the carboxylic acid unit of the organocatalyst. This model is based on Houk and Listsc alculated transition state of the Hajos-Parrish-Eder-Sauer-Wiechert reaction, and is analogous to transition states that have been proposed for proline-catalyzed intermolecular Mannich and aldol reactions. [23,78] There are several complementary methods for the cleavage of the NÀNb ond of the initial hydrazine product. Classical reduction conditions,s uch as Raney nickel, [79] SmI 2 , [80] and Na/NH 3 , [81] are most commonly used and have been applied in several total syntheses.M ore recently, amilder (non-reductive) method has been reported, wherein the N À Nb ond is cleaved via an E1cB process. [82] The development of other mild N-N cleavage methods would be beneficial for applications of azodicarboxylate-based aminations in total synthesis.
With 23 in hand, aseven-step sequence was developed to complete the synthesis.Oxidation of amino aldehyde 23 gave the corresponding carboxylic acid 28 (Scheme 6B), which was treated with (trimethylsilyl)diazomethane to give ester 29. Cleavage of the N À Nb ond of 29 proved challenging,a s treatment under reductive conditions with SmI 2 was unsuccessful. It is known that trifluoroacetylated hydrazines undergo NÀNb ond cleavage with SmI 2 ; [87] therefore 29 was converted to trifluoroacetylated hydrazine 30.Selective NÀN bond cleavage with SmI 2 was then achieved to give quaternary amino acid derivative 31.C bz deprotection, hydantoin formation and N-methylation gave BIRT-377 (32), with an overall yield of 35 %from 4-bromobenzaldehyde.
TheBarbas synthesis of BIRT-377 (32)showcases the use of organocatalyzed a-amination methodology for the introduction of an ew tetrasubstituted stereocenter in ac omplex molecule.N otably,a lthough the key C À Nb ond-forming process is efficient, the cleavage of the N À Nb ond of 29 was challenging and required several steps.C onsequently,m ethods that can address this inefficiencyw ould be desirable. Alternate syntheses of BIRT-377 (32)h ave employed either phase-transfer catalysis or ac hiral pool approach involving Seebachss elf-regeneration of chirality as am eans of introducing the key stereocenter. [88][89][90] Barbas electrophilic aminating-based approach compares favorably to these other syntheses and also allows the easy preparation of analogues.
Thec ombination of the dibenzyl azodicarboxylate electrophile 22 and tetrazole organocatalyst 27 can also be used to access tertiary amino acids.I n2 017, Lindel and co-workers exploited this for the introduction of ak ey stereocenter during an enantioselective synthesis of the marine natural product hemiasterlin (40)( Scheme 7A). [91] Aldehyde 33 was synthesized in four steps from indole,w here the side chain was introduced by aP d-catalyzed C(3)-selective allylation reaction. [92] a-Amination using azodicarboxylate 22 and organocatalyst 27 proceeded in excellent yield, and after aldehyde reduction, alcohol 34 was isolated in 98 % ee. Initial investigations for the cleavage of the NÀNb ond of 34 focussed on the aforementioned E1cB method;h owever, 35 was not observed and so hydrogenolytic methods were explored. Hydrogenation of alcohol 34 with Raney Ni, Pd/C or PtO 2 was unsuccessful. N-N cleavage was observed when polymethylhydrosiloxane (PMHS) was employed as a"green source" of hydrogen in combination with aPdCl 2 catalyst; [93] however, this approach was unreliable.The use of Pearlmans catalyst (Pd(OH) 2 /C) in EtOAc/MeOH (4:1) at 30 bar was found to be optimal and gave amine 35,w hich was immedi-ately protected to afford 36 in excellent yield. This was advanced in af urther three steps to deliver tryptophan 37. Hydrolysis of the methyl ester to give 38 was followed by the known amide coupling with dipeptide 39. [94] Finally,e ster hydrolysis and N-Boc deprotection gave hemiasterlin (40)i n an overall yield of 17 %.
TheL indel synthesis of hemiasterlin (40)d emonstrates the advantages of using electrophilic a-amination methodology as am eans of synthesizing chiral a-amino acid derivatives.A lthough there have been several previously reported syntheses of hemiasterlin, asignificant disadvantage of these approaches is that they involve ac hiral auxiliary, thereby mandating additional auxiliary installation and removal steps. [94][95][96][97] In most of these cases,t he introduction of the amino-bearing C(11) stereocenter was achieved by auxiliary-controlled asymmetric Strecker reaction, as summarized in Scheme 7B. [95,97] Most examples of azodicarboxylate-based enantioselective a-aminations of carbonyl compounds use achiral organocatalyst, but complementary transformations can be achieved with at ransition-metal catalyst. [57,[98][99][100][101] This allows the installation of CÀNb onds in more sterically demanding systems,a sw ell as enabling direct C-H amination processes. Shibasaki and co-workers have reported ap rocedure for the a-amination of carbonyl compounds using ac atalyst system comprising La(NO 3 ) 3 ·6 H 2 O, an amide-based ligand (41)a nd d-valine-tert-butyl ester. [100,102,103] It is postulated that the three catalyst components are in dynamic equilibrium and work in as ynergistic manner (Scheme 8). This method is particularly suited to enantioselective aminations of non-

