Ring Formation by 5-endo-dig Cyclization

CHAPTER ONE

Ring Formation by 5-endo-dig Cyclization David W. Knight1 School of Chemistry, Cardiff University, Cardiff, United Kingdom 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction and Theoretical Aspects 2. Furans 2.1 Gold-Catalyzed 5-endo-Cyclizations 2.2 Silver-Catalyzed Cyclizations 2.3 Furan Formation Catalyzed by Other Metals (Pd, Cu, Pt, Zn) 2.4 Iodocyclizations 2.5 Base-Catalyzed Cyclizations, Dihydrofurans, and Relatives 3. Pyrroles 3.1 Gold-Catalyzed 5-endo-Cyclizations 3.2 Copper-Catalyzed 5-endo-dig Cyclizations 3.3 Silver-Catalyzed 5-endo-dig Cyclization 3.4 Palladium and Other Metals 3.5 Iodocyclizations 3.6 Acid, Base, or Just Heat 3.7 Dihydropyrroles 4. Thiophenes 5. Benzofurans 5.1 Base- and Acid-Catalysts 5.2 Iodocyclizations and Relatives 5.3 Gold-Catalyzed Synthesis 5.4 Palladium-, Pd–Cu, and Copper-Catalyzed Cyclizations 5.5 Heteroarylfurans 6. Indoles 6.1 Gold-Catalyzed Indole Synthesis 6.2 Palladium-Catalyzed Cyclizations 6.3 Copper-Catalyzed Indole Synthesis 6.4 Other Metal-Catalyzed Methods 6.5 Iodocyclizations Leading to Indoles 6.6 Base-Induced Cyclizations 7. Benzothiophenes and Benzoselenophenes 8. Indolizines

Advances in Heterocyclic Chemistry, Volume 127 ISSN 0065-2725 https://doi.org/10.1016/bs.aihch.2018.09.004

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2019 Elsevier Inc. All rights reserved.

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9. Pyrazoles, Triazoles, Isoxazoles, and Oxazoles 9.1 Pyrazoles 9.2 Triazoles 9.3 Isoxazoles 9.4 Oxazoles 10. Carbocycles 10.1 Cyclopentenes and Cyclopentenones 10.2 Indenes and Relatives 10.3 Selective Alkyne Hydration References Further Reading

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Abstract This review attempts to cover the use of 5-endo-dig cyclizations, “favored” as defined by Baldwin’s rules, in the synthesis of heterocyclic and carbocyclic ring systems, ranging from furans, pyrroles, thiophenes, and their benzo-derivatives to cyclopentenes, indenes, and some more complex derivatives along with partly saturated examples. While some key contributions published prior to the turn of the millennium are included, the review consists predominantly of papers, which appeared after the year 2000. Despite that the original versions of Baldwin’s rules were focused on nucleophiledriven processes, much of the considerable progress made in this area during this period has featured electrophile-driven cyclizations, often in a catalytic mode, the latter feature imbuing clear environmental advantages to many of these transformations. Hence, many examples have, as a key step, the attack of a nucleophilic center onto an activated alkyne, occasionally an allene, although these may be undetected intermediates in some cases. This defines the 5-endo-dig status of a particular transformation; because of the large volume of such contributions, this means that much closely related and useful methodology has had to be omitted. Brief sections on theoretical aspects and a summary of previously published reviews are also included. Keywords: 5-endo-dig, Cyclizations, Electrophile-driven, Heteroaromatic, Synthesis, Heterocyclic, Catalytic, Ring formation, Alkynes, Nucleophilic attack

1. INTRODUCTION AND THEORETICAL ASPECTS The focus of this review is concerned entirely with 5-endo-dig cyclizations, as originally defined by Baldwin (1976CC734). Despite what looks to be a somewhat distant interaction between the two centers involved (1; Fig. 1), given activation of the alkyne group by an electrophilic species (2), cyclization to 3 does not seem so implausible and, indeed, the 5-endo-dig mode was originally suggested as “favorable” by Baldwin, in his remarkably

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Fig. 1 The basic mechanism.

perceptive contribution, which has altered the very language of synthetic organic chemistry. Applications of the 5-endo-dig cyclization mode were relatively rare at this time and subsequently slowly became more popular, especially for the elaboration of heteroaromatic systems, such as furans, indoles, and latterly carbocycles. In more recent times, there has been a veritable explosion of interest in such reactions, especially as it has been found that such processes are highly amenable to catalytic activation, especially using gold complexes and often in minute amounts (2007JCS(CC)333, 2007AGE3410, 2007NAT395, 2007CRV3180, 2007NAT7160, 2008CRV3266, 2008CRV3239, 2015CRV9028). Added to this, the facts that the vast bulk of modern pharmaceuticals and many other useful chemical products are based on heteroaromatic residues and that existing synthetic methodology in the alkyne area offers plenty of opportunities for relatively facile precursor synthesis goes a long way to explaining this heightened activity (2011JCS(CC)6536). Once the basic viability of a particular cyclization has been established, very often featuring the use of a transition metal complex (2004CRV2285, 2013CRV3084), the imaginative incorporation of additional functional groups and structural features has resulted in some spectacular contributions to general heterocyclic, heteroaromatic, and carbocyclic synthesis, often employing methodology which is both mild, relatively simple and especially environmentally attractive. Ligand effects in homogeneous gold catalysis have been reviewed (2008CRV3351). Not surprisingly, such chemistry has played a key role in many target syntheses (2008CSR1766,2016CSR1331). Of course, all such advances are usually based on older insights. Others might disagree, but in my view, a seminal contribution in this area, and a portent of what was to follow, came from the Castro group in 1966 (1966JOC4071) with the discovery that 2-iodoanilines 4 could be sequentially coupled with copper acetylides and the resulting amino-alkynes 5 cyclized to form indoles 6, often in excellent yields, especially when carried

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Scheme 1 One of the original starting points of the 5-endo-dig cyclization method.

out in two separate steps (Scheme 1). Benzofurans can similarly be synthesized from iodophenols, albeit in poor yield, but this is the basis of one of the most used and subsequently modified tactics in this area: sequential Sonogashira coupling, cyclization, and perhaps additional functionalization, as will be illustrated in the following paragraphs. In the original deductions made by Baldwin, the rules were applied only to first row elements. However, subsequent results have shown the viability of extending them to heavier elements, including sulfur and selenium; hence, thiophene and benzothiophene syntheses are included herein. It was also originally suggested that the rules should be applied to nucleophiledriven cyclizations; however, as will become apparent from the following examples, the vast majority of 5-endo-dig cyclizations appear to rely on electrophilic activation of the alkyne group to subsequent attack by the waiting nucleophile. Perhaps oddly, however, there are a few purely base-driven processes, wherein it is difficult to see how the alkyne is activated in any way, for example by being conjugated to a carbonyl group or the equivalent. In addition, one wonders about the veracity of the mechanistic details concerning the manner in which a metal bonds with and activates the alkyne: the usual description looks very much like the three-membered intermediate which is usually used to depict the additions of a halogen to an alkene or alkyne. Is this really correct and sufficient? Naturally, there have been a number of subsequent theoretical studies of 5-endo-dig cyclizations and Baldwin’s rules in general, following their initial publication. It was deduced some time ago that this type of ring closure has a rapidly formed but late transition state (1985JST79) and that such ring formation from 2-hydroxy-4-yn-3-ones, when acid catalyzed, features alkyne protonation as a rate-limiting step rather than at the carbonyl oxygen (1989JCS(P2)957). The results also concur with Baldwin’s original suggestion of an acute 60 degree approach of the nucleophilic center. These and other related methodology have recently been the subject of two reviews (2011CRV6513, 2013JCS(CC)11246).

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In a substantial publication (2011JA12608), a largely computer-based update of Baldwin’s rules has been reported. Substantive conclusions among many are that, in contrast to the foregoing work, endo processes may well feature obtuse rather than acute nucleophile trajectories as originally suggested, although this may be masked by the intrinsic stability of the various products. One encouraging conclusion from this chapter is that “the 5-endo-dig closure looks special!” Furthermore, for all diagonal cyclizations, exo-closures are always stereoelectronically preferred over the related endo-closure, independent of the linker, and the nature of the nucleophile. Thus, endo closures can only compete when thermodynamic contributions overcome such preferences. Alkyne polarization can also sometimes be overwritten when a ring closure such as a 5-endo-dig reaction is coupled with a [3.3]-sigmatropic rearrangement (2009CEJ838). Further studies (2012JA10584) have suggested that anion-driven 5-endo-dig ring closures are aborted sigmatropic shifts and the first unambiguous examples of nonpericyclic reactions having transitions states stabilized by aromaticity—an in-plane 5-centered, 6-electron arrangement. A study of counter-ion effects in homogeneous gold catalysts of the type so often used to trigger 5-endo-dig and related closures should find use in the future design of such activators (2015ACS(CAT)1638), a feature also emphasized in the exploitation of mixed gold–palladium catalysts for combined ring closure arylation of conjugated allenic esters 7 with aryliodides 8 leading to butenolides 9 (Scheme 2) (2016JA3266). The synergistic catalysts benefit from the Lewis acidity of the gold and the redox properties of the palladium. It is possible that in some cases at least, nucleophilic addition to alkynes, such as when potassium methoxide adds to a 1-arylalkyne in N,Ndimethylformamide (DMF), involves an single-electron transfer (SET) mechanism leading to (Z)-alkenes (2015T4385). A similar (Z)-selectivity

Scheme 2 The importance of careful ligand design in an Au–Pd-catalyzed butenolide synthesis.

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occurs in the hydroamination of 1-alkynes using secondary amides and a Ru–Yb-based catalyst system (2011JOM170). The implications to 5-endo-dig closures are unclear. Iodocyclizations have made many useful contributions to 5-endo-dig methodology, particularly as the iodine atom so introduced provides a channel for subsequent elaboration of the initial products. An extensive study of such reactions concludes that a molecular iodine–alkyne complex is involved, meaning that both alkyne carbons are activated toward nucleophilic attack, as opposed to when an iodonium ion is involved, when only one center is activated (2015CEJ10191). An additional and very useful finding is that when an attempted cyclization, in the case of a recalcitrant substrate, results instead in iodine addition to the alkyne to give a trans-vicinal diiodide, such an unwanted process can be reversed simply by heating the reaction mixture and thus allowing the desired cyclization to take place. For example (Scheme 3), treatment of the “blocked” 2-alkynylanisoles 10 with iodine in 1,2-dichloroethane (DCE) at ambient temperature results in the almost exclusive formation of the diiodide 11 but heating to 80°C reverses the addition and induces sequential cyclization and O-demethylation to give exclusively the 3-iodobenzofurans 12. Mechanistic uncertainty surrounded a sequence whereby an alkynyl azirine 13 is transformed into a pyridine using a gold(I) catalyst (Scheme 4). Computational studies suggested an initial 5-endo-dig cyclization to give the cationic species 14, but which could conceivably be followed by no less

Scheme 3 A contribution to understanding iodocyclization reaction, here leading to β-iodobenzofurans.

Scheme 4 Elucidation of the mechanism of a new Au-catalyzed pyridine synthesis starting from propargylic azirines.

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than five pathways to the final products. Further calculations showed that CdN bond cleavage to give the isomeric cations 15 and a final proton loss are most likely the pathway followed (2015JOC3547). 5-Endo-dig pathways are not always favored: photochemically generated radical intermediates derived from N-propargylic amides cyclize to give β-lactams via a 4-exo mechanism (2009TL3628). The ordering of the following sections will be by reagent rather than structural type. Hence, in some areas, similar precursor structures will appear in more than one subsection.

2. FURANS Although many stoichiometric reagents and even more commonly catalyst systems have been used to induce 5-endo-dig cyclizations in this area (2008CHC497), no doubt the most significant and numerous contribution have come from applications of gold complexes as catalysts (2013BEILJC1774).

2.1 Gold-Catalyzed 5-endo-Cyclizations A classical method for furan synthesis involves hydration of 1,3-diynes 16; this can be efficiently carried out using a gold catalyst in wet tetrahydrofuran (THF) to give a general range of furans 17, as well as 2,5-diamino derivatives and examples of the corresponding pyrroles (2010OL2758) (Scheme 5). A more limited method consists of exposing a diaryl-1,3-diyne to mineral acid in hot, aqueous dioxane in the presence of 1 mol% Au(IPr)OH [IPr ¼ 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene] (2011CATST58). A somewhat related method, but which may not involve a 5-endo-dig cyclization, features coupling between a 1-alkyne and a ketosulfur ylide followed by gold(I)-catalyzed ring formation leading to 2-aryl-4-alkyl furans 18 (2012AGE4681).

Scheme 5 An example of Au-catalyzed 2,5-disubstituted furan synthesis from a 1,3-diyne.

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A very general method for the elaboration of furans 20, as well as pyrroles and thiophenes 21(X ¼ S), is the gold(I)-catalyzed 5-endo-cyclization of alkynyl diols 19 (2014ACR939), which is both efficient and mild and requires only 2 mol% of both metallic catalysts (Scheme 6). The method is similarly effective for the synthesis of both pyrroles and thiophenes (2009OL4624) and can also be triggered by gold(I) chloride and (Ph3P) AuCl-AgOTf (2009OL5002). Given the ready ease of precursor synthesis (see iodofurans, Section 2.4) and the simple reaction conditions, these should become methods of choice for the synthesis of many such heteroaromatics. Polyfunctional substrates can also respond well in such cyclizations. The same catalyst gold(I) system [(Ph3P)AuCl-AgOTf] selectively and rapidly converts the diols 22 into the furans 23 despite having potentially competing hydroxyl groups set up for 5-endo-dig cyclization (Scheme 7) (2010TL1899). The reason for this high level of selectivity is not certain but may be associated with both the differing geometries of the two chains holding the hydroxyl groups and perhaps their relative nucleophilicities. Cyclizations of alkynyl polyols can also be highly regioselective. For example, treatment of the tetraol 24 with gold(I) chloride in tetrahydrofuran (THF) gives an 85% isolated yield of the furan diol 25 (Scheme 8) (2014BEILJOC2580).

Scheme 6 Conversion of 3-alkynyl-1,2-diols into furans using a gold or an Au–Ag catalyst; related methods lead to both pyrroles and thiophenes.

Scheme 7 2,4-Disubstituted furans from 2-alkylidene-3-alkynyl-1-ols using a gold catalyst.

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Scheme 8 Selectivity for 5-endo cyclizations in alkynyl polyols.

Fig. 2 Rearrangement of epoxyalkynes to furans.

Epoxides are also valuable as furan precursors: a really neat and efficient approach to 2,4-disubstituted furans 27 consists of gold(I)-catalyzed isomerization of epoxy-alkynes 26 (Fig. 2) (2004ASC432). Perhaps not surprisingly, many related methods and applications of this type of reaction have subsequently been reported. A surprising outcome when the more complex epoxy-alkynes 28 are exposed to a gold(I) salt is formation of the symmetrical bis-furans 29 (Fig. 2) (2008TL6437). Initial cyclization through attack of the epoxide oxygen onto the activated alkyne is likely followed by the addition of water and reorganization to give a furfuryl carbenium ion, dimerization and, finally, loss of an equivalent of aldehyde (R3CHO) but only when R3 is alkyl. Gold(III) salts are also effective in triggering this type of transformation (2007ASC2493) and also for the elaboration of bisfurylmethanes 29 (2008ASC1275,2009OBC2501). More generally, epoxy-alkynes 30 can be converted into trisubstituted furans 33 by treatment with both gold(I) and silver(I) complexes (2010EJO1644). The subtlety here is that, after the epoxide oxygen has added to the activated alkyne, the resulting cation is neutralized by addition of the cosolvent methanol (Scheme 9). In the case of gold catalysis, both possible regioisomers [31 and 32] are formed, both of which are subsequently converted into the furans 33 (2009JOC5342). In the case of silver catalysis, however, additional acid is required when only the regioisomer 32 is formed, which is then readily converted into the same furans 33 (2009JOC4360). This methodology can also be used to obtain indoles; a range of primary and secondary alcohols can also be used as well as ethanethiol (but not amines) as the intermediate nucleophiles.

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Scheme 9 Furans from epoxy alkynes.

Scheme 10 Polyaryl furans from cyclizations of cumulenes.

That 5-endo-dig cyclizations are best regarded as “special” (see above) is further illustrated by both experimental and computational studies of the gold(I)- and palladium(II)-catalyzed cyclizations of the cumulenes 34, which selectively lead to the furans 35 via such a mechanism (Scheme 10). While it is conceivable that a 5-exo process is involved, this idea is negated by computational data, which strongly suggests that the formation of dihydrofurans, such as 36, follows a significantly lower energy pathway. (2016CEJ11667). Some indole derivatives behave similarly, leading to carbazoles. The idea of incorporating additional unsaturation into a furan precursor so that the heteroaromatic state is readily reached from a readily available precursor is well illustrated by a report from the Hashmi group (2011EJO667) of a general and very efficient method for the synthesis of 4-methyl-2-substituted furans 38 from enynols 37 using a Au(I)/Ag(I) catalyst (Scheme 11). At this point, the impression may have been given that finding a suitable gold(I) catalyst, which will trigger a particular transformation, is an easy matter: however, in many cases, this one included, it is clear that quite a number of catalyst candidates had to be assessed, as well as solvents and temperatures, prior to success being achieved. The generality of

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Scheme 11 4-Methyl-2-substituted furans from 2-methylene-3-alkynyl-1-ols related to Scheme 7.

Scheme 12 A gold-catalyzed route to β-carboxyfurans.

