Synthesis of Nitrogen Heterocycles Using Samarium (II) Iodide

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Synthesis of Nitrogen Heterocycles Using Samarium(II) Iodide Shicheng Shi and Michal Szostak *

ID

Department of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102, USA * Correspondence: [email protected]; Tel.: +1-973-353-5329 Received: 27 October 2017; Accepted: 13 November 2017; Published: 21 November 2017

Abstract: Nitrogen heterocycles represent vital structural motifs in biologically-active natural products and pharmaceuticals. As a result, the development of new, convenient and more efficient processes to N-heterocycles is of great interest to synthetic chemists. Samarium(II) iodide (SmI2 , Kagan’s reagent) has been widely used to forge challenging C–C bonds through reductive coupling reactions. Historically, the use of SmI2 in organic synthesis has been focused on the construction of carbocycles and oxygen-containing motifs. Recently, significant advances have taken place in the use of SmI2 for the synthesis of nitrogen heterocycles, enabled in large part by the unique combination of high reducing power of this reagent (E1/2 of up to −2.8 V) with excellent chemoselectivity of the reductive umpolung cyclizations mediated by SmI2 . In particular, radical cross-coupling reactions exploiting SmI2 -induced selective generation of aminoketyl radicals have emerged as concise and efficient methods for constructing 2-azabicycles, pyrrolidines and complex polycyclic barbiturates. Moreover, a broad range of novel processes involving SmI2 -promoted formation of aminyl radicals have been leveraged for the synthesis of complex nitrogen-containing molecular architectures by direct and tethered pathways. Applications to the synthesis of natural products have highlighted the generality of processes and the intermediates accessible with SmI2 . In this review, recent advances involving the synthesis of nitrogen heterocycles using SmI2 are summarized, with a major focus on reductive coupling reactions that enable one-step construction of nitrogen-containing motifs in a highly efficient manner, while taking advantage of the spectacular selectivity of the venerable Kagan’s reagent. Keywords: samarium iodide; nitrogen heterocycles; nitrogen; radicals; reductive coupling; SmI2 ; radical cyclizations; samarium diiodide; umpolung cyclizations; aminoketyl radicals

1. Introduction Since its introduction to organic synthesis by Kagan in 1980, samarium diiodide (SmI2 , Kagan’s reagent) has, arguably, become the most useful single electron transfer reagent to effect polarity inversion in challenging transformations [1–5]. The synthetic utility of SmI2 is evident from the numerous applications in complex total syntheses [6,7] and large scale pharmaceutical manufacturing [8], where the combination of high redox potential (E1/2 of up to –2.8 V) [9] with excellent and unique chemoselectivity of SmI2 [10] enables a wide range of chemical transformations impossible to achieve with other single- or two-electron transfer reagents. The widespread adoption of SmI2 by organic chemists has been possible owing to several clear advantages of SmI2 , including: (1) the ability to fine-tune the reactivity by inorganic, protic and Lewis basic additives [11,12]; (2) the capacity to trigger reductive cyclizations via complementary radical or anionic mechanisms [13]; (3) well-defined mechanistic manifold under typically thermodynamic control [14]; (4) rapid access to complex architectures with precise stereochemistry enabled by high Lewis acidity of Sm(II)/(III) [15]; and, most importantly, (5) the operational-simplicity of preparing

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and using SmI2 in a standard laboratory setting without the requirement for special equipment or reaction set-up [16]. Historically, the use of SmI2 in organic synthesis has been focused on the construction of Molecules 2017, 22, 2018 2 of 22 carbocycles and oxygen-containing motifs [1–7]. Complex reductive cyclization processes forming carbocyclic skeletons relying the 2selective generation ketyl now become a routine Historically, the use on of SmI in organic synthesis of has beenradicals focusedhave on the construction of part of our synthetic [1–5,17,18].motifs Great[1–7]. strides have been made cyclization in applyingprocesses SmI2 to the assembly carbocycles and toolbox oxygen-containing Complex reductive forming of stereodefined oxacycles by polarity inversion of oxygen-containing [19–22]. carbocyclic skeletons relying on the selective generation of ketyl radicals carbonyl have now electrophiles become a routine part ofrecent our synthetic toolbox further [1–5,17,18]. Great strides have beenofmade SmI2synthesis to the of Moreover, elegant studies established the potential SmI2 in in applying asymmetric assembly of stereodefined oxacycles by polarity inversion of oxygen-containing carbonyl carbocycles [23]. electrophiles [19–22]. Moreover, elegant studies further SmI 2 in In this context, recently majorrecent advances have taken placeestablished in the usethe of potential SmI2 forofthe synthesis asymmetric synthesis of carbocycles [23]. of nitrogen heterocycles (Figure 1). Nitrogen heterocycles represent vital structural motifs in In this context, recently major advances have taken place in the use of SmI2 for the synthesis of biologically-active natural products and pharmaceuticals [24–26]. A plethora of nitrogen heterocycles nitrogen heterocycles (Figure 1). Nitrogen heterocycles represent vital structural motifs in have gained privileged status in medicinal chemistry [27]. However, the full potential of SmI2 biologically-active natural products and pharmaceuticals [24–26]. A plethora of nitrogen heterocycles in thehave synthesis of nitrogen-containing motifs is yet to However, be fully the realized. This ofisSmI likely due to gained privileged status in medicinal chemistry [27]. full potential 2 in the two factors: (1) high Lewis basicity of nitrogen-containing functional groups, which may synthesis of nitrogen-containing motifs is yet to be fully realized. This is likely due to two factors: (1)result in preferential and displacementfunctional of ligandsgroups, required for efficient electron transfer and high Lewiscoordination basicity of nitrogen-containing which may result in preferential coordination and displacement of ligands required for efficient electronfor transfer and cyclization steps to cyclization steps using SmI2 ; and (2) high activation energy required the direct electron transfer using SmI2; and carbonyl (2) high activation nitrogen-containing groups. energy required for the direct electron transfer to nitrogencontaining groups. This reviewcarbonyl summarizes the current-state-of-the-art in the use of SmI2 for the synthesis of nitrogen This review summarizes the current-state-of-the-art in The the use of SmI 2 for the synthesis of heterocycles, including the literature through October 2017. major focus is placed on reductive nitrogen heterocycles, including the literature through October 2017. The major focus is placed on coupling reactions that enable one-step construction of nitrogen-containing motifs in a highly efficient reductive coupling reactions that enable one-step construction of nitrogen-containing motifs in a manner. The selected examples serve to demonstrate the versatility offered by SmI2 and highlight the highly efficient manner. The selected examples serve to demonstrate the versatility offered by SmI2 areasand for further improvement. Therefore, the review is not comprehensive and only a selection of highlight the areas for further improvement. Therefore, the review is not comprehensive and the most only significant developments is presented. a selection of the most significant developments is presented.

Figure 1. Approaches to the Synthesis of Nitrogen Heterocycles using Samarium(II) Iodide. Figure 1. Approaches to the Synthesis of Nitrogen Heterocycles using Samarium(II) Iodide.

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The major focus has been placed on mechanistic pathways, selectivity and synthetic advantages of reductive coupling processes mediated by SmI2 . The review is arranged by the type of reductive coupling method that has been utilized in the synthesis of N-heterocycles with SmI2 (Figure 1). At present, SmI2 can be employed to furnish nitrogen heterocycles by four general mechanisms: (1) direct generation of aminoketyl radicals; (2) cross-coupling of α-aminyl radicals; (3) fragmentation/cyclization; and (4) indirect tethering approach. The final section of the review summarizes recent advances in the generation of aminoketyl and related radicals. These reactions provide a proof-of-principle and direction in which SmI2 technology can expand the assembly of nitrogen heterocycles for broad synthetic applications. It is our hope that the review will provide a one-stop overview of this important topic and stimulate further progress in the synthesis of nitrogen heterocycles using the venerable Kagan’s reagent. 2. Synthesis of Nitrogen Heterocycles via Aminoketyl Radicals Direct cyclization of aminoketyl radicals represents the most general method for the synthesis of nitrogen heterocycles with SmI2 . However, in contrast to the broad utility of ketyl and α-aminyl radicals, the development of practical methods for the addition of aminoketyl radicals to unactivated π-acceptors has been challenging due to the prohibitive stability of the amide bond to electron transfer, resulting from nN → π* CO conjugation [28,29]. In 2015, we have introduced the first general method for the generation of unactivated aminoketyl radicals and applied these precursors in the highly efficient cyclizations to afford 2-aza-bicycles containing up to three contiguous stereocenters with excellent stereoselectivity (Scheme 1A) [30]. The key to the successful development of this process relied on combining structural features of the amide bond in the imide template (low energy antibonding π* orbital, nN → π* CO delocalization into the remaining carbonyl, conformationally-locked system to prevent N–Cα fragmentation) with anomeric-type stabilization of the aminoketyl radical anion intermediate, facilitating electron transfer. The functional group tolerance is very broad, including halides (Br, Cl), esters, lactams, highly electron-deficient and sterically-hindered arenes. Both 5- and 6-membered imides undergo cyclization in high yields. Subsequently, a tandem, one-pot reductive cyclization/dehydration protocol was developed to conveniently access enamides featuring an endocyclic olefin for further functionalization (Scheme 1B) [31]. The advantage of using imides in cyclization is readily apparent. The highly selective SmI2 –H2 O system [12] can easily differentiate between three similar carbonyl groups, selectivity effecting SET to one of the imide carbonyls. The product 2-aza-bicycles are prominent features in a wide range of alkaloids, medicines and ligands (cf. less general products from stabilized barbituric acids). The process is scalable and the products are easy to isolate because the nitrogen is protected by the acyl group. In 2016, we have reported direct cyclizations of aminoketyl radicals using N-tethered precursors (Scheme 2) [32]. While positioning of the π-acceptor tether at the α-position to the imide carbonyl group in a 1,3-arrangement enabled efficient reductive 5-exo cyclizations, likely facilitated by the presence of a directing group [33], the N-tethered cyclization is significantly more challenging due to geometrical constraints of the planar imide template. The reaction generates fused pyrrolidine or piperidine scaffolds containing up to four functional handles for further functionalization in 2–3 steps from commercial materials. The product indolizidine and quinazolidine lactams are of particular significance in medicinal chemistry and natural product synthesis. The protocol relies on the high reducing potential of the Kagan’s reagent to selectively transfer electrons to the unactivated imide carbonyl, clearly underscoring the advantage of using the selective SmI2 –H2 O system. Moreover, we found that the reduction of imides (e.g., glutarimide, E1/2 = −2.64 V vs. SCE in CH3 CN) is favored over the model six-membered lactone (tetrahydro-2H-pyran-2-one, E1/2 = −2.96 V vs. SCE in CH3 CN) [34], which suggests that a myriad of reductive cyclization processes is feasible in analogy to the elegant reductive cyclizations of lactones [19–22].

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Scheme 1. 1. (A) (A) Synthesis Synthesis of of 2-Azabicycles 2-Azabicycles via via Reductive Reductive Cyclization Cyclization of of Cyclic Cyclic Imides; Imides; (B) (B) Reductive Reductive Scheme Cyclization/Dehydration of Cyclic Imides. Cyclization/Dehydration of Cyclic Imides. Scheme 1. (A) Synthesis of 2-Azabicycles via Reductive Cyclization of Cyclic Imides; (B) Reductive Cyclization/Dehydration of Cyclic Imides.

Scheme 2. Synthesis of Pyrrolidines and Piperidines via Reductive Cyclization of N-Tethered Cyclic Imides: (A) Construction of Pyrrolidine (B)via Construction of PiperidineofScaffolds. Scheme 2. Synthesis Synthesis of Pyrrolidines Pyrrolidines andScaffolds; Piperidines Reductive Cyclization Cyclization N-Tethered Cyclic Cyclic Scheme 2. of and Piperidines via Reductive of N-Tethered Imides: (A) (A) Construction Construction of of Pyrrolidine Pyrrolidine Scaffolds; Scaffolds; (B) (B) Construction Construction of of Piperidine Piperidine Scaffolds. Scaffolds. Imides:

Reductive cyclizations of barbituric acid derivatives proceeding via aminoketyl radicals were reported by Szostak and Procter in 2013 (Scheme 3) [35]. The reaction constituted the first example of Reductive cyclizations of barbituric acid derivatives proceeding via aminoketyl radicals were Reductive cyclizations of barbituric acid derivatives proceeding via aminoketyl radicals were selective reductive umpolung cyclizations exploiting ketyl-type radicals generated from barbituric reported by Szostak and Procter in 2013 (Scheme 3) [35]. The reaction constituted the first example of reported by Szostak and Procter in 2013 (Scheme 3) [35]. The reaction constituted the first example of acids, and provided an efficient entry toexploiting functionalized pyrimidine all selective reductive umpolung cyclizations ketyl-type radicalsscaffolds. generatedInterestingly, from barbituric selective reductive umpolung cyclizations exploiting ketyl-type radicals generated from barbituric products formedanwith excellent stereoselectivity as apyrimidine result of increased of the acids, andwere provided efficient entry to functionalized scaffolds.stabilization Interestingly, all acids, and provided an efficient entry to functionalized pyrimidine scaffolds. Interestingly, all products aminoketyl radical in this scaffold. However, it should be clearly noted that the generality of the products were formed with excellent stereoselectivity as a result of increased stabilization of the were formed with excellent stereoselectivity as a result of increased stabilization of the aminoketyl barbituric acid cyclizations much lower than that of imides due to structural of theof cyclic aminoketyl radical in this is scaffold. However, it should be clearly noted thatlimitations the generality the radical in this scaffold. However, it should be clearly noted that the generality of the barbituric 1,3-dimideacid template. barbituric cyclizations is much lower than that of imides due to structural limitations of the cyclic acid cyclizations is much lower than that of imides due to structural limitations of the cyclic Concurrently to our studies on reductive couplings of cyclic imides, the Procter group elegantly 1,3-dimide template. 1,3-dimide template. demonstrated the tosynthetic potential of aminoketyl the barbiturate ring Concurrently our studies on reductive couplingsradicals of cyclic stabilized imides, theby Procter group elegantly Concurrently to our studies on reductive couplings of cyclic imides, the Procter group elegantly (Schemes 4 and 5) [36]. In the first generation approach, radical cascade cyclizations initiated by the demonstrated the synthetic potential of aminoketyl radicals stabilized by the barbiturate ring demonstrated the synthetic potential of aminoketyl radicals stabilized by the barbiturate ring selective electron transfer to the diimide carbonyl, followed by the addition of carbon-centered (Schemes 4 and 5) [36]. In the first generation approach, radical cascade cyclizations initiated by the (Schemes 4 and 5) [36]. In the first generation approach, radical cascade cyclizations initiated by radical intermediates to theto N-tethered π-acceptor were developed (Scheme 4). This mechanistically selective electron transfer the diimide carbonyl, followed by the addition of carbon-centered the selective electron transfer to the diimide carbonyl, followed by the addition of carbon-centered distinct process from direct cyclizations of aminoketyl radicals onto N-tethered acceptors (see Scheme 2) radical intermediates to the N-tethered π-acceptor were developed (Scheme 4). This mechanistically provided the first evidence for radicals reductive cyclizations distinct process fromproof-of-principle direct cyclizations of aminoketyl ontocascade N-tethered acceptors of (seeaminoketyl Scheme 2) provided the first proof-of-principle evidence for reductive cascade cyclizations of aminoketyl