Angewandte Chemie
Reviews protected substrates containing (mild) Lewis basic functionality,f or example,s uccinimide derivatives and secondary aalkoxycarbonyl amides.S ubunits of this type are common building blocks in total synthesis and feature in many natural products. [104,105] In similar processes where an organocatalytic approach is employed, substrates with multiple coordination sites can result in poor enantioselectivity.T herefore,t his methodology constitutes ap owerful option for the construction of densely functionalized a-amino acid derivatives.
In 2011 Shibasaki and co-workers reported the application of their methodology to the synthesis of mycestericin F (49), [103] which is apotent immunosuppressant (Scheme 9). [106] It was postulated that the "polar head" of the molecule could be installed by an asymmetric electrophilic a-amination of an amide using the ternary catalytic system shown in Scheme 8. Other syntheses of this unit require lengthy synthetic routes as ar esult of the challenges associated with the highly functionalized stereocenter. [107][108][109] Shibasakiss tudies began with the evaluation of several substrates (selected examples are shown in Scheme 9A)for the key electrophilic amination; the substrates examined all possessed an sp 2 -based R 1 substituent that could undergo subsequent oxidation to introduce the C(21) hydroxyl group of the target. Upon treatment with the ternary catalytic system and di-tert-butyl azodicarboxylate electrophile 43,i tw as found that only substrate 42 b gave the desired amination product in acceptable yield and enantioselectivity.Itwas postulated that a trans N-H proton is required on the a-alkoxycarbonyl amide motif to obtain high enantioselectivity,a st his facilitates favorable hydrogen-bonding interactions with the catalyst, as shown in Scheme 8. [100] Substrate 42 d was later designed as av iable intermediate for the synthesis of mycestericin F(49)(Scheme 9B). Theo ptimized conditions for the key a-amination require use of H-d-Val-OtBu to ensure ah igh level of stereocontrol, and control experiments confirmed that every component of the catalyst system is required. Other known organo-and metal-based catalytic systems were also investigated; [54,[110][111][112] however, comparable levels of enantioinduction were not observed in most cases.W ith 44 d in hand, asequence of N-Boc deprotection (TFA) and hydrogenolytic N-N bond cleavage provided amine 45.Conventional hydrogenation catalysts,s uch as Raney Ni and Pd/C,w ere unsuccessful;i tw as eventually found that N-N cleavage could be achieved in good yield by use of Rh/C under an atmospheric pressure of hydrogen. Amine 45 was then advanced over two steps to metathesis precursor 46.T he aliphatic tail, 47,w as synthesized in three steps from commercially available n-heptanoyl chloride,f ollowing previously reported procedures. [113] Cross-metathesis of 46 and 47 (1:3 molar ratio) was executed by exposure to the Grubbs first generation catalyst, which provided 48 in 62 %y ield. A further three steps were required to access mycestericin F (49) in good overall yield.
TheS hibasaki method involves catalyst-promoted enolization. Thed irect electrophilic amination of other types of enolate equivalents can also be achieved under metalcatalyzed conditions;f or example,i nc ertain contexts,e nol ethers and related systems can be aminated using silver-o r copper-based catalysts. [99,101] Tr auner and co-workers have demonstrated the power of this approach in the synthesis of crocagin A( 57), ab ioactive compound isolated from myxobacterium Chondromyces crocatus (Scheme 10). [114] It was hypothesized that the C(14) À Nbond of 57 could be installed by electrophilic amination, prior to introduction of the N-methyl isoleucine side chain, 55.T oe xecute this strategy,p yrimidinone 51 was identified as as uitable precursor, and this was prepared in six steps from 50.T he installation of the desired CÀNb ond to 51 was challenging, Scheme 9. Shibasaki's synthesis of mycestericin F(49).

Angewandte Chemie
Reviews likely due to the diminished nucleophilicity of the C(14)-C(15) alkene double bond as aresult of conjugation with the C(13) carbonyl. Indeed, several azodicarboxylate electrophiles were investigated without success.Subsequently,itwas found that amination could be achieved using copper(II) triflate as aLewis acidic catalyst in combination with dibenzyl azodicarboxylate 22,p roviding 52 in 86 %y ield. N-N cleavage and global benzyl deprotection under hydrogenation conditions gave amine 53 in good yield after reinstallation of the benzyl ether. From here,t he C(14)-C(15) alkene double bond was reduced under substrate control [115,116] to give amine 54 with excellent diastereoselectivity.T he N-methyl isoleucine unit 55 was then installed by amide coupling to give peptide 56,w hich was advanced in af urther three steps to crocagin A( 57). This synthesis showcases the power of functionalizing readily assembled unsaturated ring systems prior to strategic (stereocenter-installing) reduction processes.

Electrophilic Ammonia-Based Reagents
Ammonia-based electrophiles are an alternative class of aminating agent that have received some attention in recent years as the NH 2 functionality can be directly installed. This offers significant advantages compared to azodicarboxylate and azide electrophiles,w hich require post C À Nb ondformation manipulations to reveal the NH 2 moiety.A commonly exploited electrophile for ammonia-based processes is monochloramine (NH 2 Cl), which can be prepared as as olution in Et 2 Ob yr eaction of NH 4 Cl, NH 4 OH and bleach. [117,118] Mechanistically,electrophilic a-aminations with NH 2 Cl are thought to proceed via direct nucleophilic attack of an enolate onto the electrophilic nitrogen center.
In 2004, Gallagher and co-workers reported as hort and efficient enantioselective synthesis of (+ +)-laccarin (65), af ungal metabolite with ad ensely functionalized piperidine core. [119] It was proposed that the five-membered ring could be accessed by at hree-step approach involving an electrophilic amination with NH 2 Cl to introduce the required amine, followed by at andem acylationa nd cyclization sequence. Studies commenced with preparation of cyclic sulfamidate 59 in four steps from commercially available ethyl (3R)-hydroxybutyrate 58 (Scheme 11). Sulfamidate 59 was treated with the sodium enolate of diethyl malonate,which resulted in stereoinvertive ring cleavage at the O-bearing carbon. In situ acidpromoted cleavage of the N-sulfate leaving group and Bocprotection of the benzylamine unit gave 60 in 81 %yield (over two steps). Thelatter step was required to prevent lactamization. Thei nstallation of the CÀNb ond at C(2) was then achieved in good yield by exposure of the potassium enolate of 60 to ethereal NH 2 Cl. Acylationo fthe resulting amine 61 with diketene was followed by cyclization of 62 under Claisen conditions to provide amide 63.S aponification of the ester, acid-promoted decarboxylation and N-Boc deprotection allowed cyclocondensation to afford 64 in 7:2 d.r. The synthesis was completed by hydrogenolytic removal of the N-benzyl group,w hich afforded (+ +)-laccarin (65)i n9 3% yield.
TheG allagher laccarin synthesis utilizes the Dowd amination reaction, [17] which exploits one of the cheapest and most simple electrophilic aminating agents,N H 2 Cl. Examples of the large-scale use of this reagent are relatively scarce; [117] this likely reflects its instability and toxicity. However,the ability to directly install an NH 2 unit is notable and contrasts other electrophilic a-amination reactions discussed so far.I nt he case of (+ +)-laccarin, the diastereoselectivity associated with the new CÀNb ond is likely under thermodynamic control. To advance the utility of this approach, it would be desirable to develop catalyst-controlled a-amination reactions that use safe and stable alternatives to monochloramine.F or example,methoxyamine (NH 2 OMe) is an alternative reagent that enables the installation of NH 2 units in other contexts.U nder basic conditions,t his reagent promotes the stereoretentive conversion of pinacol boronate esters to primary amines. [120,121] Here,t he electrophilicity associated with the N À Ob ond facilitates C À Nb ond formation. Jin, Liu and co-workers have developed ar elated method that exploits the reactivity of H 2 N-DABCO,a n aminoazanium aminating agent. [122] One could envisage developing protocols that exploit these reagents for the aamination of carbonyl compounds.
Thee xamples outlined in this section highlight the versatility of electrophilic aminating agents in the a-amination of carbonyl compounds.G oing forward, several drawbacks must be addressed to enhance the utility of this approach in synthesis.T he aminating agents used for these processes are often toxic and/or unstable,a nd these considerations necessitate handling precautions.Additionally,many of the examples described use azodicarboxylate or azide electrophiles,w hich require subsequent steps to access the target amine.N onetheless,e lectrophilic aminations of this type offer one of the most powerful methods for the de novo construction of amino acid units in complex molecules.

