Radical Cascades Initiated by Intermolecular Radical Addition to

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Radical Cascades Initiated by Intermolecular Radical Addition to Alkynes and Related Triple Bond Systems Uta Wille* School of Chemistry and BIO21 Molecular Science and Biotechnology Institute, Australian Research Council Centre of Excellence for Free Radical Chemistry and Biotechnology, The University of Melbourne, 30 Flemington Road, Parkville, Victoria 3010, Australia frameworks in only few synthetic steps. The usually mild conditions of radical reactions are compatible with many functional groups so that time-consuming protection strategies can be minimized. In addition, because of the excellent stereo-1 and enantiocontrol2 in radical reactions, numerous highly stereoselective radical cascade processes have been developed over the recent years, which were also successfully used for the synthesis of natural products.3 The majority of radical cascades involve sequences of intramolecular steps where the overall propagation is a unimolecular process (with exclusion of the initiation and termination step), and recent overviews are given in refs 3−7. In addition to these, tandem radical procedures that involve a CONTENTS combination of intra- and intermolecular steps or are even multicomponent reactions have also been developed.5,6 1. Introduction A Cascade reactions that are initiated by intermolecular addition 2. Cascade Reactions Initiated by Addition of Main of both carbon- and heteroatom-centered radicals to π systems Group IV-Centered Radicals E have predominantly been explored with CC, CN, and 2.1. C-Centered Radicals E CO double bonds acting as radical acceptor.5,6 In contrast to 2.2. Si-Centered Radicals J this, the intermolecular radical addition to CC or CN 2.3. Ge-Centered Radicals K triple bonds has been much less commonly used to trigger 2.4. Sn-Centered Radicals K cascade processes. This discrepancy is surprising particularly in 3. Cascade Reactions Initiated by Addition of Main light of the fact that the alkyne functionality has actually been Group VI-Centered Radicals T widely used as radical acceptor in intramolecular cyclizations.8,9 3.1. O-Centered Radicals T The synthetic value of radical additions to alkynes through 3.1.1. Mechanistic Studies on Self-Terminating either inter- or intramolecular reactions is due to the highly Radical Cyclizations V reactive vinyl radicals formed by this step, which can be trapped 3.2. S-Centered Radicals Y by fast cyclization or addition onto other π systems.10 In 3.3. Se-Centered Radicals AE addition, vinyl radicals readily react through hydrogen 3.4. Te-Centered Radicals AF abstraction, and rate coefficients of >105 s −1 for the 4. Cascade Reactions Initiated by Addition of Main intramolecular 1,5-hydrogen atom transfer, 1,5-HAT,11 and of Group V-Centered Radicals AG ca. 106 M−1 s−1 for the intermolecular process have been 4.1. N-Centered Radicals AG 4.2. P-Centered Radicals AH determined.12 After reaction of the vinyl radical, one is left with 5. Conclusions AJ an alkene moiety, which can in turn act as a radical acceptor at a Author Information AK later stage in the cascade. This “round trip strategy”, where the Corresponding Author AK last radical cyclization occurs at the same carbon atom as the Notes AK initial radical generation, renders tandem processes involving Biography AK vinyl radicals synthetically extremely attractive. Acknowledgments AK Vinyl radicals can be generated not only through References AK intermolecular radical addition to alkynes but also through homolytic atom abstraction from suitably substituted alkenes, for example, through reaction of vinyl halides with tin hydrides 1. INTRODUCTION in the presence of a radical initiator.10 Of the various tin hydrides used in synthetic radical chemistry, tri-n-butyltin “Cascade” radical reactions, also known as “tandem” or hydride (n-Bu 3SnH) is the most common, which will for “domino” radical reactions, are characterized by the fact that convenience simply be written as Bu3SnH in this review. they proceed through two or more consecutive steps under involvement of both intra- and intermolecular reactions. Radical cascades are synthetically very attractive because they enable Received: October 26, 2010 access to highly complex and often polycyclic molecular © XXXX American Chemical Society

A

dx.doi.org/10.1021/cr100359d | Chem. Rev. XXXX, XXX, XXX−XXX

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Table 1. Absolute Rate Coefficients for the Addition of Carbon- and Heteroatom-Centered Radicals to Alkynes in Solution and in the Gas Phase ACCB radical •

CH2OH • CH2CO2t-Bu

t-Bu•

i-Pr• Me•

n-C4F9• •

O2HCC(Ph)Rpolymer HO•

NO3•

PhS•

A CO2H H H H H Ph Me CO2Et H H H H H H Me Me Me Ph Ph Ph CH2Cl Ph Ph CO2Me CO2Et CO2 tBu CO2SiMe3 CO2H H H H Ph H H H H H H H H Me Me H H H H H Me H H H H H H H

B C-Centered Radicals CO2H CO2Et CH2Cl SiMe3 t-Bu Ph CO2Me CO2Et CO2Me CO2Et CH2Cl SiMe3 t-Bu Ph SiMe3 Ph CO2Me SiMe3 Ph CN CH2Cl CO2Me CO2Et CO2Me CO2Et CO2t-Bu CO2SiMe3 CO2H H Me Ph Ph CMe2OH O-Centered Radicals Ph H Me Me Et n-Pr n-Bu Me Me H Me Et n-Pr n-Bu n-Pr S-Centered Radicals Ph Ph 4-MeOC6H4 4-MeC6H4 4-ClC6H4 3-NO2C6H4 n-Pr B

ka (M−1 s−1)

ref

1.0 × 107 5.1 × 104 2.4 × 104 2.2 × 104 1.2 × 104 1.1 × 104 5.0 × 103 5.6 × 105 1.8 × 105 2.0 × 105 4.0 × 103 2.4 × 103 2.2 × 102 2.1 × 104 4.0 × 101 4.3 × 102 5.2 × 102 6.0 × 102 1.0 × 103 2.0 × 105 2.0 × 103 5.0 × 104 4.2 × 104 5.7 × 105 5.4 × 105 2.7 × 105 2.3 × 105 1.1 × 106 5.3 × 103 2.4 × 103 4.9 × 104 1.5 × 103 106−107

12b 19c 19c 19c 19c 19d 19d 19d 19d 19d 19c 19c 19c 19c 19c 19c 19d 19c 19c 19c 19c 19d 19d 19d 19d 19d 19c 20b 17ae 17ae 17ae 17ae 21f

2.0 5.3 3.4 1.8 5.0 6.7 7.6 1.8 1.5 3.1 1.6 2.7 4.5 9.6 1.7

× × × × × × × × × × × × × × ×

101 108 109 109 109 109 109 1010 1010 107 108 108 108 108 107

22 23ag 23ag 23bh 23bh 23bh 23bh 23ag 23bh 24ai 24ai 24ai 24ai 24ai 24bh

1.6 7.9 3.5 2.2 1.2 1.0 1.4

× × × × × × ×

106 105 106 106 106 106 104

26aj 26bk 26aj 26aj 26aj 26aj 26bk


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Table 1. continued ACCB radical

4-MeOC6H4S•

4-MeC6H4S•

4-t-BuC6H4S•

4-ClC6H4S•

4-BrC6H4S•

MeSO2• Et3Si•

18 •

F

A H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H

B S-Centered Radicals CO2Me Ph Ph 4-MeOC6H4 4-MeC6H4 4-ClC6H4 3-NO2C6H4 n-Pr CO2Me Ph Ph 4-MeOC6H4 4-MeC6H4 4-ClC6H4 3-NO2C6H4 n-Pr CO2Me Ph Ph 4-MeOC6H4 4-MeC6H4 4-ClC6H4 3-NO2C6H4 n-Pr CO2Me Ph Ph 4-MeOC6H4 4-MeC6H4 4-ClC6H4 3-NO2C6H4 n-Pr CO2Me Ph Ph 4-MeOC6H4 4-MeC6H4 4-ClC6H4 3-NO2C6H4 n-Pr CO2Me COOH Si-Centered Radicals t-Bu Ph Other CF3

ka (M−1 s−1)

ref

× × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × ×

103 105 104 105 105 105 105 103 103 105 105 106 105 105 105 103 103 105 105 106 105 105 105 103 103 106 106 106 106 106 106 104 104 106 106 107 106 106 106 104 104 107

26bk 26aj 26bk 26aj 26aj 26aj 26aj 26bk 26bk 26aj 26bk 26aj 26aj 26aj 26aj 26bk 26bk 26aj 26bk 26aj 26aj 26aj 26aj 26bk 26bk 26aj 26bk 26aj 26aj 26aj 26aj 26bk 26bk 26aj 26bk 26aj 26aj 26aj 26aj 26bk 26bk 28l

2.3 × 106 1.0 × 108

29m 29m

3.6 × 1010

30n

8.3 1.3 8.1 2.1 1.5 1.2 1.0 1.3 1.1 5.4 3.7 1.5 7.5 5.0 3.5 5.3 3.4 6.8 3.4 1.6 9.0 6.5 4.0 6.4 3.8 2.6 1.1 6.5 3.8 2.0 1.4 2.0 1.5 3.8 2.1 1.0 5.4 2.8 1.8 2.1 1.6 5.9

a The unit for second order rate coefficients, cm3 molecule−1 s−1, for gas phase reactions was converted into M−1 s−1 for comparison. b300 K in water (pH 1−2). c300 K in isopropanol. d300 K in 1,2-epoxypropane. e300 K in 1,1,2-trifluoro-1,2,2-trichloroethane. fRoom temperature in dimethylformamide and 0.05 tetrabutylammonium fluoride. g297 K, gas phase, based on competitive reaction method. h298 K, gas phase. i295 K, gas phase. j296 K in cyclohexane. k296 K in benzene. l295 K in water. m300 K in triethylsilane-dibenzoylperoxide (1:1). n283 K, gas phase, based on competitive reaction method.

However, radical-induced halogen atom abstraction from alkenes, which has been used frequently in early work on vinyl radical cyclization cascades, requires separate synthesis of the corresponding vinyl halide precursors. Whereas this is usually not a problem in the case of simple vinyl radical

cyclizations, this may very well become a serious limitation for the development of highly complex cyclization cascades.5,8b,13 The lack of a more widespread use of intermolecular radical addition to alkynes to access vinyl radicals and trigger radical cascade processes could stem from the (at first sight perhaps C


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regeneration of S-radicals through fragmentation of the initially formed vinyl radicals in those cases where irreversible trapping of the latter through hydrogen abstraction from the solvent is slow (such as in benzene), thus resulting in an apparently slower decay rate of the S-radical.26a Absolute rate coefficients for the reaction with terminal aliphatic or strongly electrondeficient alkynes are so far only available in benzene. These reactions show also only little polar effects, but the rate coefficients are lower by ca. 1−2 orders of magnitude compared with the reaction with aromatic monosubstitued alkynes. In the case of S-radicals where sulfur is in a higher oxidation state, only the addition of methyl sulfonyl radicals, MeSO2•, to propiolic acid has been studied.28 The rate coefficient of 5.9 × 107 M−1 s−1 for this reversible addition is about 2 orders of magnitude smaller than for MeSO2• addition to acrolein,28 which shows that the radical addition is controlled by polar effects. Interestingly, radicals with the unpaired electron located on silicon do not react with alkynes at a signficantly slower rate than with the related alkenes. For example, the rate coefficient for addition of the triethylsilyl radical, Et3Si•, to styrene is 2.2 × 108 M−1 s−1, which is only 2 times faster than its reaction with phenylacetylene.29 Thus, in comparison to the analogue Ccentered radicals, Si-radicals are considerably more reactive toward alkynes. Although intermolecular reactions of alkynes with a number of other heteroatom-centered radicals, namely, Sn-, Ge-, P-, N-, and Se-radicals, have meanwhile found a more widespread application in synthetic organic chemistry, it is quite remarkable that so far no absolute rate coefficients have been determined for the initial radical addition step. The configuration of the vinyl radicals formed upon radical addition depends on the nature of the substituents in the alkyne precursor. Scheme 1 shows that reaction with a terminal alkyne

not highly appealing) fact that, despite a higher exothermicity, reactions of the most common radicals with alkynes are generally slower than with the corresponding alkenes.14,15 An explanation for this seemingly contradictory behavior has been given by Fischer and Radom et al.,16,17 who suggested that the smaller electron affinities and larger ionization energies in alkynes compared with alkenes result in diminished polar effects. A consequence of this is decreased selectivites and increased activation barriers for radical additions to alkynes. It was further proposed that the singlet−triplet gap is higher for alkynes than for alkenes and that this barrier-raising effect outweighs the barrier-lowering effect of the reaction exothermicity that accompanies radical additions to alkynes. In Table 1 are compiled the available experimental absolute rate coefficients for the intermolecular addition of carbon- and heteroatom-centered radicals to mono- and disubstituted alkynes.18 It is worth noting that the comparatively low number of known absolute rate data reflects the so far somewhat limited use of such radical addition reactions in organic synthesis. The addition of nucleophilic C-centered alkyl radicals to monosubstituted alkynes occurs usually faster than to disubstituted alkynes, which can be rationalized by the lower steric hindrance in terminal alkynes.12,17a,19−21 Exceptions include those internal alkynes where the second substituent is strongly electron-withdrawing and polar effects become more dominant than steric effects.19 In the case of O-centered radicals, it appears that rate coefficients for the addition to alkynes have, so far, nearly exclusively been determined for gasphase reactions involving inorganic radicals, usually at low pressure.22−24 As expected, the reactions with the highly reactive hydroxyl radical, HO•, are very fast, and rate coefficients increase with increasing alkyl substitution at the CC triple bond and approach the diffusion-controlled limit for reactions with internal alkynes. This finding correlates with the electrophilic character of HO• and a pathway involving radical addition rather than propargylic hydrogen abstraction.23 Due to the small size of HO•, steric effects are deemed to be of minor importance. The reactions involving the highly electrophilic O-centered nitrate radical, NO3•, are generally slower by 1−2 orders of magnitude compared with HO• reactions. The rate coefficients for NO3• addition to terminal alkynes show a slight increase with increasing length of the alkyl substituent but appear to decrease in reactions involving dialkyl alkynes.24 This is in contradiction with the expected increase of the rate in the latter reactions, which is in line with my own qualitative experimental observations of NO3• reactions with terminal and internal alkynes in solution. Thus, a higher electron density at the alkyne π system should accelerate NO3• addition, especially since steric effects should not be large.25 Further kinetic studies are clearly required to obtain full insight into the mechanism of these radical additions. In the case of sulfur-centered radicals absolute rate coefficients have nearly exclusively been obtained for the reaction of arylthiyl radicals with terminal alkynes.26,27 Addition to aromatic alkynes shows small polar effects, which is indicative for a comparably low electrophilicity of S-centered radicals. The rate coefficients, which were determined by monitoring the time-dependent consumption of the thiyl radicals using transient absorption spectroscopy, are approximately 1.5−2 times larger in cyclohexane than in benzene. The considerable solvent effect has been rationalized by the reversibility of S-radical addition to alkynes. This leads to

Scheme 1

leads to formation of Z and E configured σ-type vinyl radicals in those cases where the substituent G does not stabilize the unpaired electron through resonance. Resonance stabilization leads to a linearized geometry in the vinyl radical (π-radical). E/ Z isomerizations in σ-vinyl radicals are typically associated with very low activation barriers of only a few kilojoules per mole,1,31 and the geometry of the final product is determined by the relative population of the two isomeric radicals, the rate by which the individual vinyl radical isomers are trapped, and steric effects. For example, in the case of reduction through hydrogen abstraction (X = H) it was shown that transfer of the small hydrogen atom occurs preferably from the less hindered side D


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produce one-to-one adducts, for example, trichloromethylbromo alkenes, through first addition of trichloromethyl radicals, Cl3C•, to the CC triple bond, followed by trapping of the intermediate vinyl radical by bromine in a radical chain process. This concept was further developed by Heiba and Dessau in 1967, who described an unexpected radical cyclization cascade, which was initiated by intermolecular addition of C-centered radicals to alkynes (Scheme 2).35 Thus, reaction of 1-heptynes

(anti to R), even if the thermodynamically less stable product is formed. The E/Z selectivity can further be influenced by the reactivity of the hydrogen donor. Thus, in the case of radical addition to phenyl acetylene, reduction by highly reactive hydrogen donors leads to a poorer E/Z selectivity in the resulting alkene than reduction by a less reactive hydrogen donor. This finding was rationalized by the later transition state in the latter reaction, where steric interaction between hydrogen and the alkyne substituents in the π-type vinyl radical is more pronounced so that reduction of the radical occurs preferably from the less hindered side.32 When intermolecular radical addition to alkynes is used to initiate a cascade of intramolecular reactions (e.g., cyclizations or hydrogen transfer), the geometry at the newly formed CC double bond is primarily governed by steric and conformational constraints within the molecule, and in the case of σ-vinyl radicals, subsequent reactions are often possible only out of a single configuration. This review surveys radical cyclizations and multicomponent radical cascades in solution, which are initiated by intermolecular radical addition to CC triple bond in alkynes as well as to releated CN triple bonds in nitriles and isonitriles with special emphasis on work performed in the previous decade. This shall demonstrate the outstanding synthetic potential of this methodology, in particular in cascades involving alkyne substrates that possess multiple π systems. The reactions are arranged according to the atom that carries the unpaired electron in the attacking radical and will cover main group IV− VI elements. Because of the complexity of many radical cascades, most of the reaction schemes in this review include important mechanistic key steps. It should be noted that the purpose of this review is to showcase synthetically or mechanistically interesting reactions, and the reader is encouraged to consult the given references for additional information.

Scheme 2

1 with the solvent carbon tetrachloride in the presence of benzoylperoxide (BPO) leads to 1,1-dichlorovinyl cyclopentane derivatives 2, which were formed as byproduct besides the expected substituted alkenes that result as major products from direct radical addition to the alkyne (not shown). The reaction proceeds through addition of the initially formed Cl3C• to the terminal end of the CC triple bond in 1 to give vinyl radical 3, which undergoes a 1,5-HAT, followed by 5-exo cyclization to the CC double bond in alkenyl radical 4. The sequence is terminated by β-fragmentation of a C−Cl bond in the cyclic radical intermediate 5, which forms the stable alkene moiety in 2 with release of a chlorine atom, Cl•.36 As a highly reactive species, it is very likely that Cl• initiates independent radical chain processes, but these were not explored. The terminating fragmentation, which is obviously considerably faster than reduction of the radical intermediate 5 through chlorine atom transfer from tetrachloromethane, is mechanistically interesting, since the released Cl• is a substituent of the cascade-initiating radical Cl3C•. Or in other words, the attacking radical carries its own leaving group, which is released through homolytic bond scission that terminates the cyclization cascade. This reaction can be regarded as a historical first example of “self-terminating radical cyclizations”, a recently discovered new radical cyclization concept, which will be described in sections 3 and 4 of this review. A related βfragmentation with release of Cl• has been employed as termination step in the synthesis of polycyclic vinyl cyclopropanes, which is initiated through intramolecular radical addition to alkynes (not shown).37 Radical addition of fluorinated alkyl groups to terminal alkynes has recently been reported by Piettre et al., who used selanylated difluoromethyl phosphonates and difluoromethyl phosphonothioates as precursor for phosphono difluoromethyl and phosphonothio difluoromethyl radicals, respectively.38 However, this procedure has not yet been applied to radical cascades. Organoboron compounds, which were introduced in synthetic free radical processes in the early 1970s, have

2. CASCADE REACTIONS INITIATED BY ADDITION OF MAIN GROUP IV-CENTERED RADICALS In the series of the main group IV elements, carbon, silicon, germanium, and tin, cascade reactions initiated by intermolecular addition of C- and Sn-centered radicals to alkynes have received by far the most widespread attention, whereas reactions involving Si- and Ge-radicals have not been widely employed. The major difference between reactions of C- and Sn-centered radicals is caused by the fact that addition of Cradicals to π systems is usually irreversible so that cascade reactions initiated by C-radical addition to alkynes give products in which the attacking radical forms part of the molecular framework. In contrast to this, the C−Sn bond formed in analogue reactions with Sn-radicals is much weaker, and the Sn-radical addition to the alkyne is actually also reversible. This behavior can be used to advantage in cyclization cascades that employ Sn-radicals formally as catalyst, which are regenerated at the end of the sequence through homolytic fragmentation of a C−Sn bond. 2.1. C-Centered Radicals

A very early example for a radical addition to terminal and internal alkynes was reported by Kharasch et al. already in 1950.33 In this work, which is an extension of the legendary Kharasch reaction, by which alkenes can be halogenated in the presence of peroxides,34 bromotrichloromethane was reacted with alkynes under photochemical or thermal initiation to E