Schemes 13 and 14 Furans from cyclizations of 3-alkynylketones catalyzed by gold(III) chloride.

this present methodology is illustrated by its application to a “double” cyclization, leading to the bis-furan 39. A closely related type of cyclization has been used to obtain the furyl phosphates 40 (2012TL3831) while a rather different version of the same idea has been applied to a general approach to 3-furylcarboxylates 42 by 5-endo-dig cyclization of the enol ethers 41 (Scheme 12) (2012OBC2960). Based on the foregoing discussion, one might imagine that a simple and flexible approach to many types of furan might feature as precursors 3-alkynyl ketones 43 (Scheme 13). However, following a brief initial

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contribution by the Hashmi group (2000AGE2285), this has not blossomed into a productive area, with only a few notable exceptions. Presumably this is because the precursor alkynones are quite unstable; isomeric allenes, which may of course be involved anyway in such cyclizations, are more viable in this respect. The initial Hashmi work also found that, unusually, gold(III) in the form of the trichloride was a suitable catalyst. Little beyond the simple cyclization shown in Scheme 13 (43 ! 44) has been reported with respect to this type of furan synthesis although an example of this chemistry reveals an interesting prospect for phenol synthesis: cyclization of the diynyl ether 45 gives the expected furan 46, which then undergoes an intramolecular Diels–Alder cyclization leading to the bicyclic cyclohexadiene 47 (Scheme 14). Cleavage of the ether bond then gives a stabilized carbenium ion having an hydroxyl substituent which undergoes a [1,2]-shift; a final proton loss completes aromatization to the phenol 48 (2000JA11553). An exception to the foregoing conclusions is a general route to 3-aminofuran derivatives 51, which relies on a previously established synthesis of aminoalkynes by condensations between 1-alkynes and imines generated in situ, in this case from α-ketoaldehydes 49, thereby obviating the requirement for the isolation of any intermediates (Scheme 15). The key 5-endo-dig cyclization of the intermediates 50 is again triggered by a gold(III) salt, as discovered by Hashmi. Yields are general very high, with both alkyl and aryl substituents being acceptable (2013OL2884). A single fluorine atom may also be able to stabilize 3-ketoalkynes 52 (although such compounds are reported to be unstable by these authors), judging by the excellent yields of β-fluorofurans 53 formed by the 5-endo-dig cyclizations shown in Scheme 16. Interestingly, these were found to be catalyzed by a combination of Au(I) and Ag(I), while Au(III) salts were generally unsuitable as were silver derivatives when used alone (2010ASC2761). Using rather different methodology (Scheme 17), the difluoroalkynols 54 have been shown to undergo smooth 5-endo-dig iodocyclizations when warmed with iodine monochloride in THF (2011EJO2767). The resulting β,β-difluoro-iododihydrofurans were then converted into the potentially

Scheme 15 β-Aminofurans from α-ketoaldehydes and 1-alkynes.

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Schemes 16 and 17 New routes to β-fluorofurans.

Schemes 18 and 19 Conjugated allenyl ketones as alternatives to ketoalkynes in Au-catalyzed furan synthesis.

useful fluoroiodofurans 55 by elimination of HF upon exposure to silica gel (2012OBC2395). 5-endo-dig cyclizations of conjugated allenyl ketones 56 clearly did not prove quite so easy to achieve—success was eventually achieved using recyclable tetraphenylporphyringold(III) chloride as catalyst and in the presence of trifluoroacetic acid (Scheme 18). Having said that, the effort to discover these conditions was worth it: in general, yields of the final furans 57 are excellent (2006OL325). Gevorgyan and his colleagues have developed a range of conditions for similar cyclizations of fully substituted allenyl ketones 58 (Scheme 19), when the substituent group X undergoes a [1,2]-shift during ring formation to provide a variety of useful furan derivatives 59 in good to excellent yields (2003AGE98, 2007AGE5195, 2004AGE2280, 2005JA10500). The chemistry, which is presumed to involve a 5-endo-dig cyclization, can also be applied to allenyl silanes (i.e., 58; X ¼ Me3Si) (2010JA7645). A related tactic in this area is to begin instead with a three-functionalized conjugated ynone 60, effect a [1.3]-migration to give the corresponding allenyl ketone 61, which is then induced to cyclize by a 5-endo-dig mechanism to give good to excellent yields of the highly substituted furans 62 (2007JA9868, 2008JA1440). A wide range of substrates (>50) have been examined, including those featuring sulfur migration (of PhS groups) (Scheme 20). Finally, an interesting result quoted in one of these papers (2005JA10500) indicates that, while both Au(I) and Au(III) salts can act

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Scheme 20 In situ allenyl ketone generation and cyclization to β-substituted furans by [1.3]-migration and cyclization catalyzed by copper salts.

Scheme 21 Halofuran synthesis from haloallenyl ketones, with or without halide migration.

Scheme 22 Mechanistic games.

as catalysts of 5-endo-dig cyclizations of halogenated allenyl ketones 63, the latter can also trigger halogen migration, to give 4-halofurans 65 whereas only ring closure to the isomeric 5-halofurans 64 occurs when Au(I) species are used, which is certainly a very useful feature of this chemistry (Scheme 21). For those who enjoy a mechanistic challenge, try the transformation shown in Scheme 22, which probably opens with a 5-endo-dig cyclization of the ketone oxygen onto the alkyne group set up for this in the starting material 66. After that, you’re on your own. The overall yields are very respectable and the formation of a vicinal dione group in the final product 67, not the easiest to make in general, is a notable feature (2017JOC11644). In order to overcome the problems associated with using unstable, nonconjugated three-alkynones (see above) or the corresponding allenyl ketones as starting materials, Larock came up with the idea of blocking the central 2-position by making it an sp2 center, that is incorporating an

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Scheme 23 2-Methylene-3-alkynyl ketone cyclizations triggered by Michael additions.

Scheme 24 A similar route to annulated furans.

additional alkene group. The sequence overall is then initiated by Michael attack of a nucleophile and, while the exact order of events and the nature of the intermediates may be unclear or variable, this is followed by a smooth path to the final products, as indicated in Scheme 23. In an initial model (Scheme 24), the cyclohexenones 68 were converted into ring-fused furans 69 using a gold(III) salt, although other metals are also effective, including AgOC(O)CF3, Cu(OTf )2, and Hg(OC(O)CF3) but palladium(II) salts gave poor results, probably due to reduction to Pd(0) by the nucleophile present. More examples of the use of copper-based catalysts in this area are described in Section 2.3. The latter include simple primary alcohols, indoles, 1,3diones, and anilines (2004JA11164). Subsequently, a generalized synthesis of polysubstituted furans 70 using this idea has been published (2005JOC7679) and reviewed (2005OBC387). Ionic liquids such as [bmim]BF4 have been said to be particularly useful as a medium for this methodology (2006SL1962), while a dihydropyridine can be used as a hydrogen source to remove the alkene group selectively and allow cyclization to the furan (2012RSCAD11238). A later idea for the exploitation of such substrates is not to initiate cyclization by nucleophilic attack (Scheme 23) but to allow cyclization to proceed and then trap the resulting dipole. Two examples illustrate this: Au(I)-catalyzed cyclization of the typical substrates 71 leads to the dipoles 72; when this is carried out in the presence of a nitrone 73, the furyl dipole is trapped to give the neutral products 74 (Scheme 25) (2009AGE5505). Similarly, when the trap is an unsaturated imine, azepines 75, instead of the expected pyrrolidines, are obtained in often remarkably high yields (58%–96%) (2010CEJ456). Much the same type of trapping occurs of dipoles generated from precursors 76, where a spirocyclopropyl is used as

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Scheme 25 More complex Au-catalyzed cyclizations of similar unsaturated alkynyl ketones followed by nitrone trapping.

Scheme 26 Spiro-cyclopropane groups provide an alternative substituent in the conversion of 3-alkynyl ketones into complex furans.

Scheme 27 Much the same can be applied to the synthesis of annulated furans.

a blocking group (2008JA1814); for example, using indole gives 47%–91% yields of the heterocycles 78 via the ylides 77 (Scheme 26). Ring expansion is also possible using this chemistry (Scheme 27): Au(I)-catalyzed cyclization of the fused cyclopropyl derivative 79 results in cleavage of the cyclopropane residue to leave a secondary carbenium ion which is trapped by a nucleophile (ROH, RCO2H, indole, phenol) to give very respectable yields of the cycloheptanofurans 80 (2006AGE6704). 2.1.1 β-Formylfurans Despite these many and varied advances, 3-substituted furans continue to represent challenging synthetic targets, hence this separate section on the synthesis of three-formylfurans.

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Scheme 28 Incorporation of a methoxy group leads to very useful furan-βcarboxaldehydes.

Scheme 29 Amines can be used in the same manner.

Using substrates similar to the foregoing, direct iodination by N-iodosuccinimide of the enol ether derivatives 81, no doubt assisted by the ether oxygen, leads directly to the oxonium species 82 and thence to the very useful 4-iodo-3-carboxyfurans 83 following demethylation by iodide (Scheme 28). Yields are good to excellent; the precursors are obtained using a Sonogashira coupling and are isolated by a minimal work-up and reacted immediately (2013EJO105). The amino analogs 84 (Scheme 29), prepared by the same type of Sonogashira coupling, undergo direct conversion into the 3-furaldehydes 85 upon exposure to various Cu–Pd catalysts (2011OBC1342). A rather different and very novel approach is based on a 1,2-alkynyl migration and a more familiar Au(I)-catalyzed cyclization (Scheme 30). Starting with a bis-alkynyl alcohol 86, the sequence is initiated by nucleophilic attack on one of the alkynyl groups, which has been activated by the gold(I) catalyst, similar to a hydration step. The resulting gold complex 87 then rearranges by a [1,2]-alkynyl shift; cyclization of the resulting ketoaldehydes 88 then gives the furaldehyde 89 in generally excellent yields (2014AGE3715). Unsymmetrical precursors can often show useful levels of regioselectivity in the opening step. If N-iodosuccinimide is present, then the penultimate furan–gold complex (not shown) can be converted into the corresponding 4-iodo-3-furaldehyde 83 (Scheme 28) (2014ASC2337). Much the same chemistry can also be carried out starting with the corresponding sulfonamides (NHTs in place of OH) (2014CEJ14868).

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Scheme 30 Gold-catalyzed conversion of bis-alkynyl alcohols into furan-βcarboxaldehydes, featuring a 1,2-alkynyl shift.

2.2 Silver-Catalyzed Cyclizations Inspired by the work of the Marshall group on the isomerizations of conjugated allenones and alkynyl allylic alcohols to furans using silver(I) catalysts (1995JOC5966,1999OS263), we have discovered that commercial silver nitrate supported on silica gel, more commonly associated with the chromatographic separation of alkene isomers, is an excellent catalyst for the conversion of 3-alkyne-1,2-diols 19 into the corresponding furans 20, generally in quantitative yields (see Scheme 6 for a gold(I) alternative). The latter method, while equally efficient, employs a homogeneous gold(I) catalyst whereas the heterogeneous AgNO3–SiO2 material can be recovered and reused or applied as a flow system (2007TL7709). Furthermore, the precursors 19 can be prepared easily by either addition of an acetylides to a hydroxyketone (2008TL2240) or by regioselective sharpless bishydroxylation of an enyne. While trying to apply this methodology to natural targets, we found that virtually all oxidations of 2-furylethanols gave products other than the expected 2-furylacetic acids (2010TL717). However, the silver(I) method proved to be highly suitable in selectively converting the readily prepared alkynyl–dihydroxy acids 90 into the desired acids 91 (Scheme 31). Additional applications have been to the efficient synthesis of the furan fatty acid F5 92 (2015T7436), wherein the fatty nature of the precursor had no deleterious effects on the silver-catalyzed cyclization.

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Scheme 31 Applications of the Ag(I)-catalyzed cyclization of 3-alkyn-1,2-diols in target synthesis.

Scheme 32 Pd-catalyzed cyclizations of 3-alkyn-1,2-diols to give both 2,4-disubstituted furans and the corresponding 3-carboxylates by a final carbonylation.

Scheme 33 Polysubstituted furans from conjugated allenyl ketones using palladium catalysis.

A diruthenium complex has been identified which can also been used to carry out this type of cyclization (Scheme 6). The chemistry is complementary to the silver method as almost all of the examples quoted feature a 1-alkyne of a type, which do not usually undergo cyclizations with the silver(I) salts (2008OM3614).

2.3 Furan Formation Catalyzed by Other Metals (Pd, Cu, Pt, Zn) The ability of palladium salts to catalyze 5-endo-dig cyclizations was established some time ago, a notable example being a general synthesis of 4-methyl-2-substituted furans 94 from the alkyne diols 93 (Scheme 32) (1985T3655). A really useful extension of this method is to add carbon monoxide and oxygen, when instead the furan-3-carboxylic acids 95 are the products (2010TL1663). Palladium iodide can also be used with good effect in this carbonylative process (2012JOC8657). Other familiar precursors, the allenones 96 (Scheme 33), are readily converted into the corresponding 3-metallated furans 97 using various palladium(0) species and can then be further elaborated to fully substituted furans 98 using a variety of established coupling reaction (2003CEJ2447).

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Scheme 34 Furans from 2-methylene-3-alkynyl ketones by Pd-catalyzed cyclization and a final coupling of the so-formed furylpalladium species.

Scheme 35 An extension by initial ketoester Michael addition.

Related 3-metallated intermediates can also be generated from another precursor type familiar in this area, the 2-alkynylenones 99 (Scheme 34), which can be similarly transformed into 3-metallated furans 97 and thence into furans 98 (2008AGE1908). A neat trick is to use a species suitable as both initiating nucleophile and as a final coupling agent. For example, by using a 2-allyl malonate in this role, the annulated furans 100 can be obtained in good yields (2009ASC617). When β-keto-esters are used as the triggering nucleophile, the initial adducts 101 can then cyclize through either ketone oxygen (Scheme 35). If the base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is used to trigger the initial Michael addition, then the 4H-pyrans 103 are formed but if a cationic Pd(II) catalyst, e.g., [Pd(dppp)(H2O)2] OTf2, is present, the corresponding furans 102 are obtained in 82%–99% yields (2009JCS(CC)3594). If conjugated enones 104 are used as the final traps, then reasonable to excellent yields of the ketofurans 105 can be realized by a final Michael addition (Scheme 36) (2009CEJ9303). Copper salts have also proven very useful in this area and are, of course, much cheaper than the “coinage” metals used up to now. The original Larock idea of using an initiating nucleophile (Schemes 23 and 24) was also reported by the Yamamoto group around the same time, but they employed 10 mol% CuBr in DMF at 80°C in the presence of either water or a simple alcohol as the nucleophile. The simplicity and ease of handling of this catalyst are certainly notable features (2005JOC4531). Another extension of the

Ring Formation by 5-endo-dig Cyclization

21

Scheme 36 An alternative extension by a final Michael addition.

Schemes 37 and 38 Michael additions can induce 5-endo-dig cyclizations catalyzed by copper(I) salts.

Larock idea consists of using diphenyliodonium salts as the final traps, thereby incorporating a 3-phenyl group in the final products 106 (Scheme 37) (2010JCS(CC)8839). If oxygen is used as the initiator, then a carbonyl group can appear in the final product. Thus, exposure of the 4-pyrones 107 to copper(I) chloride in oxygenated, aqueous DMF gives the furocoumarins 108 (Scheme 38). If however CuBr is used as the catalyst but four equivalents of copper(I) chloride are included, the final products are the β-chloro derivatives 109 (2008JOC4732). Similar transformations can also be induced by platinum chloride (2006TL5307). The cyclizations 3-alkyne-1,2-diols to give furans (Scheme 6), which can be catalyzed by both Au(I) and Ag(I) salts (see above) can also be brought about using copper(II) chloride in hot methanol for 1–24 h, in isolated yields of 53%–99% (2010TL3565). A copper salt, CuI, can also effect cyclization of a conjugated ynone 110 in dimethylacetamide (DMA) containing triethylamine, the latter presumably isomerizing the

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precursor to the corresponding allene prior to cyclization to the furans 111 (Scheme 39) (2002JOC95). The idea of blocking the 2-position of an unstable 3-alkynone has been put to good effect, as described above: when a spirocyclopropane is used, both ring formation (Scheme 26) and ring expansion (Scheme 27) can occur. When such substrates are treated with a copper(II) salt, in each case smooth furan formation results with the incorporation of two halogen atoms (X ¼ Cl or Br) (Scheme 40). In both structural types, the halogens can be distinguished by selective Sonogashira coupling at the furyl center and, presumably, by various SN2 displacements of the halogen attached to an sp3 center (2012EJO4609). The instability of 3-alkynones 114 has already been mentioned. However, these are reported to be viable furan precursors when treated with zinc chloride in dichloromethane at ambient temperature (Scheme 41). Yields of furans 115 are in the range 85%–97% for this very simple method, which can also be applied to ring closures in the nucleoside area (116 ! 117) (2007OL1175). Zinc chloride is clearly special in this respect: many other zinc salts are ineffective (2008JOC5881).

Schemes 39 and 40 CuI efficiently converts an ynone into a furan.

Scheme 41 Zinc salts are optimum for converting 3-alkynyl ketones into furans.