Aziridination of Olefins
Aziridines are versatile synthetic intermediates and are also found in natural products and bioactive molecules; [123][124][125] consequently,c ontinuing efforts are aimed at developing methods for their synthesis.A ziridines provide an attractive strategy for installing amines in target-directed synthesis because their opening with nucleophiles usually occurs in as tereocontrolled manner. [126][127][128][129][130][131][132] Thes ynthesis of aziridines from olefins is particularly powerful because olefinic starting materials are often commercially available or simple to synthesize. [133,134] In certain cases,t he direct synthesis of amines from alkenes can be achieved in one pot via the intermediacyofanaziridine.Such processes are complementary to the a-aminations already outlined, as they allow access to alternate substitution patterns and enable the stereoselective installation of contiguous functionality.
Thep reparation of aziridines from olefins using electrophilic aminating agents is now firmly established, and as ar esult, methods of this type are well documented in total synthesis. [37] Most of these processes involve nitrene intermediates,w hich, as already mentioned, are not discussed in this review.A lternatively,e lectrophilic aziridinations can be carried out by aza-Michael initiated ring closure (aza-MIRC) processes involving electron-poor alkenes. [135][136][137][138] Organocatalyzed variants of this reaction use an amine catalyst to activate an enone [139,140] or an enal [135,141,142] via the corresponding iminium ion. This leads to an enamine intermediate which undergoes ring closure onto the electrophilic nitrogen center to provide the product (Scheme 12). Thus,a minating agents used in these processes are ambiphilic,f unctioning as an ucleophile for the first CÀNb ond formation and as an electrophile for the second. Chiral organocatalysts can be used to achieve enantioinduction. [143] Them ost common aminating agents are hydroxylamine derivatives,inparticular, N-tosyloxycarbamates,s ome of which are commercially available.A ccordingly,m ost aza-MIRC aziridinations provide carbamate-protected aziridines,w hich is beneficial as this type of protecting group can be selected for easy removal.

Reviews
Thekey aza-MIRC aziridination involved cyclic enone 66 and TsONHCbz 67 as the aminating agent (Scheme 13). It was found that chiral diamine catalyst 68 was essential for achieving high enantioselectivity,a nd both benzoic acid and NaHCO 3 additives were required to prevent decomposition of the aminating agent. Under these conditions, 69 was generated in 75 %yield and 95 % ee. From here,athree-step sequence led to alcohol 70.Ring opening of aziridine 70 with azide was regioselective,o ccurring solely at C(4) to provide 71 in 78 %yield. It was postulated that the steric interactions of the hydroxyl group enforce the observed regioselectivity of this process.F rom 71,t hree steps were required to access known intermediate 72,w hich can be converted to (À)agelastatin A(73)inafurther five steps following apreviously reported procedure. [149] In 2018, Nemoto and co-workers reported af ormal synthesis of (À)-aurantioclavine (85), ab iologically active, biosynthetic intermediate of af amily of complex polycyclic alkaloids,the communesins. [155] Thefused tricyclic indole core is ac ommon feature of several alkaloids and so its preparation has been of interest to the synthetic community.I tw as envisaged that an organocatalytic electrophilic aziridination could be used to install the key C(7) stereocenter of (À)aurantioclavine (85)prior to Pd-catalyzed construction of the indole unit. Compared to other approaches,this is one of the only examples where the C(7) benzylic stereocenter is installed without the aid of ametal catalyst. [156][157][158] Enal 75 was prepared in five steps from commercially available 2-iodo-3-nitrobenzoic acid (74)( Scheme 14). The organocatalytic asymmetric aziridination was then investigated, and it was found that the combination of prolinederived organocatalyst 77 and commercially available TsONHBoc 76 was suitable for generating target aziridine 78.T his product was not isolated and, instead, was immediately treated with triazolium salt 79 and MeOH to give b-aminated ester 80 in 96 %y ield and 98 % ee. From 80,s even steps were required to synthesize cascade substrate 81,a s required for construction of the indole subunit. Fort his process,P d 0 -catalyzed conditions were used to effect Hecktype reaction of the aryl iodide with the allene.This generates p-allyl intermediate 82,w hich can then undergo CÀNb ond formation to provide 83,aprocess that occurred in excellent yield. Af urther five steps were required to advance 83 to known intermediate 84,w hich can be converted to (À)aurantioclavine (85)i na nadditional four steps. [156] Although longer than other syntheses, [156][157][158][159][160] Nemotos approach is notable for the aziridinative conversion of 75 to 80.I ti simportant to highlight that this process transfers the oxidation level, such that acrylate products can be accessed from the enal starting material which is required for the aziridination step.Itcan be envisaged that adapting this twostep,o ne-pot procedure would allow access to other baminated acrylates and related species at the same oxidation level.
Theexamples highlighted in this section demonstrate the utility of electrophilic aminating agents in aziridination processes.I mportantly,t he installation of contiguous stereocenters can be achieved in one or two steps,often from cheap, achiral and commercially available starting materials.The key feature is the use of ambiphilic reagents of type 67 and 76,and these have found wider application in the development of metal-free CÀNb ond formations (see Sections 4a nd 6). Additionally,aswill be discussed in the next section, reagents 67 and 76 have been integrated into metal-catalyzed C À N bond formations.Onacautionary note,despite being used on large scale, [161,162] care should be taken when handling electrophilic hydroxylamine-based reagents,a ss pecific variants can be unstable.