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radical intermediates to the N-tethered π-acceptor were developed (Scheme 4). This mechanistically distinct process from direct cyclizations of aminoketyl radicals onto N-tethered acceptors (see Scheme 2) provided the2017, first22,proof-of-principle evidence for reductive cascade cyclizations of aminoketyl radicals, Molecules 2018 5 of 22 2017, 22, 2018 5 ofthat 22 thus Molecules generating complex nitrogen heterocycles. Importantly, the authors demonstrated by radicals, thus generating complex nitrogen heterocycles. Importantly, the authors demonstrated that 4A) fine-tuning the reaction conditions it is possible to selectively furnish hemiaminal products (Scheme radicals, thus generating complex nitrogen heterocycles. the authors demonstrated that by fine-tuning the reaction conditions is possible toImportantly, selectively furnish products or dehydrated enamides (Scheme 4B). The itprocess employed a rarely utilizedhemiaminal SmI2 –LiBr–H 2 O reagent by fine-tuning the reaction conditions it is possible to selectively furnish hemiaminal products (Scheme 4A) or dehydrated enamides (Scheme 4B). The process employed a rarely utilized system [1,2], which promote the second radical cyclization by increasing the redox potential (Scheme 4A)2Oormay dehydrated 4B). The process employed a rarely utilizedof the SmI2–LiBr–H reagent system enamides [1,2], which(Scheme may promote the second radical cyclization by increasing SmI2 –H O reagent. Theofsteric bulk–Hof2OSmBr O may also result in the slower outer-sphere process. 2 –H 2The SmI –LiBr–H 2O reagent system which may promote radical cyclization increasing the22redox potential the SmI2[1,2], reagent. steric the bulksecond of SmBr 2–H2O may alsoby result in the In addition to generating up to five new stereocenters with excellent stereoselectivity (up to >95:5 the redox potential of the SmI 2 –H 2 O reagent. The steric bulk of SmBr 2 –H 2 O may also result in the slower outer-sphere process. In addition to generating up to five new stereocenters with excellent dr), outer-sphere addition to generating up to fiveadded new stereocenters with excellent rapidslower formation of novel pyrimidine-like scaffolds is an benefit of this protocol. stereoselectivity (up process. totricyclic >95:5 In dr), rapid formation of novel tricyclic pyrimidine-like scaffolds is an stereoselectivity (up to >95:5 dr), rapid formation of novel tricyclic pyrimidine-like scaffolds is an of Subsequently, added benefit ofthe this Procter protocol.group also reported stereoselective dearomatizing cyclizations added benefit ofaminoketyl thisthe protocol. Subsequently, Procter group (Scheme also reported stereoselective dearomatizing cyclizations barbituric acids via radicals 5) [37]. Mechanistically, this process involvesofdirect Subsequently, the Procter group also reported stereoselective dearomatizing cyclizations of barbituric via aminoketyl radicals (Scheme [37]. Mechanistically, this process involves direct addition of theacids aminoketyl radical stabilized by5)the barbiturate ring onto C-tethered benzofused barbituric acids via aminoketyl radicals (Scheme 5) [37]. Mechanistically, this process involves direct addition the aminoketyl radical stabilizedorbya the barbiturate ring onto C-tethered benzofused aromatic ringof(benzofuran or benzothiazole) cascade cyclization of the C-tethered π-acceptor, addition the(benzofuran aminoketylorradical stabilizedor bya the barbiturate ring of onto aromatic of ring benzothiazole) cascade cyclization the C-tethered C-tethered benzofused π-acceptor, followed by the addition of carbon-centered radical onto the benzofused aromatic ring (benzofuran, aromatic ringthe (benzofuran benzothiazole)radical or a cascade cyclization of aromatic the C-tethered π-acceptor, followed by addition ofor carbon-centered onto the benzofused ring (benzofuran, benzothiazole, benzoxazole, benzothiophene, naphthalene). functional group tolerance has followed by thebenzoxazole, addition of carbon-centered onto theImpressive benzofused aromatic ring (benzofuran, benzothiazole, benzothiophene,radical naphthalene). Impressive functional group tolerance been benzothiazole, demonstrated, including aryl halides, ethers and heterocycles. This elegant process sets the stage benzoxazole, benzothiophene, ImpressiveThis functional tolerance has been demonstrated, including aryl halides,naphthalene). ethers and heterocycles. elegantgroup process sets the for the design of a plethora of dearomatizing cyclizations for the synthesis of nitrogen heterocycles has been demonstrated, including aryl halides, ethers and heterocycles. This elegant process sets the via stage for the design of a plethora of dearomatizing cyclizations for the synthesis of nitrogen heterocycles stage forradicals the design of a plethora aminoketyl [38,39]. via aminoketyl radicals [38,39]. of dearomatizing cyclizations for the synthesis of nitrogen heterocycles via aminoketyl radicals [38,39].

Scheme 3. SmI2-Mediated Reductive Cyclizations of Barbituric Acids (Cyclic 1,3-Diimides) via Aminoketyl

Scheme 3. SmI2 -Mediated Reductive Cyclizations of Barbituric Acids (Cyclic 1,3-Diimides) Scheme Radicals.3. SmI2-Mediated Reductive Cyclizations of Barbituric Acids (Cyclic 1,3-Diimides) via Aminoketyl via Aminoketyl Radicals. Radicals.

Scheme 4. Synthesis of Polycyclic Barbiturates via Cascade Cyclizations: (A) Synthesis of Tricyclic Scheme 4. Synthesis of Polycyclic Barbiturates via Cascade Cyclizations: (A) Synthesis of Tricyclic Barbiturates; (B) Synthesis of Tricyclic Barbiturates Cross-Coupling/Dehydration. Scheme 4. Synthesis of Polycyclic Barbiturates viaby Cascade Cyclizations: (A) Synthesis of Tricyclic Barbiturates; (B) Synthesis of Tricyclic Barbiturates by Cross-Coupling/Dehydration.

Barbiturates; (B) Synthesis of Tricyclic Barbiturates by Cross-Coupling/Dehydration.

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Scheme 5. Synthesis of Spiro-Barbiturates via Dearomatizing Cyclizations: (A) Direct Cyclizations;

Scheme 5. Synthesis of Spiro-Barbiturates via Dearomatizing Cyclizations: (A) Direct Cyclizations; (B) Cascade Cyclizations. (B) Cascade Cyclizations. Scheme 5. Synthesis of Spiro-Barbiturates via Dearomatizing Cyclizations: (A) Direct Cyclizations;

The successful construction of nitrogen viaCyclizations: aminoketyl(A) radicals depends on the Scheme 5. Synthesis of Spiro-Barbiturates viaheterocycles Dearomatizing Direct Cyclizations; (B) Cascade Cyclizations. The successful construction nitrogen via aminoketyl radicals depends on the (B) Cascade Cyclizations. capacity of the Sm(II) reagent to of generate and heterocycles stabilize the formed radical to prevent reduction to the capacity of the Sm(II) reagent to generate and stabilize the formed radical to prevent reduction anion. In an alternative mechanism, Chiara reported the SmI 2 -mediated reductive cross-coupling The successful construction of nitrogen heterocycles via aminoketyl radicals depends on the to The successful of nitrogen heterocycles via aminoketyl depends on between phthalimides and activated olefins, and oxime ethers (Scheme 6) [40]. The reaction the anion. In of an alternative mechanism, Chiara reported SmI -mediated reductive cross-coupling capacity the Sm(II)construction reagent to generate andnitrones, stabilize thethe formed toradicals prevent reduction to the the 2radical capacity of the Sm(II) reagent to generate stabilize the formed radical to prevent reduction to the affords α-hydroxy lactams in high yields and with generally good stereoselectivity. Mechanistically, between phthalimides and activated olefins, ethers (Scheme [40]. The reaction anion. In an alternative mechanism, Chiaranitrones, reportedand the oxime SmI2-mediated reductive6)cross-coupling anion. Inphthalimides aninvolves alternative mechanism, Chiaranitrones, reported theoxime SmI -mediated reductive cross-coupling the method reduction N-tethered phthalimide (E 1/2 2= −1.49 V vs. SCE6)in[40]. CH 3CN) [32] to between and olefins, and ethers (Scheme The reaction affords α-hydroxy lactams in activated highofyields and with generally good stereoselectivity. Mechanistically, between phthalimides and activated olefins, nitrones, and oxime ethers (Scheme 6) [40]. The reaction the anion, followed by anionic addition. In this case, the reactivity is limited to phthalimides, wherein affords α-hydroxy lactams in high yields and phthalimide with generally(E good = stereoselectivity. Mechanistically, the method involves reduction of N-tethered − 1.49 V vs. SCE in CH 3 CN) [32] 1/2 stereoselectivity. Mechanistically, affords α-hydroxy lactams in high yields and with generally good the benzylic position facilitates the electron transfer and stabilizes the formed anion. the method involves reduction of N-tethered phthalimide (E 1/2 = −1.49 V vs. SCE in CH 3CN) [32] to to thethe anion, followed by anionicofaddition. In this case, (E the =reactivity is limited to phthalimides, method involvesby reduction N-tethered −1.49 V vs. in CH 3CN) [32] of to In a synthetically relatedaddition. development, the Ha group1/2developed reductive cyclizations the anion, followed anionic In thisphthalimide case, the reactivity is limited toSCE phthalimides, wherein wherein the benzylic position facilitates the electron transfer and stabilizes the formed anion. the anion, followed by anionic addition. In this case, the reactivity is limited to phthalimides, wherein N-iodoalkyl tethered cyclic imides using the SmI 2 /Fe(dbm) 3 reagent system (Scheme 7) [41,42]. the benzylic position facilitates the electron transfer and stabilizes the formed anion. In synthetically development, the Ha group developed reductive cyclizations theabenzylic position facilitates the electron transfer and stabilizes the formed anion. cyclizations The reaction affords related bicyclic lactams via nucleophilic addition of organosamarium; however, a of In a synthetically related development, the Ha group developed reductive of In a synthetically related development, the Ha group developed reductive cyclizations of N-iodoalkyl tethered cyclic imides using the SmI /Fe(dbm) reagent system (Scheme 7) [41,42]. limitation of this protocol is the generation of isomeric olefin products. 2 3 N-iodoalkyl tethered cyclic imides using the SmI2/Fe(dbm)3 reagent system (Scheme 7) [41,42]. N-iodoalkyl tethered cycliclactams imides using the SmI2/Fe(dbm) 3 reagent system (Scheme however, 7) [41,42]. The reaction affords bicyclic addition of the organosamarium; however, The reaction affords bicyclic lactamsvia via nucleophilic nucleophilic addition of the organosamarium; a The reaction affords bicyclic lactams via nucleophilic addition of the organosamarium; however, a a limitation of of this protocol ofisomeric isomeric olefin products. limitation this protocolisisthe the generation generation of olefin products. limitation of this protocol is the generation of isomeric olefin products.

Scheme 6. Reductive Cyclizations of N-Substituted Phthalimides via Anionic Coupling. Scheme 6. Reductive Cyclizations of N-Substituted Phthalimides via Anionic Coupling.

Scheme 6. Reductive Cyclizations Phthalimides Anionic Coupling. Scheme 6. Reductive Cyclizationsof ofN-Substituted N-Substituted Phthalimides viavia Anionic Coupling.

Scheme 7. Synthesis of Lactams via Ionic Cyclization of N-Tethered Iodoalkyl Cyclic Imides. Scheme 7. Synthesis of Lactams via Ionic Cyclization of N-Tethered Iodoalkyl Cyclic Imides. Scheme 7. Synthesis of Lactams via Ionic Cyclization of N-Tethered Iodoalkyl Cyclic Imides.

Scheme 7. Synthesis of Lactams via Ionic Cyclization of N-Tethered Iodoalkyl Cyclic Imides.