Ring Formation by 5-endo-dig Cyclization

23

2.4 Iodocyclizations The general area of iodocyclization methodology, not just 5-endo-dig reactions, has been supported by a steady stream of helpful reviews during the past decade (2002PHC19, 2009MOL4814, 2011CRV2937, 2012CEJ5460, 2014COC341, 2016OBC7639). β-Iodofurans 118 in general can be readily obtained staring with 3-alkyne-1,2-diols 19 of the type already discussed in Scheme 6 and which can also be induced to cyclize very efficiently using Au(I), Ag(I), and Cu(I) catalysts, making these perhaps the most popular precursors in furan synthesis (2007EJO5759). The methodology is very general and the precursors easy to make by two main and flexible routes (see above). The only drawback, and something of a mechanistic puzzle, is that three equivalents of molecular iodine are required to achieve complete substrate conversion, hence wasting two equivalents of the halogen; in some examples, two equivalents of iodine monobromide suffice. On the positive side, the incorporation of the iodine atom allows many coupling reactions to be carried out effectively, which is not always so easy with an electron-rich furan (2007TL5945) (Fig. 3). How often is it that what appears to be novel is not always the case? An isolated example of such an iodocyclization was first reported 60 years ago but remained unexploited until the present reports (1959ZOB81). One application is in a synthesis of the furan fatty acid F6 119, showing that the methodology can cope with long alkyl chains at least (2015T7436). A new alternative approach to precursors for this type of iodocyclization features Sonogashira couplings of the vinyl bromides 120 followed by exposure to iodine (2011JOC1134). A similar Sonogashira coupling of the vinyl bromides 121 gives access to enynols 122, which undergo remarkably rapid cyclizations when treated with iodine monochloride in nitromethane to give reasonable to excellent yields of the useful chloromethyl-iodofurans 123 (Scheme 42) (2012TL6615). In a somewhat unusual sequence (Scheme 43), epoxy-alkynes 124 can be reorganized into

Fig. 3 Furan fatty acid synthesis.

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Schemes 42 and 43 Iodocyclizations of 2-methylene-3-alkynyl-1-ols and of epoxyalkynes result in efficient formations of β-iodofurans.

Fig. 4 More Michael additions and iodocyclizations.

ring-fused β-iodofurans 125 by heating with 10 mol% platinum chloride in the presence of N-iodosuccinimide (2008TL5021). Yields are generally excellent; the corresponding aziridines rearrange similarly to annulated pyrroles (2009S2454). 3-Alkynones 114 (Scheme 41) are also transformed into 3-iodofurans upon reaction with a variety of iodonium sources (2005OL1769) and into the corresponding 3-chloro derivatives by exposure to trichloroisocyanuric acid or commercial swimming pool bleach as chloronium sources (2008EJO3449). By adapting the Larock idea (Schemes 23 and 24) to include using iodine as a stoichiometric alkyne activating reagent, in place of a catalytic metal, together with an alcohol trigger, the iodofurans 126 are obtained in good to excellent yields (Fig. 4) (2005OL4609). Finally, using the same principle and by starting with a 4-pyrone, a masked 1,3ketoaldehyde, which acts as a trigger by a Michael addition, and stoichiometric iodine, the novel heterocycles 127 can be made in variable, and often good, yields (2015TL7193).

2.5 Base-Catalyzed Cyclizations, Dihydrofurans, and Relatives Base-driven 5-endo-dig cyclizations are much rarer and, in many cases, are no more than examples of intramolecular Michael additions. Hence, the

Ring Formation by 5-endo-dig Cyclization

25

Schemes 44 and 45 5-Endo-dig cyclizations of various alkynyl alcohols under basic conditions can result in good yields of furans.

Fig. 5 Michael additions with allenes.

method reported some time ago by Marshall and Dubay is quite remarkable wherein enynols 128 are efficiently isomerized to the furans 129 upon exposure to potassium t-butoxide (Scheme 44). Various mechanistic possibilities are described in this study, which despite its excellence does not reach a complete set of definite conclusions (1993JOC3435). Similar but unexpected examples feature conversions of the cyclic carbamates 130 into the dihydrofurans 131 using ethanolic KOH (Scheme 45) (2011T4253). What appears to be an intramolecular, base-catalyzed Michael addition to conjugated allenes leads to the dihydrofurans carboxylates 132 (Fig. 5) (2007TL1735), while a complex cumulenes system probably follows a similar mechanism in forming the phosphoranes 133 (2014OL5792). Older and very contrasting chemistry might point the way to the realization of other catalyst systems: isomerization of simple 1-alkynyl-4-ols into the corresponding dihydrofurans 134 has been achieved using both a molybdenum carbonyl complex (1996JA6648) and a related chromium carbonyl species (1987OM1424), but apparently these methods have not been further developed. Gold catalysts once again feature heavily in such cyclizations (2002S1759). A general approach to dihydrofurans 136 is by reorganization of allenyl alcohols 135 (Scheme 46). An optimum set of conditions are to use 5–10 mol% gold(III) chloride in dichloromethane at ambient temperature, although in some examples, silver nitrate can equally well be used (2001OL2537). In more demanding examples in terms of regioselectivities,

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Scheme 46 Allenyl alcohols are converted to furans in generally high yields using either a gold(III) or a silver(I) catalyst.

Scheme 47 A remarkable change of regioselectivity when treating the same allenyl alcohol with an Au or an Ag salt.

the allenic diols 137 undergo conversion into the dihydrofurans 138 under the same conditions but, in a remarkable change of selectivity, are converted instead into the furans 139 when treated with silver triflate (Scheme 47) (2008ASC547). Reactions between propargylic alcohols and diazoesters, when catalyzed by an Au(I)/Ag(I) catalyst system gives the dihydrofurans 140, probably by an anionic 5-endo-dig mechanism (2015OL5124). Ring-fused dihydrofurans 141 can be prepared slowly but cleanly directly from the corresponding alkynols using a simpler Au(I) catalyst in hot ethanol (2009JOC5523). A series of glucals 142 have been prepared from the corresponding alkynes by 5-endo-dig cyclizations, in contrast using AuCl3, which was found superior to various copper-based catalysts (2015TL5836). The same gold(III) salt is also used in a neat synthesis of the furanones 143 from 3-alkyne-1,2-diones by hemiacetal formation using a primary alcohol and 5-endo-dig cyclization (2006OL3445) although an electron-poor gold(I) phosphine catalyst p-CF3(C6H4)3PAuCl in combination with AgOTf has been found more suited to triggering cyclizations of hydroxy-alkynones in a more general approach to furanones 144, but which may not involve a 5-endo-dig cyclization (2010JOC2123,2011OBC4405) (Fig. 6). A rather different approach to such furanones 144, which probably is only effective for highly substituted substrates, features platinum chloride as the catalyst of a combined alkyl migration and cyclization of crowded hydroxyl ketones 145 (Fig. 7). The migratory groups are alkyls but the

Ring Formation by 5-endo-dig Cyclization

27

Fig. 6 Silver- and gold-catalyzed approaches to dihydrofurans.

Fig. 7 Platinum-catalyzed ring closure and alkyl migration.

method can also be applied to ring contractions of cycloalkanes, along with various nitrogen-containing heterocycles (see later) (2008T7008). Cyclic acetals 146 can be prepared from 3-alkyne-1-ols by a combination of catalyzed 5-endo-dig cyclization and acid-catalyzed addition of a simple alcohol (ROH) to the resulting 2,3-dihydrofuran (2006OL4489). Gold(I) salts or Zeise’s dimer (2006OL4907) are both effective as catalysts in methods which are also useful for spiroacetal formation (2010JA275). Acid-catalyzed addition of water forms a key part in an otherwise slightly mysterious approach to spirodihydrofurans 148 from the alkynes 147, catalyzed by silver salt AgSbF5, which may involve a 5-endo-dig addition of a carbon nucleophile, in the form of an enol, rather than the more common oxygen examples (2011NJC1355) (Fig. 7). One of the earliest contributions to this area is the conversion of the alkyne-1,4-diol 149 into the 3,4-diiodofuran 150 (1937ZOB2605), which likely is completed by a 5-endo-dig attack of a remaining hydroxyl onto an iodoallene (Scheme 48). As an alternative, IBr in wet dichloromethane can be used, when the products are unsymmetrical 3-bromo-4-iodo derivatives (2010JOC5670) while a more extensive study has shown that the method can be extended to the elaboration of 3,4-diiodofurans and the corresponding pyrroles and thiophenes as well (2011T10147). Butenolides continue to attract much synthetic interest. Recent contributions from the 5-endo-dig area include conversion of the allyl allenoates 151 into the allylated butenolides 152 using so-called “catalyzed catalysts” wherein the Lewis acidic gold(I) combines with the Lewis basic palladium (2009JA18022). The mechanism featuring the neat allyl transfer has been

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Schemes 48 and 49 Alkyne-1,4-diols are converted into 3,4-diiodo-dihydrofurans, while a range of coinage metal salts can convert conjugated allenyl esters into butenolides.

Fig. 8 Butenolide formation using coinage metals.

studied (2014ACSCAT622); overall, this provides complementary methodology to the elaboration of 4-arylbutenolides using instead an external aryl iodide (2016JA3266) (Scheme 49). 3-Alkyne-1,2-diols 153 once again are useful as cyclization precursors, in the present section when an ether group is present (Fig. 8). Thus, the phenyl ether 153; R ¼ R1 ¼ Ph is transformed very efficiently into the butenolides 154; R ¼ Ph, X¼ H optimally by silver triflate (2013OL4150) while the corresponding ethyl ether 153; R1 ¼ Et can be converted into the iodobutenolides 154; X¼ I by molecular iodine (2013JOC5878). Methoxybenzenes are also sufficiently powerful nucleophiles to participate in 5-endo-dig cyclizations: when attached to a butynoate ester, a typical Au(I)/Ag(I) combination converts such a derivatives into the spirobutenolides 155 (2014OL6008). Sequential 5-endo-dig cyclization and intramolecular Michael addition using Pd(II) catalyst can be used to form the tricyclic butenolides 156 (2015OBC5175) in good yields although initial attempts at an enantioselective version were not too productive (19% ee) (Fig. 8). Gold(I) catalysts have also been used to prepare the ylidenebutyrolactones 157 from the corresponding silylated allenyl amino acids (2011TL5740).

3. PYRROLES Naturally, many of the examples quoted in this section reflect those featured in the furan sections discussed earlier, one difference being a greater emphasis on the use of copper in place of gold catalysts (2008CHC269, 2009CJOC1924).

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29

3.1 Gold-Catalyzed 5-endo-Cyclizations Gold(I) catalysts can induce two dissimilar steps starting with the aminoketals 158: first, exchange of one of the methoxy groups using a large excess of a 1-alkyne (R3-CCH) and subsequently 5-endo-dig cyclization and loss of methanol to give the pyrroles 159 in generally excellent yields (Scheme 50) (2014OL4948). Alternatively (Scheme 51), readily prepared aziridinyl alkynes 160 can be isomerized to 2,5-disubstituted pyrroles 161 using common Au(I)/ Ag(I) combinations as catalysts (2009OL2293,2009TL6944,2011JOM159). Similar methodology can also be used to access 2,4-disubstituted isomers although in general yields are poorer. The same catalyst system can also be used to convert the annulated aziridines 162 into the ring expanded forms 163 by sequential 5-endo-dig cyclization, aziridine cleavage, loss of the OTBS group, and 1,2-migration (Scheme 52) (2009OL4002). Au(I)/Ag(I) combinations have also been used to trigger intramolecular acetylenic Schmidt reactions of the azides 164, which can be applied to the synthesis of fully substituted pyrroles (2005JA11260), while 2-aminopyrrole derivatives 165 are accessible from reactions between azirines and ynamides (2015OL30). N-Propargylic ynamides can also be used to synthesize 3,4-annulated pyrroles using Au(I) catalysts (2015OL604). This new area has recently been reviewed (2016OBC9456). The bis-alkynes 166 are readily prepared by a double Sonogashira coupling of the corresponding dibromide and can then be transformed by highly

Schemes 50 and 51 Acetal exchange with an excess of a 1-alkyne and cyclization leads to pyrroles, which can also be formed using similar catalysts from alkynyl aziridines.

Scheme 52 Propargylic aziridines are also converted into pyrroles when exposed to a gold catalyst, as are azidoalkynes, via a Schmidt reaction.

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Scheme 53 Suitable diynes give pyrroles when exposed to platinum dichloride.

Fig. 9 Use of cheaper copper salts for pyrrole formation.

controlled, separate cyclizations; first a 5-endo-dig reaction by platinum chloride to the pyrroles 167, and second, a 6-endo-dig cyclization of the ester group, to finally give the pyrrolocoumarins 168 (Scheme 53). This selectivity would be even more useful if different alkynes could be easily introduced; hopefully this will be forthcoming (2017OBC7290).

3.2 Copper-Catalyzed 5-endo-dig Cyclizations Copper salts—cheaper, simpler, easily handled when compared with many gold and other salts—have clear advantages in this area. A simple [4 + 1] annulation between N-arylpropargylamines and glyoxalates in the presence of copper(II) chloride gives good yields of the pyrrole-2-carboxylates 169; R ¼ H (2017TL63) while related 5-substituted derivatives 169 can be similarly obtained from adducts of the same alkynes and hemiaminals (Fig. 9) (2015EJO1905). Related methodology has been applied to the synthesis of the pyrrole quinazolines 170 (2016RSCADV92063) and isomeric structures (2016T6536) using copper(I) iodide along with a palladium catalyst to effect cyclization. Copper(I) iodide is also capable of catalyzing 5-endo-dig cyclizations of imines derived from conjugated ynones resulting in a general route to 2,5-disubstituted pyrroles 171 (2001JA2074). In contrast, copper(II) acetate proved to be an optimum catalyst for such cyclizations of β-hydroxy-homopropargylic sulfonamides to give similar types of pyrroles (2012ARK253). However, earlier work gave the unexpected result

Ring Formation by 5-endo-dig Cyclization

31

Fig. 10 Efficient silver-catalyzed pyrrole formation.

that a variety of alternative copper, palladium, and mercury salts can induce such cyclizations without subsequent dehydration to give excellent yields of the hydroxy-dihydropyrroles 172 (2004SL119).

3.3 Silver-Catalyzed 5-endo-dig Cyclization Silver nitrate supported on silica gel has proved to be as effective in the synthesis of trisubstituted pyrroles 174 as it did in the formation of furans (see earlier), in these examples from homopropargylamines 173 (Fig. 10). Yields are generally around quantitative for reactions at ambient temperature, the catalyst can be readily recovered and reused and the only by-product is water (2011TL2320). The hydroxy-dihydropyrroles 172 can also be made in this way; this method forms a key step in a synthesis of the natural 2,4disubstituted pyrrole, pyrrolostatin 175 (2016TL2746). Pyrrolines can be similarly prepared, especially using silver triflate as catalyst (2005JOC1791). The same salt can also catalyze carbon-centered 5-endo-dig cyclizations to give the pyrrolines 176 from the corresponding propargylamines (2013ASC3570). Subsequent base treatment causes elimination of the elements tosic acid to give the corresponding 2,3-disubstituted pyrroles (Fig. 10).

3.4 Palladium and Other Metals Cyclizations of homopropargylic amines 173, derived from epoxycycloalkanes, can also be catalyzed by palladium acetate to give pyrroles 174 in 70%90% yields (2013EJO649). The iodides 177 can be used in a two-step, one-pot palladium-catalyzed sequence, which leads to 3,5disubstituted pyrrole-2-carboxylates (cf. 169) in good yields (2008T10714), and 2,5-disubstituted examples have been synthesized from alkynyl amino acid derivatives using similar catalysts (2003SL2354). A combined one-pot Sonogashira coupling and 5-endo-dig cyclization have also been applied to the elaboration of the quinolone-based heterocycles 178 (2009TL3867), after a scaled-up example was reported (2006OPP493), exploiting the neat idea,

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first developed by the Pal group, of using readily available 10% Pd–C as the catalyst for both steps (for a review, see 2009SL2896). The viability of this 5endo-dig is perhaps surprising, given the rather low nucleophilicity of the attacking nitrogen. Homopropargylic azides 164 can be converted into trisubstituted pyrroles 174 in 41%–91% yields by heating with zinc chloride in dichloromethane (2009T1268) (cf. Scheme 62, where the amino group is retained). Relatively simple 2,5-disubstituted pyrroles 171; R1, R2 ¼ alkyl are the products when 1,4-diynes 179 are reacted with a primary amine and a pyrrole-based titanium catalyst (2004OL2957). While the precise mechanism is unclear, a 5-endo-dig cyclization is probably involved (Fig. 11).

3.5 Iodocyclizations Following on from the finding that homopropargylic sulfonamides can be smoothly converted into the dihydro-iodopyrroles and thence into the corresponding iodopyrroles following base-induced elimination of TsOH (2002JCS(P1)622), direct formation of 3-iodopyrroles 180 from 3-alkynyl-2-hydroxyamine derivatives, in essentially the same manner as the foregoing furan syntheses (see Scheme 6 and Section 2.4), proved to be both efficient and high yielding (2007TL7906). As expected, the iodopyrroles 180 can be homologated further using many of the (usually) palladium-catalyzed coupling reactions now available and can also be converted into β-pyrryl radicals, which can be trapped by a suitably positioned alkene group to give, for example, the bicycle 181, a model for the natural product roseophilin (Fig. 12) (1999TL6117). Another nitrogen analog of a foregoing furan synthesis is a somewhat unusual iodocyclization catalyzed by PtCl2 (Scheme 43: 124 ! 125), which can equally well be used to make 2,5-disubstituted-3-iodopyrroles (180; R2 ¼ H) from alkynyl aziridines (2009TL6268,2011T3194). Similarly, much the same techniques described in Scheme 48 for the synthesis of diiodo-dihydrofurans 150 can also be applied to nitrogen examples, but at a higher oxidation level, when

Fig. 11 Combined Sonogashira/5-endo-dig and iodocyclizations.

Ring Formation by 5-endo-dig Cyclization

33

Fig. 12 β-Pyrryl radicals and iodonitropyrroles.

