Applications of Radical Carbonylation and Amine Addition Chemistry

Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Applications of Radical Carbonylation and Amine Addition Chemistry: 1,4-Hydrogen Transfer of 1‑Hydroxylallyl Radicals Published as part of the Accounts of Chemical Research special issue “Hydrogen Atom Transfer”. Hiroshi Matsubara,† Takuji Kawamoto,† Takahide Fukuyama,† and Ilhyong Ryu*,†,‡ †

Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan 300, ROC

Acc. Chem. Res. Downloaded from pubs.acs.org by EASTERN KENTUCKY UNIV on 08/24/18. For personal use only.

‡

CONSPECTUS: 1,4-Hydrogen transfer from the 1-hydroxyallyl radical to give the enoxyl (α-keto) radical is an exothermic process with a high activation energy based on DFT calculations. The lack of experimental examples of such 1,4-H shift reactions lies in the difficulty of generating the 1-hydroxyallyl radical. We have shown that radical carbonylation of alkenyl radicals with CO followed by nucleophilic trapping of the carbonyl portion of the resulting radical by amines gives rise to 1-amino-substituted 1-hydroxyallyl radicals in situ. At the outset of this chemistry, we examined intramolecular trapping reactions via radical carbonylation of alkynylamines mediated by tributyltin hydride. Consequently, α-methylene lactams were obtained, for which the initially formed 1-amino-substituted 1-hydroxyallyl radical underwent a 1,4-H shift followed by subsequent β-scission, which led to the expulsion of a tributyltin radical. A competing pathway of the 1,4H shift of 1-amino-substituted 1-hydroxyallyl radicals involving hydrogen abstraction was observed, which led to the formation of α-stannylmethylene lactams as a major byproduct. However, in contrast, when intermolecular trapping of α-ketenyl radicals by amines was carried out, the 1,4-H shift from the 1-amino-substituted 1-hydroxyallyl radical became the major pathway, which gave good yields of α,β-unsaturated amides. Thus, we were able to develop three-component reactions comprising terminal alkynes, CO, and amines that led to α,β-unsaturated amides via the 1,4-H shift reaction. DFT calculations support the observation that the 1,4-H shift is more facile when 1-hydroxyallyl radicals have both 1-amino and 3-tin substituents. The choice of substituents on the amine nitrogen is also important, since N−C bond cleavage via an SH2-type reaction can become a competing pathway. Such an unusual SH2-type reaction at the amine nitrogen is favored when the leaving alkyl radicals are stable, such as PhC(•)H(CH3) and t-Bu•. Interestingly, even nucleophilic attack of tertiary amines onto α-ketenyl radicals causes cleavage of the C−N bond. For this reaction, DFT calculations predict an indirect homolytic substitution mechanism involving expulsion of alkyl radicals through the zwitterionic radical intermediate arising from nucleophilic amine addition onto the α-ketenyl radical. In contrast, the carbonylation of aryl radicals, generated from aryl iodides, in the presence of amines gave aromatic carboxylic amides in good yields. It is proposed that radical anions originating from acyl radicals and amines undergo electron transfer to aryl iodides to give aminocarbonylation products. hydrogen from the α-position of ethers and thioethers (Scheme 1, eqs 3 and 4).8 Cassayre and Zard9 found that the 1,4-H shift reaction competed with 5-exo cyclization during their study of the total synthesis of (−)-dendrobine (Scheme 1, eq 5). Easton and Merrett10 reported that the 1,4-H shift proceeds diastereoselectively on the side chains of amino acid derivatives (Scheme 1, eq 6). In sterically demanding cyclic systems, 1,4-H shifts are more commonly observed. For example, Hart and Wu11 reported a 1,4-H shift reaction to give allylic radicals (Scheme 1, eq 7). Crich and co-workers reported that a 1,4-H shift reaction takes place to generate glycoside radicals (Scheme 1, eq 8).12 Malacria and co-workers reported the site-selective 1,4-H shift of a substituted vinyl radical in a