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3. Synthesis of Nitrogen Heterocycles via Aminyl Radicals Molecules 2017, 22, 2018cross-coupling of imines and equivalents via α-aminoalkyl radicals 7 of 22 SmI is 2 -mediated well-established [1,2]. Broadly speaking, formation of α-aminoalkyl radicals using SmI2 is generally 3. Synthesis of Nitrogen Heterocycles via Aminyl Radicals much easier than aminoketyl radicals owing to the higher reactivity of precursors [43], which could 2-mediated and equivalents via α-aminoalkyl radicals is wellSmI potentially lead to widecross-coupling applicationsofinimines organic synthesis. However, despite significant progress [1,2]. protocols Broadly speaking, of α-aminoalkyl radicals using SmI2 isand generally much via in theestablished last 15 years, for theformation chemoselective cross-coupling of imines equivalents easier than aminoketyl radicals owing to theofhigher of precursors [43], which could α-aminoalkyl radicals are yet to reach the level utilityreactivity of their ketyl counterparts. potentially lead to wide applications in organic synthesis. However, despite significant progress in Seminal studies by Py and Vallée showed the feasibility of polarity reversal of C=N bonds in the last 15 years, protocols for the chemoselective cross-coupling of imines and equivalents via αnitrones in the cross-coupling with ketones and aldehydes [44]. Mechanistic studies demonstrated aminoalkyl radicals are yet to reach the level of utility of their ketyl counterparts. direct electron transfer group, resulting in the of formation of an α-aminoalkyl Seminal studiesto bythe Py nitrone and Vallée showed the feasibility polarity reversal of C=N bonds radical, in followed by addition to the carbonyl group. In 2003, another major breakthrough was reported nitrones in the cross-coupling with ketones and aldehydes [44]. Mechanistic studies demonstrated by Pydirect and electron Vallée in the chemoselective conjugate additions of nitrones α,β-unsaturated transfer to the nitrone group, resulting in the formation of antoα-aminoalkyl radical,esters (Scheme 8A) by [45,46]. reaction γ-N-hydroxyamino esters, which could be readily followed additionThe to the carbonylgenerates group. In 2003, another major breakthrough was reported by Py and Vallée chemoselective pyrrolidines conjugate additions nitrones to α,β-unsaturated esters (Scheme converted into in thethecorresponding upon of deoxygenation and base-induced cyclization. 8A) [45,46]. Thesimilar reactionstudies generates γ-N-hydroxyamino esters, which could Owing be readily At the same time, were reported by Skrydstrup [47,48]. toconverted the high into stability the corresponding pyrrolidines upon deoxygenation and base-induced cyclization. At the sameare time, of nitrones, ease of synthesis and high efficiency in polarity reversal using SmI2 , nitrones among similar studies were reported by Skrydstrup [47,48]. Owing to the high stability of nitrones, ease of the most versatile precursors to α-aminoalkyl radicals, while their reactivity compares favorably with synthesis and high efficiency in polarity reversal using SmI2, nitrones are among the most versatile oximes, oxime ethers, hydrazones, sulfonyl imines and N-acyliminiums [1,2,43]. precursors to α-aminoalkyl radicals, while their reactivity compares favorably with oximes, oxime Py andhydrazones, co-workerssulfonyl developed theand cross-coupling of [1,2,43]. nitrones with α,β-unsaturated acceptors as ethers, imines N-acyliminiums an attractive methodology for the synthesis of γ-lactams [49,50] with and pyrrolizidine Py and co-workers developed the cross-coupling of nitrones α,β-unsaturatedalkaloids acceptors[51–53]. as In 2005, they reported the total for synthesis of (+)-hyacinthacine A2 , aand polyhydroxylated amyloglucosidase an attractive methodology the synthesis of γ-lactams [49,50] pyrrolizidine alkaloids [51–53]. inhibitor, using between L -xylose-derived cyclic nitrone In 2005, theySmI reported the total reductive synthesis ofcoupling (+)-hyacinthacine A2,aachiral polyhydroxylated amyloglucosidase 2 -mediated inhibitor, using SmI 2 -mediated reductive coupling between a chiral L -xylose-derived cyclic and ethyl acrylate to generate the key bicyclic ring system (Scheme 8B) [52]. Mild reactionnitrone conditions, and ethyl acrylate to generate the key bicyclic ring synthesis system (Scheme 8B) [52].functionalized Mild reaction conditions, selective cross-coupling/deoxygenation and the of densely pyrrolizidine selective cross-coupling/deoxygenation and the synthesis of densely pyrrolizidine alkaloid scaffold are noteworthy. The cross-coupling approach was functionalized further highlighted by the Py alkaloid scaffold are noteworthy. The cross-coupling approach was further highlighted by the Py group in the synthesis of (+)-australine (Scheme 9) [53]. Notably, readily available β-silyl acrylates with group in the synthesis of (+)-australine (Scheme 9) [53]. Notably, readily available β-silyl acrylates silicon serving as an oxygen equivalent were demonstrated as highly viable alternatives to β-alkoxy with silicon serving as an oxygen equivalent were demonstrated as highly viable alternatives to acrylates. Anacrylates. interesting feature offeature this protocol involves the use both water and LiBr β-alkoxy An interesting of this protocol involves theof use of both water and LiBras asSmI2 additives to increase the redox potential of the reagent and stereoselectivity of the process. SmI2 additives to increase the redox potential of the reagent and stereoselectivity of the process.

Scheme 8. (A) SmI2-Promoted Cross-Coupling of Nitrones with α,β-Unsaturated Esters via Aminyl

Scheme 8. (A) SmI2 -Promoted Cross-Coupling of Nitrones with α,β-Unsaturated Esters via Aminyl Radicals; (B) Synthesis of (+)-Hyacinthacine A2 by Cross-Coupling of Cyclic Nitrones. Radicals; (B) Synthesis of (+)-Hyacinthacine A2 by Cross-Coupling of Cyclic Nitrones.

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Scheme 9. Scheme Synthesis of (+)-Australine by Cross-Coupling Cross-Coupling Cyclic Cyclic Nitrones with β-Silyl Acrylates. Scheme 9. 9. Synthesis Synthesis of of (+)-Australine (+)-Australine by by Cross-Coupling Cyclic Nitrones Nitrones with with β-Silyl β-Silyl Acrylates. Acrylates. Scheme 9. Synthesis of (+)-Australine by Cross-Coupling Cyclic Nitrones with β-Silyl Acrylates.

Intramolecular also feasible. 2005, Skrydstrup Skrydstrup and co-workers of nitrones also feasible. feasible. In Skrydstrup and and co-workers co-workers Intramolecular cross-coupling cross-coupling of nitrones is is also In 2005, Intramolecular cross-coupling of nitrones is also feasible. In 2005, Skrydstrup and co-workers demonstrated the synthesis of cyclic ureas by SmI 2-mediated intramolecular pinacol-type coupling demonstrated the synthesis of cyclic ureas by SmI 2 -mediated intramolecular pinacol-type coupling demonstrated the synthesis of cyclic ureas by SmI -mediated intramolecular pinacol-type coupling of 2 2-mediated intramolecular pinacol-type coupling demonstrated the synthesis of cyclic ureas by SmI of dinitrones (Scheme 10) [54]. The reaction forms cis-diamines in a highly diastereoselective manner. of dinitrones (Scheme 10) [54]. The reaction forms cis-diamines in a highly diastereoselective manner. dinitrones (Scheme 10) [54]. manner. of dinitrones (Scheme 10) [54].The Thereaction reactionforms formscis-diamines cis-diamines in in aa highly highly diastereoselective manner. The authors found that proton donors have aa significant impact on the efficiency and stereoselectivity The have significant impact on the efficiency and stereoselectivity The authors found that proton donors efficiency The authors found that proton donors have a significant impact on the efficiency and stereoselectivity of the coupling with MeOH providing the optimum results. reaction is an interesting results. This interesting alternative of the the coupling coupling with with MeOH MeOH providing providing the the optimum optimum results. results. This reaction reaction is is an an interesting alternative of This alternative to well-established methods for the synthesis of cyclic ureas [55]. methods for for the the synthesis synthesis of of cyclic cyclic ureas ureas [55]. [55]. to well-established well-established methods methods to for the synthesis of cyclic ureas [55]. The use of N-tert-butanesulfinyl imines [56] as precursors to α-aminoalkyl is also N-tert-butanesulfinyl α-aminoalkyl radicals The use of N-tert-butanesulfinyl imines [56] as precursors to α-aminoalkyl radicals is is also also The use of N-tert-butanesulfinyl imines [56] as precursors to α-aminoalkyl radicals promising. In 2005, in a striking development, Xu and Lin demonstrated the first SmI 2-mediated promising. In 2005, in a striking development, Xu and Lin demonstrated the first SmI 2 -mediated In 2005, in a striking development, promising. In development, Xu and and Lin Lin demonstrated demonstrated the the first first SmI SmI22-mediated -mediated intermolecular cross-coupling of N-tert-butanesulfinyl imines with aldehydes. The reaction affords The intermolecular cross-coupling of N-tert-butanesulfinyl imines with aldehydes. reaction affords intermolecular cross-coupling of N-tert-butanesulfinyl imines with aldehydes. The reaction affords β-amino alcohols in excellent diastereoand enantioselectivity [57]. The generation of chiral αalcohols in excellent diastereoand enantioselectivity [57]. The generation of chiral αβ-amino alcohols in excellent diastereoand enantioselectivity [57]. The generation of chiral β-amino alcohols in excellent diastereo- and enantioselectivity [57]. The generation of chiral αaminoalkyl radicals or highly nucleophilic aza-anions [58,59] provides novel opportunities for the aminoalkyl radicals or highly nucleophilic aza-anions [58,59] provides novel opportunities for the α-aminoalkyl radicals highly nucleophilic aza-anions [58,59] provides novel opportunities for aminoalkyl radicals or or highly nucleophilic aza-anions [58,59] provides novel opportunities for the synthesis of nitrogen heterocycles using Ellman’s N-tert-butanesulfinyl imines as the chirality source. synthesis of nitrogen heterocycles using Ellman’s N-tert-butanesulfinyl imines as the chirality source. the synthesis of nitrogen heterocycles using Ellman’s N-tert-butanesulfinyl imines as the chirality synthesis of nitrogen heterocycles using Ellman’s N-tert-butanesulfinyl imines as the chirality source. The SmI formation of β-amino alcohols has been highlighted in the The selective selective SmI222-promoted -promoted formation of chiral chiral β-amino alcohols hashas been highlighted in source. The selective SmI2 -promoted formation of chiral β-amino alcohols beenhighlighted highlightedin in the the The selective SmI -promoted formation of chiral β-amino alcohols has been synthesis of NK-1 SP receptor antagonist, (+)-CP-99,994 (Scheme 11) [60]. receptor antagonist, antagonist, (+)-CP-99,994 (+)-CP-99,994 (Scheme synthesis of of NK-1 NK-1 SP SP receptor (Scheme 11) 11) [60]. [60]. synthesis receptor antagonist, (+)-CP-99,994

Scheme 10. of Cyclic Ureas by Scheme 10. Synthesis Synthesis of Cyclic Ureas by Intramolecular Intramolecular Pinacol-Coupling Pinacol-Coupling of of Dinitrones. Dinitrones. Scheme 10. Synthesis of of Cyclic Cyclic Ureas Ureas by Scheme Synthesis Intramolecular Pinacol-Coupling of Dinitrones.

Scheme Scheme 11. 11. Synthesis Synthesis of of (+)-CP-99,994 (+)-CP-99,994 by by Cross-Coupling Cross-Coupling of of N-tert-Butanesulfinyl N-tert-Butanesulfinyl Imines. Imines. Scheme Scheme 11. 11. Synthesis Synthesis of of (+)-CP-99,994 (+)-CP-99,994 by by Cross-Coupling Cross-Coupling of of N-tert-Butanesulfinyl N-tert-Butanesulfinyl Imines. Imines.

The The reduction reduction of of N-acyliminium N-acyliminium ions ions [61] [61] with with SmI SmI222 represents represents another another method method to to generate generate The reduction of N-acyliminium ions [61] with SmI represents another method to generate α-aminoalkyl radicals for the construction of nitrogen heterocycles. In particular, this method offers The reduction of N-acyliminium ions [61] with SmI represents another method to generate 2 α-aminoalkyl radicals for the construction of nitrogen heterocycles. In particular, this method offers α-aminoalkyl radicals for the construction of nitrogen heterocycles. In particular, this method offers advanatges in terms of improved reaction efficiency and selectivity using cyclic N-acyliminium α-aminoalkyl radicals for the construction of nitrogen heterocycles. In particular, this method offers advanatges in in terms terms of of improved improved reaction reaction efficiency efficiency and and selectivity selectivity using using cyclic cyclic N-acyliminium N-acyliminium advanatges precursors. In 2011, Huang and co-workers reported the synthesis of aa hydroxylated tropane alkaloid, precursors. In 2011, Huang and co-workers reported the synthesis of hydroxylated tropane alkaloid, precursors. In 2011, Huang and co-workers reported the synthesis of a hydroxylated tropane alkaloid, (−)-bao gong teng A, by the intramolecular N,O-acetal/aldehyde coupling (Scheme 12) [62]. (−)-bao gong teng A, by the intramolecular N,O-acetal/aldehyde coupling (Scheme 12) [62]. (−)-bao gong teng A, by the intramolecular N,O-acetal/aldehyde coupling (Scheme 12) [62].

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advanatges in terms of improved reaction efficiency and selectivity using cyclic N-acyliminium precursors. In2018 2011, Huang and co-workers reported the synthesis of a hydroxylated tropane Molecules 2017, 22, 9 of 22 Molecules 2017, 22, 2018 of 22 alkaloid, (−)-bao gong teng A, by the intramolecular N,O-acetal/aldehyde coupling (Scheme 12)9 [62]. Mechanistically, BFBF generation of the N-acyliminium followed by SET Mechanistically,the thereaction reactioninvolves involves 3-promoted generation of the N-acyliminium followed by 3 -promoted Mechanistically, the reaction involves BF3-promoted generation of the N-acyliminium followed by to generated α-aminyl radical. The authors proposed that the preferential formation of the equatorial SET to generated α-aminyl radical. The authors proposed that the preferential formation of the SET to generated α-aminyl radical. The authors proposed that the preferential formation of the alcohol (dralcohol = 92:8) (dr results fromresults repulsive between N between and O lone the equatorial = 92:8) fromelectronic repulsiveinteractions electronic interactions N pairs and Oinlone equatorial alcohol (dr = 92:8) results from repulsive electronic interactions between N and O lone transition state. In cases when reactivity required, N,S-acetals provide advantageous results. pairs in the transition state. higher In cases when ishigher reactivity is required, N,S-acetals provide pairs in the transition state. In cases when higher reactivity is required, N,S-acetals provide This concept was nicelyThis demonstrated by Huang co-workers in synthesis (−)-uniflorine by advantageous results. concept was nicelyand demonstrated bythe Huang and ofco-workers in the advantageous results. This concept was nicely demonstrated by Huang and co-workers in the intermolecular acetal/α,β-unsturated ester cross-coupling as a key step 13) [63].as Mechanistic synthesis of (−)-uniflorine by intermolecular acetal/α,β-unsturated ester(Scheme cross-coupling a key step synthesis of (−)-uniflorine by intermolecular acetal/α,β-unsturated ester cross-coupling as a key step studies that in the presence of BF3 ·Et2 Othat andint-BuOH, the reaction proceeds via a radical (Schemedemonstrated 13) [63]. Mechanistic studies demonstrated the presence of BF3·Et 2O and t-BuOH, the (Scheme 13) [63]. Mechanistic studies demonstrated that in the presence of BF3·Et2O and t-BuOH, the (cf. anionic) pathway. reductive couplingpathway. product was converted to product the pyrrolizidone by reaction proceeds via The a radical (cf. anionic) The readily reductive coupling was readily reaction proceeds via a radical (cf. anionic) pathway. The reductive coupling product was readily Boc removal K2 CO3 -promoted cyclization. converted to and the pyrrolizidone by Boc removal and K2CO3-promoted cyclization. converted to the pyrrolizidone by Boc removal and K2CO3-promoted cyclization.

Scheme 12. 12. Synthesis of of (−)-Bao Scheme −)-BaoGong GongTeng Teng A A by by Cross-Coupling Cross-Coupling of of N,O-Acetals. N,O-Acetals. Scheme 12. Synthesis Synthesis of ((−)-Bao Gong Teng A by Cross-Coupling of N,O-Acetals.

Scheme 13. Synthesis of (−)-Uniflorine by Intermolecular Cross-Coupling of N,S-Acetals. Scheme 13. 13. Synthesis Synthesis of of ((−)-Uniflorine Scheme −)-Uniflorine by by Intermolecular Intermolecular Cross-Coupling Cross-Coupling of of N,S-Acetals. N,S-Acetals.

