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DOI: 10.1055/a-1827-2987
The Aryne Ene Reaction
We are grateful to the EPSRC (EP/M026221/1, C.R.J.) and the China Scholarship Council (Y.Y.) for financial support.
Abstract
Intermolecular aryne ene reactions present opportunities to arylate a wide range of unsaturated substrates in a single step, whilst intramolecular reactions provide expedient access to valuable benzofused carbo- and heterocyclic frameworks. This short review will chart the development of the aryne ene reaction from initial reports that rationalise unexpected byproduct formation in competing [4+2] and [2+2] cycloadditions through to its exploitation in contemporary synthetic methodology.
1 Introduction
2 Alkene Ene Reactions
2.1 Intermolecular
2.2 Intramolecular
3 Alkyne Ene Reactions
3.1 Intermolecular
3.2 Intramolecular
4 Allene Ene Reactions
5 Aromatic Ene Reactions
6 Hetero Ene Reactions
6.1 Enols
6.2 Enamines
6.3 Imines
7 Conclusions
# 1
Introduction
Christopher R. Jones (right) read Natural Sciences at the University of Cambridge (MSci Hons, 2005), where he later joined the group of Professor Martin D. Smith and received his Ph.D. in 2009. He then moved to the University of Oxford as a Junior Research Fellow to work with Professor Timothy J. Donohoe. In 2013 Chris joined Queen Mary University of London where he is currently a Senior Lecturer in Chemistry. His research interests are based on the development of new synthetic methodologies, with a particular focus on aryne chemistry.
The Alder-ene reaction, reported by Kurt Alder in 1943,[1] is an efficient method for C–C bond formation that has been applied to the synthesis of many complex natural products.[2] A broad range of electron-deficient π-systems have been employed as viable enophiles, often activated by a Lewis acid, including alkenes, alkynes, arynes, carbonyls, imines, diazo and cumulene-type systems. Alkenes are the most commonly encountered class of ene donor, whereby the reaction offers an effective approach to functionalise allylic C–H bonds with concomitant 1,3-transposition of the associated alkene.
Arynes are amongst the most versatile and well-studied reactive intermediates in organic chemistry. Common reactivity modes include nucleophilic additions, pericyclic reactions, multicomponent couplings and transition-metal-mediated reactions, affording valuable benzenoid and functionalised heterocyclic frameworks that are common motifs in pharmaceuticals, agrochemicals, organic materials and dyes.[3] Synthetic applications of arynes were somewhat restricted in the early years due to severe limitations on functional group tolerance caused by the harsh conditions required for aryne formation. Early precursors include 1-aminobenzotriazoles that require the use of stoichiometric lead acetate, benzenediazonium-2-carboxylates that decompose to form arynes with concomitant release of CO2 and N2 gases, as well as the dehydrohalogenation of aryl halides in the presence of strong base.[3a] The advent of precursors that act under mild conditions, namely the o-trimethylsilylaryl triflates developed by Kobayashi[4] and the hexadehydro-Diels–Alder (HDDA) reaction of polyalkynes pioneered by Hoye,[5] has led to a recent resurgence in aryne chemistry and the subsequent communication of many exciting new reactivity profiles.[3]
The ability of arynes to function as viable enophiles was first reported in the early 1960s, primarily to rationalise unexpected byproducts observed during the intended Diels–Alder and/or [2+2] cycloaddition reactions between arynes and simple alkene substrates.[6] [7] [8] [9] Initial investigations concluded that the aryne ene reaction would not be a general method for the allylation of arenes, due to a combination of poor selectivity between the competing [4+2], [2+2], and ene processes, poor regioselectivity and low chemical yields. However, the emergence of contemporary methods to generate arynes under mild conditions has led to significant advancements in the aryne ene reaction. Over the past 10–15 years a significant number of efficient and selective processes have been described, employing a wide range of substrates, including alkenes, alkynes, allenes, enols, enamines and imines. For example, the intermolecular aryne ene reaction now offers an alternative approach to arylate various hydrocarbon substrates,[10] whilst the intramolecular aryne ene reaction has been widely exploited to access benzofused carbo- and heterocyclic frameworks in a single complexity-generating step.[11] The ene donors have become increasingly tolerant of multiple heteroatoms, with different heterocycles and polycyclic hydrocarbons engaged in various transformations.[12] Furthermore, ene reactions have been incorporated into one or more steps of complex cascade processes.[13] Herein we document the evolution of the aryne ene reaction, describing the progress made and mechanistic insights gathered during the development of the innovative synthetic methodologies that exploit this reaction.
# 2
Alkene Ene Reaction
2.1Intermolecular
The first report of an aryne engaging in an ene reaction was made by Arnett in 1960 (Scheme [1]).[6] Allylic ene adduct 3 was isolated instead of the intended Diels–Alder cycloaddition product from the reaction of an aryne, generated by treatment of 1-bromo-2-fluorobenzene (1) with magnesium, with 2,5-dimethylhexa-2,4-diene (2).