Transition-Metal-Catalyzed Processes
Tr ansition-metal-promoted CÀNb ond-forming reactions are the foremost strategy for the synthesis of amines and their derivatives.T he most popular approaches in the context of total synthesis are the Buchwald-Hartwig and Ullmann-Goldberg reactions,which typically involve the reaction of an amine or amide nucleophile with an electrophilic aryl halide in the presence of apalladium or copper catalyst. [163][164][165][166][167][168] These methods offer unrivalled flexibility for the construction of aryl CÀNb onds.N evertheless,u mpoled strategies have also emerged that allow the cross-coupling of electrophilic aminating agents with aryl nucleophiles or aryl C À Hbonds. [169][170][171][172][173][174][175][176] Such processes are valuable as they offer complementary substrate scope and, in some cases,milder reaction conditions.

Aza-Heck Reaction
It is perhaps in the area of alkene functionalization that transition-metal-catalyzed reactions with electrophilic aminating agents are most prolific. Within this context, aza-Heck reactions represent ak ey emerging technology; [177] here,a n N-based unit is exploited as the initiating motif,and an alkene functions as the formal nucleophile.Processes of this type are complementary to intramolecular aza-Wacker reactions, which involve the Pd-catalyzed oxidative cyclization of an NH nucleophile with an alkene.T his is ac onceptually appealing method for accessing N-heterocycles and has been developed extensively. [178] Nevertheless,l imitations remain, including the requirement for relatively acidic NH nucleophiles,a nd al ow tolerance to sterically encumbered alkenes.Additionally,versatile chiral P-based ligands are not well tolerated because of the requirement for an external oxidant, and this limits the applicability of the method in asymmetric catalysis. [178,179] All of these issues can be addressed by instead using an aza-Heck approach, and recently developed variants of this chemistry now offer excellent scope. [180][181][182][183][184][185][186] Thef irst aza-Heck reactions were reported in 1999 by Narasaka and co-workers (Scheme 15 A). [187] In the initial report, oxidative addition of the NÀOb ond of oxime esters was used to trigger alkene aza-palladation en route to pyrrole products.T his approach has more recently been extended to other classes of N À Ob onds.F or example,h ydroxylaminebased systems cyclize to provide chiral N-heterocycles such as pyrrolidines and piperidines (Scheme 15 B). [180,181,183,184] In these processes,c hiral P-based ligands can be used to induce enantioselectivity. [181] Them ost general aza-Heck reactions employ O-based leaving groups on nitrogen, such as pentafluorobenzoate ( F BzO-), phenolate and tosylate. [181][182][183] In 2005, Fürstner reported the first synthesis of butylcycloheptylprodigiosin (94), ap urported natural product that has been the source of controversy (Scheme 16). [188][189][190] Butylcycloheptylprodigiosin (94)c onsists of an ine-membered ring fused to apyrrole,and it was proposed that this key component could be constructed using the Narasaka variant of the aza-Heck reaction. Thes ynthesis of (Z,Z)-cyclononadienone 86 was carried out in six steps from commercially available cycloctanone.F rom here,t he medium-ring was elaborated to 87 in excellent yield by 1,2-reduction of the dienone and subsequent O-acetylation. Tsuji-Trost reaction with methyl acetoacetate gave 88,which underwent Krapcho decarboxylation to provide 89.Atypical two-step sequence, involving conversion to oxime 90 and O-acylation with pentafluorobenzoyl chloride,p rovided aza-Heck precursor 91.B ecause at this stage,a vailable aza-Heck protocols were relatively inefficient, two equivalent alkene units were specifically incorporated into system 91 to enhance cyclization efficiency.Under standard Heck-like conditions,cyclization generated pyrroline 92 in 54 %y ield, and the typical pyrrole product was not observed. This outcome can be rationalized by the syn-stereospecific nature of the migratory insertion and b-hydride elimination steps,which generates the C(9)-C(10) alkene double bond. Exposure of 92 to potassium 3-aminopropylamide isomerized the C(9)-C(10) alkene double bond to generate the desired pyrrole product 93 in good yield. From here,afurther eight steps were required to advance 93 to butylcycloheptylprodigiosin (94).
Am ore concise synthesis of butylcycloheptylprodigiosin (94)h as since been reported. [191] Nevertheless,F ürstners synthesis remains significant within the context of aza-Heck cyclizations,and is also instructive from astrategy viewpoint. Thed en ovo installation of ap yrrole unit onto ac omplex, strained ring system demonstrates the value of the aza-Heck method for the construction of heterocycles at al ate stage.
Recent years have seen significant methodology development within the area of aza-Heck chemistry,a nd this has provided efficient methods for accessing other classes of Nheterocycles.I np articular,e nantioselective aza-Heck cyclizations of N-(tosyloxy)carbamatesp rovide ap owerful method for preparing a-substituted pyrrolidines and piperidines. [181] This chemistry has been used by Bower in an enantioselective,f our-step formal synthesis of caulophyllumine B( 100), aP 450 cytochrome metabolite. [181] Note that ap revious synthesis by Reddy and Krishna [192] provided caulophyllumine Bi nf ourteen steps.B owerss ynthesis commenced with Mitsunobu reaction of (E)-hept-5-en-1-ol (95)a nd electrophilic aminating agent 76 to generate hydroxylamine 96 (Scheme 17). From here,previously developed enantioselective aza-Heck conditions were adapted to at andem process.U sing aP d 0 catalyst modified with aS PINOL-derived phosphoramidite ligand, cyclization of 96 to 97 occurred efficiently. 97 was not isolated, and instead the residual Pd 0 catalyst was harnessed for asubsequent Heck reaction with aryl iodide 98.T his two-step/one-pot catalytic protocol gave piperidine 99 in excellent yield and enantioselectivity.F ollowing Reddy and Krishnasreported procedure, concomitant N-Boc reduction and ester removal provided caulophyllumine B(100)i n3 0% overall yield. [192] Thesyntheses highlighted in this section demonstrate that electrophilic oximes and hydroxylamines can engage with Pd catalysts in redox-type processes.F ollowing reaction with ap endant alkene,t his allows the construction of ar ange of substituted N-heterocyclic products.H ere,t he NÀOb ond of