An interesting strategy to generate aminal radicals for the synthesis of nitrogen heterocycles was An interesting strategy to generate aminal radicals for the synthesis of nitrogen heterocycles was An interesting toand generate aminal(Scheme radicals 14) for [64,65]. the synthesis was recently reported bystrategy Beaudry co-workers Here, of thenitrogen requiredheterocycles aminal radicals recently reported by Beaudry and co-workers (Scheme 14) [64,65]. Here, the required aminal radicals recently reportedfrom by Beaudry and co-workers (Scheme 14) Here, the required radicals were generated the corresponding amidines using a [64,65]. novel SmI 2–NH 4Cl system.aminal In some cases, were generated from the corresponding amidines using a novel SmI2–NH4Cl system. In some cases, were generated from the acid) corresponding using a novel system.efficiency. In some cases, CSA (camphorosulfonic in place ofamidines NH4Cl was shown to SmI give2 –NH higher The 4 Clreaction CSA (camphorosulfonic acid) in place of NH4Cl was shown to give higher reaction efficiency. The CSA place of NH4 Cl was shown to give higher reaction of efficiency. scope scope(camphorosulfonic of the reaction isacid) veryinbroad, including intermolecular cross-couplings various The benzenescope of the reaction is very broad, including intermolecular cross-couplings of various benzeneof the reaction is very broad, including cross-couplings of various benzene-fused fused (quinazolinones), aliphatic and intermolecular spirocyclic amidines with α,β-unsaturated esters and fused (quinazolinones), aliphatic and spirocyclic amidines with α,β-unsaturated esters and (quinazolinones), aliphatic with α,β-unsaturated estersN-tethered and acrylonitrile acrylonitrile (Scheme 14A).and Twospirocyclic examples amidines of intramolecular cyclizations using olefin acrylonitrile (Scheme 14A). Two examples of intramolecular cyclizations using N-tethered olefin (Scheme intramolecular cyclizations N-tethered olefin acceptors acceptors14A). wereTwo also examples reported, of and proceeded with excellent using diastereoselectivity (Scheme 14B).were The acceptors were also reported, and proceeded with excellent diastereoselectivity (Scheme 14B). The also reported, and proceeded with excellent diastereoselectivity (Scheme 14B). The methodology was methodology was further expanded to the use of amidinium ions as precursors to aminal radicals. methodology was further expanded to the use of amidinium ions as precursors to aminal radicals. further expanded to demonstrated the use of amidinium as precursors aminal Mechanistic studies that theions reaction involves to SET to theradicals. amidineMechanistic substrate tostudies afford Mechanistic studies demonstrated that the reaction involves SET to the amidine substrate to afford demonstrated that the reaction involves SET to the amidine substrate to afford radical, followed aminal radical, followed by addition to the π-acceptor. Importantly, the aminal SmI2-mediated process aminal radical, followed by addition to the π-acceptor. Importantly, the SmI2-mediated process by addition to the π-acceptor. the SmI process provideswaste synthetic advantages provides synthetic advantagesImportantly, in terms of mild reaction conditions, decreased generation and 2 -mediated provides synthetic advantages in terms of mild reaction conditions, decreased waste generation and in terms of mild reactionover conditions, decreased waste generation andtranslocation operational simplicity over the operational simplicity the AIBN/Bu 3SnH-promoted radical method reported operational simplicity over the AIBN/Bu3SnH-promoted radical translocation method reported AIBN/Bu SnH-promoted earlier by 3the same authorsradical [66]. translocation method reported earlier by the same authors [66]. earlier by the same authors [66].

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Scheme 14. (A) SmI2-Promoted Intermolecular Cross-Coupling of Amidines; (B) Synthesis of Bicyclic Scheme 14. (A) (A) SmI SmI2-Promoted -Promoted Intermolecular Intermolecular Cross-Coupling of Amidines; (B) Synthesis of Bicyclic Scheme 2 Aminals14. via Intramolecular Cross-Coupling. Cross-Coupling of Amidines; (B) Synthesis of Bicyclic Aminalsvia viaIntramolecular IntramolecularCross-Coupling. Cross-Coupling. Aminals

4. Synthesis of Nitrogen Heterocycles via Fragmentation/Cyclization Pathways 4. Synthesis Synthesis of of Nitrogen Nitrogen Heterocycles Heterocycles via via Fragmentation/Cyclization Fragmentation/CyclizationPathways Pathways 4. Another pathway for the synthesis of nitrogen heterocycles with SmI2 involves chemoselective involves chemoselective chemoselective Another pathway pathway for the the synthesis synthesis of of nitrogen nitrogen heterocycles heterocycles with with SmI SmI2 involves Another cleavage of C–N bondsfor of α-aminocarbonyl compounds, followed by ionic (Scheme 15) 2 cyclization cleavage of C–N bonds of α-aminocarbonyl compounds, followed by ionic cyclization (Scheme 15) cleavage of C–N bonds of α-aminocarbonyl compounds, followed by ionic cyclization (Scheme [66–68]. [66–68]. Honda reported that α-amino esters and ketones undergo selective scission of the 15) C–N bond [66–68].reported Honda reported that α-amino esters and ketones undergo selective scission of thebond C–Nupon bond Honda that esters and ketones selective scission of the C–N upon exposure to theα-amino SmI2–HMPA–ROH system undergo [67]. Although simple phenylalanine derivatives upon exposure to the SmI 2–HMPA–ROH system [67]. Although simple phenylalanine derivatives exposure the SmIdeamination, system [67]. Although phenylalanine undergo to efficient synthetic value ofsimple this method hingesderivatives upon theundergo use of 2 –HMPA–ROHthe undergo efficient deamination, the synthetic value of this method hinges upon the use of efficient deamination, the synthetic value of this method hinges the acids use of(Scheme cyclic proline cyclic proline and pipecoline derivatives, which afford γand upon δ-amino 15A). and The cyclic proline and pipecoline derivatives, afford γ- (Scheme and δ-amino acids (Scheme 15A). The pipecoline derivatives, which afford γ-with andwhich δ-amino acids 15A). The chemoselectivity of chemoselectivity of this method is high, overreduction of the ketone or ester group not observed chemoselectivity of this method is high, with overreduction of the ketone orobserved ester group not observed this method is high, with overreduction of the ketone or ester group not under the mild under the mild SmI2–HMPA conditions. The temperature-induced intramolecular cyclization of the under the mild SmI2–HMPA conditions. The temperature-induced intramolecular cyclization of the SmI The temperature-induced intramolecular cyclization the chiral amino ester chiral aminoconditions. ester products was elegantly applied in the synthesis of ofpiperidine derivatives 2 –HMPA chiral amino ester products was elegantly applied in the synthesis of piperidine derivatives products was elegantly (Scheme 15B) [68,69]. applied in the synthesis of piperidine derivatives (Scheme 15B) [68,69]. (Scheme 15B) [68,69].

Scheme 15. 15. (A) of α-Amino and Ketones; (B) Synthesis Synthesis Scheme (A) SmI SmI2-Promoted -Promoted Reductive Reductive Deamination Deamination of α-Amino Esters Esters and Ketones; (B) Scheme 15. (A) SmI22-Promoted Reductive Deamination of α-Amino Esters and Ketones; (B) Synthesis of Chiral Piperidines by Fragmentation/Cyclization Pathway. of Chiral Piperidines by Fragmentation/Cyclization Pathway. of Chiral Piperidines by Fragmentation/Cyclization Pathway.

Interestingly, Burtoloso recently engaged a related group of α-aminocarbonyl substrates in the Interestingly, Burtoloso recently engaged a related group of α-aminocarbonyl substrates in the intermolecular cross-coupling with methyl acrylate to form γ-aminomethyl-γ-butyrolactones using intermolecular cross-coupling with methyl acrylate to form γ-aminomethyl-γ-butyrolactones using

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Interestingly, Molecules 2017, 22, 2018 Burtoloso recently engaged a related group of α-aminocarbonyl substrates 11 ofin 22 the intermolecular cross-coupling with methyl acrylate to form γ-aminomethyl-γ-butyrolactones using (Scheme [70]. The reaction proceeds in with highexcellent yields and with excellent SmI2/HSmI 2O (Scheme [70]. 16A) The reaction proceeds in high yields and diastereoselectivity. 2 /H2 O 16A) diastereoselectivity. Importantly, cleavage of the N–C bond was not observed, which likely Importantly, cleavage of the N–C bond was not observed, which likely resultsresults fromfrom the the complementary Sm(II) reagent system employed. This transformation, which rapidly delivers complementary Sm(II) reagent system employed. This transformation, which rapidly delivers chiral β-amino β-amino alcohol units, represents a powerful method for the construction of piperidine, indolizidine and and quinolizidine quinolizidine alkaloids alkaloids from from readily readily available availableα-amino α-amino acid acidderivatives derivatives(Scheme (Scheme16B) 16B)[71,72]. [71,72].

Scheme 16. 16. (A) (A) SmI SmI2-Promoted -Promoted Intermolecular Intermolecular Cross-Coupling α-Amino Acids; Acids; (B) (B) Synthesis Synthesis of of Scheme Cross-Coupling of of α-Amino 2 (−)-Pumiliotoxin 251D. (−)-Pumiliotoxin 251D.

5. Synthesis Synthesis of of Nitrogen Nitrogen Heterocycles Heterocycles via via Tethered TetheredApproach Approach 5. synthesis of nitrogen heterocycles by an indirect tethered approach, wherein The SmI SmI2-mediated The 2 -mediated synthesis of nitrogen heterocycles by an indirect tethered approach, wherein the nitrogen inin radical or or ionic cross-coupling represents a common and the nitrogen atom atomisisnot notdirectly directlyinvolved involved radical ionic cross-coupling represents a common popular strategy in organic synthesis. In general, nitrogen heterocycles are formed selectively by and popular strategy in organic synthesis. In general, nitrogen heterocycles are formed selectively several complementary mechanisms exploiting the reductive and coordinating properties of SmI by several complementary mechanisms exploiting the reductive and coordinating properties of2, including (1) aryl radical/alkene cross-coupling; (2) ketyl radical/alkene cross-coupling; (3) pinacolSmI 2 , including (1) aryl radical/alkene cross-coupling; (2) ketyl radical/alkene cross-coupling; type couplings; (4) dearomatizing ketyl radical/arene cross-coupling; (4) (5) olefin/isocyanate or (3) pinacol-type couplings; (4) dearomatizing ketyl radical/arene cross-coupling; olefin/isocyanate carbodiimide cross-coupling, and (5) ionic Reformatsky-type reactions. In principle, the synthesis of or carbodiimide cross-coupling; and (6) ionic Reformatsky-type reactions. In principle, the synthesis of nitrogen heterocycles heterocyclesby byother otherradical radicalor or ionic ionic mechanisms mechanismsenabled enabledby bySmI SmI2 is is also also possible, possible, but but these these nitrogen 2 methods have not received much attention. methods have not received much attention. Tanaka reported reported an an efficient efficient intramolecular intramolecular arylation arylation of of 2-iodo-benazanilides 2-iodo-benazanilides for for the the synthesis synthesis Tanaka of spirocyclic oxindoles and 6-(5H)-phenanthridinones (Scheme 17) [73]. The reaction was initially of spirocyclic oxindoles and 6-(5H)-phenanthridinones (Scheme 17) [73]. The reaction was initially conducted using the SmI 2–HMPA system in the absence of protic additives, leading to selective conducted using the SmI2 –HMPA system in the absence of protic additives, leading to selective formation of of fused fused phenanthridinones. phenanthridinones. When was performed performed with with 2.0 2.0 equivalents equivalents of of formation When the the reaction reaction was i-PrOH, spirocyclic oxindoles products were obtained selectively in good yields. The mechanism was i-PrOH, spirocyclic oxindoles products were obtained selectively in good yields. The mechanism was proposed to to involve involve the (2)(2) 5-exo-trig cyclization to proposed the following followingsteps: steps:(1) (1)generation generationofofthe thearyl arylradical; radical; 5-exo-trig cyclization the spirocyclic radical intermediate; (3) protonation to give the spirocyclic oxindole product or rearrangement of the unstable spirocyclic radical to phenanthridinones. An interesting example of the SmI2-promoted aryl radical/alkene cyclization was recently reported by Ready and co-workers in their studies on nucleophilic addition of organometallic

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to the spirocyclic radical intermediate; (3) protonation to give the spirocyclic oxindole product or rearrangement of the unstable spirocyclic radical to phenanthridinones. An interesting example of the SmI2 -promoted aryl radical/alkene cyclization was recently reported by Ready and co-workers in their studies on nucleophilic addition of organometallic reagents Molecules 2017, 22, 2018 12 of 22 to pyridine boronic esters (Scheme 18) [74]. After initial dearomatization of the pyridine ring, the reagents to pyridine esters [74]. of the pyridine reductive cyclization of aboronic tethered aryl(Scheme iodide 18) with theAfter SmI2initial –H2 Odearomatization reagent was used to 12 generate the Molecules 2017, 22, 2018 of 22 ring, the reductive cyclization of a tethered aryl iodide with the SmI 2–H2O reagent was used to generate fused pyrrolidine ring system. The radical cyclization was accompanied by a 1,2-boron migration thereagents fused pyrrolidine system. The(Scheme radical 18) cyclization wasinitial accompanied by a 1,2-boron migration to pyridinering boronic esters [74]. After dearomatization of the pyridine and olefin transposition forming versatile allyl boronic esters. The mechanism was proposed to and olefin transposition forming versatile allyl boronic esters. The mechanism was proposed the reductive cyclization of a tethered aryl iodide with the SmI 2–H2O reagent was used to generate to involve ring, 5-exo-trig cyclization, followed by B(pin) migration; however, additional studies are required involve 5-exo-trig cyclization, followed B(pin) migration; additional studies are required the fused pyrrolidine ring system. The by radical cyclization washowever, accompanied by a 1,2-boron migration to elucidate the mechanism. The method highlights the potential of SmI to provide attractive 2 to and elucidate mechanism. The method the esters. potential SmI2 to provide attractive olefin the transposition forming versatilehighlights allyl boronic Theofmechanism was proposed to NN-heterocyclic building blocks and products. heterocyclic building blocks and products. involve 5-exo-trig cyclization, followed by B(pin) migration; however, additional studies are required to elucidate the mechanism. The method highlights the potential of SmI2 to provide attractive Nheterocyclic building blocks and products.

Scheme 17. Synthesis of Spirocyclic Oxindoles (A) and 6-(5H)-Phenanthridinones (B) by Aryl Scheme 17. Synthesis of Spirocyclic Oxindoles (A) and 6-(5H)-Phenanthridinones (B) by Aryl Scheme 17. Cross-Coupling. Synthesis of Spirocyclic Oxindoles (A) and 6-(5H)-Phenanthridinones (B) by Aryl Radical/Arene Radical/Arene Cross-Coupling. Radical/Arene Cross-Coupling.

Scheme SynthesisofofDihydropyridine Dihydropyridine Boronate Boronate Esters Cross-Coupling. Scheme 18.18. Synthesis Estersby byAryl ArylRadical/Alkene Radical/Alkene Cross-Coupling.