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determined).42 Oshima et al. used triethylborane to initiate a conjugate addition of tert-butyl iodide to enyne 16 to access 2,3,4-trisubstituted tetrahydrofurans 17 as mixture of E/Z isomers (Scheme 4b). The cascade proceeds via first regioselective addition of the nucleophilic t-butyl radicals, tBu•, to the sterically least hindered π system in 16, which is the alkyne terminus, followed by 5-exo cyclization of vinyl radical 18 and iodine abstraction by the cyclized radical intermediate 19.43 Related radical additions to alkynes involving transfer of seleno44 or tellurium45 groups have been reported in the literature, but these reactions have not yet found applications in cascade processes. In Scheme 5 is shown a radical-mediated [3 atom + 2 atom] strategy for the synthesis of variously substituted cyclopentenes

meanwhile become one of the most attractive alternatives to the toxic tin reagents in radical chain reactions.39 Scheme 3 Scheme 3

shows an early example where alkyl radicals, which were produced in the reaction of trialkylborane with oxygen, O2, undergo addition to the terminal α-epoxy alkyne 6 to give allenes 7 in good yield.40 In this sequence, the initially formed α-oxiranyl vinyl radical 8 undergoes epoxide ring-opening to the allenic alkoxyl radical intermediate 9. Trapping by trialkylborane in a chain-propagating step leads to boronate 10, which is the formal end product of the radical reaction. The experimentally observed allenic alcohol 7 is obtained through subsequent hydrolysis of 10. The intermolecular iodine atom transfer addition of alkyl iodides to alkynes has been used in a number of noncascade reactions to access vinyl iodides,41 as well as in radical cascade processes under radical-chain conditions. For example, Curran et al. described a procedure that involves a radical-mediated addition of alkyl iodides to alkynes at the final stage of the sequence (Scheme 4a). Cyclohexenyl-substituted alkyl radicals

Scheme 5

Scheme 4

of type 22.46 In this three-component sequence, the C-centered radical, which undergoes the actual intermolecular addition to an alkyne, is first generated by addition of arylthiyl radicals (usually phenylthiyl, PhS•, but arylselenyl radicals, ArSe•, can also be used) to cyclopropylalkene 20. The resulting cyclopropylmethyl radical 23 undergoes ring-opening to produce the homoallylic radical intermediate 24, which is subsequently trapped through intermolecular addition to terminal or internal alkynes 21. Vinyl radical 25 cyclizes in 5-exo fashion, followed by β-fragmentation and release of PhS•, which yields the two diastereomeric products cis-22 and trans-22 in satisfactory yields and with moderate diastereoselectivity, which could in some cases be improved through addition of a Lewis acid (e.g., trimethyl aluminum). The cis configured isomer is generally formed as the major product, which can be rationalized by a chairlike transition state of the 5-exo cyclization that leads to radical intermediate cis-26, in accordance with the Beckwith− Houk predictions,47 whereas formation of the minor product trans-22 proceeds through a boat-like transition state via intermediate trans-26. This PhS• catalyzed sequence leads, unlike “classical” radical chain reactions, which are most commonly terminated by reduction and therefore result in loss of overall functionality, to products where the net number of functional groups, in this case π systems, is the same as in the combined starting materials 20 and 21. Although oxidative electron transfer is a convenient methodology for the generation of free radical species under tin-free

13 generated from the corresponding iodide 11 using tin radicals (Bu3Sn•) as initiator undergo first a cis selective 5-exo cyclization to yield cyclohexyl-derived radicals 14, which are subsequently trapped from the sterically less congested convex side through intermolecular addition to the alkyne terminus of methyl propiolate. Reaction of the vinyl radical intermediate 15 with the starting material 11 in a chain-propagation step gives bicyclic vinyl iodide 12 as E/Z mixture (the E/Z ratio was not F


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reaction of the nearly linear π-vinyl radical 38a with carbon monoxide in such way that the sterically less hindered adduct is formed. When this reaction is performed in the absence of carbon monoxide and benzyl malonates 35b are used as radical precursors, cyclization to dihydronaphthalenes of type 41 occurs (Scheme 8).50 The initially formed vinyl radical 38b

conditions, so far only a few synthetic applications involving intermolecular radical addition to alkynes exist. Of the various one-electron oxidants, manganese(III) reagents have been most widely used for the generation of C-radicals. An interesting sequence is shown in Scheme 6, where a combination of radical Scheme 6

Scheme 8

attacks the aromatic ring to give radical intermediate 42, which is converted into the final product through a second oxidation step. The yield of this cyclization is very high with electron-rich terminal alkynes and diphenyl acetylene (since oxidation of such substrates is facilitiated), but only moderate in reactions involving electron-deficient terminal alkynes and dialkyl alkynes. In the case of the latter, reduction of the corresponding vinyl radical through propargylic hydrogen abstraction is the major pathway (not shown). Hartung et al. obtained functionalized tetrahydrofurans through aerobic oxidation of substituted 4-pentenols 43 catalyzed by cobalt(II) diketonate complexes in the presence of a terminal alkyne 44 and 1,4-cyclohexadiene (CHD) (Scheme 9).51 This stereoselective cyclization cascade involves

and in total four oxidation steps mediated by manganese triacetate is used to prepare 5-acetoxy furanones 28 from phenyl acetylenes 27.48 The complex mechanism of this cascade consists of first generation of the C-centered carboxymethyl radicals through oxidation of acetic acid, followed by their addition to the alkyne 27. The resulting vinyl radical 29 undergoes an oxidative cyclization to give the closed-shell enol ester 31, which is subsequently transformed into furanone 28 through two successive one-electron oxidation steps and capture of the intermediate allyl cation 33 by acetate. It should be noted that this sequence is not applicable to alkyl acetylenes. The reason for the failure is likely because vinyl radicals 29 derived from aryl acetylenes are of π-type (e.g., the unpaired electron is in a p orbital), whereas α-alkyl-substituted vinyl radicals are of σ-type with the unpaired electron being located in an sp2 orbital. α-Aryl-substituted vinyl radicals should be more easily oxidized since the ionization potential of the p orbital is lower than that of an sp2 orbital. A manganese(III)-induced coupling of alkynes, malonates, or cyanoesters and carbon monoxide (CO) that produces highly functionalized alkenes 36 has been reported by Alper et al. (Scheme 7).49 Diethylmalonate 35a is first oxidized to the

Scheme 9

Scheme 7

a radical cyclization prior to the actual intermolecular radical addition to the alkyne. Thus, activation of the benzylic hydroxyl group in 43 through cobalt(II) complexation, followed by 5-exo cyclization of 46 gives the C-centered tetrahydrofurfuryl radical 47. The latter is subsequently trapped by addition to the alkyne terminus in 44, and the resulting vinyl radical 48 is reduced by

corresponding C-radical 37, which is trapped through addition to phenyl acetylene (34). Reaction of the resulting vinyl radical 38a with carbon monoxide leads to acyl radical 39, which is subsequently oxidized to the acyl cation 40 by manganese(III) acetate, followed by reaction with water. The observed Z geometry at the CC double bond in alkene 36 results from G


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through hydrogen abstraction from dioxolane 60, which also acts as solvent in this reaction. Radical 62 undergoes exclusive addition to the β site of the CC triple bond in ketimine 59 to give vinyl radical 63, in which the unpaired electron is stabilized by the adjacent electron-withdrawing substituent. The subsequent reaction steps consist of a cis selective 6-exo cyclization to the imine CN double bond, followed by reduction of radical intermediate 64, which leads to the polycyclic compound 61 with good yield. Interestingly, when intermolecular addition of either S- or Sn-centered radicals is used to initate a similar cascade, a much lower selectivity is found, and products arising from initial radical addition to both α and β sites of the CC triple bond in 59 are obtained. The different outcome has been attributed to the reversibility of Sn- and Sradical additions to alkynes, which will be further discussed in sections 2.4 and 3.2, respectively. A radical cascade that involves intermolecular addition of ortho cyanoaryl radicals to terminal alkynes is shown in Scheme 12.56 Decomposition of the aryldiazonium salt 65 in pyridine

CHD to the alkene 49. A second cobalt(II)-mediated radical cyclization involving the remaining hydroxyl group in 49 leads to radical intermediate 51. Radical reduction yields bistetrahydrofuran 45 as diastereomerically pure product. Addition of α-hydroxyalkyl or α-alkoxylalkyl radicals to alkynes is a convenient method to synthesize allyl alcohols and ethers, and a number of intermolecular noncascade procedures have been reported.11,12,20,52 In recent years, N-hydroxyphthalimide (NHPI) has been increasingly used as redox catalyst in radical reactions under tin-free conditions. In Scheme 10 is Scheme 10

Scheme 12

shown an example for a solvent-free reaction, where the phthalimide N-oxyl radical (PINO) selectively abstracts the secondary hydrogen atom from isopropanol (53) to give the Ccentered α-hydroxy radical 56, which is subsequently trapped through addition to the electron-deficient acetylene 52. The resulting vinyl radical 57 is reduced by NHPI, which leads to a 1:1 E/Z mixture of alkene 54 with simultaneous regeneration of the oxidant PINO. E-54 undergoes cyclization to lactone 58, which is attacked by a further α-hydroxyalkyl radical 56. Oxidative cyclization leads to the observed bicyclic bislactone 55.53 While cobalt(II) promotes formation of PINO through involvement of a cobalt(III) complex, the role of the Lewis acid zinc chloride is to increase the rate of lactonization E-54 → 58. A related cyclization cascade, which is initiated by addition of α-hydroxyalkyl radicals to electron-deficient alkynes under photosensitized conditions, has been reported by Geraghty et al. (not shown).54 Scheme 11 gives an example for a highly regioselective intermolecular addition of α-alkoxyalkyl radicals to unsymmetrical bis-substituted alkynes.55 The 1,3-dioxolan-2-yl radical 62 is generated in the presence of a triplet photosensitizer

was used to generate aryl radical 68, which is trapped by addition to the alkyne terminus in 66 to give vinyl radical 69. 5exo Radical cyclization onto the cyano group leads to the Ncentered iminyl radical intermediate 70, which undergoes cyclization onto the phenyl ring in a subsequent step to yield the radical adduct 71. After final hydrogen abstraction, cyclopentaphenanthridine 67 is obtained. Although the yield is only moderate at best, the fact that nitrogen heterocycles with elaborate frameworks can be generated in one single step from readily available starting materials shows the potential synthetic value of this sequence. Azobisisobutyronitrile, AIBN, is possibly the most widely used radical initiator, which usually does not get involved as reactant in radical reactions itself. Montevecchio et al. found, however, that the C-centered 2-cyanoisopropyl radical, Me2C•CN, which results from AIBN decomposition, can indeed attack electron-poor alkynes. Unfortunately, this reaction yields a number of different products in very low yield and is therefore synthetically not useful.57 On the other hand, when Me2C•CN is trapped through addition to aromatic isonitriles, for example, biphenyl isonitrile 72, the intermediate imidoyl radicals (not shown) undergo a homolytic aromatic substitution (Scheme 13).58 Besides the desired phenanthridine derivative 73, which is formed as the major product, this reaction always yields also the unsubstituted phenanthridine 74 as byproduct. A related cascade that involves intermolecular addition of Cradicals to CN triple bonds in vinyl isonitriles can be used to access cyclopenta-fused pyridines 77 (Scheme 14a). C-radicals 78 derived from iodo alkynes of type 66 undergo addition to the carbon terminus of the isonitrile moiety in 75 to give imidoyl radical 79, which subsequently cyclizes in 5-exo fashion to the alkyne, followed by 6-endo cyclization of the resulting

Scheme 11

H


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followed by rearrangement via cleavage of the C−N bond in the spirocyclohexadienyl radical 89. The development of efficient methods for the activation of nonactivated C−H bonds is a major goal in synthetic organic chemistry. Geraghty et al. recently described a photochemical procedure that enables intermolecular addition of unactivated cycloalkanes to terminal electron-deficient alkynes, but this strategy has so far not been applied in radical cyclization cascades.62 An interesting intermolecular radical addition/fragmentation sequence that leads to rapid access of complex alkynes has been developed by Renaud et al.63 Although strictly speaking this reaction cannot be considered as a typical radical cascade, the high synthetic potential of this sequence warrants its presentation in the context of this review. Scheme 16 shows

Scheme 13

Scheme 14

Scheme 16

vinyl radical 80.59 Because of the shortness of the methylene bridge that separates the radical site from the alkyne moiety in 78, a competing intramolecular cyclization in 78 does not occur. When iodo nitriles are used as C-radical precursor (instead of 76), pyrazines are obtained through an analogue cyclization cascade (not shown). In a mechanistically similar reaction involving bromoalkyne 81 and phenyl isonitrile, Curran et al. prepared the tetracyclic compound 82 to access the A−D rings in (±)-camptothecin (Scheme 14b).60 2,4-Disubstituted quinolines can be synthesized in moderate to good yields through addition of aromatic imidoyl radicals to phenyl acetylene (34) (Scheme 15).61 Diisopropyl peroxyldi-

a representative example for this procedure, by which alkynes are added to the exocyclic CC double bond in alkene 90 in a one-pot process mediated by catecholborane (CatBH) in the presence of dimethyl acetamide as catalyst. The key step in this sequence consists of regioselective radical addition (the radical is produced through reaction of CatBH with the alkene) to an alkynyl sulfone, for example, phenyl phenyl ethynylsulfone in the example shown, to give the most stabilized vinyl radical intermediate. Subsequent β-fragmentation and elimination of phenylsulfonyl radicals installs the CC triple bond in alkyne 91. A radical-mediated group transfer coupling of carbonyl compounds 92, terminal alkynes 93, and trimethylsilyl phenyl telluride (TMSTePh) has been used to prepare silylated allylic alcohols 94 (Scheme 17).64 The reaction is initiated by addition of TMSTePh to the carbonyl group in 92 to give telluride 95. The weak C−Te bond can be thermally cleaved, and the resulting α-siloxy radical 96 is trapped by addition to the terminus in alkyne 93, followed by quenching of vinyl radical 97 with TMSTePh. The reaction is very general and proceeds with high E selectivity, since the group transfer occurs from the

Scheme 15

Scheme 17

carbonate (DPDC) was used to generate the imidoyl radicals 86 through H abstraction from N-arylidene aniline 83, which are trapped through addition to the alkyne terminus in 34. The resulting radical adduct 87 undergoes a homolytic aromatic substitution that leads ultimately to quinoline 84. Formation of the unexpected regiosiomeric major product 85 was suggested to proceed through a pathway involving ipso cyclization in 87, I


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be noted that the reaction conditions could be modified in such way that even water-insoluble substrates can be used. Pattenden et al. applied TTMSS as mediator to access angular triquinanes in good yield using a highly complex cascade consisting of radical cyclization/fragmentation/ring expansion as key steps (Scheme 19).68 Cyclobutyl oxime 101 is

least sterically hindered site in 97. From the synthetic point of view, it is interesting to note that product 94 is a masked vinyl radical (e.g., 97), which can be used in subsequent radical group transfer reactions (not shown). 2.2. Si-Centered Radicals

Compared with that of C-centered radicals, intermolecular addition of Si-radicals to alkynes has received considerably less attention. This difference is very likely due to the long existing lack of convenient methods to generate Si-centered radicals for synthetic purposes. Nowadays, Si-radicals are predominantly prepared in solution through hydrogen abstraction from organosilanes, of which tris(trimethylsilyl)silane ((SiMe3)3SiH) appears to be the most versatile precursor.65 A thorough study of the regio- and stereochemistry of the reaction of tris(trimethylsilyl)silyl radicals ((SiMe3)3Si•, TTMSS) with various terminal and internal alkynes has been perfomed by Chatgilialoglu, Giese, and co-workers.66 The increased emphasis during recent years to employ environmentally benign synthetic procedures put a strong focus toward the use of water as solvent. Apart from its low cost, water has also been found to increase the reactivity and selectivity of many organic reactions. Chatgilialoglu et al. devised a highly efficient method by which radical reactions involving TTMSS can be performed in water using a heterogeneous aqueous mixture of water-soluble starting material, for example, propiolic acid (98), (SiMe3)3SiH, the amphiphilic 2-mercaptoethanol as reducing thiol, and 1,1′azobis(cyclohexane carbonitrile) (ACCN) as initiator. Although this hydrosilylation has not yet been used in radical cyclization cascades, the mechanistic and stereochemical aspects of this sequence are interesting and will very likely find application in more complex tandem processes in the future (Scheme 18).67

Scheme 19

converted into bicyclo[4.3.0]nonene oxime 102 through the initially formed vinyl radical 103, which undergoes a cis selective 6-exo cyclization to produce bicyclic aminyl radical 104. Subsequently β-fragmentation gives the eight-membered monocyclic radical intermediate 105, which reacts through a cis selective transannular 5-exo cyclization to the alkene π system, followed by 3-exo cyclization onto the oxime CN double bond. The resulting tricyclic radical intermediate 107 undergoes opening of the cyclopropyl ring, which leads to ring expansion and formation of the bicyclic species 108, in which the unpaired electron is located at the bridgehead carbon. The cascade is terminated by homolytic fragmentation of the C−Si bond with elimination of TTMSS. Overall, this multistep sequence is a remarkable example for a reaction in which the initiating radical acts formally as a catalyst and does not appear in the final product. A double radical hydrosilylation of bisalkyne 109 using silylated cyclohexadienes 110 as metal-free transfer-hydrosilylating agents has been developed by Studer et al. (Scheme 20).69 Radical initiation leads to release of Si-radicals from aryl radicals 112, which are trapped by addition to the alkyne 109. Following 5-exo cyclization, vinyl radical 114 is reduced

Scheme 18

Scheme 20 Generation of the Si-radicals occurs in a two-step process through first hydrogen abstraction from the thiol by initiator radicals (R•) in the aqueous phase, followed by migration of the resulting S-radicals into the lipophilic dispersion of the silane, where a second hydrogen abstraction produces the desired Siradicals. Reaction of the latter with the alkyne 98 is believed to occur at the interface between the organic and aqueous phase to give vinyl radical 100, which is reduced to the Z-alkene 99 by the thiol in a chain-propagating step. It was speculated that the high Z selectivity of this radical addition is because a Z configured vinyl radical intermediate 100 occupies a smaller volume than the E isomer and may therefore be preferably formed in such heterogeneous reaction mixtures. It should also J


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“sluggish” and synthetically virtually useless into a highly powerful methodology in chemistry. Nowadays, because of the recognized toxicity of organotin compounds, the focus has shifted toward the development of alternative tin-free and environmentally less problematic radical chain processes. Regardless of this, organotin compounds are versatile reagents in their own right and are key compounds in various transition metal-promoted reactions (for example, Stille couplings),76 which can be readily accessed through radical hydrostannylation of alkenes and alkynes.72,77 Cyclization cascades initiated by intermolecular addition of Sn-radicals to alkynes can formally be distinguished between reactions where the tin moiety is retained in the final product and those where the Sn-radical essentially acts as a catalyst, which is eliminated in the final step through homolytic cleavage of the labile C−Sn bond. As mentioned previously, the weakness of the latter bond and the general reversibility of Snradical additions to alkynes is the origin for the major difference between Sn-radical reactions with π systems and the analogue reactions involving C-centered radicals. One of the earliest examples of a radical cascade initiated by intermolecular addition of Sn-radicals to alkynes was reported by Stork et al.,78 who studied the regioselectivity of vinyl radical cyclizations onto CC double bonds (not shown). Scheme 22

through reaction with 110 in a chain-propagating step. The resulting conjugated diene 115 acts as acceptor for Si-radicals in a subsequent reaction, which is terminated through reduction of the allyl radical 116 from the least hindered site. In Scheme 21 is shown the addition of Si-radicals to cyclopropyl-substituted alkynes 117, which has been studied to Scheme 21

explore the mechanism of the ring-opening rearrangement of cyclopropyl vinyl radicals in comparison to that of cyclopropyl alkyl radicals.70 In addition to the mechanistic aspect, this radical cascade has also a considerable synthetic value, since silylated allenes 118 are formed. The reaction proceeds via initial TTMSS addition to the alkyne terminus, which leads to α-cyclopropyl vinyl radical 119. Regioselective opening of the cyclopropyl ring leads to the stabilized benzylic radical intermediate 120, which is subsequently reduced to the final product 118. It should be noted that trapping of the α-cyclopropyl vinyl radical 119 could already occur prior to ring-opening under certain conditions. For example, addition of S-centered aryl sulfonyl radicals (ArSO2•) to the CC triple bond in unsubstituted 117 leads to the respective α-cyclopropyl vinyl radical, which is rapidly quenched before opening of the cyclopropyl ring occurs (not shown).71

Scheme 22

illustrates a radical cyclization sequence, which is triggered by regioselective addition of Sn-radicals to the terminus of the alkyne moiety in the glucofuranose derivative 121 and leads to the tricyclic product 122 with very good stereoselectivity.55b This sequence is mechanistically closely related to the cascade shown in Scheme 11 and can also be performed with aromatic S-centered radicals. A triethylborane-mediated hydrostannylation has been used to generate oxolanes 124 from the open-chain precursor 123 in a radical chain process (Scheme 23).79 The reaction proceeds through vinyl radical 125 resulting from Sn-radical addition to the less electron-rich alkyne π system, which undergoes a highly stereoselective 5-exo cyclization through a chair−equatorial transition state in accordance with the Beckwith−Houk rules.47 Following reduction of 126, substituted tetrahydrofurans 124

2.3. Ge-Centered Radicals

In general, the synthetic potential of Ge-centered radicals has barely been explored. It was shown, however, that hydrogermylation of alkynes using triphenyl germyl radicals, Ph3Ge•,72 or tris(trimethylsilyl)germyl radicals, (SiMe3)3Ge•,73 produces the corresponding alkenyl germanes, but this radical addition has not yet been used to initiate radical cyclization cascades. 2.4. Sn-Centered Radicals