Angewandte Chemie
Reviews the aminating agent is analogous to the CÀX( X = halide, OTf) bond used in conventional Heck reactions,a nd, as ar esult, the fundamental mechanistic steps are the same. [193] Through judicious use of chiral ligand, asymmetric processes can also be realized. Interestingly,b ulky electron-rich phosphine ligands typically used in conventional Heck processes are not usually effective for aza variants,w here instead electron-poor P-based ligands are optimal. Theu se of the conventional Heck reaction in total synthesis is well established; [194][195][196][197] however,t here are relatively few examples of the use of aza variants.T his is likely to change as the methodologies become more sophisticated.
In 2018, Buchwald reported the application of coppercatalyzed hydroamination in the preparation of 105,akey intermediate in the synthesis of DMP 777 (106). [233] DMP 777 (106)i saknown inhibitor of leukocyte elastase,a nd has potential for treatment of cystic fibrosis and rheumatoid arthritis. [239] Previous syntheses of 105 have relied on the use of expensive chiral starting materials or enzymatic resolution to introduce the required stereocenter. [240] Buchwalds approach allows the introduction of the key amino-bearing stereocenter from cheap,achiral starting materials by employing an asymmetric copper-catalyzed hydroamination reaction (Scheme 19).
Compound 103 was prepared by subjecting alkene 101 to the Cu I Hh ydroamination conditions,i nt he presence of the chiral ligand (S)-DTBM-SEGPHOS.I nt his particular case, 1,2-benzisoxazole (102)w as selected as the aminating agent and this provided the Schiff base product 103 in excellent yield and enantioselectivity.F rom here,h ydrolysis of the imine gave the desired chiral amine,w hich was advanced to the corresponding isocyanate, 105.T his can be coupled with known amide 104 to generate DMP 777 (106)i ne xcellent yield. [240] To demonstrate the applicability of Cu I H-catalyzed hydroamination to other types of p-unsaturated systems, Buchwald reported as uccinct two-step synthesis of rivastigmine (114), ad rug compound used for the treatment of Alzheimersa nd Parkinsonsd isease (Scheme 20). [230] The synthesis commenced with the formation of carbamate 108 by addition of N-ethyl-N-methylcarbamoyl chloride to commercially available 3-hydroxyphenylacetylene (107). From here, the amino-bearing stereocenter was introduced by at andem process involving Cu I H-catalyzed reduction of the alkyne and hydroamination of the resulting alkene.T he reduction step required the addition of i-PrOH, which is postulated to protonate vinyl copper species 110,a nd thereby prevent formation of enamine 111.T he resulting alkene 112 then engages in another CuH-catalyzed hydroamination event via the alkylcopper species 113 to provide rivastigmine (114)i n excellent yield and enantioselectivity.
Thes yntheses outlined in this section show that electrophilic aminating agents can combine with transition metals in redox-type processes to provide new CÀNb onds.T he two process classes that have been discussed both involve aminations of unsaturated carbon-based units (e.g. alkenes), but it is important to recognize that they are mechanistically distinct. Aza-Heck reactions initiate on the amino partner, whereas CuH-catalyzed hydroaminations initiate on the alkene or alkyne.I mportantly,b oth process classes can engage non-polarized alkenes in an enantioselective manner.T he flexibility and control provided by these methods means that they are likely to see increasing use in total synthesis.I ts hould be noted that recently developed enantioselective photocatalytic hydroaminations with sulfonamides offer ap owerful alternative approach for effecting olefin hydroamination. [241]

Electrophilic N-Centered Radicals
Processes involving carbon-centered radicals offer unique reactivity and functional group tolerance. [242] In recent years, interest in the use of heteroatom-centered radicals has gained traction, and within this area, the use of nitrogen-based radicals has been extensively investigated. This has resulted in ar ange of interesting methods for the construction of C À N bonds. [243][244][245] Awell-established method for the generation of nitrogencentered radicals is by photochemical or thermal dissociation of an N À Xb ond, where Xi sah eteroatom-based unit or ahalogen. Conventionally,this approach has been hampered by the requirement for toxic radical initiators,h igh temperatures and/or high-energy UV irradiation. Thea dvent of photocatalytic methods has enabled milder protocols for the generation of nitrogen radicals in ac ontrolled manner,a nd this bodes well for future developments in this area. [246,247] The

Reviews
properties of nitrogen-centered radicals are strongly influenced by the specific N-substituents.W ith the exception of iminyl radicals,which are usually considered ambiphilic,most N-centered radicals can be classed as either electrophilic or nucleophilic (Scheme 21). [248][249][250] Electrophilic nitrogen radicals include amidyl, sulfamidyl and aminium variants, whereas aminyl radicals are nucleophilic.Itisalso important to note that aminyl radicals can be converted to aminium species by protonation. All radicals can be generated from readily available functional groups and as ar esult, are well suited to application in total synthesis.
Electrophilic nitrogen radicals engage in am ultitude of processes,m ost notably intramolecular and intermolecular additions to alkenes.U nder photocatalytic conditions,p rimary and secondary alkyl amines can be converted directly to the corresponding aminium radical, and these can be used for hydroaminations of non-activated alkenes. [251,252] Related radical-based processes that use electrophilic nitrogen sources enable,f or example,a lkene aminochlorination reactions. [253,254] Less commonly,e lectrophilic nitrogen radicals are employed in hydrogen-atom-transfer reactions and fragmentations related to the classical Norrish Ia nd II reactions. [255,256] It is important to note that, due to differences in philicity,n ot all electrophilic nitrogen radicals are amenable to all types of transformations.Adistinct highlight is that electrophilic nitrogen radicals can engage in the functionalization of typically unreactive bonds,a nd this feature can be harnessed for the synthesis of complex N-heterocycles.