Scheme 18. Synthesis of Dihydropyridine Boronate Esters by Aryl Radical/Alkene Cross-Coupling. The ketyl/alkenecross-coupling cross-coupling reported reported by by Shirahama illustration The ketyl/alkene Shirahamaand andco-workers co-workersis isanother another illustration ofketyl/alkene the synthesis pyrrolidinesusing using SmI22 (Scheme (Scheme 19) process used 2is –HMPA to form The cross-coupling reported by Shirahama and co-workers another illustration of the synthesis ofofpyrrolidines SmI 19) [75]. [75].This This process usedSmI SmI 2–HMPA to form trans-substituted heterocycles, while in the the presence of aa protic additive, MeOH, cis-pyrrolidines heterocycles, while in presence of protic additive, MeOH, cis-pyrrolidines of thetrans-substituted synthesis of pyrrolidines using SmI (Scheme 19) [75]. This process used SmI –HMPA to form 2 2 were formed selectively.This Thiswas wasexplained explained on on the basis of aathermodynamic preference to to adopt were formed selectively. the basis of thermodynamic preference adopt trans-substituted heterocycles, while in the presence of a protic additive, MeOH, cis-pyrrolidines trans-conformation by minimizing steric repulsion between the samarium(III) alkoxide and by minimizing steric repulsion between thea samarium(III) alkoxide and to were trans-conformation formed selectively. This was on the basis of thermodynamic preference methoxycarbonyl groups during theexplained reversible electron transfer/cyclization steps. methoxycarbonyl groups during the reversible electron transfer/cyclization steps. adopt trans-conformation by minimizing steric repulsion between the samarium(III) alkoxide and methoxycarbonyl groups during the reversible electron transfer/cyclization steps.

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Scheme 19. Synthesis KainoidAmino AminoAcids Acids by by Ketyl Cross-Coupling. Scheme 19. Synthesis of of Kainoid KetylRadical/Alkene Radical/Alkene Cross-Coupling. Scheme 19. Synthesis of Kainoid Amino Acidscould by Ketyl Radical/Alkene Carbonyl compounds (pinacol-type coupling) be utilized in placeCross-Coupling. of the electron-deficient Carbonyl (pinacol-type coupling) could20) be[76]. utilized in cyclopropyl place of theradical electron-deficient π-acceptor compounds to generate nitrogen heterocycles (Scheme Using clocks, Carbonyl compounds (pinacol-type coupling) could 20) beof utilized in placecyclopropyl ofketone-ketone the electron-deficient π-acceptor to nitrogen heterocycles [76]. Using radical clocks, Handa andgenerate co-workers demonstrated that the(Scheme mechanism SmI2-mediated pinacol π-acceptor nitrogen heterocycles (Scheme [76]. Using of cyclopropyl radical clocks, coupling into thegenerate synthesis of pyrrolidines involves 20) the of cyclization a ketylketone-ketone radical anion. The Handa and co-workers demonstrated thatlikely the mechanism SmI2 -mediated pinacol Scheme 19. Synthesis of Kainoid Amino by Ketylof Radical/Alkene Cross-Coupling. Handa andparticularly co-workers demonstrated that the Acids mechanism SmI2-mediated ketone-ketone pinacol method for the synthesis of involves substituted pyrrolidine vicinal with high coupling in is the synthesisuseful of pyrrolidines likely the cyclization of acis-diols ketyl radical anion. coupling in the synthesis of pyrrolidines likely involves the cyclization of a ketyl radical anion. The diastereoselectivity. The method is particularly useful for the synthesis of substituted pyrrolidine vicinal cis-diols Carbonyl compounds (pinacol-type coupling) could be utilized in place of the electron-deficient method is particularly useful for the synthesis of substituted pyrrolidine vicinal cis-diols with high with π-acceptor to generate nitrogen heterocycles (Scheme 20) [76]. Using cyclopropyl radical clocks, high diastereoselectivity. diastereoselectivity.

Handa and co-workers demonstrated that the mechanism of SmI2-mediated ketone-ketone pinacol coupling in the synthesis of pyrrolidines likely involves the cyclization of a ketyl radical anion. The method is particularly useful for the synthesis of substituted pyrrolidine vicinal cis-diols with high diastereoselectivity.

Scheme 20. Synthesis of Cyclopropyl Pyrrolidines by Pinacol Coupling by Handa. Scheme 20. Synthesis of Cyclopropyl Pyrrolidines bydearomatization Pinacol Coupling by Forming nitrogen heterocycles by SmIPyrrolidines 2-promoted by ofHanda. Scheme 20. Synthesis of Cyclopropyl Pinacol Coupling byreadily Handa. available aromatics is attractive because of the potential to build-up of molecular complexity for the synthesis Forming high nitrogen heterocycles of by the SmI 2-promoted dearomatization of readily available of alkaloids, diastereoselectivity SmI 2-mediated processes and the capacity of radical Forming nitrogen heterocycles by SmI -promoted dearomatization of by readily available aromatics aromatics is attractive because of the potential to build-up ofcascade molecular complexity for the synthesis Scheme 20. Synthesis of Cyclopropyl Pyrrolidines by Pinacol Coupling Handa. 2 intermediates to participate in complex radical-anionic transformations. Ketyl/indole of alkaloids, high diastereoselectivity of the SmI 2-mediated complexity processes and the capacity of radical is attractive because of the potential to build-up of molecular for the synthesis of alkaloids, dearomatizing cross-coupling have been pioneered by the Reissig group [77,78]. The synthetic utility Formingto nitrogen heterocycles by SmI 2-promoted dearomatization of readily available intermediates participate in complex radical-anionic cascade transformations. Ketyl/indole high of diastereoselectivity ofshowcased the SmI2 -mediated processesofand the capacity radical intermediates this method has been inpotential the totalto synthesis strychnine (Schemeof21) [79–81]. The key aromatics is attractive because of the build-up of molecular complexity forsynthetic the synthesis dearomatizing cross-coupling have been pioneered by the Reissig group [77,78]. The utility to participate in complex cascade transformations. Ketyl/indole dearomatizing reaction involves a SmI 2radical-anionic –HMPA-mediated intramolecular 6-exo-trig ketyl/indole radical addition, of alkaloids, highbeen diastereoselectivity of total the SmI 2-mediated processes and the capacity of radical of this method has showcased in the synthesis of strychnine (Scheme 21) [79–81]. The key followed byhave reduction and intramolecular acylation, furnishing the tetracyclic intermediate in 77% cross-coupling been pioneered the Reissig group [77,78]. The synthetic utility of this method intermediates to participate in by complex radical-anionic cascade transformations. Ketyl/indole reaction involves a SmI 2–HMPA-mediated intramolecular 6-exo-trig ketyl/indole radical addition, yield as a single diastereoisomer. Quenching the reaction with bromoacetonitrile improved the overall has been showcasedcross-coupling in the totalhave synthesis of strychnine (Scheme [79–81]. The key dearomatizing been pioneered by the Reissig group 21) [77,78]. The synthetic utilityreaction followed bythe reduction and intramolecular acylation, furnishing the tetracyclic intermediate in 77% yield due to undesired C–C fragmentation andsynthesis loss of acetonitrile under the reaction conditions. ofathis method has been showcased in the total of strychnine (Scheme 21) [79–81]. The key involves SmI –HMPA-mediated intramolecular 6-exo-trig ketyl/indole radical addition, followed by 2 yield as a single diastereoisomer. Quenching the reaction with bromoacetonitrile improved the overall reaction involves a SmI 2–HMPA-mediated intramolecular 6-exo-trig ketyl/indole radical addition, reduction andtointramolecular acylation, furnishing theoftetracyclic in 77% yield as a single yield due the undesired C–C fragmentation and loss acetonitrileintermediate under the reaction conditions.

followed by reduction and intramolecular acylation, furnishing the tetracyclic intermediate in 77%

diastereoisomer. Quenching the reaction with bromoacetonitrile improved the overall yield due to the yield as a single diastereoisomer. Quenching the reaction with bromoacetonitrile improved the overall undesired C–C andfragmentation loss of acetonitrile under the reaction yield due fragmentation to the undesired C–C and loss of acetonitrile under theconditions. reaction conditions.

Scheme 21. Intramolecular Ketone/Indole Dearomatizing Cross-Coupling: Synthesis of Strychnine. Scheme 21. Intramolecular Ketone/Indole Dearomatizing Cross-Coupling: Synthesis of Strychnine. Scheme 21. Intramolecular Ketone/Indole Dearomatizing Cross-Coupling: Synthesis of Strychnine.

Scheme 21. Intramolecular Ketone/Indole Dearomatizing Cross-Coupling: Synthesis of Strychnine.

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More recently, the Reissig group extended their SmI2 -mediated dearomatizing cross-coupling methodology to the intramolecular addition of sulfinyl imines to indoles (Schemecross-coupling 22) [82]. Under the More recently, the Reissig group extended their SmI 2-mediated dearomatizing Molecules 2017, 22, 2018 14 ofthe 22in good methodology to the intramolecular addition of sulfinyl imines to indoles (Scheme 22) [82]. Under optimized conditions (SmI2 –H2 O–LiBr), sulfinyl imines undergo addition to the indole ring optimized conditions (SmI 2–H2O–LiBr), sulfinyl imines undergo addition to the indole ring in good yields and modest to high diastereoselectivity. The preparation of enantiopure tertiary amines has More Reissig group extendedThe their SmI2-mediated dearomatizing cross-coupling yields and recently, modest tothe high diastereoselectivity. preparation of enantiopure tertiary amines has been demonstrated; however, it shouldaddition be noted that atimines present the major limitation of this the method is methodology to the intramolecular of sulfinyl to indoles (Scheme 22) [82]. Under been demonstrated; however, it should be noted that at present the major limitation of this method reductive N–S cleavage prior cyclization andand substrate-dependent diastereoselectivity. optimized conditions (SmIto 2–H 2O–LiBr), sulfinyl imines undergo addition to the indole ring in good is reductive N–S cleavage prior to cyclization substrate-dependent diastereoselectivity. yields and modest to high diastereoselectivity. The preparation of enantiopure tertiary amines has been demonstrated; however, it should be noted that at present the major limitation of this method is reductive N–S cleavage prior to cyclization and substrate-dependent diastereoselectivity.

Scheme 22. Intramolecular Sulfinyl Imine/Indole Dearomatizing Cross-Coupling.

Scheme 22. Intramolecular Sulfinyl Imine/Indole Dearomatizing Cross-Coupling. Nitrogen heterocycles can be obtained via SmI2-mediated cross-coupling of stabilized radicals Scheme 22.can Intramolecular Sulfinyl Dearomatizing Cross-Coupling. generated from activated π-acceptors with heterocumulenes, such cross-coupling as isocyanates andof carbodiimides. Nitrogen heterocycles be obtained viaImine/Indole SmI2 -mediated stabilized radicals In an impressive development, Wood and co-workers reported intramolecular cross-coupling of generated from activated π-acceptors with heterocumulenes, such as isocyanates and carbodiimides. Nitrogen heterocycles can bespiro-oxindoles obtained via SmI 2-mediated cross-coupling of stabilized radicals enones with isocyanates to afford under very mild conditions (Scheme 23A) [83]. The In an impressive development, Wood with and heterocumulenes, co-workers reported intramolecular cross-coupling of generated from activated π-acceptors such as isocyanates and carbodiimides. SmI 2–LiCl–t-BuOH system was found to give optimal performance in this reaction, likely due to enones increasing with isocyanates to afford spiro-oxindoles under very mild conditions (Scheme [83]. In an impressive development, WoodThe andmethodology co-workers reported intramolecular cross-coupling of redox potential of Sm(II). was showcased in the total synthesis 23A) of enones with isocyanates to afford spiro-oxindoles under very mild conditions (Scheme 23A) [83]. The The SmIwelwitindolinone –LiCl–t-BuOH system was found to give optimal performance in this reaction, likely due 2 A isonitrile (Scheme 23B) [84]. The high chemoselectivity of this process, tolerating SmI2–LiCl–t-BuOH systemofwas found to reaction give optimal performance in this reaction, to to increasing redox potential Sm(II). The methodology was showcased thelikely totaldue synthesis of several sensitive functional groups, mild conditions and full control of in diastereoselectivity increasing redox potential of Sm(II). The methodology was showcased in the total synthesis of are particularly noteworthy. welwitindolinone A isonitrile (Scheme 23B) [84]. The high chemoselectivity of this process, tolerating welwitindolinone A isonitrile (Scheme 23B) [84]. The high chemoselectivity of this process, tolerating several sensitive functional groups, mild reaction conditions and full control of diastereoselectivity are several sensitive mild 1. reaction TEA, THFand full control of diastereoselectivity Cl2CO,conditions A: functional groups, O O particularly noteworthy. 2. SmI (4 equiv) are particularly noteworthy. 2

A:

O NH 2

B: Me B: O Me O

Cl

Cl

NH 2 H Me Me H NCO

Me Me

NCO steps

steps

LiCl (16 equiv) equiv) TEA, THF 1.t-BuOH Cl2CO, (1 2. SmI 2 (4 equiv) THF, °C LiCl (16-78 equiv) t-BuOH (1 equiv) THF, -78 °C SmI 2 (4 equiv) LiCl (16 equiv) t-BuOH (1 equiv) SmI 2 (4 equiv) THF, °C LiCl (16-78 equiv) t-BuOH (1 equiv) THF, Cl -78 °C Me NC Me

Cl

H Me Me HO

O

O

N H 88% yield ClN H Me 88% yield O Me H O

Cl

O

H Me Me HO

N H

Me Me 75% yield, dr >95:5 O N H H

75% yield, dr >95:5

N Me H Me W elwitindolinone A Isonitrile O N Scheme 23. (A) Synthesis of Spirocyclic Oxindoles by Olefin/Isocyanate Cross-Coupling; (B) Application H in the Synthesis of Welwitindolinone A Isonitrile. W elwitindolinone A Isonitrile NC

(A) Synthesis of Spirocyclic Oxindoles by by Olefin/Isocyanate Cross-Coupling; (B) Application SchemeScheme 23. (A)23. Synthesis of Spirocyclic Oxindoles Olefin/Isocyanate Cross-Coupling; (B) Application in the Synthesis of Welwitindolinone A Isonitrile. in the Synthesis of Welwitindolinone A Isonitrile.