In contrast to the patchy application of Si- and Ge-radicals in tandem sequences, cascade reactions that are initiated by addition of Sn-radicals to alkynes have been widely used. The research on Sn-radicals as reagents in synthesis was triggered by studies in the 1960s by Neumann et al.,74 which showed that hydrostannylation of alkenes and alkynes proceeds through a free radical mechanism and not through ionic processes (it is worth noting that the proposed radical pathway contradicted common belief at that time). The development of radical chain reactions, specifically the Giese reaction, which comprises the reductive addition of radicals to electron-poor alkenes, about 3 decades ago has shown that the nucleophilic Sn-radicals are highly versatile radical chain carriers.75 These discoveries have without any doubt played the most important role in the remarkable transformation of radical reactions from being

Scheme 23

K


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possessing (Z)-trans geometry are obtained, which can be oxidatively destannylated in a subsequent step to give αmethylene-γ-butyrolactones (not shown). The formation of a single geometrical isomer as product was rationalized by a more rapid cyclization of the E configured vinyl radical 125. The remarkable regioselectivity of the initial Sn-radical addition in enyne 123, which occurs with high preference at the alkyne moiety, results from several factors. It is believed that less steric hindrance at the CC triple bond80 in addition to polar effects, which cause the nucleophilic Sn-radical to react more rapidy with the less electron-rich alkyne, are mainly responsible for this selectivity. Further, although the Sn-radical addition to π systems is principally reversible, because of the high reactivity of the vinyl radicals, subsequent forward reactions are much faster than the reverse fragmentation into alkynes and Sn-radicals. In contrast to this, the lower reactivity of alkyl radicals, which are obtained from Sn-radical attack at the alkene moiety, renders fragmentation often the more favorable pathway. Functionalized vinyl stannanes can be prepared through homolytic allylstannylation of alkynes using a radical addition/ fragmentation process to generate the chain-carrying Snradicals. In Scheme 24 is shown an exemplary sequence

Scheme 25

Scheme 24 gives zwitterionic intermediate 138, which rearranges to hydroxyallyl radical 139. Subsequent 1,4-HAT followed by βelimination of Sn-radicals from intermediate 140 leads to αmethylene lactam 135. Formation of the α-stannylmethylene lactam 134 requires a chain-terminating formal oxidation of radical intermediate 139. The destannylated product 135 can also be exclusively obtained in 71% yield by treating the crude reaction mixture with an excess of trimethylsilyl chloride in methanol. The crucial step in the proposed mechanism is the radical translocation 139 → 140 through a 1,4-HAT, which is generally less common compared with a 1,5-HAT process. Density functional theory (DFT) calculations showed that the 1,4-HAT in 5−8-membered model lactams is associated with an activation barrier of about 71−106 kJ mol−1, which is feasible under the usual experimental conditions, especially since this process is also exothermic.83b An intermolecular variation of this sequence was applied to access α-methylene amides from terminal alkynes, carbon monoxide, and amines (not shown).84 The observed unusual regioselectivity of the cyclization shown in Scheme 25a, where nucleophilic acyl radicals seemingly attack the more electronegative atom of the imine CN double bond, was rationalized by polarity-matching, for example, the electronegative nitrogen of the amine attacks the electropositive carbonyl carbon atom in a nucleophilic reaction (this mechanism can be best rationalized from the α-ketenyl resonance form of 137). A detailed computational study of the orbital interactions in the transition state of these radical cyclizations confirmed that the major contribution is indeed the interaction of the lone pair at nitrogen with the LUMO of the CO π system, which is characteristic for a nucleophilic addition. In contrast to this, the contribution of the interaction between SOMO (radical) and HOMO (imine), which is the actual radical cyclization, to the total orbital interactions in the transition state are very small.85 Further DFT studies revealed that similar “multicomponent obital interactions” in the transition state should also control the inter- and intramolecular addition of Si-, Ge-, and Sn-radicals to carbonyl, imine, and

where reaction of initiator radicals with allylstannane 127 leads to the β-stannyl radical 129, which decomposes to release Bu3Sn•.81 Regioselective attack at the alkyne terminus in phenyl acetylene (34) yields vinyl radical 131, which reacts with 127 through radical addition/fragmentation via intermediate 132 to give exclusively the Z configured vinyl stannane 128. This sequence works well with both terminal and highly electrondeficient internal alkynes, whereas with disubstitued alkynes that carry an electron-withdrawing ester and either an alkyl or a phenyl substituent the initial Sn-radical addition occurs preferably at the carbon atom adjacent to the ester moiety (not shown). The Z configuration at the internal alkene in 128 results from steric interactions in the transition state of the vinyl radical addition to 127, which are smaller in the case of a Z configured 131 than for its E configured isomer. Ryu et al. developed a one-pot stannyl-carbonylation procedure of ω-alkynyl alcohols,82 ω-alkynylamines, and ωalkynylimines.83 In the sequence outlined in Scheme 25a, vinyl radicals 136, which are obtained from addition of Bu3Sn• to ωalkynyl amine 133, are trapped by carbon monoxide to give the α,β-unsaturated acyl radical intermediate 137, which can also be described as an α-ketenyl radical. Nucleophilic cyclization of the amine to the ketene carbonyl moiety (e.g., 6-exo attack via nitrogen, the mechanism for this step will be detailed below) L


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nitrile π systems. In these cases the unpaired electron is essentially acting only as “observer” of a nucleophilic reaction.85,86 These findings demonstrate that, against common belief, the unpaired electron is not necessarily always the most reactive site in free radicals. A related trapping of polar radical intermediates by nucleophiles has been used for the carbostannylation of azaenynes of type 141 (Scheme 25b).87a,b The resulting αstannylmethylene lactam 142 was obtained with Z configuration at the alkene, whereas the analogue radical cascade initiated by addition of Si- (e.g., TTMSS) or S-radical to 141 resulted in exclusive formation of the E configured alkene (not shown).87c Computational studies revealed that the E/Z selectivity is governed by the thermodynamic stability of the products so that the alkene with the lowest steric hindrance at the CC double bond is preferably formed. Ryu’s carbostannylation methodology has recently been extended to the synthesis of α,β-unsaturated lactams 144 using secondary ω-alkynyl amines 143 as precursor, which are equipped with a suitable radical leaving group at nitrogen (Scheme 25c).88 This sequence can be formally considered as intramolecular homolytic substitution (SHi) following initial Sn-radical addition to the alkyne, which is applicable to the synthesis of five- to seven-membered rings with good yields and generally good E/Z selectivity. A 6-exo cyclization, which follows the initial Sn-radical addition to the alkyne moiety in 145, is the key step in the synthesis of conformationally locked adenosine 146, which possesses a base−ribose bridge that could have interesting biological properties (Scheme 26).89 The reaction yields an E/

cis selective 5-exo cyclization of the vinyl radical 149, followed by reduction of the resulting cyclohexyl radical intermediate 150 and (nonradical) destannylation of alkene 151. The reaction shown in the previous scheme clearly outlines the power of radical cyclization strategies to access complex polycyclic frameworks in one single step with excellent stereocontrol. It is therefore not surprising that tandem cyclizations induced by Sn-radical addition to terminal alkynes have been successfully used as key steps in a number of natural product syntheses, and some examples are outlined in Scheme 28.91 In the total synthesis of the pentacyclic sesquiterpene Scheme 28

Scheme 26

Z mixture with a significant preference for the E isomer of the modified adenosine, which could be enhanced by longer reaction times and higher dilution of the starting material, thus suggesting that Z to E isomerization occurs through the course of the reaction. The tricyclic lactone 148, which features the bicyclo[3.2.1]octane substructure of the anti-inflammatory diterpene kaurenoic acid, has been synthesized in excellent yield through a procedure initiated by Sn-radical addition onto the alkyne terminus in enyne 147 (Scheme 27).90 The sequence involves a

(±)-merrilactone A by Frontier et al., the core tricyclic motif 153 was produced through regioselective 5-exo cyclization of the initially formed nucleophilic vinyl radical to the less electron-rich π system in the dihydrofuranone ring in dienyne 152 (Scheme 28a).92 Similar polar effects were also used by Kaliappan et al. to direct the 5-exo cyclization of the vinyl radical formed after addition of Sn-radicals to the alkyne moiety in 154. The resulting product 155 was subsequently transformed into the oxatetracyclic compound 156, which is a core structure of the antibiotic platensimycin (Scheme 28b).93 In order to access the structural isotwistane core motif 159 of the fungal metabolite CP-263114 (structure not shown), a 5-exo vinyl radical cyclization onto a carbonyl group was used by Wood et al. to transform the tricyclic enynone 157 into the tetracyclic species 158 (Scheme 28c).94 The tricyclic ring system in (−)-4a,5-dihydrostreptazolin was generated by Cossy et al. from a 3:2 diastereomeric mixture of the propargyl alcohols 160 using a cascade consisting of Sn-radical addition and cis selective 5-exo cyclization that leads to 161 (Scheme 28d).95 The heptacyclic framework of the hetisine-type aconite

Scheme 27

M


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Scheme 29

Scheme 30

to compete with the 5-exo cyclizations to 168 and 170, respectively. The outcome of the radical hydrostannylation of propargyloxy substrates of type 171 shows a remarkable dependence on the relative concentration of substrate and stannane (Scheme 30).98 Thus, when the reaction is performed with high concentrations of both triphenyl stannane and alkyne 171, the hydrostannylation product 173 is formed with high preference, which results from initial Ph3Sn• addition to the α-site of the CC triple bond, followed by reduction of vinyl radical 172. In contrast to this, when 171 is used as minor compound Sn-radical attack at the β-position is more favorable. Under these conditions, the cyclic product 175 is formed through a stereoselective 5-exo cyclization of the initial vinyl radical adduct 174 according to the Beckwith−Houk rules.47 The regiocontrol of this reaction is caused by several factors, in particular the moderately enhanced Lewis acidity and steric bulk of the stannane in combination with the reversibility of the initial Sn-radical addition to the alkyne. Thus, under usual hydrostannylation condititions (e.g., 1.5 equiv of Ph3SnH, 0.1 equiv of Et3B, and [alkyne] = 0.1 M), complexation of the stannane by the propargylic oxygen is significant, which renders Ph3SnH in the resulting complex 177 a more potent hydrogen atom donor than the uncoordinated stannane. The Ocoordinated Ph3Sn• attacks preferentially the α-carbon of the alkyne. On the other hand, at low stannane concentrations an

alkaloid (±)-nominine has been synthesized by Muratake and Natsume through a 6-endo vinyl radical cyclization following Sn-radical addition to the alkyne terminus in 162 (Scheme 28e).96 Apart from the desired major product 163, small amounts of a product that results from the competing 5-exo cyclization were also obtained (not shown). Sn-radical addition to terminal and internal alkyne moieties in chiral 1,3-cyclohexadienes 164 leads to vinyl radicals, which subsequently undergo cyclization to the arene ring in a regioand diastereoselective fashion (Scheme 29).97 In the case of disubstituted alkynes (164, R ≠ H), the reaction leads to cistetrahydroindenes 165 through a pathway involving intermediate formation of vinyl radical 167, followed by 5-exo cyclization to the unsubstituted end (C1) of the conjugated π system. In contrast to this, in the reaction of the terminal alkyne 164 (R = H), initial Sn-radical addition occurs exclusively at the alkyne terminus. In the subsequent 5-exo cyclization of vinyl radical 169, the conjugated π system is attacked at C4 to give the bicyclic allylic radical 170, which is reduced to the isomeric bicyclic alkenes 166a,b. The different reaction paths for terminal and internal alkynes were rationalized by steric effects, which govern the site of initial radical attack at the alkyne system. It should be noted that, although the addition of Snradicals to alkynes is in principle reversible, mechanistic studies revealed that fragmentation of the vinyl radicals 167 and 169 into the starting materials 164 and Bu3Sn• is not sufficiently fast N


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Scheme 31

undirected attack at the more electron-rich β-acetylenic carbon is slightly preferred. Kim et al. demonstrated that the outcome of Sn-radical mediated tandem processes can be significantly influenced by the radical transfer reagent itself.99 In Scheme 31a is shown that enyne 179 undergoes cyclization to the tetrahydrofuran 180 when Bu3SnH is used. On the other hand, in the presence of excess allytributyl stannane, which was first explored by Hosomi et al. in radical cyclization cascades,100 diastereoselective formation of the tetrahydropyran 181 occurs. Because of the strong hydrogen donating power of Bu3SnH, the benzylic radical intermediate 183 obtained through 5-exo cyclization of the initially formed vinyl radical 182 is rapidly reduced to 184. Allytributyl stannane, on the other hand, has a much lower reactivity as chain transfer reagent, and allylation of 183 cannot compete with rearrangement, which proceeds through a reversible 3-exo cyclization and leads to the bicyclic intermediate 185. This pathway ultimately produces the thermodynamically more favorable pyranyl radical 186, which is subsequently trapped through reaction with the allyl stannane. The synergistic potential offered by the different reactivity of Bu3SnH and allyltributyl stannane has been successfully applied to generate dihydronaphthalenes 190 from enynes of type 188 through two subsequent tandem radical cyclizations involving intermediately formed vinyl iodide 189 (Scheme 31b).101 Intramolecular homolytic allylstannylations in analogy to the processes shown in Scheme 31 have also been used to cyclize tributylstannyl substituted enynes (not shown).102 Hosomi et al. developed a carbometalation procedure, which uses trialkylstannyl enolates as radical transfer reagents (Scheme 32).103 In this sequence, enolate 191 reacts with terminal alkyne 192 in the presence of AIBN to give the carbostannylated product 193 with good yield. The mechanism likely involves generation of Sn-radicals through an initial SH2′ reaction of initiator radicals with enolate 191, followed by βfragmentation in 194. Addition to alkyne 192 gives vinyl radical 196, which reacts with enolate 191 to form the final product 193 with release of Bu3Sn• in a chain propagating process. The

Scheme 32

observed anti selectivity for the vinyl radical addition to the enolate can be rationalized by steric effects that lead to preferred attack from the side opposite to the bulky stannyl group. Three sequencial 5-exo cyclizations, which are initiated by addition of Sn-radicals to the terminus in dienynes of type 197, have been applied to construct highly strained oxa cage compounds, such as 198, with very good yield (Scheme 33).104 The course of the radical cyclization cascade is driven by the topology of the starting material and intermediates 199−202, which still operates, albeit with lower overall yield, when one 5exo cyclization step is replaced by a 4-exo cyclization (not shown). A similar approach can be used to prepare aza cages.104 Bicyclic oxygenated tetrahydrofurans can be synthesized through a cascade process initiated by Sn-radical addition to alkynyl-substituted cyclohexanones of type 203 (Scheme 34).105 The outcome of the photoinduced cyclization sequence depends strongly on the chain length of the substituent bearing the alkyne moiety. Thus, cyclization of 203a leads to an E/Z mixture of the anellated tetrahydofuran derivative 205 possessing a bridgehead hydroxy substituent, which is obtained O


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Scheme 33

Scheme 35

Alcaide et al. used a tin-promoted radical cyclization of allenynes 216 to produce bicyclic β-lactams 217 containing a seven-membered ring (Scheme 36).107 Cyclization of the Scheme 36

Scheme 34

through a cis selective 5-exo cyclization of the initially formed vinyl radical 206 (n = 1). The resulting alkoxyl radical 207 (n = 1) is subsequently quenched by reduction. In contrast to this, the reaction pathway of the less strained, larger homologue 203b involves β-fragmentation in 207, followed by cis selective 5-exo cyclization onto the CC double bond to give radical intermediate 209, which is subsequently reduced to bicyclo[5.3.0]oxadecanone 204. The finding that radical cyclization of 203a (with n = 1) does not follow a similar reaction pattern as the larger homologue 203b can be rationalized by the fact that in the case of the former the pathway 208 → 209 would require a kinetically unfavorable 4exo cyclization. Thus, when n = 1, the equilibrium between the bicyclic alkoxyl radical intermediate 207 and the monocyclic Ccentered radical 208 lies on the side of 207, which is removed from the reaction by reduction to the alcohol 205. Elongation of the alkynyl side chain by a further methylene unit, as in 210, enables a remarkably complex cyclization/ring expansion sequence, which leads to a fused bicyclic system containing an eight-membered ring (Scheme 35).105 The first steps in this thermally initated cascade are similar to those leading to radical intermediate 209 shown in Scheme 34. However, instead of reduction, 213 undergoes a 3-exo cyclization to the carbonyl group that leads to cyclopropyloxyl radical 214. Fragmentation of the three-membered ring results in ring expansion and formation of the bicyclo[6.3.0]undecane framework in 215. The final product 211 is obtained through βfragmentation and elimination of Sn-radicals. An analogous Ph3Sn•-induced rearrangement of cyclopentanones to hydroazulenones has been applied in the formal synthesis of damsinic acid.106

initially formed vinyl radical 218 proceeds regioselectively in a 7-exo fashion to the central carbon of the allenic motif to give the energetically favorable allylic radical intermediate 219, which is reduced to the final product in a subsequent step. The alternative cyclization pathways for 218 via either an 8-endo or 6-exo process are both energetically not feasible, since they would lead to highly reactive vinyl radicals. The excellent Z selectivity of this reaction is likely due to steric hindrance between the vinyl radical moiety and the allene π system in the transition state of the 7-exo radical cyclization, which is smaller when the tin substituent assumes a pseudoaxial position. A stereoselective synthetic procedure to polysubstituted oxepanes through a tin-mediated 7-endo vinyl radical cyclization has been developed by Shanmugam and Rajasingh.108 Functionalized fused ethers with ring sizes of up to eight can be accessed through Sn-radical promoted 5-, 6-, 7-, and 8-exo cyclizations of β-(alkynyloxy) acrylates derived from carbohydrates.109 A radical cyclization across bis-vinyl ethers, which is initated by addition of Sn-radicals to an alkyne moiety, is shown in Scheme 37.110 Using the dienyne 220 as substrate under high dilution conditions, the initially formed vinyl radical 222 undergoes a selective 6-endo cyclization to give the tertiary radical intermediate 223. A subsequent 5-exo cyclization yields 224 and establishes the bicylic framework found in the final product 221, which contains two adjacent quaternary centers. The cyclization cascade proceeds with moderate to good cis stereoselectivity through a chairlike transition state according to the Beckwith−Houk rules,47 but it should be noted that with increasing size of the substituents, in particular R1 and R2, the second cyclization becomes less preferable and reduction of the P


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mention whether initial radical addition occurred also at the αsite of the alkyne moiety in 225. Bachi et al. used Sn-radicals as mediator for the cyclization of β-lactam substituted alkynes 231 through a sequence, that involves first Sn-radical addition to the alkyne to give vinyl radical 234, which is followed by 1,5-HAT. The resulting radical intermediate 235 undergoes a 6-endo cyclization, and subsequent β-fragmentation in 236 yields the bicyclic β-lactam 232 with elimination of Bu3Sn• (Scheme 38b).112 Products arising from a competing 5-exo cyclization in 235 were not found. The moderate yield of this cyclization cascade is due to the fast direct reduction of vinyl radical 234 by Bu3SnH, which leads to alkene 233 as the major product. A tin promoted 6endo radical cyclization has also been used as a key step in the construction of constrained tricyclic tropane analogues (not shown).113 Regioselective 6-endo radical cyclizations are initiated by Snradical addition to the alkyne terminus in enynes of type 237, which leads to formation the epimeric carbahexopyranoses 238a,b as E/Z mixtures (Scheme 39).114 The remarkably high

Scheme 37

Scheme 39 monocyclic radical intermediate 223 occurs as a major pathway (not shown). The ease by which C−Sn bonds undergo homolytic fragmentation under certain conditions is an interesting feature of cyclization cascades that are initiated by Sn-radical addition to alkynes. The reactions outlined in Schemes 32 and 35 demonstrate how Sn-radicals formally catalyze the rearrangement of the molecular framework without appearing as substituents in the final product, and this concept has been used in a number of cyclization cascades. For example, Baldwin et al. reported that in the presence of Sn-radicals 5cyclodecynone (225) undergoes rearrangement into the bicyclic α,β-unsaturated ketone 226 (Scheme 38a; no yield

diastereoselectivity of the radical reduction leading to 238 is due to the strain imposed by the two acetal rings in the radical intermediate 240, which cannot be achieved when noncyclic acetals are used as substrates. Carbohydrate-derived dienynes are used as substrates in a formal free-radical promoted [2 + 2 + 2] cycloaddition, which has been reported by Marco-Contelles (Scheme 40).115 The reaction is initiated by regioselective Ph3Sn• addition to the alkyne terminus in 241. The resulting vinyl radical 245 undergoes a 5-exo cyclization to give the bicyclic intermediate 246, which is directly reduced to form 242 as the major product. Through a minor pathway 246 reacts in a second 5exo cyclization, which leads to a diastereomeric mixture of the primary radical intermediate 247 possessing either R or S configuration at the chiral center α to the radical site. The R configured isomer selectively undergoes a 5-exo cyclization that ultimately leads to the tetracyclic product 243 after reduction. In contrast to this, the S configured isomer reacts through 6endo cyclization exclusively to give 248, which is followed by βfragmentation and elimination of Ph3Sn•. The high regioselectivity of the reactions of both diasteromers 247 is likely due to the particular steric and stereoelectronic constraints caused by the rigid backbone. Analogous reaction conditions were used to access spirocyclic polyhydroxylated compounds using alkynyl-substituted furanose derivatives as substrate.116 A double radical cyclization/β-fragmentation cascade, which is triggered by Sn-radical addition to the alkyne moiety in acyclic ω-yne vinyl sulfides 249a,b is shown in Scheme 41.117 The initially formed nucleophilic vinyl radicals 251a,b undergo