Fig. 13 Base-catalyzed pyrrole formation.

tosylamino ynones are converted directly into 3,4-diiodopyrroles 182 (2011T10147). Rather unusual representatives of this area are the 3-iodo-4nitropyrroles 184, but which have been prepared by a very reasonable mechanism consisting of Michael addition of an amine to the vinylnitro function of 183, 5-endo-dig cyclization, and a final oxidation by iodination/elimination (2013OL4996). Yields are generally very good in this very well-exemplified chemistry. A similar mechanistic sequence is in operation in a new synthesis of the dibromo (or diiodo) β-trifluoromethylpyrroles 185 from 2-trifluoromethyl enynes (2017OL4968). A serendipitously discovered but rather useful transformation features heating a 1-arylalkynylcyclopropane-1-carboxaldehyde with a primary amine when the products are the 2,4-disubstituted pyrroles 186 (2016EJO5294), rather than the expected imines. Under differing conditions, a range of other products can also be made for these precursors, including potentially useful β-halo derivatives (Fig. 13).

3.6 Acid, Base, or Just Heat In view of their sensitivity to acids, it would seem to be something of a forlorn hope to develop a pyrrole synthesis using an acid catalyst. However, this is perfectly possible and indeed efficient as shown by an approach to pyrroles 187, which probably relies on the presence of two powerful electron-withdrawing groups (CO2Me and NTs) in analogs of the previously described precursors 173 (2003SL2258). A curious example of a

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Fig. 14 Base- and thermally catalyzed pyrrole syntheses.

base-catalyzed 5-endo-dig cyclization is that found when the alkynyl thiazoles 188 are briefly heated with KOBut in N-methyl-2-pyrrolidone (NMP) at 90°C (2010S3152). Cyclization to the pyrrolothiazoles 189 does not occur during the previous Sonogashira reaction used to make the precursors 188 (Fig. 13). Basic tetra-n-butylammonium fluoride (TBAF) triggers the 5-endo-dig cyclization of benzylic amine precursors when heated together at 80°C to give the 2,5-diarylpyrroles 190 (2014RSCADV4897). While heating can obviously trigger an initial azaMichael addition of an amine to the bis-alkyne 191, the subsequent 5-endo-dig cyclization is in the opposite sense, that is, goes against the alkyne polarization, which is probably overwritten by the subsequent [3,3]-sigmatropic rearrangement that completes the formation of the final products 192 (2009CEJ838). Finally, an oddity: when pyrrole precursors 173 (Fig. 10) are simply heated (but to 160–170°C), cyclization to the pyrroles 192a takes place within 1 h with no (obvious) catalyst present—the cyclizations even occur at ambient temperature slowly over a period of months (2016CEJ7262) (Fig. 14).

3.7 Dihydropyrroles Simple 2,3-dihydropyrroles have been made from the corresponding 1-aminobut-3-yne carbamates using various metal carbonyls, including those containing molybdenum, tungsten, and chromium (1997TL7687), as well as some cyclopentadienyl ytterbium complexes (2004H467), but little further development of these methods seems to have taken place. Similarly, an assessment of many gold complexes for the 5-endo-dig cyclization of such relatively simple precursors has shown many otherwise popular species to be unsuited to the task, the best one found being the charmingly named BrettPhosAuNTf2 (2015JCS(CC)2126). Variable yields (37%–92%) of 2,3-dihydropyrroles have also been obtained using microwave heating and PdCl2 or AuCl as catalysts (2017OBC3783). A completely different approach, which delivers decent yields of the pyrrolizidines 194 involved deprotonation of the prolines 193 and carboncentered 5-endo-dig cyclization (2013IJC(A)1086). Phosphazene bases can

Ring Formation by 5-endo-dig Cyclization

35

Scheme 54 Base- and gold-catalyzed dihydropyrrole synthesis.

Fig. 15 Au- and Fe-catalyzed dihydropyrrole synthesis.

be similarly effective (2013JCS(CC)10254) (Scheme 54). Gold once again is the key catalyst in catalyzing another carbon-centered 5-endo-dig cyclization to give the keto-pyrrolidines 196 by rearrangement of the enones 195 (2011EJO2610,2011TL6541). Gold(I) catalysts are also useful for synthesis of the pyrrolidines 197 (Fig. 15) by nitrogen-centered 5-endo-dig cyclizations of the corresponding β-amino-alkynes (2014JOC5569). Geminal difluorine atoms do not interfere with such cyclizations and hence the difluoropyrrolidines 198 can also be obtained from related acetylenic precursors, but not using a gold catalyst rather a cationic complex generated from Pd(PPh3)4 and AgSF6 (2008JFC1047). In contrast to the results obtained for a dihydrofurans synthesis (Fig. 7, Section 2.5) where Au(I) salts were effective, elaboration of the related lactams 199, and similar structures were much better carried out using iron(III) salts such as FeCl3 in hot acetonitrile (2013S3164). For those who like their reactions to be combined, a splendid sequence of an Ugi reaction followed by a carbon-centered 5-endo-dig cyclization and finally a retro-Claisen condensation has been put together to form the lactams 200 (2014EJO6390), starting from a primary amine, a 2-alkynoic acid, an isonitrile and phenylglyoxal. A carbon-centered 5-endo-dig cyclization involving an amino malonate has been used to prepare the related lactams 201 (Fig. 16) in usually excellent yields but, in these cases, the catalyst was a zinc halide (2011ASC2966).

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Fig. 16 Iodocyclizations leading to dihydropyrroles.

Schemes 55 and 56 An unusual oxidative cyclization to give a pyrrolidinone and an Hg(II)-induced 5-endo-dig process leading to a ketopyrroline.

The power behind iodocyclizations are illustrated by the formation of the spirolactam 202 from the corresponding benzenoid derivative by an ipso attack onto an alkyne group (2011SL2657). The yield is very high if three equivalents of iodine are used in the presence of 1.5 equivalents of methanol and a base (NaHCO3). A novel synthesis of rare 3-alkynyl amides 203 has permitted a study of their iodocyclization behavior (2010OL416). If carried out using N-iodosuccinimide (NIS) in the presence of an alcohol (R1OH), the final products are the lactams 204, formed by a somewhat convoluted mechanism involving initial iodocyclization, a second iodination driven by the ring nitrogen to give a gem-diiodide, alcohol addition, and elimination of HI (Fig. 16). A rather unusual and unexpected 5-endo-dig cyclization under oxidative conditions occurs when the allenyl phosphonates 205 are reacted with ceric ammonium nitrate (CAN) when the final products are the spirolactams 206 (2015JCS(CC)3612). Iminium ions are early intermediates; addition of water and ipso-attack on the central carbon of the allene are likely steps in completion of the sequence (Scheme 55). An older report (1994JOC4721) of a neat synthesis of the natural pyrrolidine preussin features a mercury(II)-induced 5-endo-dig or intramolecular azaMichael cyclization of the ynone 207 which gives, after mercury removal, an excellent yield of the keto-pyrrolidine 208 (Scheme 56) (1994JOC4721). Of course, toxicity concerns make the use of a mercury salt disfavored, so that it is not surprising that alternatives have been

Ring Formation by 5-endo-dig Cyclization

37

identified. One of the best is the gold(III) oxide, Au2O3, an uncommon catalyst in this area (2009JOC5614). Following reflux in THF, the expected products 208 are isolated in 83%–95% yields with 50%–99% retention of stereochemistry. Platinum chloride is a good alternative (2013JOC2698), which can also be used to trigger migrations and ring contractions prior to cyclization (2008T7008). In the case of a “doubly activated” ynone (RC(O)C  CCO2R) attached to a pyrrolidine, no catalyst other than bicarbonate is required to induce the azaMichael step leading to related pyrrolizidines (2011OL5964).

4. THIOPHENES Despite not being in the first row of elements and hence not formally members of the “Baldwin class” with respect to being involved in cyclizations, both sulfur and selenium are included here as the chemistry turns out to be closely related to the foregoing (2008CH843, 2014MOL15687). The classic method for the synthesis of 2,5-disubstituted thiophenes 210 by adding hydrosulfide or sulfide to a conjugated diyne 209 has been revisited: the method has been shown to work well in the absence of KOH and at ambient temperature (2012RSCAD5488) while using a 1-alkyne as precursor can lead to symmetrical examples [210; R1 ¼ R2] when the former is heated with a combination of Na2S, CuI, and 1,10phenanthroline in DMF at 60°C (2012JOC5179). Yields of up to 90% are obtainable (Scheme 57). Other popular thiophene (and benzothiophene) precursors are the bromo-enynes 211. Replacement of the bromine atom by sulfur can be achieved using triisopropylsilanethiol (TIPS-SH), together with a palladium catalyst and lithium hexamethyldisilamide (LHMDS) (2011OL5100); the resulting vinyl thiols can be converted into both disubstituted thiophenes (212; E ¼ H), benzothiophenes, and more functionalized derivatives (212; E ¼ I, SR, etc.) (Scheme 58). The related intermediates 213 can be readily cyclized using molecular iodine in dichloromethane at ambient temperature to give 61%–92% yields of the iodothiophenes 212;

Schemes 57 and 58 An old thiophene synthesis from 1,3-diynes revisited and other approaches using enyne precursors.

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E ¼ I (2014TL52). The same group has also developed an optimized route to the precursors 213 from conjugated diynes using base-induced addition of a thiol (2012TL5733). An unusual three-step route to the thiophenes 215 involves ring opening of the thiiranes 214 by a 1-alkyne (R3CCH) by treatment with CuCl and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) in warm toluene (Scheme 59). Subsequent ring closure of the resulting vinyl thiol and aromatization completes the sequence, which can also be applied to the synthesis of 1,3-bisthienybenzenes (2009JCS(CC)4729). Without doubt, however, the most popular approach to thiophenes features 5-endo-dig iodocyclizations of the hydroxyl thiols 216 to give the iodothiophenes 217 (Scheme 60). As in the related approaches to iodofurans (Scheme 6, Fig. 3) and iodopyrroles (Fig. 11), direct cyclization using molecular iodine does require 2–3 equivalents of the reagent and hence is rather wasteful but does deliver decent yields (65%–88%) of these useful derivatives (2012JOC7640), which can be improved by carrying out the cyclizations in a recyclable ionic liquid (2014OBC651). Perhaps surprisingly, there seems to be little or no interference from disulfide formation, a commonly encountered oxidation reaction when thiols are exposed to iodine. An alternative is to use a combination of potassium iodide and palladium iodide as catalyst with or without an ionic liquid (2012JOC9905) or in choline chloride–glycerol eutectic mixture, an unconventional green solvent (2016T4239). In general, however, most yields seem to be quite similar to the original method employing molecular iodine. Simpler S-benzyl thiobutynes 218 also undergo smooth iodocyclizations to give the dihydrothiophenes 219, which can be oxidized to the corresponding thiophenes using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (2001BMCL2341). The requirement for a “protecting” benzyl group, which is lost late in the cyclization, indicates that in the foregoing cyclizations of hydroxyl thiols 216, there must be an element of “protection” or activation by the hydroxyl group presumably, which prevents disulfide formation (Fig. 17). Diiodo-dihydrothiophenes 220; X1 ¼ X2 ¼ I are formed in similar manner and yields (39%–98%) to the corresponding diiodo-furans and -pyrroles described

Scheme 59 and 60 Thiirane and hydroxy thiol precursors to thiophenes.

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Fig. 17 Iodo- and acid-catalyzed approaches to thiophenes and dihydrothiophenes.

Fig. 18 Halocyclizations leading to selenophenes.

earlier (Schemes 48 and 182) by iodination of 4-(thio)-2-alkyne-1-ol derivatives (2011T10147). By using iodine monobromide, a higher degree of asymmetry can be introduced [220, X1 ¼ Br, X2 ¼ I, R3 ¼ H] (2011TL936,2000TL5637). An unusual example of an acid-catalyzed 5endo-dig cyclization is in the formation of the complex thiophenes 221 from the corresponding symmetrical alkyne (2007JFC1300). Selenophenes can be obtained from the selenium analogs of thioethers 213 (Scheme 58) and in the same manner: copper(II) bromide turns out to be the optimum catalyst, hence the better yields (46%–79%) are of the bromides 222; X ¼ Br (2011EJO6713). The corresponding iodides [222, X ¼ I] can similarly be synthesized using molecular iodine (2017OCF277). Copper(II) bromide is also effective in catalyzing 5-endo-dig cyclizations of the selenium analogs of 3-butynyl thioethers 218 (Fig. 17) to give the dihydroselenophenes 223 (51%–72%) (2013CEJ13059). Prolonged reaction times can then lead to the corresponding selenophenes. 3-Chloro derivatives can be prepared in the same way in 35%–77% yields using CuCl2. Bis-diynyl alcohols 224 are converted into β-seleno-selenophenes 225; X ¼ BuSe using a combination of N-bromosuccinimide (NBS) and dibutyl diselenide and, oddly, into the corresponding iodides 225; X ¼ I using molecular iodine and the same diselenide (Fig. 18) (2015JOC12470).

5. BENZOFURANS 5.1 Base- and Acid-Catalysts Given all of the more or less sophisticated catalysts described both earlier and later, it is amusing to note the following benzofuran syntheses under both basic and acidic conditions. While these have their limitations, so do many

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Scheme 61 2-Alkynylphenols and derivatives as benzofuran precursors.

other methods. For example, many 2-alkynylphenols are converted into the corresponding benzofurans 226 in >90% yield by heating with 5 mol% potassium carbonate in water (2014T3798). Obviously, product isolation is very easy even when the yields are not so good, which can be the case when the substituent “R” is alkyl or is an electron-rich aryl. Much the same can be achieved in the case of nitrophenols but using KOBut in NMP at ambient temperature (2002TL9377) or, with cyclizations onto alkynols (1997JCSP12815) or extended conjugated systems (2004CEJ518), sodium ethoxide, or hydroxide in hot alcohol. Acid-catalyzed cyclizations of methyl ethers 227, derived from corresponding to 2-alkynylphenols, probably proceed via alkyne hydration prior to cyclization and demethylation (2009TL3588,2010T3775). Nonetheless, these are perfectly valid methods in this area (Scheme 61).

5.2 Iodocyclizations and Relatives In general, 3-iodobenzofurans 228 are best prepared from the 2-alkynyl anisoles 227 rather than the corresponding phenols (1999SL1432,2002OL2409,2005JOC9985,2005JOC10292,2005JCC809). This is certainly true when the alkyne is conjugated to an ester group, when very poor yields of the 3-iodobenzofuran-2-carboxylate are obtained from the phenol, but which can be raised to 65% but only under relatively forcing conditions (CHCl3, 100°C) (2009CMC780). However, nonparticipating phenol groups can be present elsewhere on the benzene ring although in a preparation of the 5- and 6-hydroxy derivatives of benzofuran 228, five equivalents of iodine were required for complete conversion (Scheme 61) (2016OBC10454). A whole range of other electrophiles can be used in combination with the alkynyl ethers 227 to enable access to a large group of derivatives (229; E ¼ SePh, SeBu, SPh, SMe, Br) along with many products from subsequent couplings such as Negishi and Sonogashira reactions (2009JOC2153). For synthesis of the latter β-bromides 229; E ¼ Br, the mild reagent N-methylpyrrolidin-2-one hydrotribromide has been

Ring Formation by 5-endo-dig Cyclization

41

Fig. 19 Solving problems in 5-endo-dig approaches using iodocyclizations.

recommended even though yields are quite variable (50%–98%) (2010EJO4492). Other tactics to access such β-iodo derivatives 228 include using a less stable mixed acetal to mask the phenol group together with I(coll)2PF6– BF3 OEt2 as the iodonium source (2008OL4967) or a combination of N-iodosuccinimide (NIS) and BCl3 (2005EJO3334); respective yields are 51%–100% and up to 80%. Another way around the problem of a conjugated ester group deactivating the alkyne function, especially when there are free phenol groups also present, is to “not have it there”—that is, substitute a protected propargyl alcohol group and oxidize to the ester level after cyclization (2009S1175). This tactic was used to reach the hydroxylated benzofuran 230. However, examples of phenols being cyclized successfully are known, such as the synthesis of the highly substituted benzofuran 231 (Fig. 19) (1999AJC767), so this remains a somewhat uncertain area.

5.3 Gold-Catalyzed Synthesis A notable feature of examples of both gold and platinum catalysts in this area is their ability to transfer an allylic or benzylic substituent intermolecularly from the reacting oxygen to the 3-position of the final benzofuran. The contrasting properties of these two metals in this methodology have been reviewed (2009CSR3208). For example, the precursor aryl ynamides 232 are converted into the benzofurans 233 when treated with IPrAuCl in dichloromethane (2013CEJ12504). The polyaromatic systems 234 have been elaborated starting from a vic-aromatic diyne and 2-iodophenol, the first two steps being benzofuran formation by sequential Sonogashira coupling and 5-endo-dig cyclization, followed by two 6-endo-dig ring formations, using a combination of Pd(II) and Au(I) catalysts (2012OL6032). During Au(I)catalyzed cyclizations of O-propargylic phenyl ethers, benzofurans are sometimes formed as side products, possibly via cyclizations of intermediate 2-allenyl phenols (2009JOC8901,2011EJO2334). Further applications of this methodology seem not to have been reported (Fig. 20).

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Fig. 20 Gold catalysis in α-amino- and β-boryl benzofuran synthesis.

Novel β-boronates 235 can be derived from 2-alkynylphenols by O-borylation and gold-catalyzed cyclization usually using IPrAuCl as the catalyst (2014JA4740,2016OM655). Clearly, these initial products should prove very useful for additional elaboration using Suzuki–Miyaura coupling and perhaps other aspects of boron chemistry (2016OS228). This current area has been reviewed (2017ACR2598).