Amidyl Radicals
Amidyl radicals have found extensive use in synthesis due to their high reactivity,f unctional group tolerance and profoundly electrophilic character. [248,[257][258][259][260][261][262] However,t heir high reactivity presents challenges because competitive intramolecular H-atom abstraction reactions can often occur in preference to the target CÀNb ond formation. [256,263] Despite this,a midyl radicals provide ap opular platform for the synthesis of polyheterocycles.U ntil recently,a midyl radicals were typically prepared by homolysis of an NÀOo rNhalogen bond under harsh reaction conditions.H owever, there are now anumber of milder photocatalytic methods for this transformation. [246,264,265] Them ost common precursors used in total synthesis are hydroxylamine derivatives, [266] thiosemicarbazides [267] and thiosemicarbazones. [268] All are easily prepared, and hydroxylamine-based systems are particularly advantageous as the NÀObond is weak.
In 2013, Wang reported ac oncise synthesis of several phenanthroindolizidine alkaloids,whereby an unusual amidyl radical cascade/rearrangement sequence was employed as ak ey step. [269] There are over sixty reported alkaloids in this family, [270] and many are known to have potent bioactivities. As ar esult, there have been several reported syntheses; however, very few allow access to aw ide array of these alkaloids. [271,272] In the Wang approach, ar adical cascade provides rapid access to the common polyheterocyclic core, thus enabling ag eneral route to many members of the alkaloid family.I nt his process,5 -exo cyclization of electrophilic amidyl radical 120 with the internal olefin is followed by 6-endo cyclization of the resulting carbon-centered radical 121.For the purposes of this review,only the synthesis of (AE)tylophorine (123)w ill be discussed in detail, but it is worth noting that the strategy has been used for the synthesis of several related alkaloids,including antofine (124), hypoestestatin 1 (125)and deoxypergularinine (126)(Scheme 22). The synthesis of (AE)-tylophorine (123)commenced with preparation of amidyl radical precursor 119.Phenanthrene carbaldehyde 115 underwent condensation with 1-phenylhydrazinecarbodithioate 116,which is available in two steps [273] to give 117 in excellent yield. Lewis acid mediated hydrostannation gave hydrazide 118,w hich was acetylated with pent-4-enoyl chloride to give the electrophilic radical precursor 119.F rom here,a ddition of as toichiometric quantity of dilauroyl peroxide (DLP), aw ell-known radical initiator and oxidant, led to the formation of the key amidyl radical 120.T his engaged in the expected radical cascade to give amide 122 in good yield. Finally,amide reduction generated (AE)-tylophorine (123)injust five steps from 115.Although rapid, an issue with this strategy is that it is not well suited to an asymmetric synthesis.T his aspect has since been addressed through alternative syntheses developed by several groups. [274][275][276] Amidyl radicals have been exploited in the design of other types of polycyclizations cascades.Anotable example was reported by Zard and co-workers in 2002 in the first synthesis of (AE)-13-deoxyserratine (136). [277] Their route commenced with the preparation of the Pauson-Khand precursor 128, which was synthesized in four steps from commercially available 5-hexyn-2-one (127) Angewandte Chemie Reviews triggering 6-endo cyclization of the ensuing carbon-centered radical. This sequence installs the two adjacent and hindered tetrasubstituted stereocenters of the target molecule.T he inclusion of achlorine atom at C(10) was required to enforce 6-endo (rather than 5-exo)s electivity during the second cyclization. As econd equivalent of Bu 3 SnH was therefore required to remove the chlorine atom in situ after the radical cascade,thereby allowing access to 134 in good yield. Finally, protection of the ketone as its silyl enol ether was followed by amide reduction and deprotection to give (AE)-13-deoxyserratine (136). Thec ore structural motif is common in several alkaloids and so ac ascade reaction of this type could be exploited in the synthesis of other alkaloids.P revious strategies to install as imilar core have required lengthy and low-yielding synthetic routes. [278] Thefield of photoredox chemistry has led to the development of mild photocatalytic methods for the formation of amidyl radicals,a nd these are likely to find wide use in the design of total synthesis oriented cascades. [246,265] An instructive example of the utility of this approach is showcased in Wangss ynthesis of (AE)-flustramide B ( 146), am arine alkaloid that has the potential as am uscle relaxant. [279] The synthesis begins with N-prenylation of commercially available indole 137 to give 138 in excellent yield (Scheme 24). Subsequent amide coupling with 139 gave the electrophilic amidyl radical precursor 140 in good yield. Theelectron-poor aryloxy amide was selected as the NÀObond is weak, and this allowed the generation of amidyl radical 142 under mild photocatalytic conditions,i nt his case using Eosin Ya st he photocatalyst. 5-endo cyclization of 142 provided carboncentered radical 143,w hich was trapped in situ with vinyl sulfone 141 to yield the pyrroloindoline core 144 in good yield. Reduction of the C À Sb ond of the vinyl sulfone gave 145 and, finally,cross-metathesis with 2-methyl-2-butene gave (AE)-flustramide B( 146)i nj ust five steps and in excellent yield. Ac hallenge going forward is to reengineer the key radical-based cascade to provide an asymmetric synthesis.

Aminyl Radicals
Aminyl radicals are generally considered to be nucleophilic;h owever, they are often generated from electrophilic sources of nitrogen. As with amidyl radicals,a minyl radicals are also valuable intermediates in the synthesis of polyheterocycles,a lthough in comparison, this area of chemistry is relatively underdeveloped, with only af ew examples reported. [243,[280][281][282][283][284][285] Thef ormation of an aminyl radical is typically carried out from an electrophilic N-halogen moiety using ar adical initiator or harsh photolytic methods, [280] although their generation from the dissociation of N À O [286] and N À Sb onds [287,288] has also been reported. As these intermediates are less commonly exploited, the development of photocatalytic methods for their formation are not well advanced.