Scheme 38

was reported).111 The proposed mechanism consists of initial formation of vinyl radical 227 through addition of Sn-radicals to the β-carbon of the CC triple bond, followed by 5-exo cyclization to the carbonyl group. The resulting allyloxyl radical 228 undergoes β-cleavage to give intermediate 229, which subsequently cyclizes in 5-exo fashion to produce vinyloxyl radical 230. The cascade is terminated through β-fragmentation and release of Sn-radicals. The authors of this work did not Q


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Scheme 40

Scheme 41

Scheme 42

a 5- or 6-exo cyclization, respectively, to the CC double bond, which is activated by one electron-withdrawing group (the reaction does not occur when the alkene moiety in 249 carries two electron-withdrawing substituents). β-Fragmentation in 252 leads to an electrophilic thiyl radical intermediate, which in the case of 253a cyclizes in a highly unusual 5-endo fashion (6-endo for the larger homologue 253b) to the more electron-rich, tin-substituted alkene π system to give allylic radical 254a,b. Subsequent β-scission and elimination of Snradicals yields the S-heterocyclic conjugated diene 250a,b in good yield. As can be seen from the previous schemes, the majority of tin-mediated vinyl radical cyclizations were performed with enynes or dienynes, respectively, but a number of radical tandem procedures have also been reported that use substrates equipped with more than one CC or CN triple bond. Lee et al. developed a general tin-mediated cascade radical process to access complex polycyclic molecular scaffolds from cyclic enones and enynes in a single operation.118a,b Scheme 42 shows a representative example of this approach, where the enediyne 255 is cyclized to give the tricyclo[4.3.2.01,5]undecane framework in 256 for the total synthesis of (±)-suberosenone.118b

The mechanism includes formation of vinyl radical 257 through Bu3Sn• addition to the terminal alkyne moiety in the higher substituted side chain, followed by 6-endo cyclization to radical intermediate 258, in which the unpaired electron is stabilized by the adjacent oxygen substituent (in fact, this radical stabilization is believed to be the driving force for the unusual endo selectivity of the cyclization). A subsequent 5-exo cyclization establishes the tricyclic framework. The resulting vinyl radical intermediate 259 is subsequently transformed into the desired product 256 through sequential radical reduction, followed by removal of the trimethylsilyl and tin moieties in 260 using standard deprotection and destannylation methods. When the Sn-radical initiated cyclization cascade is performed with dienynes that are similar to 255, except that the enolate moiety in the cyclopentyl ring is replaced by an exomethylene group, [3.3.3]propellanes can be obtained in one operation.119a This sequence has been used as the key step in the total synthesis of (−)-13-acetoxy modhephene and (+)-14acetoxy modhephene (not shown).119b R


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Scheme 43

Scheme 44

Rainier et al. employed a free radical cyclization of ortho alkynyl arylisonitriles 261 to access substituted indoles 262 and quinolines 263 (Scheme 43).120 The initial radical attack is controlled by electronic effects, which direct addition of the nucleophilic Sn-radicals regioselectively to the less electron-rich isonitrile π system. The resulting vinyl radical 264 cyclizes onto the bis-substituted alkyne moiety in either 5-exo or 6-endo fashion. The regiochemistry of the cyclization is governed by steric effects, which direct the reaction along the 5-exo pathway when R is large. The products of the actual radical cyclization cascade are the tin-containing compounds 266 and 268, respectively, which are converted into the final products during acidic workup.120b Alabugin et al. explored radical cascade processes in aryl enediynes 269 by which fulvenes and indenes 270 can be accessed (Scheme 44a).121a The initial Sn-radical addition occurs nonregioselectively at the internal CC triple bond in 269 to give the isomeric vinyl radicals 271 and 272. However, a radical cyclization in 271, which would proceed through either

a 4-exo or 5-endo pathway is kinetically not feasible. Because of the reversibility of Sn-radical additions to alkynes, 271 and 272 establish a thermal equilibrium with the starting material from which vinyl radical 272 is removed by undergoing a 5-exo cyclization. The final product 270 is obtained by reduction of the resulting radical intermediate 273. When this reaction is performed with Bu3SnD, selectively deuterated tin-free fulvenes and indenes can be obtained after destannylation with DCl.121b It is interesting to note that no products of type 274, which would arise from a competing 6-endo cyclization in 272, were formed. Computational studies revealed a slightly lower activation barrier for the 5-exo cyclization, and it is assumed that due to the steric bulk caused by the aryl substituents the 6endo cyclization pathway is disfavored. This concept has further been expanded to include triynes, and Sn-radical promoted cyclization of tribenzocyclane 275 under similar conditions, followed by acidic destannylation gives dihydrobenzoindenofluorene 276 in good yield (Scheme 44b).121c S


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3. CASCADE REACTIONS INITIATED BY ADDITION OF MAIN GROUP VI-CENTERED RADICALS Radicals with the unpaired electron located on a main group VI element are principally more electrophilic than C- and Sncentered radicals. The latter are generally considered as nucleophilic species, although exceptions do exist, especially in the case of C-radicals where the radical center is flanked by one or two electron-withdrawing substituents, for example malonyl radicals 37 (see Scheme 7). In the group of main group VI-centered radicals, cascade reactions initiated by intermolecular addition of S-radicals to alkynes are by far most widely explored. Only recently also tandem radical reactions initiated by addition of O-centered radicals to alkynes have been developed. In contrast to this, both Se- and Teradicals have in general found very limited application as initiator of radical cascades involving alkynes.

Scheme 46

Whereas TEMPO is very unreactive in its reactions with closed-shell compounds, some inorganic O-centered radicals and radical ions, in particular nitrate, NO3•, and sulfate, SO4•−, are highly reactive but also less prone to fragmentation or hydrogen abstraction, compared with the organic O-radicals RO• or RC(O)O•, and appear therefore suitable to initiate tandem radical cyclizations in acetylenic compounds. These reactions were explored in-depth using the medium sized cyclic alkyne 281 as a model system (Scheme 47). The reaction with NO3•, for example, which was obtained by anodic oxidation of lithium nitrate in the presence of the alkyne, leads to formation of a mixture of the cis fused bicyclic ketones 282 and 283 in 72% combined yield.123 The mechanism was explored by DFT studies, and the calculated activation barriers, Ea, and reaction energies, ΔE, for the individual steps of the sequence are included in Scheme 47 (the energies include zero-point vibrational energy correction, zpc).124 Addition of NO3• to 281, which is associated with a low Ea of only a few kilojoules per mole and exothermic,125 leads to vinyl radical 284, which subsequently undergoes a 1,5- or 1,6-HAT to give the secondary radicals 285/287. The latter compounds subsequently cyclize in a cis selective 5-exo or 6-exo fashion, respectively, to the CC double bond that produces the αoxynitro radicals 286/288. The cascade is terminated by rapid β-fragmentation of the weak O−NO2 bond, which yields the isomeric bicyclic ketones 282 and 283 with release of nitrogen dioxide, NO2•. All individual steps in this cascade following initial radical addition are exothermic and involve low activation barriers. NO2• is the byproduct in this sequence, which is a comparatively stable free radical species and does not initiate a radical chain process under the experimental conditions. The cascade has therefore been termed a “self-terminating” oxidative radical cyclization, which is characterized by the fact that the cascade-initiating radical contains the (largely unreactive) leaving group that is eliminated in the final step. NO3• can therefore be formally regarded as a synthon for oxygen atoms, which enables oxidation of alkynes to carbonyl compounds under mild conditions typical for radical procedures. In contrast to “classical” radical chain reactions, which are nearly always associated with a loss in overall functionality due to reductive quenching of radical intermediates, self-terminating radical cyclizations lead to products in which the net amount of functional groups is unchanged compared with the starting material. The initially formed nucleophilic vinyl radical can also be trapped through cyclization onto a carbonyl bond. For example, reaction of electro- or photochemically generated NO3• with 5-

3.1. O-Centered Radicals

In contrast to the well-studied intramolecular cyclizations of alkoxyl radicals, RO•,6a the intermolecular addition of Ocentered radicals to π systems to initiate complex radical cyclization cascades has only recently attracted some attention. With few exceptions, attack of O-radicals at alkenes and alkynes is irreversible, which can be rationalized by the strength of the newly formed C−O bond. Therefore, the combination of Oradicals as being both oxidizing species and initiators of tandem radical cyclizations should be synthetically highly attractive for the one-pot generation of complex molecular frameworks with simultaneous oxidative functionalization. The reason for the low number of papers published on intermolecular O-radical addition to alkenes and alkynes could originate from the perception that typical organic O-centered radicals, such as RO• or acyloxyl radicals, RC(O)O•, may not react with π systems through addition at rates that are competitive with other pathways, in particular allylic hydrogen abstraction and β-fragmentation in the case of RO• or decarboxylation in the case of RC(O)O• (Scheme 45). Scheme 45

A potential solution to this problem is the use of O-centered radicals that are less prone to fragmentation or hydrogen abstraction. One example for this approach is outlined in Scheme 46, in which TEMPO (2,2,6,6-tetramethylpiperidineN-oxyl) reacts with the endiyne 277 to give the TEMPOsubstituted fulvene 278 as a mixture of E/Z isomers.122 Because of the stability of TEMPO, which is due to steric hindrance and spin delocalization over both N and O, the initial addition to the CC triple bond in 277 is slow and reversible. However, once vinyl radical 279 is formed, a rapid 5-exo cyclization leads to intermediate 280, which is subsequently quenched by reduction. Similar to the reaction outlined in Scheme 44a, the initial radical addition could occur at both sites of the alkyne system in 277. However, a subsequent cyclization is kinetically only possible in vinyl radical intermediate 279, which carries the spin at the terminus of the conjugated π system. T


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Scheme 47

Scheme 48

290 with release of NO2•. This radical cyclization cascade is therefore one of the very few reported examples for the synthesis of epoxides through a 3-exo cyclization of allyloxyl radicals. Interestingly, this sequence can also formally be considered as a “retro-Eschenmoser−Ohloff” fragmentation,127 although it is important to point out that the mechanism of these two reactions is entirely different. NO3•-induced oxidative cyclization of cycloalkyl-clamped alkynes 297 leads to anellated tetrahydrofurans (298 with X = O)128a−c or pyrrolidines (298 with X = NTs, NTf)128d possessing four asymmetric centers in good yields through a sequence consisting of radical addition, rate-determining 1,5HAT,128a,c 5-exo cyclization, and terminating β-scission with release of NO2• (Scheme 49a). The diastereoselectivity of this cyclization cascade ranges from moderate to very high, and often only one stereoisomer was obtained. The stereochemical outcome was found to depend strongly on the nature of the heteroatom X, the substituent R, and the size of the cycloalkyl ring.128a,d The 5-exo cyclization did not follow the Beckwith−Houk rules47 in all cases, which suggests that the stereoselectivity of the radical cyclization is influenced not only by steric but also by

cyclodecynone (225) leads to epoxyketones 289 and 290 with the latter being formed with slight preference (Scheme 48).123 NO3• addition to 225 occurs non-regioselectively and leads to the isomeric vinyl radicals 291 and 294. According to DFT studies, the lowest energy pathway for equilibration of both vinyl radicals proceeds through dissociation into NO3• and the respective alkyne, which is associated with a considerable activation barrier of some 80 kJ mol−1, followed by radical readdition.126 In contrast to this, the unimolecular 1,2rearrangement of NO3-substituted vinyl radicals via a cyclic five-membered transition state is energetically less favorable and requires an activation energy of ca. 96 kJ mol−1. These energy barriers are both higher than those for the transannular 5-exo or 6-exo cyclization of 291 and 294, which proceeds to the less electron-rich carbon site of the CO double bond. The resulting allyloxyl radicals 292 and 295 rearrange through a 3-exo cyclization to yield the respective α-oxiranyl radicals 293 and 296. In accordance with literature,1 DFT calculations show that this latter step is highly reversible, and the only reason why the reverse ring-opening does not occur in this cascade is the ease by which the radicals 293/296 undergo β-fragmentation of the O−NO2 bond to give the respective epoxy ketones 289 and U


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Scheme 49

Table 2. Representative Results for the Reaction of Cyclodecyne (281) with Various O-Centered Radicals LO•

stereoelectronic effects in the transition state that are not yet understood.128c The role of the cycloalkyl clamp in alkyne 297 is to restrict the conformational flexibility in the initially formed reactive vinyl radical 299 and to facilitate alignment of the vinyl radical SOMO and the σ-orbital of the respective C−H bond, which is required for the 1,5-HAT process. A similar conformational restriction of the intermediate vinyl radical was also obtained using the Thorpe−Ingold effect129 provided by two geminal ester groups. This is shown in Scheme 49b for the reaction of the open-chain alkyne 302 with NO3•, which leads to the trisubstituted cyclopentane 303 possessing a cis stereochemistry at the newly formed bond.130 Apart from NO3•, also various other classes of inorganic and organic O-centered radicals react with alkynes in a similar fashion. Thus, it was found that SO4•−,131 hydroxyl (HO•),132 acyloxyl [RC(O)O•],133 alkoxycarbonyloxyl [ROC(O)O•],134 alkoxycarbonylacyloxyl [ROC(O)C(O)O•],134 carbamoyloxyl [R2NC(O)O•],134 nitroxyl [R2NO•],134 and alkoxyl radicals [RO•]134,135 promote oxidative cyclization of, for example, cycloalkyne 281 to the bicyclic ketones 282 and 283. In Table 2 are shown representative outcomes of these reactions. 3.1.1. Mechanistic Studies on Self-Terminating Radical Cyclizations. The suggested homolytic scission of an O−L bond in the terminating step in “self-terminating radical cyclizations” with elimination of a radical leaving group L• requires additional consideration. Thus, while the fragmentation of an O−NO2 bond is practically barrierless (L• = NO2•), some radicals that are released in self-terminating radical cyclizations of alkynes with organic O-centered radicals are not considered as stabilized. For example, radical cyclization cascades initiated by RC(O)O• addition to alkynes would require, in analogy to the mechanism outlined in Schemes 47−49, an unprecedented homolytic fragmentation of an O− acyl bond in α-oxyacyl radicals with release of an acyl radical [L• = RC•(O)]. It was found, however, that independently generated α-oxyacyl radicals are indeed able to undergo unimolecular decomposition to yield the respective ketone, which supports the proposed mechanism.133 DFT studies of the potential energy surface for the reaction of cycloalkynone 225 with NO3•, SO4•−, and AcO• revealed some interesting differences among these chemically very diverse O-centered radicals (Figure 1).124 While the overall radical cyclization cascade ranging from the initial intermolecular radical addition to the terminating βfragmentation is exothermic, the rate of the terminating βfragmentation step itself depends strongly on the nature of the leaving radical L•. It is instantaneous and strongly exothermic

when L• = NO2•, whereas with L• = Ac• the bond homolysis is associated with a considerable activation barrier of about 104 ± 18 kJ mol−1 and is endothermic by ca. 50 kJ mol−1. In contrast to this, the fragmentation of an O−SO3•− bond requires on average ca. 37 kJ mol−1 activation energy and is exothermic by ca. 66 ± 4 kJ mol−1. The different behavior of these three radicals becomes apparent from the different experimental outcome in the reactions involving 5-cyclodecynone 225.136 As mentioned above, the 3-exo cyclization of allyloxyl radicals of type 295 to the oxiranyl radical 296 occurs readily but is reversible (Scheme 50 and Figure 2). However, when L• = NO2•, the forward reaction for 296 through β-fragmentation, which leads to the epoxyketone 290 and NO2•, is fast and quantitative. In the case of L• = SO3•−, the analogous fragmentation 296 → 290 is slower so that a fraction of 296 undergoes reverse ring-opening to regenerate allyloxyl radical 295. The latter can undergo a competing but irreversible β-fragmentation that leads to the primary alkyl radical 304. Although this process is associated with an activation barrier of some 67 kJ mol−1, it is in fact exothermic (about −50 kJ mol−1), because a stabilized push−pull alkene is formed. Compound 304 cyclizes in 5-exo fashion to yield αoxyradical 305, which subsequently undergoes fragmentation to give spirodiketone 306. The latter is formed as minor product in the reaction of SO4•− with cyclodecynone 225, in addition to the isomeric epoxy ketones 289/290 (see table inset in Scheme 50). On the other hand, in the reaction of AcO• with 225 spirodiketone 306 is formed as the major product. This can be rationalized by a very slow fragmentation 296 → 290, which cannot compete with the irreversible pathway leading to 306. Further DFT studies on the mechanism of the homolytic O− L bond scission revealed for the simplified model reaction 307 → 309 that, apart from L = NO2 and SO3−, only for L = Bn this fragmentation is kinetically (low to moderate Ea) and thermodynamically favorable (ΔE < 0) (Scheme 51 and V


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Figure 1. Calculated potential energy surface for the reaction of cycloalkynone 225 with NO3•, SO4•−, and AcO•. The energy data are relative to the energy of the initial association complex of 225 and the respective O-centered radical LO•.

Scheme 50

Figure 2. Calculated potential energy surface for the competing unimolecular reaction pathways in allyloxyl radical 295. The energy data are relative to 295.

of the poorly stabilized Me• is energetically more favorable than fragmentation of O−phosphate bonds, where the resonancestabilized P-radicals P(O)(OMe2)• or P(O)(OMe)O•− would

Table 3). In contrast to this, β-fragmentation of O−acyl or O− H bonds require high activation energies and are considerably endothermic.124 Fragmentation of an O−Me bond and release W


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cally impossible (data not shown).124 Homolytic β-fragmentation of the O−acyl bond, for example, 307 → 309, appears to be therefore the only feasible unimolecular pathway by which αoxyacyl radicals undergo decomposition into carbonyl compounds. In self-terminating radical cyclizations, the majority of the Ocentered radicals were generated through photolysis of either Barton PTOC (pyridine-2-thione-N-oxycarbonyl) esters6 or dithiocarbamates developed by Kim et al.139 (see Table 2).132−136 DFT studies on a simplified model system showed that trapping of α-oxy radicals 307 through addition to Barton or Kim esters (310 or 313, respectively) in a radical chain propagation process is associated with moderate activation barriers of around 40 kJ mol−1 and is exothermic for both cases (Scheme 52).124 Homolytic fragmentation of the respective adducts 311 and 314 is also fast and leads to the mixed thioacetals 312 and 315, which under the experimental conditions could be hydrolyzed to give 309. Support for such a bimolecular termination pathway has been obtained in recent experiments, where adducts of type 315 were identified by GC/ MS.140 NO3• is synthetically highly interesting, because it can also be used for the oxidation of alkynes to 1,2-diketones under mild conditions. In Scheme 53 is outlined the reaction of diarylalkynes 316 with excess NO3•, which gives 1,2-diketones 317 as the major product in addition to varying amounts of benzophenones 318.141 DFT studies revealed that the diketones 317 are likely formed through a strongly exothermic 5-endo cyclization of the initially formed vinyl radical 319, followed by loss of NO• in 320 through a virtually barrierless process, which can be rationalized by the fact that two weak N−O bonds are broken and two stable CO bonds in diketone 317 are formed together with release of (comparably) unreactive NO•. Interestingly, the benzophenones 318, which contain one carbon atom less than the starting alkyne 316, are likely formed through γ-fragmentation of the labile O−NO2 bond in vinyl radical 319, followed by Wolff rearrangement of the intermediate α-oxo carbene 321 to yield ketene 322. The latter undergoes decarboxylation upon further oxidation either by NO3• or directly at the anode, if NO3• is produced electrochemically.142 This unprecedented γ-fragmentation of a vinyl radical is quite remarkable, since it could provide a rapid

Scheme 51

be formed (it should be noted that the two latter reactions were not studied experimentally). This indicates that radical stabilization effects are not the primary driving force in these homolytic β-fragmentations. Indeed, the energetically most favorable processes (e.g., where L = NO2, SO3−, or Bn) show early transition states, in line with the Hammond postulate,137 which are characterized by a low spin density on the residue L. In contrast to this, the later transition states of the less favorable fragmentations (e.g., where L = acyl, phosphate, or H) show a significant spin density on L, which can amount to up to 67% in the case of L = H. This shows that the rate of the β-fragmentation of the O−L bond in radicals of type 307 depends primarily on the strength of this bond, which increases in the order O−N (ca. 230 kJ mol−1) < O−S (ca. 365 kJ mol−1) ≈ O−C (ca. 360 kJ mol−1) < O−P (ca. 380 kJ mol−1) < O−H (ca. 465 kJ mol−1).138 However, the ability of L to stabilize an unpaired electron in the transition state must not be entirely undervalued, which is apparent from the lower activation barrier for the O−SO3− bond cleavage compared with that for the O−Me bond, although the bond strengths are essentially equivalent. Because of the slow β-fragmentation of O−acyl bonds in αoxyacyl radicals of type 307 (L = Ac), a number of alternative termination steps were explored by DFT. A potential scenario involves oxidation of 307 to the respective cation, followed by heterolytic bond scission with release of an acyl cation (Ac+). However, although RC(O)O• are oxidizing radicals and principally capable of oxidizing the corresponding α-oxyacyl radical intermediates, a heterolytic fragmentation is energeti-

Table 3. Calculated Activation Energy, Ea, Reaction Energy, ΔE, and Selected Geometrical Parameters for the Homolytic βFragmentation of the O−L Bond 307 → 309a rO−L (Å) entry

L

Ea

ΔEb

307

308

bond elongation (%) in 308

spin density (%) on L in 308

1 2 3 4 5 6 7 8 9 10 11

NO2 SO3− Bn Me C(O)NMe2 C(O)Ph Ac C(O)OMe P(O)(OMe)O− P(O)(OMe)2 H

−2.6 39.9 74.0 97.6 116.6 123.4 125.5 133.7 134.0 144.3 150.0

−192.6 −65.5 −61.8 −8.8 37.8 47.4 44.1 49.7 73.1 85.8 109.3

1.395 1.688 1.404 1.404 1.352 1.342 1.345 1.330 1.579 1.656 0.951

1.499 2.111 1.805 1.859 1.912 1.841 1.803 1.859 2.119 2.377 1.457

107 125 129 132 141 137 134 140 134 144 153

19 47 58 53 52 60 55 55 55 60 67

In kJ mol−1; BHandHLYP/6-311G**. Energies contain zero-point vibrational energy correction (zpc). bBased on association complex of 309 and L•. a

X


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Scheme 52

Scheme 53

3.2. S-Centered Radicals

and novel access to α-oxo carbenes simply through addition of suitable O-radicals to alkynes. The synthetic scope of such reactions is currently explored in our laboratory.