1. INTRODUCTION Hydrogen atom transfer (HAT) reactions are a popular class of organic radical reactions that have broad synthetic applications.1 By far the most popular intramolecular HAT reactions are 1,5-hydrogen (1,5-H) shifts, such as the Barton nitrite ester reaction,2 the Hoffman−Löffler−Freitag reaction,3 and vinyl radical abstraction of C(sp3)−H bonds.4 In contrast, 1,4-hydrogen (1,4-H) transfer reactions are seldom reported, as discussed in a recent review by Nechab, Mondol, and Bertrand.5 The 1,4-H shift reactions reported in the literature to date are given in Scheme 1. For example, Ingold and co-workers investigated the 1,4-H shift from 2,4,6-tri-tert-butylphenyl radical to give the 3,5-di-tert-butylneophyl radical (Scheme 1, eq 1).6 o-Phenyl-substituted phenyl radicals are known to undergo a reversible 1,4-H shift (Scheme 1, eq 2).7 It has also been reported that alkenyl radicals are able to abstract © XXXX American Chemical Society

Received: June 12, 2018

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DOI: 10.1021/acs.accounts.8b00278 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research Scheme 1. Known Examples of 1,4-H Shift Reactions

Scheme 2. General Scheme for the 1,4-H Transfer Reaction of 1-Hydroxyallyl Radical To Give Enoxyl (α-Keto) Radical

Scheme 4. Two-Step Strategy To Access 1-Hydroxyallyl Radicals by Sequential Radical Addition and Nucleophilic Addition

Scheme 3. DFT Calculations for the 1,4-H Shift Reaction of 1-Hydroxyallyl Radical A Leading to Enoxyl (α-Keto) Radical B

sterically rigid spirocyclic system (Scheme 1, eq 9).13 Although photogenerated biradicals often undergo 1,4-H shift reactions, we only mention here the Norrish type 1 reaction of cyclopentanone, in which the ring-opened biradical species undergoes a 1,4-H shift to give 4-pentenal (Scheme 1, eq 10).14 Given the scarcity of 1,4-H transfer reactions in the literature, we set about designing a system that would favor this transformation. In this regard, we considered that it may be possible to promote 1,4-H transfer of 1-hydroxyallyl radicals to give the corresponding enoxyl (α-keto) radicals (Scheme 2). 1,4-Hydrogen transfer from O to C gives the enoxyl radical, a B


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Accounts of Chemical Research

Scheme 8. Synthesis of α-Methylene Lactams by Tin Hydride-Mediated Radical Carbonylation of Alkynylamines and in Situ Protodestannylation

Scheme 5. Radical Cyclization Reactivity of Acyl Radicals onto Imine C−N Double Bonds

Scheme 6. Radical Cyclization Reactivity of Acyl Radicals onto Amine Nitrogens

that this may be due to the difficulty of generating 1-hydroxyallyl radicals. In contrast, the product radical, an α-keto radical, is readily accessible from α-heteroatom-substituted ketones via homolytic substitution (SH 2) reaction or one-electron oxidation of the ketone in its enol form.15 Density functional theory (DFT) calculations were carried out on the parent system of 1-hydroxyallyl radical (A) and 1-propenoxyl radical (B), and they predicted that the 1,4-H transfer reaction from A to B is highly exothermic (Scheme 3).16 For example, at the ROBHLYP/6-311G**//BHLYP/6-311G** level of theory, the energy barrier for the forward 1,4-H shift was calculated to be 144.5 kJ mol−1, while that of the reverse 1,4-H shift was calculated to be 178.5 kJ mol−1. These very high calculated activation energies suggested that the 1,4-H shift for the parent system would not proceed under standard reaction conditions. While the activation energies of the parent

canonical form of the α-keto radical. After a thorough survey of the literature, we realized that to the best of our knowledge this transformation had not previously been reported. We reasoned Scheme 7. Reaction of 5-Amino-1-Pentyne 4 with CO/Bu3SnH

C


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Scheme 9. Effects of NH2 and SnH3 Substituents on the Activation Energy for the 1,4-H Shift of 1-Hydroxyallyl Radical A