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In a mechanistically related process, Takemoto reported the SmI2 -mediated intramolecular Molecules 2017, 2018 15 ofamidines 22 cross-coupling of22,α,β-unsaturated amides with carbodiimides to give spirocyclic Molecules 2017, 22, 2018 15 of 22 (Scheme 24A) [85]. In the model study, they found that SmI2 –t-BuOH system provided the In a mechanistically related process, Takemoto reported the SmI2-mediated intramolecular highest cross-coupling yields. Subsequently, the process, reaction was utilized in give theSmI synthesis ofintramolecular a core system of In a mechanistically related amides Takemoto reportedto the 2-mediated of α,β-unsaturated with carbodiimides spirocyclic amidines (Scheme perophoramidine (Scheme 24B) [86]. This very challenging cyclization involving SET reduction of a cross-coupling of model α,β-unsaturated amides give spirocyclic amidines 24A) [85]. In the study, they foundwith thatcarbodiimides SmI2–t-BuOH to system provided the highest(Scheme yields. sterically-hindered olefin proceeded smoothly the presence of 24A) [85]. In tetrasubstituted the study, they found SmI 2–t-BuOH system provided theSmI highest yields. Subsequently, themodel reaction was utilized in thethat synthesis of a corein system of perophoramidine (Scheme 2 –HMPA–t-BuOH the reaction was gave utilized in the synthesis of a core of perophoramidine (Scheme 24B) [86]. This very challenging cyclization involving SET system reduction of a sterically-hindered at roomSubsequently, temperature. The reaction a highly-functionalized spiro-2-iminoindoline ring system as a 24B) [86]. This very challenging cyclization involving SET reduction of a sterically-hindered tetrasubstituted olefin proceeded smoothly in the presence of SmI 2–HMPA–t-BuOH at room single diastereoisomer in 86% yield. tetrasubstituted proceeded smoothly in the presence of SmI2–HMPA–t-BuOH room temperature. Theolefin reaction gave a highly-functionalized spiro-2-iminoindoline ring system asata single In addition to reactions involving cross-coupling of radical intermediates, convenient methods for temperature. Theinreaction gave a highly-functionalized spiro-2-iminoindoline ring system as a single diastereoisomer 86% yield. the preparation of nitrogen heterocycles via SmI2 -mediated anionic coupling have been methods developed [13]. diastereoisomer in yield.involving In addition to 86% reactions cross-coupling of radical intermediates, convenient In particular, intramolecular Reformatsky reactions ofofα-halo amides have have emerged as an important Inpreparation addition to of reactions involving cross-coupling radical intermediates, convenient methods for the nitrogen heterocycles via SmI2-mediated anionic coupling been developed ofintramolecular nitrogen heterocycles via example, SmIreactions 2-mediated coupling haveabeen developed [13]. Inpreparation particular, Reformatsky of anionic α-halo amides have emerged as an methodfor tothe prepare nitrogen heterocycles. For Pettus demonstrated general method for [13]. Inofparticular, intramolecular Reformatsky reactions of α-halo amides have as an–HMPA important method to prepare nitrogen For example, Pettus demonstrated a general the synthesis 3-methyl tetramic acids byheterocycles. cyclizing α-bromo amides into estersemerged using SmI 2 to prepare nitrogen heterocycles. For example, Pettus amides a general method formethod of 3-methyl tetramic acids by cyclizing α-bromo using (Schemeimportant 25) [87]. the A synthesis variety of chiral α-bromo amides provided gooddemonstrated yieldsinto of esters the tetramic acid method for the synthesis 3-methyl tetramic acids α-bromo by cyclizing α-bromo amides intoyields esters of using SmI2–HMPA (Scheme 25)of[87]. A variety of chiral amides provided good the products with excellent diastereocontrol. Importantly, racemization of the chiral stereocenter was not SmI2–HMPA [87].excellent A variety of chiral α-bromo amides provided good of yields the tetramic acid (Scheme products25) with diastereocontrol. Importantly, racemization the of chiral observed, highlighting theobserved, mild of the themild SmIconditions protocol. 2 -mediated tetramic acidwas products withconditions excellent diastereocontrol. Importantly, racemization of the chiral stereocenter not highlighting of the SmI 2-mediated protocol. stereocenter was not observed, highlighting the mild conditions of the SmI2-mediated protocol.

Scheme 24. (A) Synthesis of Spirocyclic Amidines by Olefin/Carbodiimide Cross-Coupling; (B)

Scheme 24. (A) Synthesis of Spirocyclic Amidines by Olefin/Carbodiimide Cross-Coupling; Scheme 24. in (A) Spirocyclic Amidines by Olefin/Carbodiimide Cross-Coupling; (B) Application an Synthesis Approachof to Perophoramidine. (B) Application in an Approach to Perophoramidine. Application in an Approach to Perophoramidine.

Scheme 25. Synthesis of Tetramic Acids by Intramolecular Amide Reformatsky Cyclization. Scheme 25. Synthesis of Tetramic Acids by Intramolecular Amide Reformatsky Cyclization.

Scheme 25. Synthesis of Tetramic Acids by Intramolecular Amide Reformatsky Cyclization.

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6. 6. Reactions Involving Involving Aminoketyl Aminoketyl and and Related Related Radicals Radicals As As outlined outlined in in the previous previous sections sections of this review, review, direct direct cyclizations cyclizations of of aminoketyl aminoketyl and and related related radicals provide one of the most efficient methods for the synthesis of nitrogen heterocycles. radicals provide one of the most efficient methods for the synthesis of nitrogen heterocycles. In In this this regard, regard, recently recently significant significant advances advances have have been been made made in in the the generation generation of of simple, simple, unfunctionalized unfunctionalized aminoketyl aminoketyl and and related related radicals. radicals. These methods provide aa proof-of-concept proof-of-concept demonstration demonstration and and direction in which SmI -mediated electron transfer reactions can be used to expand the portfolio direction in which SmI22 to expand the portfolio of of nitrogen nitrogen heterocycles heterocyclesfor forbroad broadsynthetic syntheticapplications. applications. The reduction of ofamides amidesbybyelectron electron transfer mechanism represents a major challenge as a The reduction transfer mechanism represents a major challenge as a result result of N → π* conjugation. In 2013, Szostak and Procter demonstrated the first reduction of Nlp → π*lp CO conjugation. In 2013, Szostak and Procter demonstrated the first reduction of aliphatic CO of aliphatic amides using [88].is The method due is noteworthy due amides using SmI2–H 2O–EtSmI 3N (Scheme 26A) [88]. The26A) method noteworthy to the exquisite 2 –H2 O–Et 3 N (Scheme to the exquisite selectivity for the C–O vs. the more commonly observed N–C scission of the selectivity for the C–O vs. the more commonly observed N–C scission of the carbinolamine carbinolamine in amethod practicalfor method for the reduction of all types of amides to intermediate, intermediate, resulting in aresulting practical the reduction of all types of amides to the the corresponding alcohols under mild conditions.More Moreimportantly, importantly,the theoptimized, optimized, highly reducing corresponding alcohols under mild conditions. reducing Sm(II) of up to –2.8 Sm(II) reagent reagent system system (E (E1/2 1/2 of –2.8 V) V) [89], [89], relying relyingon oncooperative cooperativeLewis-base/proton Lewis-base/proton donor donor coordination coordination [90], [90], enables enables generation generation of ofaminoketyl aminoketylradicals radicalsfrom fromsimple simpleamides. amides. In In 2017, 2017, we we have havedemonstrated demonstratedthat thatboth bothmild mildSmI SmI 2–H 2O (E (E1/2 1/2 = = –1.3 V vs. vs. SCE) and more more 2 –H 2O reducing SmI –H O–amine systems can be employed to reduce all types of benzamides with excellent reducing SmI22–H22 systems employed reduce benzamides with excellent N–C/C–O scissionselectivity selectivity(Scheme (Scheme26B) 26B)[91]. [91].InInthis thiscase, case,generation generationofofthe theaminoketyl aminoketyl radical N–C/C–O scission radical is is more facile by virtue of weakened amidic resonance, while the formed benzylic radicals show more facile by virtue of weakened amidic resonance, while the formed show significantly significantly higher higher stability stability due due to to delocalization. delocalization. This bodes bodes well well for for the the development development of of reductive reductive umpolung umpolung cyclizations cyclizations via via benzylic benzylic aminoketyl aminoketylradicals radicalsas asaakey keystep. step.

Scheme 26. 26. SmI SmI22-Promoted -Promoted Reduction Reduction of of Amides Amides via via Aminoketyl Aminoketyl Radicals: Radicals: (A) (A) Reduction Reduction of of Alkyl Alkyl Scheme 2 /H 2 O/Et 3 N; (B) Reduction of Aromatic Amides with SmI 2 /H 2 O. Amides with SmI Amides with SmI2 /H2 O/Et3 N; (B) Reduction of Aromatic Amides with SmI2 /H2 O.

Another promising alternative was demonstrated by Procter and co-workers in the reduction of Another promising alternative was demonstrated by Procter and co-workers in the reduction of selenoamides using SmI2–H2O (Scheme 27A) [92]. They found that these precursors are selectively selenoamides using SmI2 –H2 O (Scheme 27A) [92]. They found that these precursors are selectively reduced to the corresponding amines under mild conditions. Moreover, an example of reductive reduced to the corresponding amines under mild conditions. Moreover, an example of reductive cyclization of the formed aminoketyl-type radical onto an unactivated π-acceptor was demonstrated cyclization of the formed aminoketyl-type radical onto an unactivated π-acceptor was demonstrated (Scheme 27B). The higher propensity of the selenoamide bond to reduction can be the basis for the (Scheme 27B). The higher propensity of the selenoamide bond to reduction can be the basis for the development of selective cyclization cascades in the synthesis of nitrogen heterocycles. development of selective cyclization cascades in the synthesis of nitrogen heterocycles. Furthermore, selective generation of nitrogen-centered radicals in the course of reduction of aryl Furthermore, selective generation of nitrogen-centered radicals in the course of reduction of sulfonamides via N–S scission (Scheme 28A) [93] and aminoketyl-type radicals during reductive aryl sulfonamides via N–S scission (Scheme 28A) [93] and aminoketyl-type radicals during reductive C–O cleavage of a carbamate protecting group (CBTFB, 3,5-bis(trifluoromethyl)benzyloxycarbonyl) C–O cleavage of a carbamate protecting group (CBTFB, 3,5-bis(trifluoromethyl)benzyloxycarbonyl) (Scheme 28B) [94] using SmI2–H2O–amine systems developed by Hilmersson should also be noted in this context. The first of these processes involves electron transfer to the sulfone aromatic ring, followed by fragmentation. Importantly, the reaction is fully selective for the reduction of aromatic

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(Scheme 28B) [94] using SmI2 –H2 O–amine systems developed by Hilmersson should also be noted in this context. The first of these processes involves electron transfer to the sulfone aromatic ring, followed Molecules 2017, Importantly, 22, 2018 17 of 22 by fragmentation. the reaction is fully selective for the reduction of aromatic sulfonamides Molecules 2017, 22, latter 2018 17 of 22 [95,96], (cf. aliphatic). The process involves C–O scission at the activated benzylic position sulfonamides (cf. aliphatic). The latter process involves C–O scission at the activated benzylic position followed by two additional electron transfer events, and is highly selective for CBTFB cleavage in [95,96], followed by two additional electroninvolves transferC–O events, andatisthe highly selective forposition CBTFB sulfonamides (cf. aliphatic). The latter process scission activated benzylic presence[95,96], of other groups, including t-Boc, Bn, and CBz. cleavage in electrophilic presence other electrophilic groups, including t-Boc, Bn, CBz.selective for CBTFB followed by of two additional electron transfer events, and is and highly cleavage in presence of other electrophilic groups, including t-Boc, Bn, and CBz.

Scheme 27. (A) SmI2-Promoted Reduction of Selenoamides; (B) Intramolecular Cycylization of

Scheme 27. (A) SmI2 -Promoted Reduction of Selenoamides; (B) Intramolecular Cycylization of Selenoamides via Aminyl-Type Radical with SmI /H2O. Scheme 27. (A) SmI2-Promoted Reduction of 2Selenoamides; (B) Intramolecular Cycylization of Selenoamides via Aminyl-Type Radical with SmI2 /H2 O. Selenoamides via Aminyl-Type Radical with SmI2/H2O.

A: A:

Me Me

SmI 2 (6 equiv) pyrrolidine equiv) SmI 2 (6(12 equiv) equiv) H2O (18(12 pyrrolidine equiv) H2O (18 equiv) THF, RT O S O (11THF, examples) RT O N S O R1 R2 (11 examples) N RAr, R1, R2 =Ralkyl, 1 2 Boc R1, R2 = alkyl, Ar, Boc

B: B: O R1 O N Ar O R1 N Ar R2 O R2 Ar = 3,5-(CF 3)2-C6H3 Ar = 3,5-(CF3)2-C6H3

SmI 2 (4 equiv) Et3N2 (8 SmI (4 equiv) equiv) equiv) H Et23ON(12 (8 equiv) H2O (12 equiv) THF, RT (5 THF, examples) RT (5 examples)

Me Me

O S O O N S O R2 R N 1 R2 R1

O R1 O N OH R1 N R2 OH R2

-TolSH -TolSH +e +e

H N R1 H R2 N R2 R1 93-96% yield 93-96% yield

+ 2e + 2e

H N R1 H R2 N R2 R1 82-99% yield 82-99% yield

Scheme 28. (A) Reductive Cleavage of Aryl Sulfonamides with SmI2/H2O/pyrrolidine; (B) Reductive 2O/Et Cleavage28. of (A) Carbamates with SmI2/Hof Scheme Reductive Cleavage Aryl3N. Sulfonamides with SmI2/H2O/pyrrolidine; (B) Reductive Scheme 28. (A) Reductive Cleavage of Aryl Sulfonamides with SmI2 /H2 O/pyrrolidine; (B) Reductive Cleavage of Carbamates with SmI2/H2O/Et3N.

Cleavage of Carbamates with SmI2 /H2 O/Et3 N. 7. Conclusions and Outlook

7. Conclusions and Outlook In conclusion, recently significant advances in the synthesis of nitrogen heterocycles using

7. Conclusions andiodide Outlook samarium(II) have been achieved.advances These reactions been enabled by the precise control of In conclusion, recently significant in thehave synthesis of nitrogen heterocycles using electron transfer events by theThese strong reductant SmI 2 in enabled combination thecontrol excellent samarium(II) iodide havemediated been achieved. reactions have been by thewith precise of

In conclusion, recently significant advances in the synthesis of nitrogen heterocycles using chemoselectivity of the mediated reductive by cyclization steps. High reducing potential ofwith SmI2the thatexcellent can be electron transfer events the strong reductant SmI2 in combination samarium(II) iodide been achieved. These reactions have been enabled by the precise rationally tunedhave by accessible ligands and additives, operational-simplicity of 2the processes chemoselectivity of readily the reductive cyclization steps. High reducing potential of SmI that can be control of electron transfer mediated by the strong SmIexquisite with the in excellent mediated by events SmI excellent functional group tolerance diastereoselectivity, 2 in combination rationally tuned by2,readily accessible ligands and reductant additives, and operational-simplicity of the processes particular in cascades,functional triggered by the coordinating ability of potential Sm(II)/(III) areSmI among the chemoselectivity ofcomplex the2, reductive cyclization steps. High and reducing of that can be mediated by SmI excellent group tolerance exquisite diastereoselectivity, in 2 major advantages of this reagent in the construction of nitrogen heterocycles. Importantly, as particular in complex cascades, triggered by the coordinating ability of Sm(II)/(III) are among the rationally tuned by readily accessible ligands and additives, operational-simplicity of the processes demonstrated in this the synthetic routes enabled SmI2 are often inaccessible by other major advantages of review, this reagent in the construction of by nitrogen heterocycles. Importantly, as mediated by SmI 2 , excellent functional group tolerance and exquisite diastereoselectivity, in particular methods, highlighting the practical importance of SmI 2 in organic synthesis. demonstrated in this review, the synthetic routes enabled by SmI 2 are often inaccessible by other in complex The cascades,recent triggered by theinclude coordinating ability of ofSm(II)/(III) are among the major developments selective generation aminoketyl radicals by direct methods, major highlighting the practical importance of SmI2 in organic synthesis. advantages of this reagent in the construction of nitrogen heterocycles. Importantly, asofdemonstrated in electron to the amide carbonyl group, efficient methods the synthesis complex The transfer major recent developments include selective generation of for aminoketyl radicals by direct this review, the synthetic routes enabled by SmI are often inaccessible by other methods, highlighting electron transfer to the amide carbonyl group, efficient methods for the synthesis of complex 2 the practical importance of SmI2 in organic synthesis.