Whereas the addition of O-radicals to alkynes is generally irreversible, addition of S-centered radicals to alkynes is a reversible process and formation of the vinyl radical is slightly endothermic in most cases.143,144 Despite this, radical cyclization cascades initiated by intermolecular S-radical addition to alkynes have received attention at a level comparable to that of Sn-radicals (see section 2.4), and a number of unique synthetic applications of S-radicals have been reported. The radical-mediated thiol addition to alkynes has been used to prepare S-functionalized alkenes and to obtain kinetic data and some mechanistic insight into these reactions.26,143,145 Apart from thiyl radicals, thiocyanato (NCS•)145e and pentafluorosulfanyl radicals (F5S•)145f have also been studied. The radical-mediated addition of two thiols to one alkyne moiety has recently been discovered as very useful methodology to access complex materials.146 An example for this socalled “thiol−yne click” procedure is shown in Scheme 54, where rotaxanes are produced in a light-induced reaction.147 Although strictly speaking this reaction cannot be considered as a radical cascade, it is a very impressive demonstration of the synthetic power of thiyl radical addition to alkynes that

Scheme 54

Y


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warrants mentioning in the context of this review. The reaction uses the dumbbell-shaped thread 323 as template for the macrocycle, which was obtained through irradiation of equimolar amounts of the prop-2-yne benzoate 324 and dithiol 325 in the presence of catalytic amounts of the photosensitizer 2,2-dimethoxy-2-phenyl acetophenone (DMPA). Using the apolar dichloromethane as solvent effective hydrogen bonding between the poly(ethylene glycol) units of the macrocycle and the ammonium core in the thread enabled formation of the interlocked molecule 326 in very good yield. Radical cyclization cascades initiated by addition of Scentered radicals to alkynes are predominantly performed with phenylthiyl radicals, PhS•, which are usually generated from thiophenol (PhSH) or diphenyldisulfide [(PhS)2] under various initiation conditions. Aliphatic thiyl radicals are most commonly obtained from the parent thiol.148 One of the earliest examples of S-radical mediated cascade processes performed under radical chain conditions was reported in 1987. In the reaction by Broka et al., PhS• was added to the terminal end of the CC triple bond in enyne 327 (Scheme 55a).149 The initially formed vinyl radical 330

larger than that for alkynes.143 However, the reversibility is less pronounced for the S-radical addition to alkynes, which can be rationalized by the high reactivity of the resulting vinyl radicals (compared with alkyl radicals), which undergo subsequent reactions at faster rates than the competing reverse fragmentation to the initial S-radical and alkyne. Therefore, similar to Sn-radicals, S-radicals promote cyclization of enynes through a mechanism consisting of radical addition to the C C triple bond, followed by cyclization to the alkene moiety.27b A complex two-component radical addition/cyclization/ rearrangement is shown in Scheme 56.151 Addition of thiyl

Scheme 55

radicals 340, which are derived from thiol 337 using a radical initiator, to the alkynyl azide 338 leads to vinyl radical 341, which cyclizes in 5-exo fashion to the aromatic ring to give spiro radical intermediate 342. Ring-opening of the latter with rearomatization, followed by reduction of the thiomethyl radical intermediate (not shown) gives the final product 339 with good yield. The presence of the para cyano group is crucial for stabilizing the unpaired electron in 342. Indeed, such a 5-exo cyclization does not occur in systems lacking a radical stabilizing substituent at the aromatic ring; in these cases the vinyl radical is directly reduced to the corresponding Ssubstituted alkene (not shown). On the other hand, the cyano group in 337 is too deactivated to act as acceptor for the Sradical 340 so that polymerization of 337 does not occur. The reversibility of S-radical additions to alkynes is a highly valuable feature, which can be used to promote regioselective vinyl radical cyclizations of internal alkynes that are usually attacked by a radical nonregioselectively at both sites of the π system. This strategy was applied by Montevecchi et al., who developed a highly efficient S-radical mediated vinyl radical cyclization onto azido groups (Scheme 57).151 Thus, initial reversible addition of PhS• to diphenyl acetylene 343 gives an equilibrium mixture of the two vinyl radicals 344 and 347. The former undergoes 5-exo cyclization onto the azide moiety, which leads to a zwitterionic radical intermediate 345, followed by elimination of nitrogen and reduction, which yields indole 346. The isomeric vinyl radical 347, on the other hand, cannot cyclize at a rate that competes with the reverse fragmentation and regeneration of the starting materials so that 346 is obtained as exclusive product in this reaction. The selectivity of the S-radical addition favoring the CC triple bond over the azide π system is unique to these radicals, whereas analogous reactions of alkynyl azides with the more nucleophilic Sn- or Sicentered radicals proceed via initial addition at the less electronrich azido group and not at the alkyne moiety. Substituted thiophenes and benzothiophenes can be obtained through addition of PhS• to mono- and bis-aromatic acetylenes, followed by vinyl radical cyclization onto a double bond or aromatic residue (not shown).152 An alternative source for PhS•, which avoids the ill-smelling PhSH as radical precursor, has been recently used by Ishibashi

Scheme 56

undergoes cyclization in both 6-endo (preferred) and 5-exo fashion, and reduction of the resulting radical intermediates 331 and 332 leads to the final products 328 and 329, respectively, which are obtained as a mixture of E/Z isomers. It was suggested that the high preference for formation of the cyclohexylidene product 328 is due to equilibration of the initially formed cyclopentyl methyl radical 332 with its thermodynamically more favorable cyclohexyl radical isomer 331 prior to reduction. Oshima et al. used Et3B to generate thiyl radicals from allyl thiol 333, which are trapped by addition to phenyl acetylene (34) (Scheme 55b). Subsequent 5-exo cyclization 334 → 335, followed by reduction leads to the dihydrothiophene derivative 336 in very good yield.150 The reaction rate can be increased significantly through addition of an excess of methanol. The example in Scheme 55a shows that, similar to the reactions of Sn-radicals, addition of S-radicals to enynes occurs with preference at the CC triple bond. However, whereas Snradicals are generally considered as being nucleophilic, Sradicals are (slightly) electrophilic so that the observed preference for the less electron-rich alkyne moiety in enyne 327 seems somewhat surprising. Indeed, addition of S-radicals to both alkenes and alkynes is reversible with rate coefficients for the reaction with alkenes being ca. 3 orders of magnitude Z


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Scheme 57

Scheme 58

et al. in S-radical mediated enyne cyclizations (Scheme 58).153 The radicals are generated by reduction of (PhS)2 with excess tripropylamine to give disulfide radical anions, which dissociate into PhS• and phenylthiolate. The former is trapped through regioselective addition to the alkyne terminus in enyne 348 to give vinyl radical 350, which is followed by 5-exo cyclization. The resulting intermediate 351 is quenched through reduction by PhSH, which is generated in situ during the course of the reaction, to yield an E/Z mixture of the cyclopentane derivative 349. The yield of the latter can be increased through addition of water, which suppresses the competing rearrangement pathway 351 → 352 that ultimately leads to the 6-endo product 353. Manganese(III) promoted oxidative electron transfer was used by Zou and Zhang et al. to generate thiyl radicals for the synthesis of thiolated indenones from 1,3-diarylpropynones (not shown).154 S-Radical mediated vinyl radical cascades have been employed to access medium-sized rings (e.g., seven to nine ring members) in very good yields under dilution conditions (alkyne concentration in millimolar range) using endo cyclizations as a key step. Scheme 59a shows a typical enyne substrate for the transformation reported by Majumdar et al. (e.g., 354).155 The cyclooctane derivative 355 is obtained after regioselective PhS• addition to the terminus of the alkyne moiety, followed by 8-endo cyclization and reduction (mechanism not shown). The planar and rigid molecular scaffold provided by the bicyclic framework in 354 limits the conformational degrees of freedom of the alkyne and alkene

Scheme 59

side chains so that a highly unusual 8-endo vinyl radical cyclization can occur with high efficiency. This methodology could also be applied to access pyrimidine-fused azocines,156 furo- and pyrano-coumarin derivatives,157 9-deazaxanthine analogs,158 as well as benzoxepins,159 and benzoxocines.160 Mechanistically related endo radical cyclizations of enynes 356 enabled Alcaide et al. to access β-lactams 357, which are fused to seven to nine membered rings (Scheme 59b).161 Indole-annulated sulfur heterocycles were obtained through PhS•-mediated tandem radical addition/cyclizations using alkynyl indoles 358 as substrates (Scheme 60).162 The regioselectivity of the cyclization of the initially formed vinyl AA


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reduction into the final product 367. It is interesting to note that the reaction of 366 with Bu3Sn• proceeds regioselectively through radical addition at the α carbon of the CC triple bond, which is a result of steric hindrance caused by the bulky substituents at tin. In Scheme 62 is shown a radical-mediated diastereoselective formal addition of the E-2-(phenylthio)vinyl moiety to chiral α-

Scheme 60

Scheme 62

radical 361 is directed by the substituent R at the indole nitrogen. Thus, when R is electron-donating the cyclization proceeds through an intramolecular nonradical addition of the enamine moiety to the π system of the thioenol ether in 362, which is formed through reversible reduction of 361 by PhSH. The resulting tetrahydrothiopyrano indole 359 can be formally considered as product of a 6-endo cyclization. On the other hand, when R is electron-withdrawing, the lone pair at nitrogen is less available so that nucleophilic addition of the enamine is suppressed. Under these conditions, vinyl radical 361 exclusively undergoes 5-endo cyclization, which is followed by reduction of 364 to give the closed-shell species 365. The latter is suggested to undergo two successive proton exchanges (not shown), which ultimately lead to rearomatization and formation of the trihydrothieno indole 360. Vinyl radical cyclizations onto ketimines or ketoximes, which are triggered by S-radical addition to alkynes have been studied by a number of groups.55,163 Keck et al. used a diastereoselective thiyl radical addition/cyclization cascade to generate the key-compound 367 for the total synthesis of ent-lycoricine (Scheme 61).164 In this sequence, photogenerated PhS•

hydroxy hydrazones 370.165 This procedure overcomes the lack of a synthetically viable intermolecular vinyl radical addition to CN double bonds by linking the alkyne unit to a temporary silicon tether (e.g., 371) so that the desired vinyl radical addition proceeds in fact intramolecularly. The conformation of the transition state for the 5-exo cyclization of the initially formed vinyl radical 373 shows minimized allylic strain in accordance with the Beckwith−Houk predictions47 and leads to aminyl radical 374 in which ether and amino groups are anti. Radical reduction and removal of the silicon tether without prior isolation of the formal end product of the radical cyclization cascade, e.g. 375, yields the α-amino alcohol 372. The reaction leads to a mixture of various stereo- and geometrical isomers with the E-anti product being formed with high preference. This strategy can also be applied to the diastereoselective synthesis of polyhydroxylated amines and amino sugars (not shown).166 An effective, tin-free route for the generation of alkyl radicals R• using homolytic substitution at the sulfur atom has been reported by Minozzi, Nanni, Spagnolo, and co-workers (Scheme 63).167 The procedure uses easily accessible 4-

Scheme 61

Scheme 63

pentenyl sulfides 376 as substrates, which react with PhS• to form vinyl radicals 377. The subsequent homolytic substitution releases R• generally with yields higher than 90% and simultaneous formation of thiophenes 378 as byproducts. This concept is very general and can also be applied to access other C-centered radicals, such as acyl168 and carbamoyl radicals,169 as well as P-centered radicals.170 Reaction of diphenyl acetylene (316) with PhS• generated through autoxidation of thiophenol under O2 pressure leads to formation of 1,2-diketone 317 in very good yield (Scheme 64).144 Although this oxidation does not involve a radical cyclization cascade, the proposed mechanism, which is based on a combination of experimental and DFT studies, is of fundamental interest and will therefore be presented here.

undergoes exclusive addition at the β-site of the CC triple bond in alkyne 366 to produce the resonance-stabilized vinyl radical 368. The subsequent 6-exo radical cyclization proceeds, due to the constraints imposed by the cis fused dioxolane ring, in a highly diastereoselective fashion through a boat-like transition state, in which the oxime CN double bond and the hydroxy substituent are both pseudoequatorial. This leads to a cis arrangement of the hydroxy and amino substituent in the cyclized radical intermediate 369, which is transferred through AB


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Scheme 64

Scheme 65

exothermic γ-cleavage of the peroxyl O−O bond already in vinyl radical 379, followed by trapping with O2. Further investigations, specifically time-resolved transient absorption spectroscopic studies, are clearly required to gain fundamental mechanistic understanding of this unusual oxidation reaction. Reaction of the ten-membered cycloalkyne 281 with photogenerated PhS• leads to a mixture of three isomeric bicyclic thioethers in approximately equal amounts, which all possess the bicyclo[4.4.0] framework with either cis (S/R-cis384) or trans fusion (trans-384; the configuration at the carbon bearing the thiyl substituent could not be determined) (Scheme 65).173 The reaction proceeds through (reversible) intermolecular PhS• addition, followed by transannular radical translocation consisting of 1,6-HAT and 6-exo cyclization to give the α-thio radicals cis/trans-387, which are subsequently reduced. The likely hydrogen donors in this system are

In this sequence, O2 is activated through formation of Ocentered phenylthioperoxyl radicals, PhSOO•, through reversible trapping of PhS• with O2.171 Although the latter reaction competes with the direct addition of PhS• to alkyne 316, formation of PhSOO• becomes the favorable pathway with increasing O2 pressure. PhSOO• addition to 316 gives vinyl radical 379 in a slightly exothermic process, which could be converted into the diketone 317 through various routes. One possibility is the highly exothermic trapping by O2, which leads to peroxyl radical 380. Subsequent fragmentation of the weak peroxyl O−O bond with elimination of a resonance-stabilized sulfinyl radical, PhS•O, leads to biradical 381, which could isomerize (via intersystem crossing, ISC) to carbonyl oxide 382. The latter has been suggested as intermediate in the ozonolysis of alkynes leading to 1,2-diketones.172 Alternatively, 382 could be formed via biradical 383, which results from AC


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Scheme 66

aromatic thiols, such as PhSH, and di- and trisulfides of type 391 and 392, which are formed in situ through light-induced coupling of PhS• with (PhS)2 via intermediate radical adducts of type 388 (the para coupling product is exemplarily shown in Scheme 65). Formation of the bicyclic thioether trans-384 through a radical cyclization is unusual, since these generally proceed with high cis selectivity when small rings, such as cyclohexanes, are formed.1 DFT calculations revealed that trans-384 results from a cyclization cascade similar to that leading to the cis bicyclic framework in cis-384 but involves a different low-energy conformational isomer of the Z configured vinyl radical 385. Rather than through rotation around C−C single bonds, which is energetically quite unfavorable in medium-sized ring systems due to significant transannular strain, the existence of different conformational isomers of the cyclic vinyl radical 385 are a consequence of the reversibility of the PhS• addition to 281.173 Unlike the reaction of 281 with O-centered radicals (see Scheme 47), the reaction involving PhS• does not lead to formation of a product possessing a bicyclo[5.3.0] framework. DFT calculations showed that the activation barrier for the 1,5HAT in vinyl radical 385 is ca. 15 kJ mol−1 higher than that for the alternative 1,6-HAT.173 It must therefore be concluded that the regioselectivity of vinyl radical reactions depends heavily on the substitution pattern of the vinyl π system itself, which is partially defined by the nature of the radical that attacks the alkyne in the first step of the cascade. These obviously strong stereoelectronic effects on the regioselectivity demand further mechanistic exploration through experimental and computational studies. The synthetic scope of radical translocation through 1,5HAT in vinyl radicals derived from S-radical addition to alkynes has been extensively explored by several groups.152b,174−176 Scheme 66 outlines an example for a radical addition/ translocation/cyclization cascade, which forms the key step in the stereoselective synthesis of the spirocyclic compound (−)-erythrodiene.174a The reaction proceeds through addition of photogenerated PhS• to the alkyne terminus in 393 to give vinyl radical 395, which undergoes a regioselective 1,5-HAT. The resulting tertiary radical 396 subsequently cyclizes in 5-exo fashion, which is followed by reduction of 397 to yield the product 394 as a mixture of four diastereomers. The high trans selectivity (e.g., a trans arrangement of the phenylthio moiety and the isopropyl substituent) of the 5-exo cyclization can be

rationalized by a transition state in which the newly formed C−C bond assumes an axial position, as is shown in Scheme 66. It should be noted, however, that the stereochemical outcome of this reaction is very sensitive to temperature and solvent polarity. Simpkins et al. used the alkynyl substituted diketopiperazine 398 as precursor to access the pentacyclic core structure of the asperparalines (Scheme 67).177 The sequence consists of a 1,6Scheme 67

HAT in the initially formed vinyl radical 400, followed by two consecutive 6-exo and 5-exo cyclizations, for example, 401 → 402 → 403. Although the overall yield is only moderate, product 399 can be obtained as single diastereomer, which possesses the correct configuration for the majority of all known natural products. An interesting four-component radical cascade, which leads to β-arylthio-substituted acrylamides 406 using S-radicals, aromatic acetylenes, and isonitriles in the presence of an oxidant, was reported by Nanni et al. (Scheme 68).178 The sequence is initiated by chemoselective addition of photogenerated PhS• to phenyl acetylene (34; the CC triple bond in the alkyne is more electron-rich than the isonitrile π system in 404). The resulting nucleophilic vinyl radical 407 is trapped through intermolecular addition to the NC triple bond in 404 to give imidoyl radical 408, which reacts with 1,3AD


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Scheme 68

Scheme 70

A related intermolecular bromine atom transfer addition of tosyl bromides has been used for the diastereoselective synthesis of bicyclic β-lactams 421 (Scheme 71).183 Thus,

dinitrobenzene (405). The latter acts as an oxidant to produce amidyl radical 410 via the intermediate radical cation 409. The cascade is terminated by reduction using in situ generated mono- and polyaromatic thiols (as outlined in the lower part of Scheme 65) as hydrogen source. The mixed (PhS)2−(PhTe)2 system has been used for the photoinduced thiotelluration of arylisocyanides through a cascade initiated by S-radical addition to the isonitrile moiety (not shown).179 Sulfonyl radicals (RSO2•) contain sulfur in a higher oxidation state. Although the spin density is delocalized over sulfur and both oxygen atoms, sulfonyl radicals react with π systems exclusively to form C−S bonds.143 They have therefore gained considerable synthetic value, since their addition to π systems, usually CC double bonds, provides a facile method to introduce the sulfonyl moiety into a molecule.180 An interesting [5 + 1] radical annulation with sulfur dioxide, which uses PhS• as catalyst, has been developed by Braslau et al. (Scheme 69).181 The reaction is initiated by addition of photogenerated

Scheme 71

regioselective addition of sulfonyl radicals to the terminal alkyne in the β-lactam-substituted enyne 420 leads to vinyl radical 422, which undergoes a 5-exo cyclization to give the bicyclic benzylradical intermediate 423. After bromine abstraction, the final product 421 is obtained as a 90:10 mixture of epimers at the newly formed exocyclic chiral center. The reaction of alkynes with sulfonyl radicals and trapping of the resulting vinyl radicals with diaryl ditellurides has been used to prepare stereodefined functionalized vinyl tellurides (not shown).184