Scheme 10. Preferred Axial Alignment of the Stannyl Group in the Transition State for the 1,4-H Shift

system A and B were high, we reasoned that appropriate substitution may lead to a decrease in the energy barrier for the 1,4-H shift. Spin densities are also provided in Scheme 3. Substrate radical A has nearly equal spin densities located on C1 and C3, whereas for product radical B, most of the spin density is distributed onto the α-carbon of the carbonyl group. The spin density in the transition state was highly delocalized over the oxygen and all three carbon atoms, which may suggest a concerted 1,4-H shift mechanism. We postulated that consecutive radical/ionic reactions may provide 1-substituted 1-hydroxyallyl radicals on the basis of a

number of previous observations: (i) carbonylation of alkenyl radicals generates α,β-unsaturated acyl radicals as the first intermediates;17 (ii) computational studies predicted that α,β-unsaturated acyl radicals and α-ketenyl radicals are interconvertible;18 and (iii) a ketene carbonyl is attacked by nucleophiles. Cascade radical reactions involving α-ketenyl radicals have been well-documented.19 We previously reported the remarkable polar nature of radical cyclization reactions of α,βunsaturated acyl radical/α-ketenyl radical onto imine bonds, which proceed selectively at the nitrogen of the imine irrespective of the orientation of the double bond (N−C or C−N).20 D


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Accounts of Chemical Research Scheme 11. Influence of Ring Size on the 1,4-H Shift

Scheme 12. Products Obtained from Stannylcarbonylation of (Benzyl)(4-pentynyl)amine (9)

Scheme 13. Stannylcarbonylation of (α-Phenethyl)(β-phenethyl)(4-pentynyl)amine (14)

Therefore, we thought that the carbonyl group of an α-ketenyl radical would potentially react with nucleophiles such as

amines and that the α-ketenyl radical could serve as a precursor to a 1-amino-1-hydroxyallyl radical (Scheme 4). Consequently, E


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Alternatively, hydrogen abstraction from E by tributyltin radical and/or AIBN leads to the formation of tin-substituted unsaturated lactam 6.26 Through additional studies we found that subsequent treatment of the product mixture with TMSCl/MeOH converted α-stannylmethylene lactam 6 to α-methylene lactam 7 quantitatively. By the use of a combined protocol (radical carbonylation followed by protodestannylation), α-methylene lactams with five-, six-, seven-, and eight-membered rings were prepared in moderate to good yields (Scheme 8).21 If the starting aminoalkynes contained cyclic amine moieties, bicyclic and tricyclic lactams could be prepared. To investigate the influence of the amino and/or stannyl group on the 1,4-H shift, DFT calculations were carried out on 1-hydroxyallyl radical derivatives.16 As shown in Scheme 9, the energy barrier for the 1,4-H shift of nonsubstituted 3-hydroxyallyl radical A (X = Y = H) is predicted to be 144.5 kJ mol−1 at the ROBHLYP/6-311G**ECP(Sn)//BHLYP/6-311G**ECP(Sn) level of theory. Introducing a stannyl group into A (X = SnH3, Y = H) reduced the energy barrier by 20.9 kJ mol−1, whereas introducing an amino group into A (X = H, Y = NH2) reduced the energy barrier by 41.6 kJ mol−1. This means that the amino group stabilizes the transition state twice as much as the stannyl group does. Consequently, the energy barrier for the reaction of 1-hydroxyallyl radical A bearing both amino and stannyl groups (X = SnH3, Y = NH2) was estimated to be 84.6 kJ mol−1, some 59.9 kJ mol−1 lower than that of the parent 1-hydroxyallyl radical A. Accordingly, employing tributyltin hydride to mediate the radical carbonylation of aminoalkynes was crucial to discovering the 1,4-H shift of 1-hydroxyallyl radicals.

we found that the 1,4-H shift played a key role in the synthesis of lactams21 and unsaturated amides.22 In this Account, we describe the formation and subsequent trapping of carbonyl-containing radicals through sequential radical carbonylation and nucleophilic addition reactions of alkenyl and aryl radicals with CO and amines. When this reaction strategy was applied to alkenyl radicals, we were able to access unusual reactive species, 1-amino-1-hydroxyallyl radicals, and develop a synthesis of unsaturated lactams and amides by taking advantage of a 1,4-H shift reaction. Carbonylation of aryl radicals in the presence of amines provides a similar zwitterionic radical species, but in this case electron transfer was the favored reaction pathway, and aromatic carboxylic acid amides were obtained. We also discuss competing reaction pathways, such as homolytic substitution and hydrogen abstraction, to demonstrate the diversity of synthetic routes that are possible using combined radical/ionic systems. To support the experimental work, DFT studies are presented to provide a better understanding of the energetic requirements of the reactions.