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The major recent developments include selective generation of aminoketyl radicals by direct electron transfer to the amide carbonyl group, efficient methods for the synthesis of complex heterocycles using α-aminoalkyl radicals, and the synthesis of nitrogen-containing molecular architectures by direct and tethered pathways. In addition, applications to the synthesis of natural products have highlighted the generality of nitrogen heterocycles accessible with SmI2 . Despite the significant progress, future research will need to address: (1) the synthesis of nitrogen heterocycles using SmI2 still lacks the generality of the construction of carbocyclic and oxygenated motifs; (2) it remains to be seen if the developed methods can be translated into the target synthesis of valuable products; (3) recent studies in asymmetric SmI2 -mediated processes provide ample opportunities to apply this reactivity platform to the synthesis of nitrogen heterocycles, including by an indirect approach; (4) development of catalytic systems based on Sm(II) is indispensable to accelerate future research by reductive cross-coupling using lanthanides. Given the recent advances and the vital role of nitrogen heterocycles in organic synthesis and medicinal chemistry, we are convinced that SmI2 will serve as a valuable springboard for this area of research. Acknowledgments: Financial support of our program by Rutgers University is gratefully acknowledged. Author Contributions: The manuscript was written through the contributions of all authors. Conflicts of Interest: The authors declare no conflict of interest.

References 1. 2. 3. 4. 5. 6. 7. 8.

9.

10.

11. 12. 13.

Szostak, M.; Fazakerley, N.J.; Parmar, D.; Procter, D.J. Cross-Coupling Reactions Using Samarium(II) Iodide. Chem. Rev. 2014, 114, 5959–6039. [CrossRef] [PubMed] Szostak, M.; Procter, D.J. Beyond Samarium Diiodide: Vistas in Reductive Chemistry Mediated by Lanthanides(II). Angew. Chem. Int. Ed. 2012, 51, 9238–9256. [CrossRef] [PubMed] Steel, P.G. Recent developments in lanthanide mediated organic synthesis. J. Chem. Soc. Perkin Trans. 2001, 1, 2727–2751. [CrossRef] Molander, G.A.; Harris, C.R. Sequencing Reactions with Samarium(II) Iodide. Chem. Rev. 1996, 96, 307–338. [CrossRef] [PubMed] Curran, D.P.; Fevig, T.L.; Jasperse, C.P.; Totleben, J. New mechanistic insights into reductions of halides and radicals with samarium(II) iodide. Synlett 1992, 1992, 943–961. [CrossRef] Edmonds, D.J.; Johnston, D.; Procter, D.J. Samarium(II)-Iodide-Mediated Cyclizations in Natural Product Synthesis. Chem. Rev. 2004, 104, 3371–3404. [CrossRef] [PubMed] Nicolaou, K.C.; Ellery, S.P.; Chen, J.S. Samarium Diiodide Mediated Reactions in Total Synthesis. Angew. Chem. Int. Ed. 2009, 48, 7140–7165. [CrossRef] [PubMed] Austad, B.C.; Calkins, T.L.; Chase, C.E.; Fang, F.G.; Horstmann, T.E.; Hu, Y.; Lewis, B.M.; Niu, X.; Noland, T.A.; Orr, J.D.; et al. Commercial Manufacture of Halaven® : Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones. Synlett 2013, 24, 333–337. [CrossRef] Szostak, M.; Spain, M.; Procter, D.J. Determination of the Effective Redox Potentials of SmI2 , SmBr2 , SmCl2 , and their Complexes with Water by Reduction of Aromatic Hydrocarbons. Reduction of Anthracene and Stilbene by Samarium(II) Iodide-Water Complex. J. Org. Chem. 2014, 79, 2522–2537. [CrossRef] [PubMed] Szostak, M.; Spain, M.; Procter, D.J. Recent advances in the chemoselective reduction of functional groups mediated by samarium(II) iodide: A single electron transfer approach. Chem. Soc. Rev. 2013, 42, 9155–9183. [CrossRef] [PubMed] Dahlén, A.; Hilmersson, G. Samarium(II) Iodide Mediated Reductions—Influence of Various Additives. Eur. J. Inorg. Chem. 2004, 2004, 3393–3403. [CrossRef] Szostak, M.; Spain, M.; Parmar, D.; Procter, D.J. Selective reductive transformations using samarium diiodide-water. Chem. Commun. 2012, 48, 330–346. [CrossRef] [PubMed] Krief, A.; Laval, A.M. Coupling of Organic Halides with Carbonyl Compounds Promoted by SmI2 , the Kagan Reagent. Chem. Rev. 1999, 99, 745–778. [CrossRef] [PubMed]

Molecules 2017, 22, 2018

14.

15. 16.

17. 18. 19. 20. 21. 22.

23. 24. 25. 26.

27. 28. 29. 30.

31.

32.

33.

34.

35.

19 of 22

Szostak, M.; Spain, M.; Procter, D.J. Ketyl-Type Radicals from Cyclic and Acyclic Esters are Stabilized by SmI2 (H2 O)n : The Role of SmI2 (H2 O)n in Post-Electron Transfer Steps. J. Am. Chem. Soc. 2014, 136, 8459–8466. [CrossRef] [PubMed] Tsuruta, H.; Yamaguchi, K.; Imamoto, T. Evaluation of the relative Lewis acidities of lanthanoid(III) compounds by tandem mass spectrometry. Chem. Commun. 1999, 17, 1703–1704. [CrossRef] Szostak, M.; Spain, M.; Procter, D.J. Preparation of Samarium(II) Iodide: Quantitative Evaluation of the Effect of Water, Oxygen, and Peroxide Content, Preparative Methods, and the Activation of Samarium Metal. J. Org. Chem. 2012, 77, 3049–3059. [CrossRef] [PubMed] Helm, M.D.; Da Silva, M.; Sucunza, D.; Findley, T.J.K.; Procter, D.J. A dialdehyde cyclization cascade: An approach to pleuromutilin. Angew. Chem. Int. Ed. 2009, 48, 9315–9317. [CrossRef] [PubMed] Cha, J.Y.; Yeoman, J.T.S.; Reisman, S.E. A Concise Total Synthesis of (−)-Maoecrystal Z. J. Am. Chem. Soc. 2011, 133, 14964–14967. [CrossRef] [PubMed] Parmar, D.; Price, K.; Spain, M.; Matsubara, H.; Bradley, P.A.; Procter, D.J. Reductive Cyclization Cascades of Lactones Using SmI2 −H2 O. J. Am. Chem. Soc. 2011, 133, 2418–2420. [CrossRef] [PubMed] Parmar, D.; Matsubara, H.; Price, K.; Spain, M.; Procter, D.J. Lactone Radical Cyclizations and Cyclization Cascades Mediated by SmI2 –H2 O. J. Am. Chem. Soc. 2012, 134, 12751–12757. [CrossRef] [PubMed] Just-Baringo, X.; Procter, D.J. Sm(II)-Mediated Electron Transfer to Carboxylic Acid Derivatives: Development of Complexity-Generating Cascade. Acc. Chem. Res. 2015, 48, 1263–1275. [CrossRef] [PubMed] Yeoman, J.T.S.; Mak, V.W.; Reisman, S.E. A Unified Strategy to ent-Kauranoid Natural Products: Total Syntheses of (−)-Trichorabdal A and (−)-Longikaurin E. J. Am. Chem. Soc. 2013, 135, 11764–11767. [CrossRef] [PubMed] Kern, N.; Plesniak, M.P.; McDouall, J.W.W.; Procter, D.J. Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals. Nat. Chem. 2017, in press. [CrossRef] Joule, J.A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: Oxford, UK, 2010. Majumdar, K.C.; Chattopadhyay, S.K. Heterocycles in Natural Product Synthesis, 1st ed.; Wiley-VCH: Weinheim, Germany, 2011. Vitaku, E.; Smith, D.T.; Njardson, J.T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. [CrossRef] [PubMed] Taylor, R.D.; MacCoss, M.; Lawson, A.D.G. Rings in Drugs. J. Med. Chem. 2014, 57, 5845–5859. [CrossRef] [PubMed] Meng, G.; Shi, S.; Szostak, M. Cross-Coupling of Amides by N–C Bond Activation. Synlett 2016, 27, 2530–2540. [CrossRef] Liu, C.; Szostak, M. Twisted Amides: From Obscurity to Broadly Useful Transition-Metal-Catalyzed Reactions by N−C Amide Bond Activation. Chem. Eur. J. 2017, 23, 7157–7173. [CrossRef] [PubMed] Shi, S.; Szostak, M. Aminoketyl Radicals in Organic Synthesis: Stereoselective Cyclization of Five- and Six-Membered Cyclic Imides to 2-Azabicycles Using SmI2 –H2 O. Org. Lett. 2015, 17, 5144–5147. [CrossRef] [PubMed] Shi, S.; Lalancette, R.; Szostak, M. Cyclization of Imides to 2-Azabicycles via Aminoketyl Radicals by Using Samarium(II) Iodide-Water: Reaction Development, Synthetic Scope, and Mechanistic Studies. Synthesis 2016, 48, 1825–1854. [CrossRef] Shi, S.; Lalancette, R.; Szostak, R.; Szostak, M. Highly Chemoselective Synthesis of Indolizidine Lactams by SmI2 -Induced Umpolung of the Amide Bond via Aminoketyl Radicals: Efficient Entry to Alkaloid Scaffolds. Chem. Eur. J. 2016, 22, 11949–11953. [CrossRef] [PubMed] Szostak, M.; Spain, M.; Choquette, K.A.; Flowers, R.A., II; Procter, D.J. Substrate-Directable Electron Transfer Reactions. Dramatic Rate Enhancement in the Chemoselective Reduction of Cyclic Esters Using SmI2 –H2 O: Mechanism, Scope, and Synthetic Utility. J. Am. Chem. Soc. 2013, 135, 15702–15705. [CrossRef] [PubMed] Shi, S.; Szostak, R.; Szostak, M. Proton-coupled electron transfer in the reduction of carbonyls using SmI2 –H2 O: Implications for the reductive coupling of acyl-type ketyl radicals with SmI2 –H2 O. Org. Biomol. Chem. 2016, 14, 9151–9157. [CrossRef] [PubMed] Szostak, M.; Sautier, B.; Spain, M.; Behlendorf, M.; Procter, D.J. Selective Reduction of Barbituric Acids Using SmI2 /H2 O: Synthesis, Reactivity, and Structural Analysis of Tetrahedral Adduct. Angew. Chem. Int. Ed. 2013, 52, 12559–12563. [CrossRef] [PubMed]

Molecules 2017, 22, 2018

36. 37.

38.

39. 40.

41. 42.

43. 44. 45.

46. 47.

48.

49.

50.

51.

52. 53. 54.

55. 56.

20 of 22

Huang, H.M.; Procter, D.J. Radical–Radical Cyclization Cascades of Barbiturates Triggered by ElectronTransfer Reduction of Amide-Type Carbonyls. J. Am. Chem. Soc. 2016, 138, 7770–7775. [CrossRef] [PubMed] Huang, H.M.; Procter, D.J. Dearomatizing Radical Cyclizations and Cyclization Cascades Triggered by Electron-Transfer Reduction of Amide-Type Carbonyls. J. Am. Chem. Soc. 2017, 139, 1661–1667. [CrossRef] [PubMed] Huang, H.M.; Procter, D.J. Selective construction of quaternary stereocentres in radical cyclisation cascades triggered by electron-transfer reduction of amide-type carbonyls. Org. Biomol. Chem. 2017, 15, 4159–4164. [CrossRef] [PubMed] Huang, H.M.; Procter, D.J. Radical Heterocyclization and Heterocyclization Cascades Triggered by Electron Transfer to Amide-Type Carbonyl Compounds. Angew. Chem. Int. Ed. 2017. [CrossRef] Vacas, T.; Álvarez, E.; Chiara, J.L. Phthalimides as Exceptionally Efficient Single Electron Transfer Acceptors in Reductive Coupling Reactions Promoted by Samarium Diiodide. Org. Lett. 2007, 9, 5445–5448. [CrossRef] [PubMed] Ha, D.C.; Yun, C.S.; Yu, E. Reductive cyclization of N-iodoalkyl cyclic imides to nitrogen-fused polycyclic amides induced by samarium diiodide. Tetrahedron Lett. 1996, 37, 2577–2580. [CrossRef] Ha, D.C.; Yun, C.S.; Lee, Y. Samarium Diiodide-Promoted Cyclization of N-(ω-Iodoalkyl)imides to Polyhydroxylated Indolizidinones and Pyrrolizidinones: Synthesis of (+)-Lentiginosine. J. Org. Chem. 2000, 65, 621–623. [CrossRef] [PubMed] Burchak, O.N.; Py, S. Reductive cross-coupling reactions (RCCR) between CN and CO for β-amino alcohol synthesis. Tetrahedron 2009, 65, 7333–7356. [CrossRef] Masson, G.; Py, S.; Vallée, Y. Samarium Diiodide-Induced Reductive Cross-Coupling of Nitrones with Aldehydes and Ketones. Angew. Chem. Int. Ed. 2002, 41, 1772–1775. [CrossRef] Masson, G.; Cividino, P.; Py, S.; Vallée, Y. SmI2 -Induced Umpolung of the C=N Bond: First Reductive Conjugate Addition of Nitrones to α,β-Unsaturated Esters. Angew. Chem. Int. Ed. 2003, 42, 2265–2268. [CrossRef] [PubMed] Masson, G.; Zeghida, W.; Cividino, P.; Py, S.; Vallée, Y. A Concise Formal Synthesis of (S)-Vigabatrin Based on Nitrone Umpolung. Synlett 2003, 1527–1529. [CrossRef] Riber, D.; Skrydstrup, T. SmI2 -Promoted Radical Addition of Nitrones to α,β-Unsaturated Amides and Esters: Synthesis of γ-Amino Acids via a Nitrogen Equivalent to the Ketyl Radical. Org. Lett. 2003, 5, 229–231. [CrossRef] [PubMed] Johannesen, S.A.; Albu, S.; Hazell, R.G.; Skrydstrup, T. Radical addition of nitrones to acrylates mediated by SmI2 : Asymmetric synthesis of γ-amino acids employing carbohydrate-based chiral auxiliaries. Chem. Commun. 2004, 1962–1963. [CrossRef] [PubMed] Cividino, P.; Py, S.; Delair, P.; Greene, A.E. 1-(2,4,6-Triisopropylphenyl)ethylamine: A New Chiral Auxiliary for the Asymmetric Synthesis of γ-Amino Acid Derivatives. J. Org. Chem. 2007, 72, 485–493. [CrossRef] [PubMed] Xu, C.P.; Huang, P.Q.; Py, S. SmI2 -Mediated Coupling of Nitrones and tert-Butanesulfinyl Imines with Allenoates: Synthesis of β-Methylenyl-γ-lactams and Tetramic Acids. Org. Lett. 2012, 14, 2034–2037. [CrossRef] [PubMed] Desvergnes, S.; Desvergnes, V.; Martin, O.R.; Itoh, K.; Liu, H.W.; Py, S. Stereoselective synthesis of β-1-C-substituted 1,4-dideoxy-1,4-imino-D-galactitols and evaluation as UDP-galactopyranose mutase inhibitors. Bioorg. Med. Chem. 2007, 15, 6443–6449. [CrossRef] [PubMed] Desvergnes, S.; Py, S.; Vallée, Y. Total Synthesis of (+)-Hyacinthacine A2 Based on SmI2 -Induced Nitrone Umpolung. J. Org. Chem. 2005, 70, 1459–1462. [CrossRef] [PubMed] Gilles, P.; Py, S. SmI2 -Mediated Cross-Coupling of Nitrones with β-Silyl Acrylates: Synthesis of (+)-Australine. Org. Lett. 2012, 14, 1042–1045. [CrossRef] [PubMed] Ebran, J.P.; Hazell, R.G.; Skrydstrup, T. Samarium diiodide-induced intramolecular pinacol coupling of dinitrones: Synthesis of cyclic cis-vicinal diamines. Chem. Commun. 2005, 45, 5402–5404. [CrossRef] [PubMed] Volz, N.; Clayden, J. The Urea Renaissance. Angew. Chem. Int. Ed. 2011, 50, 12148–12155. [CrossRef] [PubMed] Robak, M.A.T.; Herbage, M.A.; Ellman, J.A. Synthesis and Applications of tert-Butanesulfinamide. Chem. Rev. 2010, 110, 3600–3740. [CrossRef] [PubMed]