5.4 Palladium-, Pd–Cu, and Copper-Catalyzed Cyclizations Many benzofuran syntheses which rely on a combined Sonogashira coupling and subsequent 5-endo-dig cyclization utilizes combinations of palladium and copper catalysts. However, a few employ copper-free palladium species: examples of this include the use of palladium nanoparticles (2010EJO6067), ultrasound (2008US853), which also involves such nanoparticles, and visible light (2012TL5883). The latter method is conducted in water, which apparently renders it “green” until that it is product isolation and purification and disposal of the water! A combination of PdCl2 and KI (0.5 equivalents of each), together with 6 (!) equivalents of t-butyl acrylate in hot DMF provide a neat and often very efficient combined approach to benzofuran-3-carboxylates 236 starting from a 2-alkynyl phenol (2010CEJ12746,2016CEJ2935). In much the same way as allyl and benzyl groups can migrate to the 3-position during syntheses of benzofurans 233 (Fig. 20), Pd(PhP3)4 catalyzes the cyclization–migration sequence in which allyl ethers 237 are converted into 3-allylbenzofurans 238 (1998SL746), but with the obvious symmetry limitations. Propargylic ethers can similarly be transformed into the 3-allenylbenzofurans 239 (Fig. 21) (1998SL1111). A combination of palladium and copper (2011OBC641) sources are often used to catalyze another very useful combination in this area, that of sequential, one-pot Sonogashira coupling, and 5-endo-dig cyclization, i.e., 240 ! 241. In most cases, and in contrast to iodocyclizations, there is no need to protect the phenol group during the first coupling step. Such tandem

Ring Formation by 5-endo-dig Cyclization

43

Fig. 21 Palladium-catalyzed approaches to 2,3-disubstituted benzofurans.

Fig. 22 The Sonogashira/5-endo-dig combination in benzofuran synthesis.

steps work well with propargylic alcohols (2017S4335) and chloroiodophenols, without attack at the chloro atom (2005JOC6548) using Pd(OAc)2 and CuI as the catalyst combination; Pd(Ph3P)4–CuI also works well with 1-alkynes (2016CEJ2935). Pd–Cu impregnated on magnetite is also effective for such reactions (2012T1393) as is Pd–C, but only when both CuI and proline are added to trigger the second (cyclization) step (2003TL8221). Sometimes such reactions are undesired but can readily be prevented by masking the phenolic group as the corresponding methoxy methyl ether (MOM ether) but not as a benzoate which does not prevent cyclization (2001HCA2243). The Sonogashira can be quite sensitive to the exact conditions used, so an optimized combination of iPR2NH at 60°C in DMF and PdCl2(Ph3P)4–CuI as catalyst might be very relevant in some future cases (1994T11803). Similar combinations have been used to prepare the 2-vinylbenzofurans 242; the presence of the alkene does not interfere (2011EJO4868). Some useful information on ligand recycling in this type of chemistry has also been accrued (2006OL3163). Finally, a combination of PdX2, CuX2, and Et3NHX (X ¼ Cl or Br) converts a 2-alkynylphenols directly into the 3-halobenzofurans 243 in generally good yields (Fig. 22) (2006OL3017). An optimization study of the Cacchi Sonogashira/5-endo-dig approach [240 ! 241] to benzofurans identified 10 mol% CuI accompanied by 20 mol% proline and cesium carbonate in hot dioxane as a reagent system superior to many of those based on mixed Pd–Cu examples (2013T1857). This report also highlights the prospects of incorporating an additional 7-bromo or -chloro atom, to enable further homologation following the initial ring formation. An alternative copper source, [Cu(phen)

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Fig. 23 Incorporation of heteroatoms in the β-position in benzofurans.

(Ph3P)2]NO3, again in combination with Cs2CO3, is especially suited to the synthesis of 2-arylbenzofurans (241; R ¼ Ar) from iodophenols 240 and aryl alkynes (2001OL4315,2002OL4727). Differing functional groups can also be incorporated using this type of methodology. When a 2-alkynylphenol is reacted with O-benzyl-N,Ndimethylhydroxylamine in the presence of copper(II) triflate and lithium t-butoxide in NMP, the 3-aminobenzofurans 244 are formed in decent yields (2011OL2395,2012JOC617), while rather different reagents (CuF2, MnO2) form the basis of a method for introducing an oxadiazine residue into the 3-position of a benzofuran (245) during 5-endo-dig cyclization (Fig. 23) (2011OL3076). An alternative approach to 3-halobenzofurans 228 (Scheme 61) is to convert a typical 2-alkynylphenol 225 into its lithium salt and then treat it with zinc chloride, cuprous cyanide, and lithium chloride (2006OL2803); overall yields are generally excellent and indoles can be similarly prepared. Negishi-type organozinc species are formed when the same precursors are reacted with diethylzinc or a combination of BuLi and ZnCl2 (2006AGE944), which can be subsequently coupled with a variety of species leading to 2,3-disubstituted benzofurans. Diethylzinc also features in a combined Sonogashira/5-endo-dig sequence starting with an iodophenol 240, which seems most useful for the synthesis of 2-arylbenzofurans (241; R ¼ Ar) and indoles (2017TL536). Iron(III) chloride can play a similar role when reacted with 2-alkynylanisoles and diselenides, disulfides, or ditellurides [RXXR; X ¼ Se, S, Te] to give good yields of the 3-substituted benzofurans 246 (2010JOC5701) (Fig. 23). Such precursors can also be made to undergo 5-endo-dig cyclizations and O-dealkylation using rhodium (2007OL2361) and ruthenium (2014IC12122) salts. Platinum chloride (PtCl2) at levels between 0.5 and 5 mol% is yet another salt which is capable of catalyzing 5-endo-dig cyclizations of 2-alkynylphenols 225 to the corresponding benzofurans 226 (2005JA15022,2005JA15024,2007T8670). It is also highly adept

Ring Formation by 5-endo-dig Cyclization

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at assisting the transfer of allyl, benzyl, and part of an acetal group to the 3-position of the benzofuran, in similar fashion to that shown in Fig. 21 [237 ! 238]. The alkynyl phenols necessary for such a 5-endo-dig synthesis of benzofurans can be set up by a tandem dienone-phenol rearrangement, both catalyzed by PtCl2 (2009JOC8492); in general, 5-hydroxybenzofurans are formed, usually in >80% yields. Finally, the work that gets the prize for the most complex structure, formed by the most complicated assembly of reactions (Scheme 62): the imines 247 and the 2-alkynylphenols 248 are combined under oxidative conditions and the intermediates 249 aromatized to give the final products 250 (2016OL4690). Yields are generally >80% and a range of aryl and alkyl substituents is incorporated. Readers are (i) invited to spot the 5-endo-dig step (easy) and (ii) deduce all mechanisms involved (not so easy). But why?

5.5 Heteroarylfurans Many of the foregoing reactions have been used to synthesize more complex heteroaromatic targets and these are summarized later. As perhaps expected, the tandem Sonogashira/5-endo-dig strategy features significantly. A two-step sequence is required to convert the 2-pyridinones 251 into the 3-iodo-4-pyridinones 252; R2 ¼ I, consisting of iodocyclizations using molecular iodine followed by deprotection using NaI (2006OL1113), while a more extended sequence (2003OL2441) begins with a 3-iodo-2pyridinone and ends up with 2,3-disubstituted examples (252; R2 ¼ alkyl, aryl) by adding a final coupling step. Much the same tactics have been used to prepare the 2-pyridinone isomers and coumarins 253; Y ¼ O, NR (2008JOC8619), and 3-aryl derivatives of both product types 252 and 253 (Fig. 24) (2009OL5254). In some cases, the alternative tactic of using Negishi couplings in place of the Sonogashira method followed by Pd–Cu

Scheme 62 There is a benzofuran in there somewhere.

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Fig. 24 Synthesis of furan analogues of relatives of DNA bases.

catalyzed cyclization has been recommended as superior for the formation of derivatives related to 253 (2010OBC3073). Carbohydrate residues can be incorporated into this chemistry as well, and not necessarily with protection, as illustrated by a synthesis of the iodo-furanopyrimidin-2-ones 254 by iodocyclizations (NIS) of the corresponding alkynyl pyrimidin2,4-diones (2003JOC6788); such cyclization can also be effected using silver nitrate (2014AMR405) or copper(I) iodide, but in this latter case with 3-hydroxyalkynyl-1-yl residues if the NH groups are unsubstituted (2005NNN1729); yields are otherwise poor in the absence of a hydroxyl group on the side chain. Alternatively, palladium catalysis can be encouraged by microwave irradiation (2012TL5144), while the “standard” Sonogashira/5-endo-dig combination can be extended to the synthesis of β-furylalkynes fused to pyrimidin-2-ones by using diynes as reactants (Fig. 24) (2017EJM1247). The related furoquinolines 255 can be prepared by this now-familiar combination but using Pd–C and a copper(I) salt as the catalytic duo; yields are good to excellent (2006TL7317). Many examples of the isomeric furo [2,3-c]quinolones have been similarly synthesized (2013JMC6871) while furo[3,2-h]quinolones 256 having additional chloro atoms present have also been made in the same way, but using only the palladium salt Pd(PhCN)2Cl2 as catalyst together with a novel pyridine-based ligand in an aqueous micellar medium (2013TL3805) or under optimized conditions in sonicated water in 72%–90% yields (2016TL43) (Fig. 25). A rather different route has been used to obtain the furoquinoxalines 257: condensation between a benzene-1,2-diamine and ethyl glyoxalate followed by attack on the resulting imine by a 1-alkyne and cyclization is finalized by a copper-catalyzed 5-endo-dig cyclization to establish the furan ring and oxidation to the aromatic level (2014OL4528). An alternative starts

Ring Formation by 5-endo-dig Cyclization

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Fig. 25 Azafuran heteroaromatics.

from a 2,3-dichloroquinoxaline: displacement of one halide is followed by hydrolysis of the remaining halide and 5-endo-dig cyclization (2013OBC4930,2017EJO3707). Closely related cyclizations have provided access to β-iodofuryl derivatives of quinoxalines 257 (2016RSCADV83901). Simpler but inaccessible furo[2,3-b]pyrazines 258 have been prepared by cyclizations of the corresponding alkynyl-pyrazinones using either silver(I) salts or iodine; in the latter cases, further Pd-catalyzed couplings allow additional groups to be attached (2009AJC27).

6. INDOLES 6.1 Gold-Catalyzed Indole Synthesis Despite the importance of the Cacchi and Larock indole syntheses (2015AHC1) and related strategies relying on palladium catalysis, goldcatalyzed cyclizations continue to be developed and now constitute arguably equally significant methodologies in this area. The general area of Au-catalyzed reactions of alcohols leading to CdC and CdN bond formation has been reviewed (2008T5815,2006EJO4555,2008CRV3395). A version of the “standard” disconnection in which a 2-alkynyl-aniline derivative 259 is converted into an indole 260 by a 5-endo-dig cyclization has been optimized in terms of suitable gold catalysts; the gold(III) salt NaAuCl4  2H2O in wet ethanol was found to be an optimum choice for a number of differing nitrogen protecting groups (Ac, COCF3, Ts, Ms) (Scheme 63). Another feature of this method is that subsequent conversion to the corresponding iodides 261 can be achieved very easily using a slight excess of molecular iodine, in contrast to direct iodocyclization, which often requires 2–3 equivalents of the halogen or a more complex source (see later). Hence, unusually, a two-step sequence can be superior to one involving a single step (2004S610). The same gold(III) catalyst is also the catalyst of choice for effecting such cyclizations of N-unsubstituted anilines in ionic

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Scheme 63 Gold(III)-catalyzed cyclizations of 2-alkynylanilines.

Fig. 26 Michael and related additions to the 3-position of indoles.

liquids (yields typically >90%); if carried out at ambient temperature in the presence of a Michael acceptor, the latter adds smoothly to the new indolic 3-position to give good yields of the homologs 262 from methyl vinyl ketones (Fig. 26). At higher temperatures, addition to the aniline amino group occurs instead (2007SL1775,2006ASC331). The gold(I) salt AuCl is also effective in the same way when 2-aryl-nitroalkenes are the acceptors, leading to the indoles 263 and to the double addition products 264 when aryl aldehydes are used (2009T9244), while a gold/silver combined catalyst permits addition of a second alkyne (R1CCH) to the amino group after cyclization to give the N-vinyl derivatives 265 (2007OL627). Rather dissimilar chemistry is involved in the addition of ynamides to indoles formed in the usual manner from 2-alkynyl anilines 259 when a pyridine-N-oxide is present as an oxidant and IPrAuNTf2 is the gold catalyst. The final amides 266 (Fig. 27) are most likely formed by the addition of a gold-stabilized α-ketocarbene; overall yields are in the range 43%–70% (2014JOC9313). When a precursor 2-alkynyl aniline is substituted with a protected aminoethyl group (267), a Pictet–Spengler cyclization with an aldehyde (RCHO) can be carried out after the 5-endo-dig step leading in a single flask operation to the tetrahydropyridino-indoles 268 (2012JOC11355); if a 1,2-(2-aminophenyl)alkyne is reacted in a similar way with a ketone (R1R2C]O), then the arylated analogs 269 are formed

Ring Formation by 5-endo-dig Cyclization

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Fig. 27 2,3-Annulated indoles.

Fig. 28 Azaindoles via 5-endo-dig cyclizations.

in 53%–90% yields (2014EJO3313). Fully aromatic forms, e.g., 270, of the latter have been similarly obtained (2011S626). There is an obvious dichotomy in cyclizations involving the urea 271, which can react by either 5-endo- or 6-exo pathways. Current results suggest a high degree of dependence on the catalyst used. For example, in the case of using the gold(I) salt [Au(PPh3)]Cl, together with silver carbonate, in water with microwave heating, 5-endo-dig products 272 dominate (Fig. 28) (2009GC1201) whereas using a wide variety of gold(I) salts, including IPrAuCl with AgSb6, leads to the 6-exo products, quinazolin-2-ones, or mixtures of both using a gold(III) salt such as NaAuCl4 (2010OL1900,2014ASC229). Not unreasonably in view of ring strain, such cyclizations of 2-butadiynylphenyl urea lead exclusively to 2-ethynylindoles 273, and thence to pyrimido-indolones following 6-endo-dig cyclization (2013OL2616). Using a combination of IPrAuCl and AgNTf2 together with urea having a propargylic alcohol function [272; R2 ¼ CH(OH)Ph], the selectivity to 5-endo-dig cyclization returns; the initial products can be further cyclized to give imidazo-indol-3(2H)-ones (2014CEJ292). Mixtures are often obtained when using alternative catalysts. Similar selectivity problems arise with cyclizations of related amidine structures, although 5-endo-dig processes are distinctly favored to give indoles when catalyzed by NaAuCl4 or, in some examples, copper(II) acetate; base-catalyzed cyclizations tend to lead instead to the corresponding quinazolines (2012OBC516).

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Fig. 29 β-Substituted indoles by nucleophilic trapping of the final gold complexes from 5-endo-dig cyclizations.

A number of functional groups are known to migrate from nitrogen to the indole 3-position during 5-endo-dig cyclization. Additional examples are the sulfonamides 274 which, when exposed to gold(I) bromide in hot toluene are converted into the 3-sulfonyl indoles 275 in good yield (2007AGE2284). By-products, especially those arising from aryl ring sulfonation are common when alternative catalysts are employed such as InBr3; in all cases though, the mechanism appears to be intramolecular sulfonyl group transfer (Fig. 29). Azides have also proven to be viable participants in the 5-endo-dig area, not too surprisingly when one considers the resonance form 276 suggesting a decent nucleophile to trigger cyclization and a very good leaving group to complete the sequence (Fig. 29). The intermediate gold complexes can be trapped by various nucleophiles such as anisoles, other aryls, pyrroles, and indoles, to give often very high yields of the indoles 277, given that a suitable gold complex is used such as tBuXPhosAuNTf2 (2011AGE8358). Intramolecular trapping is also possible: the tetracyclic species 278 have been made using allylsilane as the nucleophile (2014OL3138) and the tricycles 279 by including a distal hydroxy group (2011AGE7354,2015JOM63). When a 1,3-diynyl aniline carries a hydroxyethyl substituent on nitrogen, then an initial gold(I)-catalyzed cyclization will clearly be of a 5-endo-dig type (cf. 273, Fig. 28); what is somewhat surprising is that a subsequent cyclization follows a 7-endo-dig pathway to give the seven-membered ring heterocycles 280 (2015OL1774). As a general rule, gold-catalyzed cyclizations where two alkyne groups are present, e.g., 281, will first proceed via a 5-endo-dig pathway followed by a 6- (or if possible a 7-) endo-dig mechanism (2010ASC368,2011JOC1212).

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Fig. 30 Palladium-catalyzed Sonogashira/Cacchi combinations leading to indolic heterocycles.