2. INTRAMOLECULAR TRAPPING OF α-KETENYL RADICALS BY AN AMINO GROUP ACCOMPANYING A 1,4-H SHIFT First we focused on a system in which radical carbonylation of alkenyl radicals is sequenced with intramolecular trapping by an amine functionality. As mentioned in the Introduction, in our laboratory the intramolecular trapping of α-ketenyl radicals by an imino group was pursued in order to develop carbonylation methods for the synthesis of lactams.20 As shown in Scheme 5, complete N-philic cyclizations were observed in the tributylstannyl carbonylation of azaenyne 1, which gave lactam 2 in good yield.23 The selectivity is explained by the dual orbital effect,24 which is composed of the interaction between the acyl radical singly occupied molecular orbital (SOMO) and the imine π* MO and the interaction between the carbonyl π* MO and the imine bond.25 On the basis of this discovery, we envisioned that molecules 3 bearing both a terminal alkyne and an amine moiety would undergo a similar cyclization reaction because of the interaction between the acyl radical SOMO and the nitrogen lone pair (Scheme 6), which is in line with the scenario summarized in Scheme 4, leading to 1-amino-1hydroxyallyl radicals, and therefore, we expected that α-methylene lactam 4 would be formed via a 1,4-H shift followed by β-elimination.18 In accordance with our expectation, when amine-substituted terminal alkynes were exposed to tin hydride-mediated radical carbonylation reaction conditions, lactams were obtained. For example, the reaction of 4-pentynylpropylamine (5) with pressurized CO under standard Bu3SnH/AIBN conditions gave three types of six-membered-ring lactams (Scheme 7):21 α-stannylmethylene lactam 6 and α-methylene lactam 7 were formed as major products, and α-stannylmethyl lactam 8 was obtained as a minor product. From further studies we observed that the minor product 8 originated from 7 via hydrostannylation of the methylene moiety. Therefore, we focused on the mechanism of formation to give the two major products 6 and 7 in the reaction system. In the initial step, the α-ketenyl radical is trapped by the internal amino group to give 1-amino1-hydroxyallyl radical E bearing a tributyltin group; this intermediate is common to both products. A subsequent 1,4-H shift converts E to enoxyl (α-keto) radical F, which then undergoes β-scission of the carbon−tin bond to give α-methylene lactam 7.

Scheme 14. Stannylcarbonylation of Alkynylamines To Form Lactams by Radical Substitution

F


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Scheme 15. Reaction Profile for Cyclization of α-Ketenyl Radical onto the Amine Nitrogen Followed by Expulsion of α-Phenethyl Radical

in the reaction of alkynylamine 14 bearing both α- and β-phenethyl groups on the nitrogen atom (Scheme 13), β-fission of the intermediate radical zwitterion takes place selectively to give N-β-phenethyl lactam 15 as the sole product in 79% yield. As shown in Scheme 14, the α-phenethyl leaving group could be employed to synthesize five- to seven-membered-ring lactams, and the amine moiety could be either secondary or tertiary. Chiral alkynylamines could also be used as substrates for the synthesis of the corresponding chiral lactams. While SH2 reactions are frequently observed at group 14 and 16 elements, such as Si, Ge, Sn, S, Se, and Te,28 such reactions at nitrogen have scarcely been reported.29 DFT calculations suggest that an SH2-type reaction likely proceeds via the twostep mechanism shown in Scheme 15: (i) nucleophilic trapping of the α-ketenyl radical by an amine to give zwitterionic radical intermediate I and (ii) subsequent β-fission to eliminate α-phenethyl radical J. The calculated energy barriers for the two steps were similar at 34−38 kJ mol−1. While the first step would be considered reversible, the second step was predicted to be very exothermic, enabling the overall SH2-type cyclization to proceed smoothly. The bond angle (θ) of the carbonyl group in TS 1 is predicted to be 155.2°, indicating that the transition state would more closely resemble an α-ketenyl radical (θ = 180°) than an α,β-unsaturated acyl radical (θ = 120°).