Reviews
In 2014, Stockdill and co-workers reported the synthesis of the tertiary amine-containing polyheterocyclic core of the daphnicyclidin A( 153)a nd calyciphylline A( 154)a lkaloids, which are known to exhibit cytotoxicity against murine leukaemia. [289,290] Previous syntheses of this core structure have typically involved several synthetic steps,a nd very few examples have been carried out with complete diastereocontrol. [291] In the Stockdill approach, the polycyclic core is constructed in one step by acascade cyclization involving an aminyl radical (Scheme 25). Ther oute commenced with the synthesis of bicyclic lactone 148,prepared in three steps from commercially available (+ +)-(R)-carvone 147.F rom here, reduction of the lactone to the lactol was followed by reductive amination with propargylamine to give amino alcohol 149 in good yield. Thea ddition of NCS enabled the formation of the required chloroamine and the alcohol was subsequently oxidized with DMP to give cyclization substrate 150.I tw as envisaged that homolytic cleavage of the electrophilic NÀCl bond would generate an aminyl radical, which could engage in an intramolecular 6-exo addition to the cyclic enone to give the carbon-centered radical intermediate 151.
From here,5 -exo cyclization with the pendant alkyne and subsequent hydrogen-atom abstraction from Bu 3 SnH would generate the desired polycyclic core.I ndeed, upon exposure of 150 to AIBN and Bu 3 SnH, the cascade reaction proceeded as expected to generate 152 in excellent yield, and importantly as as ingle diastereomer.A lthough this sequence has not so far been employed directly in the synthesis of daphnicyclidin A(153)and calyciphylline A (154), the studies demonstrate the power of N-centered radical cascades in reaction design.
Thesyntheses highlighted in this section outline the use of conventional and photocatalytic methods for the generation of both electrophilic and nucleophilic N-centered radicals from electrophilic nitrogen sources.A lthough there are several other classes of N-centered radicals reported in the literature,these are not as well represented in total synthesis, primarily because mild photocatalytic methods for their generation are underdeveloped. Key issues in this area include competing H-atom abstraction, which necessitates careful substrate design, and the fact that asymmetric radicalbased processes are still challenging.N onetheless,t he use of N-centered radicals is one of the most powerful strategies for the construction of densely functionalized, complex polyheterocycles.

Outlook
Thee xamples highlighted in this review show how electrophilic aminating agents can be used to access Ncontaining products via aw ide array of mechanistic regimes. Clearly,wider application of these reagents in total synthesis will go hand in hand with further methodology development. It is pertinent therefore at this stage to highlight aselection of recent methodologies that seem well suited to applications in total synthesis.
Recently two new complementary CÀNb ond-forming dearomatization methods have been reported that exploit hydroxylamine-based electrophilic aminating agents (Scheme 26 C). [310] In both approaches,t he precursor is set up by Mitsunobu alkylation, which, in turn, allows the controlled installation of as tereocenter adjacent to nitrogen. Thef irst method requires substrates bearing an N-Boc group and occurs under acidic (TFA) conditions.Apossible mechanism involves acid-mediated N-Boc deprotection to afford an electrophilic nitrogen intermediate.T his highly reactive species functions as ap otent electrophile such that S E Arlike attack by the pendant arene leads to unprotected spirocycles.The products retain nucleophilic and electrophilic functionality that can be engaged directly in further bond formations.T he second approach provides products where the N-center is protected and occurs under basic conditions. Notably,t he method tolerates ar ange of protecting groups (e.g. carbamates,s ulfonamides) and offers broad scope with respect to the aromatic nucleophile. [311] Compared to prior approaches,t hese methods are relatively mild and flexible,