6.2 Palladium-Catalyzed Cyclizations As mentioned earlier, one central 5-endo-dig strategy often used in indole synthesis has become known as the Cacchi reaction, wherein sequential Sonogashira couplings of 2-haloanilines are followed by N-acetylation using trifluoroacetic anhydride (TFAA), addition of an aryl iodide or similar reactant such as an arylboronic acid (2013OBC545) and subsequent Pd(0)-catalyzed 5-endo-dig aminopalladation and finally reductive elimination leading to a 2,3-disubstituted indole (2005CRV2873). An optimized protocol, in which some of the pitfalls of this are pointed out and addressed, has now been developed which allows a one-pot sequence to be used starting at the Sonogashira step using an N-trifluoroacetylated haloaniline (2006OL3271). Metallation chemistry has been usefully employed to prepare suitable vicinal chloroiodo phenols for subsequent Sonogashira and amination reaction prior to the Cacchi sequence leading to 4- and 7-alkoxyindoles (2007JOC5113). The usual Sonogashira/Cacchi sequence has also been extended to include the synthesis of indole-2-quinoline derivatives 282 (Fig. 30) (2007T12786). The use of very readily available Pd–C as a source of palladium is both convenient, relatively cheap, and widely applicable, as pointed out elsewhere in this review. It comes as no surprise therefore that it can be used in this way in the Sonogashira/Cacchi sequence to good effect (2004SL1965), particularly a one-pot version (2011OBC3808). If an aromatic aldehyde is added to the Cacchi sequence, the final products are the bis-indoles 264 (Fig. 26) (2017OBC6997). The Sonogashira/Cacchi combination has also proven useful in the elaboration of a number of more complex heterocyclic systems, given due

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attention to optimization of reaction conditions in many cases. Halogenated pyridines respond well in a synthesis of the pyrrolopyridines 283 using this method (2017EJM202), while similar tactics starting with a dichloroaminopyrimidine lead to the pyrimidines 284, following an additional intramolecular Mitsunobu reaction to establish the fused cycloalkane ring (2016SL2368). A pyrazole ring also survives a sequence leading to the pyrrolo-indazole 285 in which Pd–C is once again used as the source of palladium (2014ARK1). Suitable conditions for the incorporation of 2-hydroxyalkyl groups into indoles formed in this way have been reported during syntheses of colchicine analogs (2016EJO5620) and of the natural product terreusinone 286 (2013T4563). The Larock indole synthesis can suffer regioselectivity limitations in examples of relatively symmetrical alkynes. One solution to this is to use silylated alkynes when single adducts 287 are formed (2009T3120). The hydroxysilane group can then either be removed to provide exclusively 3-substituted indoles or displaced by coupling reactions to give Larock-type products overall. Finally, a rather different strategy leading to indoles also features silicon chemistry but instead of the usual CdN bond formation using an alkyne, the silylallenes 288, prepared using metalation routes, undergo palladiumcatalyzed CdC bond forming 5-endo-dig cyclization using Pd2(dba)3 (other catalysts work much less well) to form the indolic 3d3a bond (2007OBC2214). A boronic acid is present during the cyclization to trap the final palladium species in a Suzuki–Miyaura step to give the final products (e.g., 289). The method looks both general and very efficient (Scheme 64).

6.3 Copper-Catalyzed Indole Synthesis Reviews of copper-catalyzed CdN bond formation provide insights into this and other areas (2007EJO4166,2008AGE3096). 2-Aryl- and 2-heteroarylindoles can be readily synthesized using the usual Sonogashira/Cacchi combination in a single operation by heating

Scheme 64 A different way: an unusual mode of cyclization leading to indoles.

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53

N-trifluoroacetyl 2-iodoanilines with a 1-alkyne in toluene containing K3PO4 and specifically the copper(I) catalyst [Cu(phen)(PPh3)2]NO3. Yields are in the range 57%–96% but very much less (10%) for 2-alkyl-1-alkynes (2003OL3843). Mixtures of CuI and PPh3 in hot dioxane are nearly as effective as catalysts. 2-Substituted indoles in general can also be obtained by 5-endo-dig cyclizations of Sonogashira products triggered by copper(II) salts; specifically Cu(OCHO)2 and Cu(OAc)2 are particularly effective but the reactions are slow (27–40 h) in refluxing 1,2-DCE (2004JOC1126). A third ring can be created by carrying in a functionalized hydroxyalkyl group on the alkyne (cf. 284, Fig. 30). N-azoylindoles 290 can be obtained in related reactions wherein 2-(2-aminophenyl)-1-arylethynes are heated with copper(II) acetate and phenanthroline and the parent azole (2012OL664). Copper salts rather than palladium-based species are better catalysts for a useful extension of the Cacchi reaction wherein the substrates are 2-aminoarylpropargylic alcohols: the usual sequence is followed by displacement of the alcohol group by an added secondary amine (2014JOC401). In a perhaps surprisingly simple experimental method, this idea has been extended to N-tosyl-2-ethynylanilines: when these are heated in dioxane at 80°C with copper(I) bromide, an aldehyde, and a secondary amine, (2-aminoalkyl)indoles are formed in good yields (2015ASC1053). In a conceptually different approach to 3-substituted indoles, halogen–metal exchange (BuLi, 78°C) in the presence of CuCN 2LiCl of the bromoarenes 291 leads on warming to formation of the indoles 292 (34%–58%) (Fig. 31) (2013OL3122) (cf. 228 ! 289 above). One wonders if there is an intermediate carbanionic species, which could be intercepted. Boron compounds now play important roles in general organic synthesis, especially because of the Suzuki–Miyaura method, and hence it is not surprising that examples of their elaboration using 5-endo-dig mechanisms have

Fig. 31 An unusual “reverse” 5-endo-dig cyclization leading to indoles with an aryl anion as the trigger.

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Fig. 32 Boron-substituted indoles.

been developed. The familiar cyclization of 2-alkynyl aniline derivatives has been used to prepare the salt 293, in an illustration of frustrated Lewis pair chemistry (2010CEJ3005). The Sonogashia/Cacchi combination can be used to convert 2-iodoaniline into the protected borate 294 by reaction with ethynyl BMIDA (Fig. 32) (2016JCSCC8703), requiring both palladium [PdCl2(PPh3)2] and copper(I) [CuI and Cu(OAc)2] salts to achieve high conversions of up to 87%. The related tactic of aminoboration has been used in a general approach to the useful polysubstituted indoles 295 from the corresponding alkynes by sequential N-borylation and Au(I)-catalyzed 5-endo-dig cyclization with transfer of the boron group to the indolic 3-position (2015JA10144). Boron plays a different role in the synthesis of the N-arylindoles 296: starting with a 2-alkynyl aniline, a boronic acid is used to arylate the nitrogen which then undergoes the usual 5-endo-dig cyclization, all catalyzed by copper(II) salts (2014JOC9000). Copper(II) acetate emerges as the optimum catalyst under carefully defined conditions.

6.4 Other Metal-Catalyzed Methods A simple cyclization of the oxalates 297, prepared not especially efficiently by photooxidation of the corresponding glycinates, can be achieved with loss of the oxalate residue to give the 2-arylindoles 298; X ¼ H in excellent yields by heating with silver nitrate and potassium carbonate in acetonitrile (2015RSCADV17383). Silver(I) is also capable of catalyzing the efficient formation of bis-indoles 264 (Fig. 26) from two equivalents of a 2-ethynyl aniline and one equivalent of an aryl aldehyde; a double

Ring Formation by 5-endo-dig Cyclization

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condensation is followed by two 5-endo-dig cyclizations (2016OL5200). Silver hexafluoroantimonate was found to be the best salt to use in 5-endo-dig cyclizations of 2-arylethynylanilines to give the intermediate silver salts 298; X ¼ Ag, which undergo various further elaborations by, for example, Michael additions leading to a diversity of heteroaromatic systems (Fig. 32) (2018AJOC123). N-(2-ethynylphenyl)isothiocyanates 299 are selectively converted into the indoles 300, or the corresponding N-thioamides, when treated with a secondary amine (R1R2NH) and silver triflate, but when a primary amine is used, 6-exo cyclization is preferred, to give the corresponding benzothiazines (2012TL748,2013T6478). The reasons behind such selectivities seem quite subtle; the same precursors 299 when reacted with an arene and triflic acid are converted into mainly 4-aryl-quinolone-2-thiones (2009TL3853). Somewhat related carbodiimides can also undergo smooth iodocyclizations to give 3-iodoindoles protected as the N-amidines (2012CHLC1807). A ruthenium-p-cymene complex is effective in catalyzing a Larock-style synthesis of the 2,3-disubstituted indoles 301 with good regioselectivity when R1 is alkyl and R2 aryl (2017T1238). The pyrimidine substituent can be regarded as an N-protecting group, although removal is rather savage—a solution of sodium ethoxide in dimethyl sulfoxide (DMSO) at 120°C for 24 h! If the usual 2-alkynyl aniline precursors are heated with ruthenium salts in chlorobenzene at 110°C then 1,2-migration of the distal alkyne substituent occurs leading to vinylidene ruthenium intermediates and thence to excellent yields of 3-substituted indoles (2017JA7749). Vinylidene ruthenium species are also intermediates in an approach to unsaturated 3-substituted indoles 302 by a route which probably also involves an aza-Claisen rearrangement (2010OM5776). Migration, but of an acyl group, also features in cyclizations of 2-alkynyl acetanilides, when using platinum chloride, to give 3-acyl indoles 303 (2004JA10546); just the same type of migration occurs in similarly catalyzed cyclizations of the corresponding urea when the products are the related 3-amides 303; R2 ¼ NR2 (2009TL2075). Heating N-protected 2-ethynylaniline with BuLi and ZnCl2 in toluene at reflux affords the double metallated dizinc species 304 (2017JA23), which often reacts selectively at the 3-position (Fig. 33). This far, however, only a limited range of electrophiles have been studied and many yields are not spectacular—some interesting potential however. If alternatively a 2-alkynyl aniline is treated with diethylzinc in the presence of CO2

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Fig. 33 N-Protection in indoles, aza-Claisens, and 2,3-bis-zinc species.

cyclization and carboxylation occurs to give the indole-3-carboxylic acid, usually in excellent yield (2016OL2556). Similar chemistry can be used to make the 2-isomers (2017OL2710). The usual cyclizations can also be achieved using 0.5 mol% of an iridium catalyst; despite the small amount required, the overall cost must surely preclude this option until all others have failed! (2005OL5437). In complete contrast, 3-arylindoles can be made from aryl hydroxylamines and an arylalkyne using an iron(II) phthalocyanine (2009T3829), although the mechanism may involve a cyclocondensation following oxidation to aryl nitroso intermediates. The usual precursors, 2-alkynyl anilines having N-tosyl protecting groups, undergo very smooth cyclization to 2-substituted indoles upon exposure to 5 mol% Hg(OTf )2 (2007TL1871). Despite the toxicity of mercury, this does seem to be an attractive method, being easy to perform (dichloromethane, 20°C), simple, and very high yielding.

6.5 Iodocyclizations Leading to Indoles A key value of such cyclizations of 2-alkynyl anilines 305 lies in the prospects for further elaborations of the initial 3-iodo derivatives 306 using one of the plethora of coupling reactions, usually catalyzed by palladium, which are now available (Fig. 34). Treatment of the precursors 305 with the iodonium source IPy2BF4 at low temperature (60°C) in dichloromethane delivers up to 87% yields of the 3-iodo-indoles 306 (2003AGE2406). A variety of N-protecting groups can be used including Boc, CO2Me, and Ms, whereas an ambient temperature method employs N-tosyl anilines and delivers 81%– 96% yields of the iodides 306; R1 ¼ Ts, but does require excess iodine (2004TL539) as does a related method starting with N,N-dimethylanilines, which requires an additional in situ demethylation step (2004OL1037), although yields are similarly very good (73%–100%). Imines derived from 2-alkynyl anilines are also very useful in the synthesis of 3-iodo-NH-indoles (2013JOC4708). The N-tosyl-based method has been used to prepare the

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Fig. 34 Iodocyclizations leading to indoles.

coumarin derivatives 307 (2012MC1067) whereas N-demethylation is featured in an unusual approach to the indolic ketones 309 by treatment of the tertiary alkynyl alcohols 308 with iodine, specifically in ethanol (2006OL243). Presumably the reaction proceeds by allene generation and 5-endo-dig iodocyclization onto the latter; remarkably, when the solvent is altered to acetonitrile, quinolines are the products! A whole range of differing substituents (X, Y) and electrophiles (E) have been reacted with the unsymmetrical diaryl alkynes 310 to provide valuable guidance in this and related areas. Many such reactions give single products and multifaceted explanations are provided of the outcomes; too many to describe in detail here but which are of use in future planning (2009JOC1141,2010JOC1652). By starting with a 2-aminophenyl-1,3diyne, the iodoindoles 311 are selectively formed; subsequent Sonogashira couplings then lead to the 2,3-bis-alkynyl indoles 312 (2011SL517). The method can also be applied to both benzofurans and benzothiophenes. The Larock demethylation method has been used in more complex cyclizations of the diynes 313, which lead smoothly to the benzocarbazoles 314 in generally good yields, using only 1.2 equivalents of iodine in dichloromethane at ambient temperature (Fig. 35) (2011JOC10209).

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Fig. 35 Indoles from other iodocyclizations and a remarkable base-catalyzed approach.

Both 3-thienyl- and 3-seleno-indoles 315 can be prepared in similar fashion to the corresponding iodides using ArSCl or ArSeCl as electrophiles in place of an iodonium source, in the presence of Bu4NI at 70°C in dichloroethane (2009JOC6802). The same 3-thienyl indoles (315; SAr) can also be made starting with an aryl thiol (ArSH) and using oxidative conditions, thereby avoiding both the use of noxious sulfonyl chloride and metals (2014OL6508). Yields are 51%–74% for aryl thiols but the method fails with alkyl thiols; the mechanism is uncertain but may involve disulfides (ArSSAr), which are also capable of inducing the key 5-endo-dig cyclization. Much the same, with similar advantages, can be achieved using sulfonyl hydrazides as electrophiles under microwave irradiation (2017TL3823).

6.6 Base-Induced Cyclizations When a 2-alkynyl aniline is protected by an N-benzyloxycarbonyl group, tetrabutylammoinium fluoride (TBAF; three equivalents) in THF at reflux is capable of inducing 5-endo-dig cyclizations to give often respectable yields of 2-arylindoles and, especially, bis-indoles (2011TL3726,2016ARK36). Perhaps the most controlled and remarkable finding in this area is that 5-endo-dig cyclizations of 2-alkynylanilines 316 can be brought about by treatment with 1.3–2.1 equivalents of potassium t-butoxide or related bases in NMP at ambient temperature; yields of all types of 2-substituted indoles 317 are usually around 80% (Fig. 35) (2000AGE2488,2003T1571). This unexpected advance has facilitated various azaindole syntheses

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Scheme 65 Very different chemistry involving isonitriles.

(2009BMC1879,2015OBC2273), suggesting a wide applicability, although some alterations were necessary to the original conditions in some cases, including using DMSO as the polar solvent and applying heat (90°C). A somewhat more brutal method (K2CO3 in water at 130°C for 10 h) is reported to give essentially quantitative yields of N-tosylindoles having both 2-aryl and 2-alkyl substituents from the corresponding N-tosyl-2alkynylanilines (2017CCL231). And going to the extreme—simply heating of 2-(arylalkynyl)anilines in water at 200°C using microwaves gives 28%– 77% yields of 2-arylindoles (2009TL6877). Although nothing else is actually added, one does wonder if catalytic species are produced. Finally, a conceptually very different type of 5-endo-dig cyclization has been reported in which a stabilized carbanion attacks an isonitrile to give an isoindole (Scheme 65). This requires a carefully chosen Bronsted acid–base combination to ionize the nitriles 318; cyclization then gives the products 319 presumably by a simple nucleophilic attack mechanism (2013CSCI2907). Chiral induction to impressive levels (96% ee) has been achieved by adding an asymmetric phase-transfer catalyst. In an extension of this idea, incorporation of a nucleophilic side chain (e.g., 320) leads to the pyrroloindoline systems (e.g., 321) (2014CEJ3005). One wonders whether this principle could be further applied.

7. BENZOTHIOPHENES AND BENZOSELENOPHENES Not surprisingly, much of the chemistry that follows is closely related to various of the foregoing methods, especially in the iodocyclization and Au/Pd-catalyzed themes. The thiobenzene derivatives 322, prepared by sequential couplings of 2-bromoiodobenzenes with benzylthiol and a zinc alkyne, both using Pd(0) catalysis, undergo smooth iodocyclization when treated with molecular iodine to give the 3-iodobenzothiophenes 323 (Fig. 36) (2001OL651). Protection of the sulfur is necessary to prevent iodine-mediated oxidation to

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Fig. 36 Iodocyclizations and borylation approaches to β-substituted benzothiophenes.

the corresponding disulfides. S-methyl derivatives can equally well be used as precursors, as can a variety of alternative electrophile sources and electrophiles, including bromine, NBS, p-O2NC6H4SCl, and PhSeCl (2001TL6011,2002JOC1905). Such S-methyl precursors can also be converted into the iodides 323 using five equivalents each of copper sulfate and sodium iodide (or bromide) in a somewhat wasteful “green” procedure (2013TL4373) or by using sodium iodide and iron(III) chloride in ethanol (2016TL411). Propargylic alcohol analogs 324 require the presence of an alcohol (R2OH), along with molecular iodine for successful iodocyclization, but which gives the ethers 325 by an uncertain mechanism (2014TL6812). Precursor synthesis by carbamate-directed metalation followed by sulfenylation is useful for the elaboration of 7-carbamoyl derivatives of the iodides 323 (2010JOC7443). Of course, the 3-iodo derivatives 323 offer plenty of opportunities for subsequent elaboration, especially using palladium-catalyzed processes. Similarly useful, but arguably in an opposite sense, are the 3-boron derivatives 326, which are formed by catalyst-free 5-endo-dig thioborylation reactions of the S-methyl precursors described earlier using B-chlorocatecholborane in hot toluene (2016AGE14286), for which mechanistic details have been provided (2017JOC8165). The method can also be used to prepare dihydrothiophenes. A quite vigorous palladium-catalyzed reaction can be used to introduce sulfur into haloarenes (e.g., 327) employing thiourea as a surrogate for hydrogen sulfide; subsequent 5-endo-dig cyclization then ensues leading to 2-arylbenzothiophenes 328. Perhaps of more interest are its applications to thiophene analogs such as 3-bromo-2-alkynyl derivatives, when good to excellent yields of the thienothiophenes 329 are obtained (2011OL4100) and to the “double” analogs 330 which are converted into the bis-thiophenes 331 (2016ASC3770,2016CEJ18559). In these later examples, KSAc is used as the source of sulfur in a method that can also be used to make tris-thiophenes and pyridine derivatives (Fig. 37). Gold(I) catalyst is particularly adept at transferring substituents from sulfur to the 3-position of a benzothiophene when the latter is formed using

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Fig. 37 Aryl benzothiophenes and thienobenzothiophenes.