In the transition state of the 1,4-H shift, the stannyl group can adopt either an axial or equatorial position. DFT calculations predicted that the activation energy for transition state G with an axial stannyl group (C−C−C−Sn dihedral angle = −78.9°) is 84.6 kJ mol−1 (Scheme 10), which is ∼20 kJ mol−1 lower than that with an equatorial stannyl group (C−C−C−Sn dihedral angle = 149.3°). The SOMO of the transition state with an axial stannyl group is depicted in the lower part of Scheme 10, which shows that delocalizing the SOMO of the C−Sn σ bond might act to stabilize the transition state. Next, we investigated the effect of ring size on the energy barrier for the 1,4-H shift. DFT calculations for the 1,4-H shift involving five- to eight-membered rings were carried out at the ROBHLYP/6-311G**ECP(Sn)//BHLYP/6-311G**ECP(Sn) level of theory as before. As shown in Scheme 11, the energy barrier for the forward 1,4-H shift (ΔE⧧1 ) was predicted to decrease as the ring size increased. These results are in line with the experimental results, where the yields of products with larger rings were higher.

3. COMPETING RADICAL C−N BOND CLEAVAGE The nitrogen-philicity of acyl radicals also led to unusual intramolecular SH2 reactions of the acyl radical at the nitrogen atom.27 For example, when we used (benzyl)(4-pentynyl)amine (9) as the substrate, we noticed that the products contained lactam 13 arising from loss of the benzyl group from the common intermediate H in addition to the expected lactams 10, 11, and 12 (Scheme 12). After screening a variety of nitrogen substituents, we found that α-phenethyl and tert-butyl substituents are excellent leaving groups to compete with the 1,4-H shift. For example,

4. INTERMOLECULAR TRAPPING OF α-KETENYL RADICALS BY AMINES ACCOMPANYING A 1,4-H SHIFT While free-radical-mediated intermolecular addition reactions onto unsaturated bonds are abundant, intermolecular additions of nucleophiles onto radical species are seldom reported. G


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Scheme 16. Synthesis of 2-Hexylacrylamide 18 by Intermolecular Trapping of the α-Ketenyl Radical and Subsequent 1,4-H Shift

To our delight, intermolecular trapping of α-ketenyl radicals by amines was successful, in which a 1,4-H shift from the 1-amino-1-hydroxyallyl radical occurred without the ring torsion. The reaction system was quite simple, comprising a terminal alkyne, CO, and an amine, to which typical radical reaction conditions (AIBN/Bu3SnH) were applied.22 Alternatively, palladium-catalyzed carbonylation of terminal alkynes with CO in the presence of amines provides a useful method to prepare α,β-unsaturated amides.30 However, these methods were often plagued by the formation of regioisomeric products originating from carbonylation at either carbon atom of the alkyne. Fortunately, the regioselectivity could be enhanced by the addition of a tributyltin radical onto the less hindered alkyne terminus. Indeed, when we examined the AIBN-initiated radical reaction of 1-octyne (16), CO, and tributyltin hydride (30 mol %) in the presence of a large excess of propylamine, N-propyl-2-hexylacrylamide (18) was obtained in 82% yield (Scheme 16).22 The formation of 18 was attributed to the 1,4-H shift from intermediate K, formed by intermolecular trapping of the α-ketenyl radical by propylamine, to afford enoxyl (α-keto) radical L, which then undergoes β-scission of the tributyltin radical. Under these reaction conditions, α-stannylmethylene amide 17 was formed as a minor byproduct. Combined with a subsequent protodestannylation procedure using TMSCl and MeOH, 16 was converted to α-methylene amide 18. The major reaction pathway leading to 18 is able to sustain the radical chain reaction by reforming the tin radical, while the reaction pathway leading to 17 breaks the radical chain reaction. The fact that a 20−30 mol % loading of tin hydride sufficed for complete reaction of the substrate indicates that the reaction pathway leading to 17 is slow. Scheme 17