Scheme 69

3.3. Se-Centered Radicals

In contrast to the large amount of S-radical mediated cascade reactions, only few examples for radical cascades that are triggered by intermolecular Se-radical addition to alkynes have been reported.185 The most commonly used Se-radicals are phenylselenyl radicals, PhSe•, which can be obtained from diphenyl diselenide, (PhSe)2, through photochemical or thermal decomposition.186 An early example for a Se-radical induced cyclization of alkynes was reported by Back et al., who studied addition of PhSe• to dimethyl acetylenedicarboxylate 424 (Scheme 72a).187 The initially formed vinyl radicals 427 undergo 5-exo cyclization to yield radical adduct 428, which is rearomatized through hydrogen abstraction. The benzoselenophene 425 is obtained with very modest yield, whereas the major products in this reaction, E/Z-426, result from the radical 1,2-addition of (PhSe)2 to the acetylene. Ogawa and Sonoda et al. used the photoinitiated addition of diselenides to enynes 429 to access five-membered bis-selenylated products 430, which were obtained as single stereoisomers (Scheme 72b).188 A highly selective multicomponent radical coupling of alkynes with alkenes mediated by PhSe• was developed by Ogawa et al.189 In Scheme 73 is shown an example for a fourcomponent reaction, which uses (PhSe)2, ethylpropiolate, and a large excess of two different alkenes possessing either an

PhS• to the alkyne terminus in enyne 411 to give vinyl radical 413, which is trapped by sulfur dioxide. The subsequent radical cyclization of the resulting sulfonyl radical 414 is governed by steric effects and occurs exclusively in 6-endo fashion. The cascade is terminated by release of PhS• through βfragmentation in 415 and formation of the dienylsulfone 412. In contrast to the previous example, where sulfonyl radicals were produced in the course of the radical cyclization cascade, Simpkins et al. used an intermolecular tosylphenyl selenide transfer addition to enynes of type 416 to access cis fused selenyl substituted N-heterocycles 417 (Scheme 70).182 The initially formed vinyl radical 418 obtained from regioselective addition of tolylsulfonyl radicals, TolSO2•, to the alkyne terminus, undergoes a cis selective 5-exo cyclization to give the bicyclic radical intermediate 419. The subsequent chain-propagating homolytic substitution occurs stereoselectively from the sterically less hindered site of the bicyclic ring system and leads to incorporation of the phenylselenyl substituent into the molecular framework. AE


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radicals act as catalysts, has been reported by Byers et al. (Scheme 74).191

Scheme 72

Scheme 74

Scheme 73

The reaction is initiated by addition of photogenerated PhSe• to the alkyne terminus in 436, followed by opening of the cyclopropyl ring in vinyl radical 439. The resulting allenic intermediate 440 is a highly electrophilic C-radical, which is trapped by an excess of the electron-rich alkene 437. Interestingly, rather than cyclizing onto the central carbon of the allene moiety, in analogy to the cyclization shown in Scheme 36 (which would lead to a stabilized allyl radical), the radical adduct 441 undergoes a 5-exo cyclization to the nearest carbon atom of the π system give vinyl radical 442. Subsequent β-fragmentation with elimination of PhSe• restores the alkyne moiety. Although both yield and stereoselectivity are only moderate, highly substituted alkynylated cyclopentanes can be accessed through this cascade, which appears to be unique to catalysis by PhSe•. A similar reaction cannot be performed using either PhS• or Bu3Sn• as initiating radicals. It should be noted that it was not possible to unequivocally assign the stereochemical relationship between the ethynyl and R substituent in 438.

electron-withdrawing group (EWG, for example, acrylates) or an electron-donating substituent (e.g., 2-methoxypropene), respectively, to access substituted, diastereomeric cyclopentanes 431a−c in good yields.189b The regiochemistry of this cascade, which is initiated by addition of PhSe• to the alkyne, is controlled by polar effects in the respective radical intermediates. Thus, the initially formed electrophilic vinyl radical 432 is selectively trapped by addition to the electronrich olefin to give the nucleophilic radical adduct 433, which subsequently reacts with the electron-poor olefin, followed by 5-exo cyclization of 5-hexenyl radical 434. From the major product 431a, which shows trans arrangement of the substituents at the newly formed C−C bond, the transition state of the 5-exo cyclization could be rationalized as being either chair axial (TSca) or boat equatorial (TSbe). It is not clear why the transition state does not follow the Beckwith−Houk rules,47 but on the other hand the directing effects of substituents in highly substituted 5-hexenyl radicals such as 434 are complex and difficult to predict. It may be suggested that radical stabilization by the electron-withdrawing substituent leads to a late transition state of the cyclization, in which steric interactions between the EWG substituent and the CC double bond can be avoided by a trans arrangement. Trapping of the resulting cyclized intermediate 435 by phenylselenide gives 431a. The minor diastereomers 431b and 431c likely result from 5-exo cyclizations through chair equatorial transition states in which the methoxy substituent at C-3 is either axial or equatorial (and vice versa for the methyl substituent; transition state not shown). The synthetic potential of diphenyl diselenide as promoter of such multicomponent radical cascade reactions has been recently reviewed.190 An interesting radical-mediated addition of ethynyl cyclopropanes to electron-rich alkenes, in which phenylselenyl

3.4. Te-Centered Radicals

The thermal-, photochemical-, or radical-induced cleavage of the weak carbon−tellurium bond in organotellurides is a very useful source for C-centered radicals,64,186 and this methodology has been used in various noncascade processes for the carbotelluration of alkynes through free radical group transfer addition.45a,192 Examples for reactions that are actually initiated by Te-radical addition to alkynes are very rare. In these cases, photochemical cleavage of the weak Te−Te bond in diphenyl ditelluride (PhTe)2 has been used to generate Te-radicals. Apart from ditelluration of alkynes through 1,2-addition,193 Ogawa et al. reported a PhTe•-mediated radical cyclization of 2ethynylaryl isocyanides 443, which leads to bistellurated quinolines 444 in satisfactory yield (Scheme 75).194 The Teradical attacks the isonitrile π system in 443 regioselectively at the carbon terminus to produce imidoyl radical intermediate 444, which subsequently undergoes cyclization to the alkyne moiety in 6-endo fashion. The resulting arylradical intermediate 446 is quenched by reaction with (PhTe)2. With sterically demanding substituents R on the alkyne, such as tert-butyl or trimethylsilyl, the vinyl radical cyclization in 445 does not occur. AF


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indication for a cascade initiated by Br• addition to the cycloalkyne 281 was found. Self-terminating radical cyclizations have been explored with both aminium and amidyl radicals using the reaction with cyclodecyne (281) as model system.199 Interestingly, instead of the expected nitrogen-containing compounds, the bicyclic ketones 282 and 283 were exclusively obtained in moderate to good yields (Scheme 77). Their formation could be explained by the mechanism that is exemplarily outlined for the reaction involving N-benzyl acetamidyl radicals, AcBnN•. In analogy to the mechanism outlined in Scheme 47, Nradical addition to cycloalkyne 281 should initiate a radical translocation/cyclization cascade, which leads to the α-aza radical intermediates 459 and 460, respectively. Termination through β-fragmentation gives the bicyclic imides 461/462, which are hydrolyzed to the ketones 282/283. Although at first sight this mechanism appears plausible, no clear correlation between radical stability and yield of cyclized products 282/283 was found. Indeed, N-radicals possessing primary alkyl substituents, which should not be easily released as radicals, performed better in this cyclization sequence than N-radicals with seemingly highly suitable radical leaving groups, such as benzyl or tosyl (see table inset in Scheme 77). This indicates that the proposed mechanism may, at least in part, not be correct. DFT calculations on the mechanism of this radical cyclization cascade revealed that the initial AcBnN• addition to 281 and the subsequent 1,6-HAT/6-exo cyclization pathway 456 → 457 → 459 are kinetically and thermodynamically highly feasible. In contrast to this, the homolytic scission 459 → 461 is slightly endothermic and associated with a considerable activation barrier of about 120 kJ mol−1. Thus, this fragmentation should be a very slow, if not impossible, process at room temperature. Therefore, in order to gain a detailed general insight into the energies associated with βfragmentation of N−L bonds in α-amino, -amido, and -imido radicals, DFT studies were performed using the simplified model system 465 → 467 (Scheme 78 and Table 4). It was found that in α-amino radicals cleavage of the N−benzyl bond is, as expected, energetically significantly more favorable than scission of an N−methyl bond. N-Protonation in 465, which occurs under the acidic conditions in the reactions involving aminium radicals, has a significant effect of the β-fragmentation by lowering the activation barrier Ea and rendering this process in principle thermodynamically more favorable. Compared with

Scheme 75

4. CASCADE REACTIONS INITIATED BY ADDITION OF MAIN GROUP V-CENTERED RADICALS Generally, and in contrast to reactions involving main group IVand VI-centered radicals, the intermolecular addition of main group V-centered radicals to alkynes has been significantly less explored and is, so far, restricted to N- and P-centered radicals. 4.1. N-Centered Radicals

Only very few examples for radical cascades that are initiated by addition of N-centered radicals to alkynes have been reported.195 Neutral aminyl radicals, R2N•, react with π systems in intermolecular reactions preferably by HAT and not through addition. N-Protonation increases the electrophilicity of the radical center, and successful addition of aminium radicals, R2NH•+, to alkenes has been reported.196 Compared with aminium radicals, amidyl and imidyl radicals, for example, RN•C(O)R′ and [RC(O)]2N•, respectively, are less electrophilic. Although both amidyl and imidyl radicals are delocalized π-allyl radicals, in their reactions they act exclusively as Ncentered radicals.197 Scheme 76 shows that treatment of cyclodecyne (281) with phthalimidyl radicals, Im•, which can be generated through photolysis of N-bromo phthalimide (ImBr), leads to formation of small amounts of unsaturated bicyclic compounds 447 and 448 (yields were not determined; other reaction products were not obtained).198 This sequence likely proceeds via initial addition of Im• to the CC triple bond, which initiates a sequence of transannular processes consisting of HAT (449 → 450/453), followed by 5-exo or 6-exo-cyclization (450/453 → 451/454). Trapping of 451/454 through atom transfer from ImBr gives the closed-shell tertiary bromides 452/455, which eliminate hydrogen bromide to give the final products. No Scheme 76

AG


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Scheme 77

oxidized to the respective iminium ions 463/464. The reduction potentials, E°, were calculated in nonaqueous acetonitrile for simplified model systems and are given in Table 5. With regards to the oxidizing agent in these reaction systems, the data show that aminium radicals have a considerable oxidation power (entries 1, 2). In comparison, amidyl radicals (entries 3 and 4) have a slightly weaker oxidation capability. The most important finding is, however, that the various aminium and amidyl radicals used in the radical cyclization cascade shown in Scheme 77 are in principle all thermodynamically capable of oxidizing their corresponding α-nitrogen radical intermediates to iminium ions (the relevant half reactions are 1 and 8, 2 and 7, 3 and 5, and 4 and 6). The latter are hydrolyzed in a subsequent step to give the observed ketones. Based on these findings, it can therefore be concluded that N-radicals play a dual role in self-terminating radical cyclizations first by initiating the actual radical cyclization cascade and second by enabling its termination through a redox process.199

Scheme 78

the unprotonated system, the transition state 466 of the bond scission is earlier with a less elongated N−L bond and lower spin density on the L moiety. The energy required for βfragmentation of an N−C bond in α-amido or α-imido radicals depends on the nature of the remaining substituent R. Generally, release of alkyl and acyl radicals is energetically unfavorable, whereas in particular β-fragmentations by which stabilized sulfonyl radicals are eliminated should readily occur. These computational predictions clearly contradict the experimental findings (see Scheme 77). Since the proposed β-fragmentation is an unlikely process in these reactions, exploration of potential alternative pathways that could lead to termination of the radical cyclization cascade revealed that α-nitrogen radicals of type 459/460 are readily

4.2. P-Centered Radicals

Most recently, phosphorus hydrides such as hypophosphites, ROP(O)H 2 , phosphites, (RO) 2 P(O)H, thiophosphites, (RO)2P(S)H, and phosphinates, R(RO)P(O)H, have received considerable attention as nontoxic replacements for the commonly used tin hydrides in radical chain reactions.200 AH


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Table 4. Calculated Activation Energy, Ea, Reaction Energy, ΔE, and Selected Geometrical Parameters for the Homolytic βFragmentation of the N−L Bond 465 → 467a rO−L (Å) entry 1 2 3 4 5 6 7 8 9 10 11

L

R

Bn Bnc Me Mec

Me Me Me Me −(CH2)5− Bn Ac Ac Bn Me Ac Ac Ac PhSO2 Bn Bn PhSO2

Ea

ΔEb

465

466

bond elongation (%) in 466

spin density on L (%) in 466

82.4 41.1 110.8 90.6 108.6 108.0 154.2 143.2 155.3 27.1 88.2

−10.9 −35.4 40.4 10.0 45.1 21.2 100.2 68.2 97.5 −29.5 −11.8

1.452 1.537 1.449 1.498 1.455 1.466 1.370 1.456 1.395 1.668 1.473

1.952 2.030 2.034 2.069 2.045 2.039 1.909 2.096 2.109 2.021 2.004

34 32 40 38 41 39 39 44 51 21 36

66 53 60 53 58 63 67 62 57 39 60

a In kJ mol−1; BHandHLYP/6-311G**. Energies contain zero-point vibrational energy correction (zpc). bBased on association complex of 467 and L•. cProtonated N.

Table 5. Calculated Reduction Potentials Eo (in V), Using BHandHLYP/6-311++G** Gas-Phase Energies with Solvation Energies Obtained via CPCM Models, at B3LYP/ 6-31+G* Level

Scheme 79

P-Radicals generated from manganese(III) acetate-mediated oxidation of dialkyl phosphonates have been used to prepare phosphonylated indenones 474 from 1,3-diarylpropynones 473 (Scheme 80).154 The cascade is initiated by addition of the Scheme 80

a

Versus nonaqueous SCE. energies.

b

BHandHLYP/6-31++G** gas-phase

Whereas the addition of P-centered radicals to alkenes is frequently used for the synthesis organophosphorous compounds, the related intermolecular addition to alkynes has been much less explored. Most of the existing literature on intermolecular addition of P-radicals to alkynes is aimed at developing methods to generate P-substituted alkenes through direct reduction of the vinyl radical intermediate,201 and only very few cascade reactions initiated by P-radical addition to CC triple bonds have been reported. Renaud et al. developed a radical chain process for the cyclization of terminal alkynes 468 to bicyclic ketones 469 mediated by dialkyl phosphites (Scheme 79).202 Addition of dialkyl phosphoryl radicals, (RO)2P•O, to the CC triple bond in alkyne 468 triggers a radical translocation cascade consisting of 1,5-HAT, 470 → 471, followed by a cis selective 5-exo cyclization, 471 → 472, and reduction to 469, which is obtained as a mixture of diastereomers. The stereochemistry of the major product was not determined.

electrophilic dimethylphosphonyl radicals to the more electronrich α-site of the conjugated alkynone 473. The resulting vinyl radical 475 undergoes cyclization onto the aryl ring to give the bicyclic radical intermediate 476. Termination of the sequence involves oxidation of the latter to the respective cation 477, followed by rearomatization through deprotonation. Like most of the other main group IV−VI radicals, P-radicals react with enynes through addition to the alkyne moiety. Thus, AI


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diphenylphosphanyl radicals, Ph2P•, generated from diphenyl phosphane in the presence of a radical initiator, were used to cyclize enyne 478 in a radical addition/5-exo cyclization sequence to give the bicyclic deoxysugar derivative 479 after reduction of the intermediate 481 by diphenyl phosphane (Scheme 81).182 The diphenyl phosphane/AIBN system was

radicals can also be generated through atom abstraction from suitably substituted vinyl precursors, synthesis of the latter can be a tedious task, in particular with increasing structural complexity of the substrate. In contrast to this, numerous procedures exist for the incorporation of alkyne moieties into molecular frameworks. Radical addition to CC triple bonds appears therefore to be the most convenient way for the generation of vinyl radicals, and the synthetic possibilities are, in principle, endless. One particularly attractive synthetic feature of vinyl radicals in reaction cascades is the fact that after their use one is left with an alkene moiety, which can act as radical acceptor at a later stage in the sequence. The exceptional synthetic scope of these round trip radical cyclizations, where the last cyclization step occurs at the same carbon where the intitial radical was formed, is demonstrated by many examples where this method has been used to access highly complex polycyclic structures found in naturally occurring products. The initial radical addition is highly regioselective and in reactions with substrates possessing several π systems, for example, enynes and dienynes, the alkyne moiety is usually attacked with high preference. This selectivity can be rationalized by the reversibility with which the initial radical addition occurs in many cases, in particular with Sn- and Scentered radicals. Due to their high reactivity, vinyl radicals that are formed through radical attack at the alkyne moiety in enynes, for example, are rapidly and irreversibly trapped through subsequent reactions. In contrast to this, alkyl radicals resulting from radical addition to an alkene are far less reactive so that the competing dissociation and regeneration of the starting materials is often faster than the forward reaction steps. Most of the reactions performed to date use terminal alkynes so that the initial radical addition is directed toward the less sterically hindered alkyne terminus. When disubstituted (internal) alkynes are used as substrates, the site of radical attack is governed by steric interactions, but usually occurs nonregioselectively at both sites of the π system. This is not a disadvantage in those cases where the subsequent radical cascade is only possible for one vinyl radical isomer, while the nonreactive isomer undergoes dissociation to regenerate the alkyne and attacking radical. Thus, through this thermal equilibration, the isomeric vinyl radicals are ultimately channeled along the one desired reaction pathway. This review has outlined the research carried out to date in this area. The vast majority of synthetic work has been performed with C-, Sn- and S-centered radicals, whereas the synthetic potential of O- and N-centered radicals in selfterminating radical cyclizations has only lately been unveiled. Recent successes in the development of methods to generate Si- and P-centered radicals on a preparative scale has resulted in first highly promising applications in radical cyclization cascades, and further expansion of this powerful methodology will be expected. On a final note, it is worth pointing out that, despite the undoubtly enormous synthetic scope of these radical cascades, which is demonstrated by the work outlined in this review, the clear lack of available solution-phase kinetic data for intermolecular radical addition to alkynes is highly surprising. This applies not only to the radical species themselves (for example, absolute rate coefficients for O-, Se-, Sn-, P-, and Nradical additions to alkynes in the condensed phase have not been determined so far) but also to the limited range of alkynes studied. Since radical reactions are usually kinetically controlled processes, it would be desirable if rate coefficients would be

Scheme 81

also used for a highly efficient and diastereoselective Ph2P•mediated cyclization of the enyne-substitued β-lactam 420 to bicyclic β-lactams (see Scheme 71).183 A radical diphosphanylation of dialkynes, in which in situ generated tetraorgano diphosphanes are used as precursor for phosphanyl radicals, has been applied to the synthesis of the doubly phosphinated, conjugated diene 483 from diyne 482 (Scheme 82).203 Thus, reaction of diphenyl phosphane with an Scheme 82

excess of chlorodiphenyl phosphane in the presence of triethylamine leads to tetraphenyl diphosphane, which undergoes cleavage of the P−P bond under radical initiation conditions. The resulting Ph2P• are trapped through addition to the alkyne moiety in dialkyne 482 to give vinyl radical 484, which undergoes a 5-exo cyclization (the latter step proceeds through a Z configured vinyl radical in order to minimize steric hindrance). This leads to the exocyclic vinyl radical intermediate 485, which is trapped by a second phosphine moiety through a radical substitution pathway to give the closed-shell bisalkene 486 as final product of the radical cyclization cascade. Treatment of the latter with sulfur gives bisphosphane sulfide 483.