Fig. 38 β-Functionalized benzothiophenes.

a 5-endo-dig cyclization (Fig. 38). For example, exposure of the mixed acetal 332 to gold(I) chloride in toluene at ambient temperature gives the rearranged ether 333 (2006AGE4473); in similar fashion, an S-silylated precursor undergoes both cyclization and migration to form the 3-silylbenzothiophenes 334 (2007OL4081) in essentially quantitative yields, while an enantiopure S-alkyl derivative cyclizes with complete stereochemical retention during the migration to the 3-alkyl derivatives 335 (2008OL2649). Selenophenes 336 can be prepared in exactly the same way as the related benzothiophenes 323, starting with a 2-alkynyl methyselenolbenzene; a range of electrophiles (E ¼ I, Br, PhSe, Hg) are all suitable for carrying out the cyclizations (2006JOC2307). Much the same can be achieved using a sodium halide and copper sulfate (five equivalents of each) in good to excellent yields (2017TL638), in similar fashion to a foregoing 3-halobenzothiophene synthesis. Bis-selenophenes 338, along with a variety of “mixed” heteroaromatics (e.g., a furan in place of a selenophene), can be obtained in respectable yields from the conjugated diynes 337 by reaction with a diselenide and iron(III) chloride in refluxing dichloromethane (2016ASC3572). The mechanism is most likely to involve double dealkylative 5-endo-dig cyclizations (Fig. 39).

8. INDOLIZINES These structures have become key components in many drug discovery programs and many neat and effective synthetic approaches to them have recently been reported, although many of these are somewhat reminiscent of

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Fig. 39 Halo and related cyclizations leading to selenophenes.

Scheme 66 Indolizines from pyridine derivatives.

what has been described earlier, in terms of the application of 5-endo-dig cyclizations (2011ELM5237). Copper-catalyzed methods are important in this area. Straightforward copper(I)-catalyzed 5-endo-dig cyclizations of the pyridines 339 followed by double bond reorganization gives good yields of the indolizines 340 (Scheme 66). However, in the case of the homologs 341 having a tertiary alcohol, the same type of cyclization leads to pyridinium intermediates 342 and thence to the indolizinones 343 by a 1,2-migration (2007JOC7783). If the precursors 341 are chiral, nonracemic derivatives, then the migration step proceeds with retention of configuration (2008JA9942). Altering the base used in such cyclizations (339 ! 340) from triethylamine to DBU or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) and adding a bromoalkyne allows an additional coupling to take place to give the homologs 344 (54 examples; 32%–92% yields) (2016OL2204). Copper(I)-catalyzed 5-endo-dig cyclizations are also effective when starting with the enynes 345 and also allow the trapping of the intermediate benzylic carbenium ions with nucleophiles such as hydride (from a dihydropyridine), phenols (2017AJOC1857), and phosphites (Fig. 40) (2017EJO2698). Ferrocenyl indolizines can similarly be prepared using a ferrocenyl alkyne as a couple component (2017AJOC686). A similar tactic has been used to synthesize the imidazo-thiazoles 347 and related structures from 2-thioimidazole and the copper salt of phenylacetylene by sequential S-alkynylation and 5-endo-dig cyclization (2012RSCAD5054).

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Fig. 40 Functionalized indolizines.

Fig. 41 Palladium-catalyzed routes to indolizines.

If precursors 339 (Scheme 66) are reacted with an aryl halide and a palladium(0) catalyst under basic conditions then 50%–96% yields of the aryl derivatives 348 are obtained (2010OL3242). In much the same way, palladium(0) can catalyze both cyclization with migration (see 341, Scheme 66) and arylation to give the related ketones 349 (2010OL2500,2012T5464). Somewhat dissimilar substrates 350 lacking an oxygen substituent undergo smooth palladium-catalyzed carbonylation and arylation (CO, ArI) to provide fair to outstanding yields of the ketones 351 (2012OL6056). Palladium can also facilitate the formation of the polycyclic analogs 352; X ¼ O, O(CO) (Fig. 41) by cascade cyclizations (2010OL5558), similar to those used to make compounds 347 (Fig. 40). In examples where both copper and palladium are effective as catalysts, the former group would seem to offer the advantages of greater structural simplicity and lower cost and maybe are more readily removed from the final products. The cyclization–migration sequence leading to indolizinones 341 (Scheme 66) and 349 (Fig. 41) can also be catalyzed by platinum dichloride (2007OL1169); yields are similarly very good and the migration step again proceeds with stereochemical retention. Other expensive metals (“coinage” metals; 2008CRV3395) almost inevitably include both gold and silver as key catalyst components for these types of cyclizations. An novel migration contrasting with the foregoing examples (cf. 341 ! 343; Scheme 66) features reactions of the pyridines 353 having an

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Fig. 42 Simple but useful routes to indolizines.

alkyne function substituted with silicon, tin, or germanyl groups, which migrate during cyclization when this is catalyzed by Au(I)/Ag(I) to give the unusual derivatives 354 (Fig. 42) (2006JA12050). The simpler cyclization 339 ! 340 (Scheme 66) can also be carried out with optimum efficiency using the silver(I) salts AgBF4 or AgPF6 when yields can be quantitative of these and some related derivatives (2007OL3433,2008T6876). In an extraordinary duplication, two groups (2014TL6922,2014T6717) have contemporaneously published the same method for the conversion of pyridine-2-acetates into the indolizines 356 (Fig. 42); even the experimental details are almost the same (Ag2CO3, KOAc, DMF, 110–120°C). The necessity for inclusion of an electron-withdrawing group suggests enol or enolate involvement, perhaps bound to silver (355), to which a silver acetylide can add allowing 5-endo-dig cyclization to complete the sequence. The second report also features the use of disubstituted alkynes, in which cases a radical mechanism is suggested. Such sequences can also be triggered by 10 mol% iodine in hot NMP (2016TL1074). In contrast to copper and palladium catalysts (Scheme 66), which induce cyclization and migration in tertiary alcohols (341 ! 343) (Scheme 66), some ruthenium species have been identified which only catalyze the cyclization step to give the isolable metal species 357 (2013OM3583). Given the foregoing methods, it comes as no surprise that iodocyclizations have featured in this area. However, although iodocyclizations of the typical precursor 339 (Scheme 66) proceed smoothly in dichloromethane at ambient temperature to give the iodo derivatives 358 in >90% yields, similar reactions fail when attempting to use alternative electrophilic sources including bromine, NBS, and PhSeCl (2007TL6863). Fortunately, subsequent couplings (Suzuki–Miyaura, Sonogashira, etc.) all proceed well. Iodine can also trigger the cyclization–migration sequence (Scheme 66): iodination of the tertiary alcohol 359 leads to the iodo-indolizinones 360 in 75%–90% yields (Scheme 67) (2008SL1243). The scheme is also successful when phenyl or alkyl groups are used as migrating groups.

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Scheme 67 More ways to obtain indolizines from pyridines.

Scheme 68 Pyrazoles from iodocyclizations of hydrazine derivatives.

9. PYRAZOLES, TRIAZOLES, ISOXAZOLES, AND OXAZOLES 9.1 Pyrazoles The “half-Mitsunobu” adducts 361 (i.e., products from Mitsunobu reactions when no additional nucleophile is added) undergo smooth iodocyclizations when treated with I(col)2PF6 to give decent yields of the dihydropyrazoles 362 (2010OL3506, 2011JPJ1323) (ICl gives much lower returns) but when using three equivalents of NIS in the presence of BF3 etherate, then a second iodination occurs and, following elimination of the elements of HI, formation of the iodopyrazoles occurs 363, again in high yields (Scheme 68). A very straightforward route to iodopyrazoles 365 in general features iodocyclizations of the hydrazones 364 using three equivalents each of iodine and sodium hydrogen carbonate in dichloromethane or acetonitrile at ambient temperature for 2 h (2011JOC6726). The stereoisomer problem is mitigated in two ways: first, the required (Z)-isomers 364 are major components, presumably because of the lesser steric bulk of the

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Scheme 69 Pyrazoles from propargylic alcohols and pyrazole-N-oxides from N-Nitrosamines using a silver(I) catalyst.

alkyne group, and second, (E)- to (Z)-isomerism occurs with both time and heat, hence high overall yields can usually be obtained. The foregoing substrates 364 can also be cyclized efficiently to give pyrazoles 368 using copper(I) iodide with triethylamine in 44%–99% yields (2011JOC9379). At a lower oxidation level, the same disubstituted pyrazoles 368 can be obtained in around 80% yields from propargylic alcohols 366 by sequential alkylation of the hydrazine derivative 367 and elimination of toluenesulfinic acid (Scheme 69) (2013S830). The intermediate hydrazines may well undergo base-catalyzed 5-endo-dig cyclization prior to elimination to the pyrazole, in similar fashion to the Knochel indole synthesis (Fig. 35). Silver nitrate adsorbed onto silica gel is an excellent reagent for catalyzing formation of the pyrazole-N-oxides 370 in essentially quantitative yields, following 5-endo-dig cyclizations of the N-nirosoamines 369 and proton loss (Scheme 69) (2008SL2188). The N-oxides can then be readily deoxygenated using phosphorus trichloride, for example.

9.2 Triazoles New gold(I) complexes 372 based on triazoles can be prepared by goldcatalyzed 5-endo-dig cyclizations of the alkynyl triazoles 371 (2010JCS (CC)6147). In a more general synthesis, a later proton-induced loss of the metal affords the neutral species 373 (2014JCS(CC)7303). N-Propargylic benzotriazoles can be cyclized using IPrAuNTf2 as catalyst to give the mesomeric betaines 374 which react further with a second alkyne (R3CCH) and a nitrile (R4CN) under acidic conditions finally to give the pyrazole-imidazoles 375 in very respectable yields, especially when carried out in one pot (2016ASC1398). The final step may well be a second 5-endo-dig cyclization of the nitrile nitrogen (? as an imine) (Fig. 43).

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Fig. 43 Triazoles and bis-imidazoles.

9.3 Isoxazoles Both silylated pyrazoles and isoxazoles 376 can be prepared without the use of metal catalysts from silylated conjugated ynones simply by treating these with hydroxylamine hydrochloride (2002T4975). The related pyrazoles can be similarly prepared using hydrazine, but a second, electrophile-driven step is required (see Scheme 68), as pointed out in an older review (2005COC925). O-Methyl oximes 377 derived from ynones can be cyclized to isoxazoles using a mixture of palladium(II) and copper(II) chlorides accompanied by potassium carbonate under the rather brutal conditions of DMF at 155°C (2012JOC3627). In the example shown (378), no doubt the t-butyl group aids formation of the favorable oxime stereoisomer; if an acrylate is also present, this is added to the 4-position of the isoxazole to give the useful homologs 379 in 95% yield using an optimized combination of reagents [Pd(O2CCF3)2, Li2CO3, Bu4NBr]. The same O-methyl oximes 377 can also be converted into the seleno-isoxazoles 380 using a diselenide and iron(III) nitrate in dichloromethane (2013JOC1630). While the mechanism is not entirely clear, the process does seem to involve a 5-endo-dig cyclization, in contrast to a more recent method (2018JOC145) featuring a related iron(III) nitrate-induced reaction sequence, which relies on nitration and reduction to form the key NdO bond (Fig. 44). Iodocyclization of the oximes 377 also works well, to give decent yields of the iodo-isoxazoles 381 but with some loss from the presence of the unreactive stereoisomer (2005OL5203). Bromo- and seleno- (cf. 380) analogs can also be thus prepared; an optimum iodination method employs 1.2

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Fig. 44 Cyclizations leading to isoxazoles.

equivalents of ICl, thereby avoiding the often large excesses of molecular iodine required. The iodo-isoxazoles can be effectively participating in many types of coupling reactions, such as in a Suzuki–Miyaura reaction with a pinacol borane (2007JOC9643) and in the creation of isoxazole libraries (2008JCOC658). Iodo-isoxazoles 381 can be obtained in the reverse sense by formation of a CdN bond during cyclization: the masked hydroxylamines 382 are converted efficiently into the iodo-dihydroisoxazoles 383, subsequent Pd(0)-catalyzed couplings of which can also result in the elimination of TsH to give fully substituted isoxazoles (Fig. 44) (2007TL647). Both the iodo-dihydro-383 and the fully aromatic iodo-isoxazoles 381 can also be obtained from the same type of precursor by using the appropriate choice of iodonium source, as shown for the syntheses of the corresponding pyrazoles (Scheme 68) (2011JOC3438). Oximes derived from conjugated ynones can also be converted into the boryl-isoxazoles 384 by reaction with a borane (R2BH) and overall 5-endo-dig cyclization of the resulting O-BR2 species with transfer of the latter to the 4-position, using a gold(I) catalyst (2016OL480); longer reaction times can obviate the need for the gold catalyst. In methodology similar to that outlined in Scheme 69 (366 ! 368), propargylic alcohols 366 can also be converted into 3,5-disubstituted isoxazoles using an acidic catalyst (p-TSA) to trigger hydroxylamine formation and a basic catalyst (TBAF) to trigger both cyclization and elimination of TsH (2012EJO5767). Some additional, mild methods have been reported for the synthesis of dihydroisoxazoles (isoxazolines) (Scheme 70). O-Propargylic hydroxylamines (385, R ¼ Boc) are converted into the 2,5-dihydroisoxazoles 386; R ¼ Boc upon exposure to gold(I) catalysts (2007SL2292), while the general precursors 385; R ¼ H, CO2R2 react smoothly with silver nitrate on silica

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Scheme 70 Diverse dihydroisoxazoles from Ag(I)-catalyzed cyclizations.

Scheme 71 Oxazoles from an unusual type of 5-endo-dig cyclization mode.

gel to give either the 4,5-dihydro derivatives 387 from the free amine or the 2,5-isomers 388 when the nitrogen is blocked (2010SL628). Such cyclizations are especially rapid (0.25 h at ambient temperature) and clean. Remarkably (and cheaply!), the free amines 385; R ¼ H can also be converted into the 4,5-isomers 387 simply by heating with potassium carbonate in methanol for 7.5 h (2006SL463). The protected precursors 385 are also convertable into the corresponding dihydroisoxazoles under basic conditions, by heating in acetonitrile with TBAF for 1 h (2017OL3695). This latter methodology may involve an unusual vinyl carbanion as an intermediate, which can be trapped by aldehydes to give additional 4-functionalized derivatives 389.

9.4 Oxazoles An unusual type of 5-endo-dig cyclization is central to a novel approach to oxazoles 392 (Scheme 71) (2011JA8482). Gold(I)-mediated oxidation (by a quinoline-N-oxide) of a 1-alkyne gives an intermediate ketonic species 390, thereby avoiding the use of a dangerous diazoketone (Scheme 71). If this is carried out in acetonitrile, the latter adds to the initial gold complex 390 to give the charged intermediate 391, which undergoes a 5-endo-dig cyclization in which the carbonyl oxygen attacks the carbon of the acetonitrile residue leading directly to the oxazoles 392 in up to 95% yields (2011JA8482). Amides can be used in place of the acetonitrile but a more sophisticated gold complex is required; yields of the oxazoles are just as high though (2012JA17412).

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5-endo-dig iodocyclizations of the acylated aminoalkynes 393 work smoothly given the correct conditions—iodine in dichloromethane—to give good yields of the iodo-oxazolones 394 (Scheme 71) (2015OL2510). If such reactions are carried out in acetonitrile, a common enough solvent for such transformations, then an alternative 6-exo-dig pathway incorporating a molecule of the solvent is followed. 3,5-Disubstituted oxazolones (394 but without the iodine) can also be prepared from the same precursors 393 using a rhodium–nitrene complex in 63%–99% yields (2017JOC11897). Additional rings can be attached if there is a nucleophile (e.g., OR) in a side chain (Scheme 71).

10. CARBOCYCLES 10.1 Cyclopentenes and Cyclopentenones Recurrent themes in this area are 5-endo-dig cyclizations of 2-alkynyl 1,3dicarbonyls (395; R1, R2 ¼ alkyl, aryl, or OR; R3 ¼ H, alkyl, aryl) or silyl enol ethers to give cyclopentenes 396, catalyzed by a wide range of transition metal species, some simple, some highly complex, along with extensions to indenes and many other structural types (Scheme 72). In essence, much of this represents an alternative to the Conia-ene reaction for cyclopentene synthesis (1975S1), with the advantages of usually requiring much lower temperatures, applicability to much more complex targets and amenable to the incorporation of product chirality, often derived from an enantiomerically pure catalyst. Clearly, in some of the following examples, there is mechanistic ambiguity, so it may sometimes be more appropriate to refer to the transformation as an “overall” 5-endo-dig process; indeed, such reactions are often referred to as Conia-ene cyclizations and can also (formally) be regarded as following both 5-exo-dig and 6-exo-dig pathways. A simple early example (Scheme 72), which sets the scene for the considerable utility of this chemistry, is conversion of the 1,3-diones 395 (R1 ¼ R2 ¼ Me; R3 ¼ H) into the cyclopentenes 397 using Mo(CO)6 (1997TL7691). The corresponding β-keto-esters (395; R2 ¼ OMe) can also

Scheme 72 Cyclopentenes from 5-endo-dig cyclizations of nucleophilic carbon.