Scheme 17. Radical/Ionic Hybrid Chain Mechanism

illustrates the combined radical/ionic chain mechanism leading to 17, in which both an ionic reaction and the 1,4-H shift participate effectively in the free radical chain and the tributyltin radical acts as a “catalyst”. We propose that the amine attacks preferentially at the carbonyl carbon of ketenyl radical H


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Scheme 18. Comparison of Reaction Profiles for the Expulsion of the Stannyl Radical To Afford (top) Acrylamide and (bottom) γ-Lactam

M to avoid the steric repulsion caused by the tributyltin group. This leads to the Z form of 1-hydroxyallyl radical N, which is ready to undergo the 1,4-H shift. DFT calculations were carried out on the destannylation step for both the acyclic and cyclic amides arising from the intermolecular and intramolecular trapping of α-ketenyl radicals, respectively (Scheme 18).16 The calculated energy barrier for the expulsion of the stannyl group to afford the acyclic acrylic amide is 67.5 kJ mol−1, which is ca. 5 kJ mol−1 smaller than that to give the six-membered-ring alkene lactam. This energetic difference is due to the smooth rotation inherent in the more flexible linear structure and ensures excellent catalytic activity of tributyltin radical in the synthesis of acyclic acrylic amides. A variety of primary and secondary amines could be used for the α-ketenyl radical trapping reaction leading to α-substituted acrylic amides (Scheme 19). Terminal alkynes with hydroxyl, chloro, phenylthio, acetoxy, and benzyloxy functionalities were tolerated in this reaction. In the case of a substrate containing both terminal and internal alkynyl groups, the reaction proceeded at the terminal alkyne selectively to provide the corresponding acrylic amide. It should be noted that in a similar concept where tin radical acts as a catalyst, we recently reported a [2 + 2 + 1] cycloaddition comprising terminal alkynes, CO, and amidines.31

Scheme 19. Synthesis of 2-Substituted Acrylic Amides from Alkynes, CO, and Amines

I


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Accounts of Chemical Research Scheme 20. Photoinduced Aminocarbonylation of Iodoarenes

“Radical”-catalyzed reactions are an innovative area, and the combination with modern free-radical technology would hold promise for future development.

Scheme 21. Electron-Transfer-Based Radical/Ionic Hybrid Chain Mechanism

5. INTERMOLECULAR TRAPPING OF α-AROMATIC ACYL RADICALS BY AMINES It has been well-established that aryl radicals add to CO to generate aromatic acyl radicals.32 Both alkenyl and aryl radicals are σ radicals, and the behaviors of these radicals are somewhat akin. However, the structure of the benzoyl radical was elucidated on the basis of electron spin resonance measurements and resembles benzaldehyde, retaining its aromaticity.33 While we have previously established metal-free carbonylation of alkyl iodides via radical carbonylation and iodine atom transfer,34 several groups recently reported metal-free carbonylation of aryl halides and related substrates, such as aryl diazonium salts, leading to esters35 and ketones.36 We also reported that aminocarbonylation of aryl iodides was achieved using CO and amines under photoirradiation conditions with a Xe lamp through quartz glass.37 For example, as shown in Scheme 20, when an acetonitrile solution of 4-acetyliodobenzene (19) and morpholine was reacted with CO under photoirradiation, amide 20 was obtained in 88% yield. Scheme 20 also summarizes some results for the aminocarbonylation of aromatic iodides, which demonstrates the broad applicability of the method. A radical chain mechanism involving electron transfer as a key step is proposed for the aminocarbonylation reaction, which is supported by DFT calculations (Scheme 21).38 An intramolecular version of the aminocarbonylation was carried out using aryl iodides bearing an amino group and gave good yields of benzolactams.39

acyl radicals, in a variety of cascade reactions. Acyl radicals are polar species exhibiting radical reactivity unique to the carbonyl functionality. In this Account, we have focused on the unique behaviors of α,β-unsaturated acyl radicals toward amines. Radical carbonylation of alkenyl radicals in the presence of amines generates 1-amino-1-hydroxyallyl radicals in situ, which undergo a 1,4-H shift to give enoxyl (α-keto) radicals. Subsequently we developed methods for β-scission to follow the 1,4-H shift, which led to the synthesis of unsaturated lactams and amides. In addition to the 1,4-H shift, the combined radical/ionic reaction system also led to some other unique reactions. Carbonylation and subsequent homolytic