Molecules 2017, 22, 2018

57.

58.

59.

60.

61. 62. 63.

64. 65. 66. 67. 68. 69.

70.

71.

72. 73. 74. 75. 76. 77.

21 of 22

Zhong, Y.W.; Dong, Y.Z.; Fang, K.; Izumi, K.; Xu, M.H.; Lin, G.Q. A Highly Efficient and Direct Approach for Synthesis of Enantiopure β-Amino Alcohols by Reductive Cross-Coupling of Chiral N-tert-Butanesulfinyl Imines with Aldehydes. J. Am. Chem. Soc. 2005, 127, 11956–11957. [CrossRef] [PubMed] Zhong, Y.W.; Izumi, K.; Xu, M.H.; Lin, G.Q. Highly Diastereoselective and Enantioselective Synthesis of Enantiopure C2 -Symmetrical Vicinal Diamines by Reductive Homocoupling of Chiral N-tert-Butanesulfinyl Imines. Org. Lett. 2004, 6, 4747–4750. [CrossRef] [PubMed] Wang, B.; Wang, Y.J. SmI2 -Promoted Intramolecular Asymmetric Pinacol-Type Ketone−tert-Butanesulfinyl Imine Reductive Coupling: Stereoselectivity and Mechanism. Org. Lett. 2009, 11, 3410–3413. [CrossRef] [PubMed] Liu, R.H.; Fang, K.; Wang, B.; Xu, M.H.; Lin, G.Q. Concise Asymmetric Synthesis of (+)-CP-99,994 and (+)-L-733,060 via Efficient Construction of Homochiral syn-1,2-Diamines and syn-1,2-Amino Alcohols. J. Org. Chem. 2008, 73, 3307–3310. [CrossRef] [PubMed] Maryanoff, B.E.; Zhang, H.C.; Cohen, J.H.; Turchi, I.J.; Maryanoff, C. Cyclizations of N-Acyliminium Ions. Chem. Rev. 2004, 104, 1431–1628. [CrossRef] [PubMed] Lin, G.J.; Zheng, X.; Huang, P.Q. A new method for the construction of the hydroxylated tropane skeleton: Enantioselective synthesis of (−)-Bao Gong Teng A. Chem Commun. 2011, 47, 1545–1547. [CrossRef] [PubMed] Liu, X.K.; Qiu, S.; Xiang, Y.G.; Ruan, Y.P.; Zheng, X.; Huang, P.Q. SmI2 -Mediated Radical Cross-Couplings of α-Hydroxylated Aza-hemiacetals and N,S-Acetals with α,β-Unsaturated Compounds: Asymmetric Synthesis of (+)-Hyacinthacine A2 , (−)-Uniflorine A, and (+)-7-epi-Casuarine. J. Org. Chem. 2011, 76, 4952–4963. [CrossRef] [PubMed] Schiedler, D.A.; Lu, Y.; Beaudry, C.M. Reductive Synthesis of Aminal Radicals for Carbon–Carbon Bond Formation. Org. Lett. 2014, 16, 1160–1163. [CrossRef] [PubMed] Schiedler, D.A.; Vellucci, J.K.; Lu, Y.; Beaudry, C.M. The development of carbon–carbon bond forming reactions of aminal radicals. Tetrahedron 2015, 71, 1448–1465. [CrossRef] Schiedler, D.A.; Vellucci, J.K.; Beaudry, C.M. Formation of Carbon–Carbon Bonds Using Aminal Radicals. Org. Lett. 2012, 14, 6092–6095. [CrossRef] [PubMed] Honda, T.; Ishikawa, F. Reductive deamination of α-amino carbonyl compounds by means of samarium iodide. Chem. Commun. 1999, 12, 1065–1066. [CrossRef] Honda, T.; Takahashi, R.; Namiki, H. Syntheses of (+)-Cytisine, (−)-Kuraramine, (−)-Isokuraramine, and (−)-Jussiaeiine A. J. Org. Chem. 2005, 70, 499–504. [CrossRef] [PubMed] Honda, T. Development of Samarium Diiodide-Promoted Reductive Carbon-Nitrogen Bond Cleavage Reaction of α-Amino Carbonyl Compounds: Application to the Synthesis of Biologically Active Alkaloids. Heterocycles 2011, 83, 1–46. [CrossRef] Pinho, V.D.; Procter, D.J.; Burtoloso, A.C.B. SmI2 -Mediated Couplings of α-Amino Acid Derivatives. Formal Synthesis of (−)-Pumiliotoxin 251D and (±)-Epiquinamide. Org. Lett. 2013, 15, 2434–2437. [CrossRef] [PubMed] Bernardim, B.; Pinho, V.D.; Burtoloso, A.C.D. α,β-Unsaturated Diazoketones as Platforms in the Asymmetric Synthesis of Hydroxylated Alkaloids. Total Synthesis of 1-Deoxy-8,8a-diepicastanospermine and 1,6-Dideoxyepicastanospermine and Formal Synthesis of Pumiliotoxin 251D. J. Org. Chem. 2012, 77, 9926–9931. [CrossRef] [PubMed] Burtoloso, A.C.D.; Dias, R.M.P.; Bernardim, B. α,β-Unsaturated Diazoketones as Useful Platforms in the Synthesis of Nitrogen Heterocycles. Acc. Chem. Res. 2015, 48, 921–934. [CrossRef] [PubMed] Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T. The first samarium(II)-mediated aryl radical cyclisation onto an aromatic ring. Chem. Commun. 2004, 2228–2229. [CrossRef] [PubMed] Panda, S.; Coffin, A.; Nguyen, Q.N.; Tantillo, D.J.; Ready, J.M. Synthesis and Utility of Dihydropyridine Boronic Esters. Angew. Chem. Int. Ed. 2016, 55, 2205–2209. [CrossRef] [PubMed] Kamabe, M.; Miyazaki, T.; Hashimoto, K.; Shirahama, H. Formal Synthesis of FPA, a Kainoid Amino Acid, via Ketyl Radical Cyclization. Heterocycles 2002, 56, 105–111. [CrossRef] Foster, S.L.; Handa, S.; Krafft, M.; Rowling, D. Samarium(II) iodide-mediated intramolecular pinacol coupling reactions with cyclopropyl ketones. Chem. Commun. 2007, 45, 4791–4793. [CrossRef] [PubMed] Schmalz, H.G.; Siegel, S.; Bats, J.W. Radical Additions to (η6 -Arene)(tricarbonyl)-chromium Complexes: Diastereoselective Synthesis of Hydrophenalene and Hydrobenzindene Derivatives by Samarium(II) Iodide Induced Cyclization. Angew. Chem. Int. Ed. 1995, 34, 2383–2385. [CrossRef]

Molecules 2017, 22, 2018

78. 79. 80.

81. 82.

83.

84.

85. 86. 87. 88.

89. 90.

91.

92. 93. 94. 95. 96.

22 of 22

Beemelmanns, C.; Reissig, H.U. Samarium diiodide induced ketyl-(het)arene cyclisations towards novel N-heterocycles. Chem. Soc. Rev. 2011, 40, 2199–2210. [CrossRef] [PubMed] Beemelmanns, C.; Reissig, H.U. A Short Formal Total Synthesis of Strychnine with a Samarium Diiodide Induced Cascade Reaction as the Key Step. Angew. Chem. Int. Ed. 2010, 49, 8021–8025. [CrossRef] [PubMed] Szostak, M.; Procter, D.J. Concise Syntheses of Strychnine and Englerin A: The Power of Reductive Cyclizations Triggered by Samarium Iodide. Angew. Chem. Int. Ed. 2011, 50, 7737–7739. [CrossRef] [PubMed] Beemelmanns, C.; Reissig, H.U. New samarium diiodide-induced cyclizations. Pure Appl. Chem. 2011, 83, 507–518. [CrossRef] Rao, N.C.; Lentz, D.; Reissig, H.U. Synthesis of Polycyclic Tertiary Carbinamines by Samarium Diiodide Mediated Cyclizations of Indolyl Sulfinyl Imines. Angew. Chem. Int. Ed. 2015, 54, 2750–2753. [CrossRef] [PubMed] Ready, J.M.; Reisman, S.E.; Hirata, M.; Weiss, M.M.; Tamaki, K.; Ovaska, T.V.; Wood, J.L. A Mild and Efficient Synthesis of Oxindoles: Progress towards the Synthesis of Welwitindolinone A Isonitrile. Angew. Chem. Int. Ed. 2004, 43, 1270–1272. [CrossRef] Reisman, S.E.; Ready, J.M.; Weiss, M.M.; Hasuoka, A.; Hirata, M.; Tamaki, K.; Ovaska, T.V.; Smith, C.J.; Wood, J.L. Evolution of a Synthetic Strategy: Total Synthesis of (±)-Welwitindolinone A Isonitrile. J. Am. Chem. Soc. 2008, 130, 2087–2100. [CrossRef] [PubMed] Ishida, T.; Tsukano, C.; Takemoto, Y. Synthesis of 2-Iminoindolines via Samarium Diiodide Mediated Reductive Cyclization of Carbodiimides. Chem. Lett. 2012, 41, 44–46. [CrossRef] Ishida, T.; Takemoto, Y. Synthetic study of perophoramidine: Construction of pentacyclic core structure via SmI2 -mediated reductive cyclization. Tetrahedron 2013, 69, 4517–4523. [CrossRef] Bai, W.J.; Jackson, S.K.; Pettus, T.R.R. Mild Construction of 3-Methyl Tetramic Acids Enabling a Formal Synthesis of Palau’imide. Org. Lett. 2012, 14, 3862–3865. [CrossRef] [PubMed] Szostak, M.; Spain, M.; Eberhart, A.J.; Procter, D.J. Highly Chemoselective Reduction of Amides (Primary, Secondary, Tertiary) to Alcohols using SmI2 /Amine/H2 O under Mild Conditions. J. Am. Chem. Soc. 2014, 136, 2268–2271. [CrossRef] [PubMed] Dahlén, A.; Hilmersson, G. Instantaneous SmI2 –H2 O-mediated reduction of dialkyl ketones induced by amines in THF. Tetrahedron Lett. 2002, 43, 7197–7200. [CrossRef] Dahlén, A.; Hilmersson, G. Mechanistic Study of the SmI2 /H2 O/Amine-Mediated Reduction of Alkyl Halides: Amine Base Strength (pKBH+ ) Dependent Rate. J. Am. Chem. Soc. 2005, 127, 8340–8347. [CrossRef] [PubMed] Huq, S.; Shi, S.; Diao, R.; Szostak, M. Mechanistic Study of SmI2 /H2 O and SmI2 /Amine/H2 O-Promoted Chemoselective Reduction of Aromatic Amides (Primary, Secondary, Tertiary) to Alcohols via Aminoketyl Radicals. J. Org. Chem. 2017, 82, 6528–6540. [CrossRef] [PubMed] Thurow, S.; Lenardao, E.J.; Just-Baringo, X.; Procter, D.J. Reduction of Selenoamides to Amines Using SmI2 –H2 O. Org. Lett. 2017, 19, 50–53. [CrossRef] [PubMed] Ankner, T.; Hilmersson, G. Instantaneous Deprotection of Tosylamides and Esters with SmI2 /Amine/Water. Org. Lett. 2009, 11, 503–506. [CrossRef] [PubMed] Ankner, T.; Stålsmeden, A.S.; Hilmersson, G. Selective cleavage of 3,5-bis-(trifluoromethyl)benzylcarbamate by SmI2 –Et3 N–H2 O. Chem. Commun. 2013, 49, 6867–6869. [CrossRef] [PubMed] Dahlén, A.; Hilmersson, G. Instantaneous SmI2 /H2 O/Amine-Mediated Reductions in THF. Chem. Eur. J. 2003, 9, 1123–1128. [CrossRef] [PubMed] Ankner, T.; Hilmersson, G. SmI2 /H2 O/amine promoted reductive cleavage of benzyl-heteroatom bonds: optimization and mechanism. Tetrahedron 2009, 65, 10856–10862. [CrossRef] © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).