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be cyclized but slowly using W(CO)5L in the presence of 1,4-diazabicyclo [2.2.2]octane (DABCO) and using photolytic activation at 350 nm, suggesting a radical mechanism might be involved (2012SL1960). In examples having an alkyne substituent (395 R3 6¼ H), the conversion into cyclopentenes can readily be achieved using 10 mol% iron(III) chloride in dichloroethane, usually at ambient temperature, to give products 396 in over 70% yields (2012JOC5239). Two gold-based catalysts are capable of converting the β-keto-ester 398 into the cyclopentene 399: a thiourea–Au(I) complex delivers a 93% yield (2007S2539) while a thiazolium–Au(I) carbene achieves a somewhat lower 63% return (2017JCS(CC)7585). Gold(I) is also the catalyst of choice for effecting cyclizations of the allenyl butyrolactones 400 to the cyclopentenes 401, giving 39%–93% yields of products having usually one or two substituents on the carbocyclic ring and with some degree of stereocontrol (2017OL3394,2008T3885,2008T7847). Returning to the Conia-ene process (395 ! 396), this can be carried out equally well using palladium(0) along with bulky XPhos ligands and a strong base, NaHMDS (2012OL2914). Furthermore, when an additional halide, R4X (R4 ¼ Ar, alkenyl, alkynyl), is included, this is incorporated into the final products 402 (Scheme 73). The opportunity to achieve chiral induction in this area has not yet met with much success, perhaps because of the similarity of the two electron-withdrawing groups. A notable exception is the synthesis of the cyclopentenes 403 with enantiomeric enrichments of up to 90%, although this requires a complex, four-component catalyst cocktail comprising Zn acetate, ytterbium triflate, and (S,S)-Box-Ph ligands (20 mol%) in hexafluoro-2-propanol under carefully controlled conditions (2012AGE4131). A very viable and useful alternative to the foregoing Conia-ene methodology is the use of iodocyclizations which, of course, also introduce an iodine atom with the potential for being substituted by many types of functionality (Scheme 73). 5-endo-dig iodocyclizations of the usual precursors (395 as β-keto-esters or 1,3-diones, Scheme 72) were first reported in

Scheme 73 Similar cyclizations using nucleophilic carbon but featuring allenes.

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2007 and lead slowly to the iodocyclopentenes 404 in decent yields, which can subsequently be homologated using the Sonogashira and other coupling methods (2007OL2823). The method is not so effective for the synthesis of bicyclic systems, but a clever extension is to apply it to cyclizations of the bromoalkynes 405 which gives good yields of the unusual bromo-iodocyclopentenes 406 (Scheme 74). Iodo-bicyclic derivatives 408 can however be efficiently formed from the corresponding cyclopentane 407 featuring the same idea of starting with an iodoalkyne but using a gold(I) catalyst (2004AGE5350). This attractive and simple method can be applied to a number of other structural types: the 4-alkynyl cyclohexanone 409 is converted into the [3.2.1]-bicyclooctane 410 and the indole 411 into the tricycle 412. In both examples, yields are essentially quantitative. Silyl enol ethers can also act as the nucleophilic source in such 5-endo-dig cyclizations (Scheme 75): an early version features the formation of

Scheme 74 Iodocyclizations using carbon nucleophile leading to iodocyclopentenes.

Scheme 75 Metal-catalyzed enol ether cycloadditions to alkynes, to give cyclopentenes.

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cyclopentenes 414 from the ethers 413 using W(CO)5  thf in aqueous THF as catalyst (cf. the formation of cyclopentenes 397 in Scheme 72) (1998JA1928). In just the same way, the bicyclic system 416 can be accessed from the corresponding ether 415 (2002OL4463). Such chemistry probably proceeds via formation of vinylidene complexes: when applied to the iodoalkyne 417, using a stoichiometric amount of the tungsten carbonyl, this also results in iodine migration, finally leading to the useful bicyclic product 418 in 59% yield (Scheme 75). Gold(I) salts, in combination with a silver(I) species, turn out to also be highly effective in inducing this type of cyclization (415 ! 416) and work well for making more complex products (419; R ¼ Ar, heteroaryl; 73%–85%) and a few of the isomeric products 420 by starting with the corresponding allene in place of the alkyne (2006AGE5991). The method is also applicable to the cyclization of iodoalkynes (see 408, Scheme 74) and has been used to prepare a key iodocyclopentene during a synthesis of the natural pyridine, (+)-lycopladine A. Much the same reaction is also a key step in a total synthesis of the alkaloid fawcettimine (2007AGE7671). In a study which probably took a while to bring to fruition, a series of sophisticated cationic gold(I) phosphine complexes have finally been identified which are able to induce chirality into the products 414 (Scheme 75); using these catalysts, enantiomeric enrichments are typically in excess of 90%, a spectacular achievement (2012JA2742). During this project, a novel tandem cyclization mode was also uncovered, wherein the extended precursors 421 are converted into the bicycles 422 using the same catalysts; again, ees are >90% (Scheme 76). Rather different chemistry is involved in many other approaches to cyclopentenes, which nonetheless still feature 5-endo-dig mechanisms. Rather brutal thermolysis of the enynol 423 leads to the cyclopentenone 424, via isomerization to the corresponding aldehyde followed by metal insertion between the new aldehyde group and the alkyne. Hence, this might be better regarded as an “overall” 5-endo-dig process (2001JA11492). A synthesis of the cyclopentenones 427 (Scheme 76) starts with the diynyl ketones 425 and likely involves Au(I)-catalyzed selective hydration of the unconjugated alkyne group to give the yne-dione 426 followed by a (formal) Michael addition (2008JOC8479). The overall yields (50%) might reflect a lack of regioselection in the first step. A review of Au-catalyzed cyclizations of such diynes, along with 1,6- and 1,7-homologs has recently been published (2016CSR4471). The easily obtained diynyl acetates 428 are converted into the useful cyclopentenones 431 upon

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Scheme 76 Cyclopentenones and relatives by initial additions to an alkyne or rearrangement.

reaction with a gold(I) catalyst; an indication of a likely mechanism, omitting the metal, is shown in Scheme 76: Au(I)-induced rearrangement leads to the allenyl acetates 429, which then cyclize to the acetal form 430; decomposition and 5-endo-dig cyclization complete the sequence (2009JOC370). Nonconjugated enynes feature in many catalyzed routes to cyclopentenones of various types. Similarly, conjugated 2-alkynylphenyl alkenes are important precursors to indenes and related structures. Mechanistically, many of these schemes rely on sequential alkyne activation followed by nucleophilic attack by the alkene; the final outcome is then dependent on both substrate structure and added reagents. However, the first example chosen is an exception to this: heating the enynes 432 with dicobalt octacarbonyl with (2003OL2409) or without trimethyl phosphite (2000OL1753) results in allylic CdH oxidation and subsequent 5-endo-dig cyclization onto the alkyne to give the final products 433. A more typical example consists of exposing the enyne 434 in dichloromethane containing methanol to a highly hindered Au(I)–phosphine complex when the latter adds to the alkyne group, which causes the alkene to attack the resulting electron-deficient species forming the five-membered ring 435 and perhaps subsequently the bicyclic species 436. Addition of methanol

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Scheme 77 Cyclopentenes from cyclizations of nonconjugated enynes.

Scheme 78 Conversions of alkynyl cyclopropenes to benzenes.

and demetallation completes the formation of the product 437 (2007AGE1141) (Scheme 77). Such a sequence is fairly general: for example, the acetoxy group need not be present. Very much the same chemistry can be used in conjunction with a variety of alternative nucleophiles, including methoxybenzenes and 1,3-diones, when scandium triflate can be used as an alternative to the gold(I)–phosphine complex (2008JOC7721). Essentially the same mechanism, initially at least, is involved in the Au(I)/Ag(I)-catalyzed conversion of the alkynyl cyclopropenes 438 into the arenes 441 (Scheme 78). The highly regioselective generation of the first carbocations 439 depends on the nature of the substituents R2 and R3 (Ph, nBu); either way, gold assists in the penultimate reorganization to the six-membered cationic species 440 (2014JA1505). Density function theory applied to this sequence suggests this involvement of two consecutive 1,3-cationic alkylidene migrations of nonclassical carbocationic intermediates.

10.2 Indenes and Relatives The same mechanistic theme also applies to catalyzed cyclizations of 2-alkynylarenyl alkenes, illustrated by the Au(I)/Ag(I)-catalyzed conversion

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Scheme 79 Indene formation from 2-alkynylarenyl alkenes featuring Au/Ag-catalyzed cyclizations.

of the conjugated unsaturated precursors 442 into the indenes 443 by sequential alkyne activation, 5-endo-dig cyclization, to give a carbocation, and finally proton loss to create the alkene group or trapping by methanol to give the corresponding ether 444 (Scheme 79) (2010AGE4633). If enantiopure, Binap-modified complexes are used, and ees of up to 85% can be obtained (Scheme 79). Another common feature of these reactions in general is their simplicity and speed, often reaching completion in a few minutes at ambient temperature. The addition of alcohol as a carbocation trap in related Au(I)-catalyzed cyclizations can be crucial in driving the cyclization into a 5-endo-dig mode leading to indenes (2015CEJ3042). Ruthenium complexes can also be used as outlined in Scheme 79, but yields can be somewhat compromised by the concomitant formation of smaller amounts of naphthalenes initiated by 6-endo-dig cyclizations (2004JA15560). Iodocyclizations are also very effective in this type of chemistry: treatment of the enynes 442 with NIS in refluxing dichloromethane gives >80% yields of the iodo-indenes 445 or the corresponding ethers (cf. 444) if methanol is present (2010JCS(CC)7427,2016CAJ3001). Subsequent Suzuki–Miyaura and Stille couplings also work well. Frustrated Lewis pairs feature in a novel way to induce these cyclizations (442 ! 443) although 20 mol% of a boron catalyst, B(C6F5)PPh3 is necessary to deliver 50%–98% yields of the final products (2016AGE4336). A sequence with some potential for polyaromatic synthesis features the usual initial Au(I)-catalyzed cyclization but of the cyclopropylidene derivative 446 (Scheme 80). The resulting complex 447 then rearranges to the carbocation 448 and finally, following Friedel–Crafts alkylation and reorganization, gives the polyaromatic product 449 (2017JCS(CC)11666). While conversion of the epoxides 450 to the indanones 451 may look like related 5-endo-dig processes, these ruthenium-catalyzed reactions involve a complex mechanism, so may best be regarded as “overall” examples (2004JA6895). A unique example of chirality transfer in this area features transformation of the optically pure ether 452 into the indene 453 in 92% yield with 95% ee using a typical Au(I)/Ag(I) catalyst (2006JA12062).

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Scheme 80 Polyaromatics from 2-alkynylarenyl alkenes.

There does seem to be scope in this area for examining substrates, which can undergo competing cyclization pathways, with the aim of revealing new methodology. A good example of this comes from the gold(I)-catalyzed cyclizations of the diynes 454, wherein one alkyne is activated while the second acts as the nucleophile: these give the 5-endo-dig products 455 when reacted with a bulky gold–carbene complex at the expense of a competing 6-endo pathway (2014CEJ2213). This outcome, which is surprising as the alternative 6-endo route would lead to production of a benzene ring, has been rationalized theoretically as based on electronic rather than steric effects (Scheme 81). The enynes described herein certainly offer the potential for incorporating more substituent types into the final products, as illustrated by the iron(III)-catalyzed cyclizations (dce, 75°C) of the dihydroindole derivatives 456, which lead smoothly to the indenes 457 (2016OL6512). In these examples (Scheme 81), the indole residue is essentially a bystander, which is certainly not the case in silver nitrate-catalyzed cyclizations of the indoles 458 to give the spirocyclopentenones 460 (2016AGE13798) wherein the alkyne is presumably doubly activated by being a Michael acceptor and by complexation to silver(I), while the alkene is effectively an enamine. Yields are excellent and the method can also be applied to syntheses of the pyrrole derivatives 460 and the hemiacetals 461 from the corresponding benzofurans. In most cases, silver nitrate adsorbed on silica gel is the reagent of choice rather than just silver nitrate but cyclizations leading to the spiroindolines 459 can also be induced using silver triflate (2015AGE7640) or Ph3PAuNTf2 (2016CEJ8777). In the latter examples, the intermediates 462 immediately react further to give the tetracyclic species 463 and thence the carbazoles 464 (cf. Scheme 78). Not surprisingly, the spiroproducts 459 are unreactive to these conditions (Scheme 81).

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Scheme 81 Annulated thiophenes, spiro-indoles and -pyrroles, and carbazoles from alkynyl precursors.

A different form of 5-endo-dig iodocyclization has been used to prepare the iodoinenes 466 from the aryl malonates 465, the necessary conditions being 1.5 equivalents each of iodine and sodium hydride in hot THF (2009OL229). Subsequent Heck reactions are only moderately successful, with an equal amount of deiodination occurring (Scheme 82). 2-Alkynylaryl malonates can also be converted into indenes (e.g., 467) using nickel phosphate and cesium carbonate in DMF at 60°C (2008JOC3837), while the latter base is suitable for triggering intramolecular Michael additions to give the diones 468 from the corresponding β-keto-esters (1986TL5455). Contrasting outcomes are a feature of platinum-catalyzed cyclizations of the acetals (469; X ¼ O): using PtCl2, both the alkyne substituent and an alkoxy group migrate to leave the indenes 470 (2002AGE4328) while in the case of the sulfur analogs (469; X ¼ S), using PtI2, the alkyne substituent remains unmoved but a sulfur group undergoes a [1.3]-shift to give the indenes 471 (2004JA15423). Intermediate stabilities would seem to be responsible for this diversity. A rather different iodocyclization sequence (Scheme 83) can be used to obtain diiodo-indenes 473 consisting of treating the tertiary alkynols 472

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Scheme 82 Cyclizations induced by iodine or platinum salts leading to highly functionalized indenes.

Scheme 83 More substituted indenes and some unusual 5-endo-dig cyclizations involving alkynyl nitriles.

with molecular iodine in dichloromethane containing a trace of water, presumably to generate the necessary acidic conditions; an iodoallene intermediate seems highly likely in this procedure which delivers variable yields depending upon the substituents “R” (2012T2844). Such diiodides 473 can also be made from 1-phenylpropargylic alcohols again using molecular iodine but optimally in nitromethane; allenic intermediates are equally

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likely (2011OL684). 4-Methoxyphenyl substituents can be effective as nucleophiles in iodocyclizations: in the special case of the quinoxalines 474, reaction with iodine monochloride gives the spiroheterocycles 475 (2016EJO4207). 4-But-3-ynyl-1-naphthols are similarly converted into spirocyclohexadienones 476 in excellent yields using Ph3PAuCl and a silver salt (2016CSCI3427); many substituents and additional heteroatoms can be incorporated into such products. A closely related synthesis of spirocyclic dienones from aryl ynones has also been reported, which can be catalyzed by a variety of metals ions, including Sn(II), Cu(II), and Ag(I) (2017OBC233). 2-Alkynylaryl diazoesters undergo smooth decomposition when reacted with a typical gold/silver catalyst system (Ph3PAuCl/AgOTf ); the resulting gold species then inserts into the alkyne in a 5-endo-dig fashion to give 60%–97% yields of the indenes 477 (2016JCS (CC)9351). Nitriles feature in some quite unusual 5-endo-dig chemistry: first, enolization of the chromene derivative 478 gives the isolable 5-endo-dig product 479 directly, despite the fact that the alkyne group is hardly electron poor (Scheme 83). A neat trick here is the use enolized benzyl nitrile as an equilibrating base as other, stronger bases tend to react at the relatively acidic chromone methyl group (2012OL6122). Further optimized base treatment results in the new alkene group moving into conjugation with the nitrile and cyclization to give the aniline 480 in up to 80% overall yield. Extraordinarily (the lab. must be infected with a 5-endo-dig virus), enolization of the benzyl homolog 481 gives a second example of such a product, the diene 482. Clearly, this particular alkyne is quite special in this respect. Some time ago, during a detailed theoretical study, it was stated that 5-endo-dig radical cyclizations are the “poor cousins” of the radical cyclization family (2005JA9534). The foregoing material suggests that little has altered in this time. Despite more sophisticated theoretical support (2008JA10984), only a few such reactions giving workable yields have been reported. Of course, when a viable example is found, two come along at once: single-electron reduction of the diones 483 by lithium naphthalenide occurs at the two ketone groups to give the diradicals 484, which cyclize by a “double 5-endo-dig” reaction to give diastereoisomeric mixtures of the diols 485 and the derived dienes 486 (2009OL3076). The total overall yield is 60% at most; although the proposed mechanisms are supported by both theoretical and experimental evidence, but alternatives are conceivable (Scheme 84).

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Scheme 84 5-Endo-dig radical cyclizations.

Scheme 85 Selective alkyne hydration.

10.3 Selective Alkyne Hydration Several of the foregoing methods rely upon alkyne hydration, either directly or indirectly (See Schemes 5, 30, 61, and 76), hence results in this area may be of interest. Not surprisingly, acid-catalyzed hydration of the perfluoro-Sonogashira products 487 gives predominantly the acetophenones, together with usually lesser amounts of the isomeric β-ketones, isolated as the corresponding indoles (2015TL5328). The diynes 488 can be hydrated at the position indicated using a “standard” catalyst—Ph3PAuCl/AgOTf; subsequent Conia-ene reaction (or, formally, 5-endo-dig cyclization) and intramolecular aldol condensation then leads to the spiroindene derivatives 489 (2008OL4061). Various platinum complexes are able to direct the hydration of simple alkynyl alcohols: for example, 3-pentyn-1-ol gives exclusively 4-ketopentanol, via a 5-endo-dig process (2001OM4237). Copper(I) triflate is a useful catalyst for the conversion of ethynyl arenes into the corresponding acetophenones (conjugated ketones) by regioselective Markovnikov hydration (2015T2719), as outlined in the thiophene section (2012JOC5179); by contrast, titanium tetrachloride reacts at the other alkyne position in the haloarenes 490 in an anti-Markovnikov sense (2017SCIB352) to provide the furan precursors 491 (2007JOC6149) (Scheme 85).

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