6. CONCLUSION Radical carbonylation reactions have a broad range of applications in organic synthesis by engaging the first intermediates, J


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Accounts of Chemical Research substitution of acyl radicals at the amine nitrogen bearing a 2-phenethyl group gave lactams with liberation of an α-phenethyl radical. Carbonylation of aryl radicals in the presence of amines gave products by aminocarbonylation in which electron transfer is involved in the radical chain mechanism. DFT calculations predicted that all of these experimentally observed reaction courses are rational. In a general sense, ionic reactions with polar radical species provide access to hitherto-unknown reactive radical intermediates. However, there is always some difficulty to overcome because radical precursors bearing a polar moiety tend to be attacked by reagents for ionic reactions before polar radical species can be generated. In this regard, the ability to convert nonpolar radical species to polar radical species in situ is a general strategy for exploring new chemical species and novel reactions.

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awards, including the Progress Award in Synthetic Organic Chemistry, Japan (1990), the Chemical Society of Japan Award for Creative Work (2004), and the Society Award for Synthetic Organic Chemistry, Japan (2014). His research interests include new carbonylation methods, multicomponent reactions, and green synthetic approaches.

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ACKNOWLEDGMENTS We thank all of our co-workers for their experimental and intellectual contributions. We gratefully acknowledge financial support from MEXT, Japan and JSPS. I.R. thanks Dr. Sara Kyne for helpful suggestions and proofreading the manuscript.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Takuji Kawamoto: 0000-0002-1845-4700 Takahide Fukuyama: 0000-0002-3098-2987 Ilhyong Ryu: 0000-0001-7715-4727 Notes

The authors declare no competing financial interest. Biographies Hiroshi Matsubara received his Ph.D. in the field of organic chemistry in 1991 from Osaka University in Japan under the supervision of Professor Shigetoshi Takahashi. He was appointed as an assistant professor at Osaka Prefecture University in 1991 and promoted to lecturer in 2002, associate professor in 2005, and full professor in 2016. He was a visiting researcher at the University of Melbourne in the research group of Professor Carl H. Schiesser from 2002 to 2003. His research interests encompass computational investigations of radical processes and fluorous chemistry. Takuji Kawamoto obtained his Ph.D. in 2014 from Osaka Prefecture University under the supervision of Professor Ilhyong Ryu. He then studied as a postdoctoral fellow with Professor Dennis P. Curran at the University of Pittsburgh. He is currently working at Yamaguchi University as an assistant professor. His research interests include organoborane and organofluorine chemistry. Takahide Fukuyama received his Ph.D. in 1999 from Osaka University under the direction of Professor Shinji Murai. He spent 1999−2000 as a postdoctoral fellow of the JSPS at Okayama University of Science, working with Professor Junzo Otera. He was appointed as an assistant professor at Osaka Prefecture University in 2000 and was promoted to lecturer in 2007 and associate professor in 2010. He had the experience of working as visiting researcher at the University of Pierre and Marie Curie in 2006. His current research includes carbonylation chemistry, catalytic reactions of carboxylic acids, and flow chemistry. Ilhyong Ryu received his Ph.D. from Osaka University in Japan. After serving as JSPS postdoctoral fellow and research associate at Osaka University, he was appointed as an assistant professor at Osaka University in 1988 and promoted to associate professor in 1995. In 2000 he moved to Osaka Prefecture University as a full professor. Since 2016 he has also had a chair professorship at National Chiao Tung University in Taiwan. He has been the recipient of many K


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Applications of Radical Carbonylation and Amine Addition Chemistry

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