5. CONCLUSIONS This survey clearly demonstrates that intermolecular radical addition to alkynes is a very powerful synthetic methodology to initiate radical cascade processes that lead to complex structural frameworks with excellent stereo- and regiocontrol under usually mild conditions. The success of these cascades is because the initially formed highly reactive vinyl radicals rapidly undergo intra- or intermolecular reactions, which enables very complex tandem radical processes to occur. Although vinyl AJ


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(3) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195. (4) McCarroll, A. J.; Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224. (5) Albert, M.; Fensterbank, L.; Lacôte, E.; Malacria, M. Top. Curr. Chem. 2006, 264, 1. (6) (a) Radicals in Organic Synthesis; Sibi, M., Renaud, P., Eds.; Wiley: Weinheim, Germany, 2001; Vols. 1 and 2. (b) Baralle, A.; Baroudi, A.; Daniel, M.; Fensterbank, L.; Goddard, J.-P.; Lacôte, E.; Larraufie, M.-H.; Maestri, G.; Malacria, M.; Ollivier, C. Radical Cascade Reactions. In Encyclopedia of Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.; John Wiley and Sons: Chichester, U.K., 2012. (7) Yet, L. Tetrahedron 1999, 55, 9349. (8) Selected examples: (a) Stork, G.; Mook, R., Jr. J. Am. Chem. Soc. 1983, 105, 3720. (b) Stork, G.; Mook, R., Jr.; Biller, S. A.; Rychnovsky, S. D. J. Am. Chem. Soc. 1983, 105, 3741. (c) Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985, 107, 1448. (d) Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943. (e) Curran, D. P.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991. (9) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513. (10) Beckwith, A. L. J.; O’Shea, D. M. Tetrahedron Lett. 1986, 27, 4525. (11) Gilbert, B. C.; Parry, D. J. J. Chem. Soc., Perkin Trans. 2 1988, 875. (12) Gilbert, B. C.; McLay, N. R.; Parry, D. J. J. Chem. Soc., Perkin Trans. 2 1987, 329. (13) (a) Stork, G.; Baine, N. H. J. Am. Chem. Soc. 1982, 104, 2321. (b) Wang, K. K. Chem. Rev. 1996, 96, 207. (c) Maiti, S.; Takasu, K.; Katsumata, A.; Kuroyanagi, J.; Ihara, M. Arkivoc 2002, 197. (d) Aïssa, C.; Delouvrié, B.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Pure Appl. Chem. 2000, 72, 1605. (e) Stork, G. Med. Res. Rev. 1999, 19, 370. (14) Amiel, Y. In The Chemistry of Functional Groups, Supplement C; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons Ltd.: Chichester, U.K., 1983; p 917. (15) Giese, B.; Lachhein, S. Angew. Chem., Int. Ed. Engl. 1982, 21, 768. (16) Fischer, H. In Free Radicals in Biology and Environment; Minisci, F., Ed.; Kluwer Academic Publishers: Dordrecht, the Netherlands, 1997; p 63. (17) (a) Fischer, H.; Radom, L. Angew. Chem., Int. Ed. 2001, 40, 1340. (b) Gómez-Balderas, R.; Coote, M. L.; Henry, D. J.; Fischer, H.; Radom, L. J. Phys. Chem. A 2003, 107, 6082. (18) For a selection of relative rate data, see: (a) Jiang, X.-K.; Zhang, Y.-H.; Ding, W. F.-X. J. Chem. Res. 1997, 6. (b) Gazith, M.; Szwarc, M. J. Am. Chem. Soc. 1957, 79, 3339. (19) Rubin, H.; Fischer, H. Helv. Chim. Acta 1996, 79, 1670. (20) Foxall, J.; Gilbert, B. C.; Kazarians-Moghaddam, H.; Norman, R. O. C.; Dixon, W. T.; Williams, G. H. J. Chem. Soc., Perkin Trans. 2 1980, 273. (21) Calas, P.; Amatore, C.; Gomez, L.; Commeyras, A. J. Fluorine Chem. 1990, 49, 247. (22) Nekipelova, T. D.; Brin, E. F. Kinet. Katal. 1990, 31, 1092. (23) (a) Hatakeyama, S.; Washida, N.; Akimoto, H. J. Phys. Chem. 1986, 90, 173. (b) Boodaghians, R. B.; Hall, I. W.; Toby, F. S.; Wayne, R. P. J. Chem. Soc., Faraday Trans. 2 1987, 83, 2073. (24) (a) Canosa-Mas, C. E.; Smith, S. J.; Toby, S.; Wayne, R. P. J. Chem. Soc., Faraday Trans. 2 1988, 84, 263. (b) Benter, T.; Becker, E.; Wille, U.; Schindler, R. N.; Canosa-Mas, C. E.; Smith, S. J.; Waygood, S. J.; Wayne, R. P. J. Chem. Soc., Faraday Trans. 2 1991, 87, 2141. (25) Wayne, R.; Barnes, I.; Biggs, P.; Burrows, J.; Canosa-Mas, C.; Hjorth, J.; Le Bras, G.; Moortgat, G.; Perner, D.; Poulet, G.; Restelli, G.; Sidebottom, H. Atmos. Environ., Part A 1991, 25, 1. (26) (a) Ito, O.; Fleming, M. D. C. M. J. Chem. Soc., Perkin Trans. 2 1989, 689. (b) Ito, O.; Omori, R.; Matsuda, M. J. Am. Chem. Soc. 1982, 104, 3934. (c) Ito, O. Res. Chem. Intermed. 1995, 21, 69. (27) Relative rate data for S-radical addition to alkynes: (a) Fairbanks, B. D.; Sims, E. A.; Anseth, K. S.; Bowman, C. N. Macromolecules 2010, 43, 4113. (b) Montevecchi, P. C.; Navacchia, M. L. Recent Res. Dev.

available for more complex reaction systems that are actually synthetically relevant. Knowledge of these data is of fundamental importance for the future successful design of new cascade reactions that are triggered by radical addition to alkynes.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The author declares no competing financial interest. Biography

Uta Wille graduated with her Ph.D. in Science at the University of Kiel, Germany, in 1993. Her Ph.D. thesis was performed in the area of Atmospheric Chemistry. She changed her research directions when she was offered a position for a Habilitation in Organic Chemistry at the same institution, which was completed in 1999. In 1997−1998, she undertook a Postdoctoral Fellowship with Professor Bernd Giese at the University of Basel, Switzerland. In 1999, she was appointed as Privatdozent at the University of Kiel and was invited in 2000 as a Visiting Fellow in the School of Chemistry at The University of Melbourne. In January 2003, Uta Wille moved permanently to Australia, where she was appointed as a Lecturer in the School of Chemistry at The University of Melbourne. In 2006, she was promoted to Senior Lecturer and in 2011 to Associate Professor and Reader at the same institution. Uta Wille is a Chief Investigator in the ARC Centre of Excellence for Free Radical Chemistry and Biotechnology. Her research program targets the chemistry of reactive intermediates by merging radicals of atmospheric importance with organic and bio-organic chemistry.

ACKNOWLEDGMENTS Support by the Australian Research Council under the Centre of Excellence Scheme and the National Computational Infrastructure Facility is gratefully acknowledged. REFERENCES (1) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions: Concepts, Guidelines and Synthetic Applications; Wiley-VCH Verlag: Weinheim, Germany, 1996. (2) See, for example: (a) Miyabe, H.; Takemoto, Y. Chem.Eur. J. 2007, 13, 7280−7286. (b) Sibi, M. P.; Yang, Y. H.; Lee, S. Org. Lett. 2008, 10, 5349. (c) Hata, S.; Sibi, M. P. Addition of Free Radicals to Carbon-Carbon Multiple Bonds. In Stereoselective Synthesis; De Vries, J. G., Molander, G. A., Evans, P. A., Eds.; Science of Synthesis, Vol. 1, Georg Thieme Verlag: Stuttgart, Germany, 2011; p 873 and references therein. AK


Chemical Reviews

Review

Org. Bioorg. Chem. 1997, 1, 1. (c) Melandri, D.; Montevecchi, P. C.; Navacchia, M. L. Tetrahedron 1999, 55, 12227. (28) Chatgilialoglu, C.; Mozziconacchi, O.; Tamba, M.; Bobrowski, K.; Kciuk, G.; Bertrand, M. P.; Gastaldi, S.; Timokhin, V. I. J. Phys. Chem. A 2012, 116, 7623. (29) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc. 1983, 105, 3292. (30) Concannon, C.; Rowland, F. S. J. Phys. Chem. 1981, 85, 89. (31) (a) Goumans, T. P. M.; van Alem, K.; Lodder, G. Eur. J. Org. Chem. 2008, 435. (b) Nagai, S.; Ohnishi, S.; Nitta, I. Chem. Phys. Lett. 1972, 13, 379. (c) Jenkins, P. R.; Symons, M. C. R.; Booth, S. E.; Swain, C. J. Tetrahedron Lett. 1992, 33, 3543. (32) Giese, B.; Gonzáles-Gómez, J. A.; Lachhein, S.; Metzger, J. O. Angew. Chem., Int. Ed. Engl. 1987, 26, 479. (33) Kharasch, M. S.; Jerome, J. J.; Urry, W. H. J. Org. Chem. 1950, 15, 966. (34) Kharasch, M. S.; Engelmann, H.; Mayo, F. R. J. Org. Chem. 1937, 2, 288. (b) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science 1945, 102, 128. (35) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1967, 89, 3772. (36) For relative rate coefficients of β-fragmentations, see: Wagner, P. J.; Sedon, J. H.; Lindstrom, M. J. J. Am. Chem. Soc. 1978, 100, 2579. (37) Maddess, M. L.; Mainetti, E.; Harrak, Y.; Brancour, C.; Devin, P.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Chem. Commun. 2007, 936. (38) Pignard, S.; Lopin, C.; Gouhier, G.; Piettre, S. R. J. Org. Chem. 2006, 71, 31. (39) Selected reviews on free radical reactions involving organoboranes: (a) Brown, H. C.; Midland, M. M. Angew. Chem., Int. Ed. Engl. 1972, 11, 692. (b) Darmency, V.; Renaud, P. Top. Curr. Chem. 2006, 263, 71. (40) Suzuki, A.; Miyaura, N.; Itoh, M. Synthesis 1973, 305. (41) (a) Tang, Y.; Li, C. Org. Lett. 2004, 6, 3229. (b) Fang, X.; Yang, X.; Yang, X.; Mao, S.; Wang, Z.; Chen, G.; Wu, F. Tetrahedron 2007, 63, 10684. (c) Amato, C.; Naud, C.; Calas, P.; Commeyras, A. J. Fluorine Chem. 2002, 113, 55. (d) Guo, X.-C.; Chen, Q.-Y. J. Fluorine Chem. 1998, 88, 63. (e) Balczewski, P.; Szadowiak, A.; Bialas, T. Heteroat. Chem. 2005, 16, 246. (f) Balczewski, P.; Bialas, T.; Szadowiak, A.; Mikolajczyk, M. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 1579. (g) Balczewski, P.; Bialas, T.; Mikolajczyk, M. Tetrahedron Lett. 2000, 41, 3687. (h) Curran, D. P.; Kim, D.; Ziegler, C. Tetrahedron 1991, 47, 6189. (i) Slodowicz, M.; Barata-Vallejo, S.; Vázquez, A.; Nudelman, N. S.; Postigo, A. J. Fluorine Chem. 2012, 135, 137. (j) Imoto, J.; Sato, A.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2009, 38, 462. (k) Ueda, M.; Matsubara, H.; Yoshida, K.; Sato, A.; Naito, T.; Miyata, O. Chem.Eur. J. 2011, 17, 1789. (42) Curran, D. P.; Kim, D. Tetrahedron 1991, 47, 6171. (43) Ichinose, Y.; Matsunaga, S.; Fugami, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1989, 30, 3155. (44) (a) Byers, J. H.; Lane, G. C. J. Org. Chem. 1993, 58, 3355. (b) Tsuchii, K.; Ogawa, A. Tetrahedron Lett. 2003, 44, 8777. (45) (a) Fujiwara, S.; Shimizu, Y.; Shin-ike, T.; Kambe, N. Org. Lett. 2001, 3, 2085. (b) Yamago, S.; Miyoshi, M.; Miyazoe, H.; Yoshida, J. Angew. Chem., Int. Ed. 2002, 41, 1407. (46) Feldman, K. S.; Ruckle, R. E., Jr.; Romanelli, A. L. Tetrahedron Lett. 1989, 30, 5845. (47) (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985, 26, 373. (b) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959. (48) Montevecchi, P. C.; Navacchia, M. L. Tetrahedron 2000, 56, 9339. (49) Okuro, K.; Alper, H. J. Org. Chem. 1996, 61, 5312. (50) Santi, R.; Bergamini, F.; Citterio, A.; Sebastiano, R.; Nicolini, M. J. Org. Chem. 1992, 57, 4250. (51) Fries, P.; Halter, D.; Kleinscheck, A.; Hartung, J. J. Am. Chem. Soc. 2011, 133, 3906. (52) (a) Chen, Z.; Zhang, Y.-X.; An, Y.; Song, X.-Li; Wang, Y.-H.; Zhu, L.-L.; Guo, L. Eur. J. Org. Chem. 2009, 5146. (b) Liu, Z.-Q.; Sun,

L.; Wang, J.-G.; Han, J.; Zhao, Y.-K.; Zhou, B. Org. Lett. 2009, 11, 1437. (53) Oka, R.; Nakayama, M.; Sakaguchi, S.; Ishii, Y. Chem. Lett. 2006, 35, 1104. (54) Geraghty, N. W. A.; Hernon, E. M. Tetrahedron Lett. 2009, 50, 570. (55) (a) Fernández, M.; Alonso, R. Org. Lett. 2005, 7, 11. (b) Fernández-Gonzáles, M.; Alonso, R. J. Org. Chem. 2006, 71, 6767. (56) Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G. Tetrahedron Lett. 1998, 39, 2441. (57) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo, P. Tetrahedron 1997, 53, 7929. (58) Nanni, D.; Pareschi, P.; Rizzoli, C.; Sgarabotto, P.; Tundo, A. Tetrahedron 1995, 51, 9045. (59) Lenoir, I.; Smith, M. L. J. Chem. Soc., Perkin Trans. 1 2000, 641. (60) (a) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863. (b) Curran, D. P.; Ko, S.-B.; Josien, H. Angew. Chem., Int. Ed. 1996, 34, 2683. (c) Curran, D. P.; Liu, H.; Josien, H.; Ko, S.-B. Tetrahedron Lett. 1996, 52, 11385. (d) Josien, H.; Ko, S.-B.; Curran, D. P. Chem.Eur. J. 1998, 4, 67. (61) Leardini, R.; Nanni, D.; Pedulli, G. F.; Tundo, A.; Zanardi, G. J. Chem. Soc., Perkin Trans. 1 1986, 1591. (62) Doohan, R. A.; Geraghty, N. W. A. Green Chem. 2005, 7, 91. (63) Schaffner, A.-P.; Darmency, V.; Renaud, P. Angew. Chem., Int. Ed. 2006, 45, 5847. (64) Yamago, S.; Miyoshi, M.; Miyazoe, H.; Yoshida, Y. Angew. Chem., Int. Ed. 2002, 41, 1407. (65) Chatgilialoglu, C. Organosilanes in Radical Chemistry; John Wiley and Sons Ltd.: Chichester, U.K., 2004. (66) Kopping, B.; Chatgilialogly, C.; Zehnder, M.; Giese, B. J. Org. Chem. 1992, 57, 3994. (67) Postigo, A.; Kopsov, S.; Ferreri, C.; Chatgilialoglu, C. Org. Lett. 2007, 9, 5159. (68) Hollingworth, G. J.; Pattenden, G.; Schulz, D. J. Aust. J. Chem. 1995, 48, 381. (69) Amrein, S.; Timmermann, A.; Studer, A. Org. Lett. 2001, 3, 2357. (70) Gottschling, S. E.; Grant, T. N.; Milnes, K. K.; Jennings, M. C.; Baines, K. M. J. Org. Chem. 2005, 70, 2686. (71) Back, T. G.; Mualidharan, K. R. J. Org. Chem. 1989, 54, 121. (72) Review: Oshima, K. Advances in Metal Organic Chemistry; JAI Press Ltd.: Greenwich, 1991; Vol. 2, p 101. (73) (a) Bernardoni, S.; Lucarini, M.; Pedulli, G. F.; Valgimigli, L.; Gevorgyan, V.; Chatgilialoglu, C. J. Org. Chem. 1997, 62, 8009. (b) Wang, Z.; Wnuk, S. F. J. Org. Chem. 2005, 70, 3281. (c) Wnuk, S. F.; Garcia, P. I., Jr.; Wang, Z. Org. Lett. 2004, 6, 2047. (74) Neumann, W. P.; Sommer, R. Liebigs Ann. Chem. 1964, 675, 10. (75) (a) Giese, B. Angew. Chem., Int. Ed. Engl. 1985, 24, 553. (b) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon Press: Oxford, U.K., 1986. (76) (a) Davies, A. G.; Pannek, K. Tin Chemistry: Fundamentals, Frontiers and Applications. John Wiley and Sons Ltd.: Chichester, U.K., 2008. (b) Davies, A. G. Organotin Chemistry, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004. Vol. 1. (77) Examples for radical hydrostannylation of alkynes: (a) Nishida, M.; Nishida, A.; Kawahara, N. J. Org. Chem. 1996, 61, 3574. (b) Dodero, V. I.; Koll, L. C.; Mandolesi, S. D.; Podestá, J. C. J. Organomet. Chem. 2002, 650, 173. (c) Dodero, V. I.; Mitchell, T. N.; Podestá, J. C. Organometallics 2003, 22, 856. (d) Faraoni, M. B.; Dodero, V. I.; Podestá, J. C. ARKIVOC 2005, 88. (e) Faraoni, M. B.; Dodero, V. I.; Koll, L. C.; Zúñiga, A. E.; Mitchell, T. N.; Podestá, J. C. J. Organomet. Chem. 2006, 691, 1085. (f) Faraoni, M. B.; Dodero, V. I.; Gerbino, D. C.; Koll, L. C.; Zúñiga, A. E.; Mitchell, T. N.; Podestá, J. C. Organometallics 2005, 24, 1992. (g) Capella, L.; Montevecchi, P. C.; Nanni, D. J. Org. Chem. 1994, 59, 3368. (78) Stork, G.; Mook, R., Jr. Tetrahedron Lett. 1986, 27, 4529. (79) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron 1989, 45, 923. AL


Chemical Reviews

Review

(107) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett. 2003, 5, 3795. (b) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Redondo, M. C. J. Org. Chem. 2007, 72, 1604. (108) Shanmugam, P.; Rajasingh, P. Tetrahedron Lett. 2005, 46, 3369. (109) Leeuwenburgh, M. A.; Litjens, R. E. J. N.; Codée, J. D. C.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H. Org. Lett. 2000, 2, 1275. (110) Davies, K. A.; Wulff, J. E. Org. Lett. 2011, 13, 5552. (111) Baldwin, J. E.; Adlington, R. M.; Robertson, J. Tetrahedron 1991, 47, 6795. (112) Bosch, E.; Bachi, M. D. J. Org. Chem. 1993, 58, 5581. (113) Hoepping, A.; George, C.; Flippen-Anderson, J.; Kozikowski, A. P. Tetrahedron Lett. 2000, 41, 7427. (114) Gómez, A. M.; Company, M. D.; Uriel, C.; Valverde, S.; López, J. C. Tetrahedron Lett. 2007, 48, 1645. (115) Marco-Contelles, J. Chem. Commun. 1996, 2629. (116) Marco-Contelles, J.; Domínguez, L.; Anjum, S.; Ballesteros, P.; Soriano, E.; Postel, D. Tetrahedron: Asymmetry 2003, 14, 2865. (117) Journet, M.; Rouillard, A.; Cai, D.; Larsen, R. D. J. Org. Chem. 1997, 62, 8630. (118) (a) Lee, H.-Y.; Lee, S.; Kim, B. G.; Bahn, J. S. Tetrahedron Lett. 2004, 45, 7225. (b) Lee, H.-Y.; Kim, B. G. Org. Lett. 2000, 2, 1951. (119) (a) Lee, H.-Y.; Moon, D. K.; Bahn, J. S. Tetrahedron Lett. 2005, 46, 1455. (b) Lee, H.-Y.; Murugan, R. N.; Moon, D. K. Eur. J. Org. Chem. 2009, 5028. (120) (a) Rainier, J. D.; Kennedy, A. R.; Chase, E. Tetrahedron Lett. 1999, 40, 6325. (b) Rainier, J. D.; Kennedy, A. R. J. Org. Chem. 2000, 65, 6213. (121) (a) Kovalenko, S. V.; Peabody, S.; Manoharan, M.; Clark, R. J.; Alabugin, I. V. Org. Lett. 2004, 6, 2457. (b) Peabody, S. W.; Breiner, B.; Kovalenko, S. V.; Patil, S.; Alabugin, I. V. Org. Biomol. Chem. 2005, 3, 218. (c) Alabugin, I. V.; Gilmore, K.; Patil, S.; Manoharan, M.; Kovalenko, S. V.; Clark, R. J.; Ghiviriga, I. J. Am. Chem. Soc. 2008, 130, 11535. (122) König, B.; Pitsch, W.; Klein, M.; Vasold, R.; Prall, M.; Schreiner, P. R. J. Org. Chem. 2001, 66, 1742. (123) Wille, U.; Plath, C. Liebigs Ann./Recl. 1997, 111. (124) Wille, U. J. Phys. Org. Chem. 2011, 24, 672. (125) Wille, U.; Dreessen, T. J. Phys. Chem. A 2006, 110, 2195. (126) Wille, U. J. Org. Chem. 2006, 71, 4040. (127) Example: Felix, D.; Schreiber, J.; Ohloff, G.; Eschenmoser, A. Helv. Chim. Acta 1971, 54, 2896. (128) (a) Wille, U.; Lietzau, L. Tetrahedron 1999, 55, 10119. (b) Lietzau, L.; Wille, U. Heterocycles 2001, 55, 377. (c) Wille, U.; Lietzau, L. Tetrahedron 1999, 55, 11465. (d) Stademann, A.; Wille, U. Aust. J. Chem. 2005, 57, 1055. (129) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans. 1915, 107, 1080. (130) Li, C. H. Honours Thesis, The University of Melbourne, 2006. (131) Wille, U. Org. Lett. 2000, 2, 3485. (132) Wille, U. Tetrahedron Lett. 2002, 43, 1239. (133) Wille, U. J. Am. Chem. Soc. 2002, 124, 14. (134) Jargstorff, C.; Wille, U. Eur. J. Org. Chem. 2003, 3173. (135) Sigmund, D.; Schiesser, C. H.; Wille, U. Synthesis 2005, 1437. (136) Wille, U.; Jargstorff, C. J. Chem. Soc., Perkin Trans. 1 2002, 1036. (137) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334. (138) (a) Sanderson, R. T. Polar Covalence; Academic Press: New York, 1983. (b) Sanderson, R. T. Chemical Bonds and Bond Energy; Academic Press: New York, 1976. (139) Kim, S.; Lim, C. J.; Song, S. E.; Kang, H. Y. Synlett 2001, 688. (140) Gamon, L. Master's Thesis, University of Melbourne, 2011. (141) Wille, U.; Andropof, J. Aust. J. Chem. 2007, 60, 420. (142) See, for example: (a) Koenig, T. W.; Barklow, T. Tetrahedron 1969, 25, 4875. (b) Dayan, S.; Ben-David, I.; Rozen, S. J. Org. Chem. 2000, 65, 8816. (143) S-Centered Radicals; Alfassi, Z. B., Ed.; John Wiley & Sons: Chichester, U.K., 1999. (144) Tan, K. J.; Wille, U. Chem. Commun. 2008, 6239.