Angewandte Chemie
Reviews such that they seem well suited to applications in total synthesis.I ti sa lso important to note that certain types of dearomatizing aminations can be achieved under transitionmetal-catalyzed conditions,a nd these protocols will also likely find use in total synthesis. [312][313][314][315][316] It is pertinent to highlight that arange of powerful metalfree intermolecular CÀNb ond-forming dearomatization processes have been developed recently by Sarlah and coworkers. [24,317,318] In these processes,the light-promoted cyclo-addition of 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) with non-activated arenes is used to generate cycloadducts that can be exploited in further processes.T he chemistry has been applied to total syntheses of (+ +)-pancrastatin, (+ +)-7-deoxyprancrastatin, (+ +)-lycoridine,( + +)-narciclasine and (AE)-conduramine A. [24,[317][318][319] This area is not discussed in detail here because it has been the subject of arecent review,towhich the reader is directed. [320] 6.2. C-H Amination Strategies with Electrophilic Radicals As discussed already,t he most commonly exploited methods for aryl CÀNb ond formation are the Buchwald-Hartwig, Chan-Lam and Ullmann cross-couplings.T hese processes offer tremendous utility,b ut they require prefunctionalization of the C-based reaction partner,a nd in certain cases this can be problematic.C onsequently,a lternative processes have been developed that enable the formation of aryl amines by C-H amination. This area has seen rapid growth and there are now av ariety of methods available; [321][322][323][324][325][326][327][328][329][330][331] several of these involve electrophilic nitrogen sources,a nd these can operate via closed- [310] or open-shell (radical) pathways.One appealing strategy that has garnered interest is the use of aminium radicals in C-H amination processes.A sd iscussed previously,a minium radicals can be formed either by dissociation of an NÀX(X= Hal) bond and protonation of the resulting aminyl radical, or by direct photocatalytic methods.
Marsden and co-workers have reported an efficient method for intramolecular C-H amination using aminium radicals (Scheme 27 A). [332] Thek ey advance is that the Nchloroamine precursor is formed in situ by treatment of secondary amines with NCS. [333] This method constitutes one of the first examples of ao ne-pot "metal-free" aryl C-H amination, although it does require acidic reaction conditions (to aid protonate of the initially formed aminyl radical) and high-energy UV radiation. Under basic conditions,p hotoactivation of N-chloroamines affords nucleophilic aminyl radicals that can effect C-H amination of electron-poor heteroarenes.Astriking intramolecular example of this chemistry was used by Sarpong and co-workers to assemble the pentacyclic skeleton of the indole alkaloid arboflorine. [334] Complementary photocatalytic aryl C-H amination methods have been developed, and some of these use electrophilic nitrogen sources.F or example,L eonori has shown that N-O reagents of type 109 and 139 can be converted to aminium radicals using blue LEDs and Ru(bpy) 3 Cl 2 (Scheme 27 B). [335] Them ethod is relatively mild, although an acid additive (HClO 4 )i ss till required, and the N-component requires prefunctionalization. Thel atter issue has been addressed via the development of ad ouble amine activation strategy (Scheme 27 C). [336] Here,N CS is used to generate an Nchloramine in situ prior to addition of the photocatalyst and acid, which facilitates aminium radical formation. The method offers good scope and often excellent regioselectivities.The power of this strategy was demonstrated by the latestage (diversity-oriented) functionalization of several complex molecules.
Another conceptually elegant approach was reported by Nicewicz. [337,338] Here,t he aminium radical is generated directly from aprimary amine or nitrogen-containing heterocycle (rather than from an electrophilic aminating agent) using acridinium photoredox catalysis coupled with aerobic oxidation (Scheme 27 D). Importantly,noacid is required for this transformation, enabling C-H amination in the presence of acid-sensitive functional groups.T his strategy is reliant on oxidation of the primary amine to the aminium radical species by the acridinium photocatalyst. Thea ddition of the arene initiates cyclohexadienyl radical formation, which is then rearomatized by molecular oxygen, thus generating the C-H amination product. Although this method requires no prefunctionalization, at the current stage it is limited in scope with respect to the amine partner.
Thedirect installation of the NH 2 functionality can also be achieved by C-H amination processes involving electrophilic hydroxylamine-based reagents. [325,[339][340][341] Here,m etal-catalyzed or metal-mediated homolysis of the weak N À Ob ond generates the electrophilic aminium radical ( + CNH 3 ), which can engage the arene to deliver the aminated (NH 2 )product. This approach has found application in the synthesis of complex molecules;n otably,S anfordsT i III -mediated arene C-H amination was employed in the multigram preparation of akey intermediate in the synthesis of tamibarotene. [339] Them ethodologies outlined in this section demonstrate the use of conventional and photocatalytic methods for the generation of aminium radicals,w hich are able to engage in C-H amination processes,o ften removing the need for the prefunctionalization of starting materials.A lthough au seful method for the generation of aryl C À Nb onds,t he scope of these processes is limited in comparison to the classical Buchwald-Hartwig,C han-Lam and Ullmann cross-couplings;h owever,t he development of new methods for the generation of aminium radicals has opened up this approach as au seful complementary strategy for the synthesis of aryl C À Nbonds.
Ar ecent report showed that aziridines can be accessed from non-polarized alkenes by an aza-Prilezhaev type process involving an electrophilic nitrogen source (Scheme 28). [162] Here,t he precursor is assembled by Mitsunobu reaction from the corresponding alcohol. Following the addition of acid to promote N-Boc deprotection (TFA), an activated electrophilic hydroxylamine is able to engage alkenes in ap rocess that appears to be an aza analogue of the metachloroperoxybenzoic acid (m-CPBA) epoxidation reaction, allowing for the stereospecific preparation of aziridine products.I tw as proposed that the transformation occurs via ab utterfly-like transition state,t herefore the tosyl group is essential for successful reaction. Importantly,a ne xternal oxidant is not required, and this feature provides wide scope. Thei ntriguing heterobicyclic aziridine products are primed for further diversification, and seem well suited to applications in total synthesis. Scheme 27. C-H amination strategies with electrophilic radicals. Ar = aryl, HFIP = hexafluoro-2-propanol, Mes-Acr +=9-mesityl-10methylacridinium, Ru(bpy) 3 Cl 2 = tris(bipyridine)ruthenium(II) chloride, SET = single-electron transfer,V al-OMe·HCl = L-valine methyl ester hydrochloride.
Falck, Kürti and co-workers have developed ar hodiumnitrene based method for the aziridination of alkenes.T he protocol uses electrophilic hydroxylamine derivatives and, unusually,c an provide NH aziridines. [349] Similar conditions have been developed for aza-Rubottom oxidation;i nterestingly,i nm any cases the Rh catalyst was not required, such that amination could be achieved under metal-free conditions. [350] More recently,ametal-free alkene aziridination was reported, wherein unprotected aziridines were generated using an oxaziridine intermediate (Scheme 29). [351] This reactive species was generated in situ from an electron-poor ketone organocatalyst and ahydroxylamine-based aminating agent (HOSA). Themethod allows the stereospecific aziridination of unactivated, nonconjugated olefins,a nd can be thought of as an aza analogue of the Shi epoxidation. Further, by using ac hiral ketone organocatalyst (3-trifluoroacetyl-dcamphor), promising levels of enantioinduction were achieved. Thes implicity of this aziridination method bodes well for future applications in total synthesis.

Conclusion
This review has surveyed the landscape of electrophilic aminating agents in the context of total synthesis.T he examples presented give an overview of available strategies, and also highlight the relative merits and disadvantages of each approach. Thee xact choice of reaction conditions and electrophilic aminating agent allows selection between diverse reaction manifolds.A ss uch, aw ide range of specific transformations can be conducted, and these often function as key assembly steps en route to complex targets.The umpoled reactivity of electrophilic aminating agents enables the reaction of typically unreactive bonds,a sw ell as the formation of densely functionalized and sterically hindered tetrasubstituted stereocenters.O ften these processes employ simple,achiral starting materials.Ascan be seen, electrophilic aminating agents offer ac omplementary strategy to conventional nucleophilic amination processes.I nc ertain contexts, the umpoled approach is as uperior option because it can minimize step count or enable am ore powerful disconnection. Forthese reasons,itislikely that the use of electrophilic aminating agents will become more prevalent in total synthesis.