(80) A mechanistic study on the regioselectivity of Sn-radical additions to enynes has been reported: Robertson, J.; Lam, H. W.; Abazi, S.; Roseblade, S.; Lush, R. K. Tetrahedron 2000, 56, 8959. (81) Miura, K.; Saito, H.; Itoh, D.; Matsuda, T.; Fujisawa, N.; Wang, D.; Hosomi, A. J. Org. Chem. 2001, 66, 3348. (82) Ryu, I.; Fukuyama, T.; Nobuta, O.; Uenoyama, Y. Bull. Korean Chem. Soc. 2010, 31, 545. (83) (a) Tojino, M.; Uenoyama, Y.; Fukuyama, T.; Ryu, I. Chem. Commun. 2004, 2482. (b) Ryu, I.; Fukuyama, T.; Tojino, M.; Uenoyama, Y.; Yonamine, Y.; Terasoma, N.; Matsubara, H. Org. Biomol. Chem. 2011, 9, 3780. (84) Uenoyama, Y.; Fukuyama, T.; Nobuta, O.; Matsubara, H.; Ryu, I. Angew. Chem., Int. Ed. 2005, 44, 1075. (85) (a) Schiesser, C. H.; Matsubara, H.; Ritsner, I.; Wille, U. Chem. Commun. 2006, 1067. (b) Schiesser, C. H.; Wille, U.; Matsubara, H.; Ryu, I. Acc. Chem. Res. 2007, 40, 303. (86) (a) Wille, U.; Mucke, E.-K. Chem. Lett. 2007, 36, 300. (b) Wille, U.; Tan, J. C. S.; Mucke, E.-K. J. Org. Chem. 2008, 73, 5821. (87) (a) Ryu, I.; Miyazato, H.; Kuriyama, H.; Matsu, K.; Tojino, M.; Fukuyama, T.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 2003, 125, 5632. (b) Tojino, M.; Otsuka, N.; Fukuyama, T.; Matsubara, H.; Ryu, I. J. Am. Chem. Soc. 2006, 128, 7712. (c) Tojino, M.; Ostuka, N.; Fukuyama, T.; Matsubara, H.; Schiesser, C. H.; Kuriyama, H.; Miyazato, H.; Minakata, S.; Komatsu, M.; Ryu, I. Org. Biomol. Chem. 2003, 1, 4262. (88) Uenoyama, Y.; Fukuyama, T.; Ryu, I. Org. Lett. 2007, 9, 935. (89) Lang, P.; Mayer, A.; Jung, P.; Tritsch, D.; Biellmann, J.-F.; Burger, A. Tetrahedron Lett. 2004, 45, 4013. (90) Toyota, M.; Yokota, M.; Ihara, M. J. Am. Chem. Soc. 2001, 123, 1856. (91) Further examples for syntheses of natural products and biologically active compounds, where enyne radical cascades mediated by Sn-radical addition to terminal alkynes are used as key step: (a) Ko, H. M.; Lee, C. W.; Kwon, H. K.; Chung, H. S.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew. Chem., Int. Ed. 2009, 48, 2364. (b) Stork, G.; Tang, P. C.; Casey, M.; Goodman, B.; Toyota, M. J. Am. Chem. Soc. 2005, 127, 16255. (c) Bueno, J. M.; Coterón, J. M.; Chiara, J. L.; FernándezMayoralas, A.; Fiandor, J. M.; Valle, N. Tetrahedron Lett. 2000, 41, 4379. (d) Yun, S. Y.; Zheng, J.-C.; Lee, D. Angew. Chem., Int. Ed. 2008, 47, 6201. (e) Ghosh, A. K.; Chapsai, B. D.; Baldridge, A.; Ide, K.; Koh, Y.; Mitsuya, H. Org. Lett. 2008, 10, 5135. (f) Yadaf, J. S.; Maiti, A.; Sankar, A. R.; Kunwar, A. C. J. Org. Chem. 2001, 66, 8370. (92) He, W.; Huang, J.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2007, 129, 498. (93) Kaliappan, K. P.; Ravikumar, V. Org. Lett. 2007, 9, 2417. (94) Njardarson, J. T.; McDonald, I. M.; Spiegel, D. A.; Inoue, M.; Wood, J. L. Org. Lett. 2001, 3, 2435. (95) Cossy, J.; Pévet, I.; Meyer, C. Eur. J. Org. Chem. 2001, 2841. (96) Muratake, H.; Natsume, N. Angew. Chem., Int. Ed. 2004, 43, 4646. (97) Beruben, D.; Kundig, E. P. Helv. Chim. Acta 1996, 79, 1533. (98) Dimopoulos, P.; George, J.; Tocher, D. A.; Manaviazar, S.; Hale, K. J. Org. Lett. 2005, 7, 5377. (99) Gowrisankar, S.; Lee, K. Y.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2006, 47, 5785. (100) Miura, K.; Saito, H.; Fujisawa, N.; Hosomi, A. J. Org. Chem. 2000, 65, 8119. (101) Gowrisankar, S.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007, 48, 3105. (102) Miura, K.; Fujisawa, N.; Saito, H.; Nishikori, H.; Hosomi, A. Chem. Lett. 2002, 65, 32. (103) Miura, K.; Saito, H.; Fujisawa, N.; Wang, D.; Nishikori, H.; Hosomi, A. Org. Lett. 2001, 3, 4055. (104) Gharpure, S. J.; Porwal, S. K. Tetrahedron Lett. 2009, 50, 7162. (105) Nishida, A.; Takahashi, H.; Takeda, H.; Takada, N.; Yonemitsu, O. J. Am. Chem. Soc. 1990, 112, 902. (106) Nishida, A.; Miyoshi, I.; Ogasawara, Y.; Nagumo, S.; Kawahara, N.; Nishida, M.; Takayanagi, H. Tetrahedron 2000, 56, 9241. AM


Chemical Reviews

Review

(145) (a) Benati, L.; Capella, L.; Montevecchi, P. C.; Spagnolo, P. J. Org. Chem. 1995, 60, 7941. (b) Benati, L.; Capella, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1995, 1035. (c) Brace, N. O. J. Fluorine Chem. 1993, 62, 217. (d) Banerjee, B.; Litvinov, D. N.; Kang, J.; Bettale, J. D.; Castle, S. L. Org. Lett. 2010, 12, 2650. (e) Guy, R. G.; Cousins, S.; Farmer, D. M.; Henderson, A. D.; Wilson, C. L. Tetrahedron 1980, 36, 1839. (f) Dolbier, W. R., Jr.; Aït-Mohand, S.; Schertz, T. D.; Sergeeva, T. A.; Cradlebaugh, J. A.; Mitani, A.; Gard, G. L.; Winter, R. W.; Thrasher, J. S. J. Fluorine Chem. 2006, 127, 1302. (g) Nakatani, S.; Yoshida, J.; Isoe, S. J. Chem. Soc., Chem. Commun. 1992, 880. (h) Benati, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1991, 2103. (i) Sato, A.; Yorimitsu, H.; Oshima, K. Bull. Korean Chem. Soc. 2010, 31, 570. (j) Lanza, T.; Minozzi, M.; Monesi, A.; Nanni, D.; Spagnolo, P.; Chiappe, C. Curr. Org. Chem. 2009, 13, 1726. (k) Lo Conte, M.; Staderini, S.; Marra, A.; SanchezNavarro, M.; Davis, B. G.; Dondoni, A. Chem. Commun. 2011, 47, 11086. (l) Minozzi, M.; Monesi, A.; Nanni, D.; Spagnolo, P.; Marchetti, N.; Massi, A. J. Org. Chem. 2011, 76, 450. (m) Lo Conte, M.; Pacifico, S.; Chambery, A.; Marra, A.; Dondoni, A. J. Org. Chem. 2010, 75, 4644. (n) Sato, A.; Yorimitsu, H.; Oshima, K. Tetrahedron 2009, 65, 1553. (146) (a) Hoogenboom, R. Angew. Chem., Int. Ed. 2010, 49, 3415. (b) Lowe, A. B.; Hoyle, C. E.; Bowman, C. N. J. Mater. Chem. 2010, 20, 4745. (c) Massi, A.; Nanni, D. Org. Biomol. Chem. 2012, 9, 3791. (147) Zhou, W.; Zheng, H.; Li, Y.; Liu, H.; Li, Y. Org. Lett. 2010, 12, 4078. (148) For a recent review on S-radical mediated cyclizations, see: (a) Majumdar, K. C.; Debnath, P. Tetrahedron 2008, 64, 9799−9820. (b) Mondal, S. Synlett 2010, 2202. (149) Broka, C. A.; Reichert, D. E. C. Tetrahedron Lett. 1987, 28, 1503. (150) Ichinose, Y.; Nozaki, K.; Birbaum, J.-L.; Oshima, K.; Utimoto, K. Chem. Lett. 1987, 1647. (151) (a) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo, P. Tetrahedron Lett. 1997, 38, 7913. (b) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo, P. Eur. J. Org. Chem. 1998, 1219. (152) (a) Benati, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1992, 1659. (b) Capella, L.; Montevecchi, P. C.; Navacchia, M. L. J. Org. Chem. 1996, 61, 6783. (153) Taniguchi, T.; Fujii, T.; Idota, A.; Ishibashi, H. Org. Lett. 2009, 11, 3298. (154) Zhou, J.; Zhang, G.-H.; Zou, J.-P.; Zhang, W. Eur. J. Org. Chem. 2011, 3412. (155) Majumdar, K. C.; Maji, P. K.; Ray, K.; Debnath, P. Tetrahedron Lett. 2007, 48, 9124. (156) Majumdar, K. C.; Modal, S.; Ghosh, D. Tetrahedron Lett. 2010, 51, 348. (157) Majumdar, K. C.; Debnath, P.; Maji, P. K. Tetrahedron Lett. 2007, 48, 5265. (158) Majumdar, K. C.; Modal, S.; Ghosh, D. Tetrahedron Lett. 2010, 51, 5273. (159) Majumdar, K. C.; Taher, A. Tetrahedron Lett. 2009, 50, 5265. (160) Majumdar, K. C.; Ray, K.; Debnath, P.; Maji, P. K.; Kundu, N. Tetrahedron Lett. 2008, 49, 5597. (161) Alcaide, B.; Almendros, P.; Aragoncillo, C. J. Org. Chem. 2001, 66, 1612. (162) Majumdar, K. C.; Debnath, P.; Alam, S.; Maji, P. K. Tetrahedron Lett. 2007, 48, 7031. (163) Prabhakaran, E. N.; Nugent, B. M.; Williams, A. L.; Nailor, K. E.; Johnston, J. N. Org. Lett. 2002, 4, 4197. (164) Keck, G. E.; Wagner, T. T. J. Org. Chem. 1996, 61, 8366. (165) Friestad, G. K.; Jiang, T.; Fioroni, G. M. Tetrahedron: Asymmetry 2003, 14, 2853. (166) Friestad, G. K.; Jiang, T.; Fiorini, G. M. Tetrahedron 2008, 64, 11549. (167) Bencivenni, G.; Lanza, T.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Zanardi, G. Org. Lett. 2008, 10, 1127. (168) Benati, L.; Calestani, G.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Strazzari, S. Org. Lett. 2003, 5, 1313.

(169) Benati, L.; Bencivenni, G.; Leardini, R.; Minozzi, M.; Nanni, D.; Scialpi, R.; Spagnolo, P.; Zanardi, G. J. Org. Chem. 2006, 71, 3192. (170) Carta, P.; Puljic, N.; Robert, C.; Dhimane, A.-L.; Fensterbank, L.; Lacôte, E.; Malacria, M. Org. Lett. 2007, 9, 1061. (171) For formation of thiyl peroxyl radicals through reaction of aryl thiyl radicals with O2, see refs 26a, b, and 143. (172) (a) Yang, N. C.; Libman, J. J. Org. Chem. 1974, 39, 1782. (b) Griesbaum, K.; Dong, Y.; McCullough, K. J. J. Org. Chem. 1997, 62, 6129. (173) Tan, K. J.; White, J. M.; Wille, U. Eur. J. Org. Chem. 2010, 4902. (174) Selected examples: (a) Lachia, M.; Dénès, F.; Beaufils, F.; Renaud, P. Org. Lett. 2005, 7, 4103. (b) Dénès, F.; Beaufils, F.; Renaud, P. Org. Lett. 2007, 9, 4375. (c) Beaufils, F.; Dénès, F.; Renaud, P. Org. Lett. 2004, 6, 2563. (d) Beaufils, F.; Dénès, F.; Becattini, B.; Renaud, P.; Schenk, K. Adv. Synth. Catal. 2005, 347, 1587. (e) Renaud, P.; Beaufils, F.; Feray, L.; Schenk, K. Angew. Chem., Int. Ed. 2003, 42, 4230. (175) Griffiths, J.; Murphy, J. A. Tetrahedron Lett. 1992, 48, 5543. (176) Burke, S. D.; Jung, K. W. Tetrahedron Lett. 1994, 35, 5837. (177) Crick, P. J.; Simpkins, N. S.; Highton, A. Org. Lett. 2011, 13, 6472. (178) Leardini, L.; Nanni, D.; Zanardi, G. J. Org. Chem. 2000, 65, 2763. (179) Mitamura, T.; Tsuboi, Y.; Iwata, K.; Tsuchii, K.; Nomoto, A.; Sonoda, M.; Ogawa, A. Tetrahedron Lett. 2007, 48, 5953. (180) Caddick, S.; Hamza, D.; Wadman, S. N. Tetrahedron Lett. 1999, 40, 7285. (181) Tsimelzon, A.; Braslau, R. J. Org. Chem. 2005, 70, 10854. (182) Brumwell, J. E.; Simpkins, N. S.; Terrett, N. K. Tetrahedron 1994, 50, 13533. (183) Alcaide, B.; Rodríguez-Campos, I. M.; Rodríguez-Lôpez, J.; Rodríguez-Vicente, A. J. Org. Chem. 1999, 64, 5377. (184) Huang, X.; Liang, C.-G.; Xu, Q.; He, Q.-W. J. Org. Chem. 2001, 66, 74. (185) Example for noncascade addition of Se-radicals to alkynes: (a) Ogawa, A.; Obayashi, R.; Sekiguchi, M.; Masawaki, T. Tetrahedron Lett. 1992, 33, 1329. For simultaneous addition of seleno and phosphino groups to alkynes see: (b) Kawaguchi, S.; Shirai, T.; Ohe, T.; Nomoto, A.; Sonoda, M.; Ogawa, A. J. Org. Chem. 2009, 74, 1751. (c) Trofimov, B. A.; Gusarova, N. K.; Arbuzova, S. N.; Ivanova, N. I.; Artem’ev, A. V.; Volkov, P. A.; Ushakov, I. A.; Malysheva, S. F.; Kuimov, V. A. J. Organomet. Chem. 2009, 694, 677. For simultaneous addition of seleno and thio groups, seleno and telluro groups, or thio and telluro groups to alkynes, see: (d) Ogawa, A.; Ogawa, I.; Obayashi, R.; Umezu, K.; Doi, M.; Hirao, T. J. Org. Chem. 1999, 64, 86. (186) Ogawa, A. Selenium and Tellurium in Organic Synthesis. In Main Group Metals in Organic Synthesis; Yamamoto, H., Oshima, K., Eds.; Wiley VCH: Weinheim, Germany, 2004; p 813. (187) Back, T. G.; Krishna, M. V. J. Org. Chem. 1988, 53, 2533. (188) Ogawa, A.; Yokoyama; Masawaki, T.; Kambe, N.; Sonoda, N. J. Org. Chem. 1991, 56, 5721. (189) (a) Ogawa, A.; Ogawa, I.; Sonoda, N. J. Org. Chem. 2000, 65, 7682. (b) Tsuchii, K.; Doi, M.; Hirao, T.; Ogawa, A. Angew. Chem., Int. Ed. 2003, 42, 3490. (190) Tsuchii, K.; Doi, M.; Ogawa, I.; Einaga, Y.; Ogawa, A. Bull. Chem. Soc. Jpn. 2005, 78, 1534. (191) Byers, J. H.; Goff, P. H.; Janson, N. J.; Mazzotta, M. G.; Swigor, J. E. Synth. Commun. 2007, 37, 1865. (192) (a) Han, L.-B.; Ishihara, K.; Kambe, N.; Ryu, I.; Ogawa, A.; Sonoda, N. J. J. Am. Chem. Soc. 1992, 114, 7591. (b) Yamago, S.; Miyazoe, H.; Yoshida, J. Tetrahedron Lett. 1999, 40, 2343. (c) Terao, J.; Kambe, N.; Sonoda, N. Tetrahedron Lett. 1998, 39, 5511. (193) Ogawa, A.; Yokoyama, K.; Obayashi, R.; Han, L.-B.; Kambe, N.; Sonoda, N. Tetrahedron 1993, 49, 1177. (194) Mitamura, T.; Iwata, K.; Ogawa, A. Org. Lett. 2009, 11, 3422. (195) Example for non-cascade addition of N-radicals to alkynes: Neale, R. S. J. Am. Chem. Soc. 1964, 86, 5340. AN


Chemical Reviews

Review

(196) Examples: (a) Wolf, M. E. Chem. Rev. 1963, 63, 55. (b) Neale, R. S. Synthesis 1971, 1. (c) Minisci, F. Synthesis 1973, 1. (d) Chow, Y. L. Acc. Chem. Res. 1973, 6, 354. (e) Minisci, F. Acc. Chem. Res. 1975, 8, 165. (f) Chow, Y. L.; Danen, W. C.; Nelsen, S. F.; Rosenblatt, D. H. Chem. Rev. 1978, 78, 243. (g) Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337. (h) Chow, Y. L. Can. J. Chem. 1965, 43, 2711. (i) Chow, Y. L.; Colón, C. Can. J. Chem. 1967, 45, 2559. (197) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic Chemistry; John Wiley & Sons/Masson: Chichester, U.K., 1995. (198) Wille, U.; Krüger, O.; Kirsch, A.; Lüning, U. Eur. J. Org. Chem. 1999, 3185. (199) Wille, U.; Heuger, G.; Jargstorff, C. J. Org. Chem. 2008, 73, 1413. (200) For recent reviews on P-centered radicals in organic synthesis, see: (a) Leca, D.; Fensterbank, L.; Lacôte, E.; Malacria, M. Chem. Soc. Rev. 2005, 34, 858. (b) Arbuzova, S. N.; Gusarova, N. K.; Trofimov, B. A. ARKIVOC 2006, 12. (c) Coudray, L.; Montchamp, J.-L. Eur. J. Org. Chem. 2008, 3601. (201) (a) Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D. J. Tetrahedron: Asymmetry 2003, 14, 2849. (b) Heesche-Wagner, K.; Mitchell, T. N. J. Organomet. Chem. 1994, 468, 99. (c) GouaultBironneau, S.; Deprèle, S.; Sutor, A.; Montchamp, J.-L. Org. Lett. 2005, 7, 5909. (d) Antczak, M. I.; Montchamp, J.-L. Synthesis 2006, 3080. (e) Semenzin, D.; Etemad-Moghadam, G.; Albouy, D.; Diallo, O.; Koenig, M. J. Org. Chem. 1997, 62, 2414. (f) Tayama, O.; Nakano, A.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004, 69, 5494. For simultaneous addition of thio- and phosphino groups to alkynes, see: (g) Wada, T.; Kondoh, A.; Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 1155. (202) Beaufils, F.; Dénès, F.; Renaud, P. Angew. Chem., Int. Ed. 2005, 44, 5273. (203) Sato, A.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2005, 44, 1694.

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