Arnett commented that attempts to develop the transformation as a general allylation procedure were not promising; diene 2 proved anomalous as it cannot adopt the s-cis conformation required for competing Diels–Alder cycloaddition. This sentiment was echoed in subsequent reports of alkene ene reactions of arynes, as most observations recorded allylation in low yields and often as an unintended byproduct.[7] [9] One exception was reported by Wittig in 1964, wherein the reaction of 1-bromo-2-fluorobenzene (1) and magnesium in the presence of 2,3-dimethylbuta-1,3-diene (4) was reported to favour the ene adduct 5 in 27–40% yield, with only trace amounts of the competing products from [4+2] and [2+2] cycloadditions (Scheme [2a]).[8] Conversely, in 1968 Wasserman et al. found small quantities of aryne ene adducts, such as ethyl α-phenylallyl ether (9), during the preparation of benzocyclobutenes 8 from electron-rich alkenes and arynes (Scheme [2b]).[9] The ene product was more prevalent when trans-alkenes 7 were used, as the conformation enables a more favourable geometry in the ene transition state (e.g. 14% ene adduct isolated for trans-ethyl propenyl ether 7 cf. 1% ene adduct using the cis-isomer). This reactivity was also observed shortly afterwards via independent studies into benzocyclobutene formation by the groups of Friedman and Tabushi.[14] [15] Friedman found that the ratio of ene adduct to cyclobutene increased significantly when trans-acetoxypropene was used, attributed to both the increased steric bulk of the acetyl group and the decrease in alkene electron density that rendered competing [2+2] cycloaddition less favourable.[15] Similar observations were later reported by Wasserman and Keller, in 1974, with related acyl vinyl ethers.[16]
The observed influence of sterics on the propensity for vinyl ethers to undergo alkene ene reactions suggested a concerted transformation was in operation. Further evidence in support of this hypothesis was presented in 1970 by Ahlgren and Åkermark (Scheme [3a]).[17] The reaction between 1,2-dideuteriocyclohexene (10) and benzyne afforded solely the concerted product 11 and none of the isotopomeric adduct 12 that would be expected if the reaction proceeded in a stepwise manner through cyclohexene radicals. A later study by Arnold and co-workers provided additional support for a concerted process (Scheme [3b]).[18] The reaction between benzyne and β-pinene was shown to proceed in a highly stereoselective manner, engaging the C-3 hydrogen that is trans to the gem-dimethyl bridge. For example, isotope-labelled trans-(3-D)-β-pinene 13 afforded the corresponding ene adduct 14 in 53% yield and with >95% of the deuterium label attached to the benzene ring.
Crews and Beard identified substrate conformation as the key factor in controlling the relative distribution of competing [4+2], [2+2], and ene pathways in reactions between benzyne and a range of cyclic polyenes 15 (Scheme [4]).[19] The propensity to undergo ene and [4+2] cycloaddition reactions was found to be highly dependent upon the substrates being able to adopt conformations that enabled correct orbital alignment with benzyne; attributed to the concerted nature of the two processes. Conversely, higher levels of the stepwise [2+2] pathway were observed with substrates that experienced significant degrees of bond angle distortion.
In 2013, the group of Yin and Liu reported a more general study of the aryne ene reaction of simple cyclic and acyclic alkenes 19 that do not contain heteroatoms (Scheme [5a,b]).[20] This was particularly noteworthy as the transformation affords a range of allylarenes 21 in consistently good yields, which was the first time this had been reported. Key to the success is the use of mild reaction conditions (CsF at room temperature) facilitated by Kobayashi’s method of aryne generation from o-trimethylsilylphenyl triflate 20. Dubrovsky and Larock reported a single example of a double alkene ene reaction during a study of the broader reactivity of arynes with acrylic acid derivatives.[21] Using similar conditions to Yin and Liu, Larock found that methyl methacrylate (22) did not undergo an initial heteroatom addition to the aryne that was typical of all the other acrylic acid derivatives investigated. Instead, an unexpected double ene transformation furnished trisubstituted alkene 23 in 80% yield (Scheme [5c]).
In 2015, Pérez and Domingo studied the mechanism of alkene ene reactions of simple alkene donors using DFT methods at the MPWB1K/6-311G(d,p) level (Scheme [6]).[22] It was found that the reactions proceed through a single step process in which the C–C single bond formation is slightly more advanced than hydrogen transfer. All the reactions studied were consistent in showing very low activation energies (typically <1 kcal mol–1) and strong exothermic character (more than 73 kcal mol–1). It was proposed that the lack of an appreciable energy barrier to C–C bond formation was due to the benzyne operating via a 1,2-pseudodiradical vinyl structure 25, rather than the C–C triple bond resonance structure 24.
More recently, Lee and co-workers have investigated the ene reaction of functionalised ene donors 29 with HDDA-generated arynes, which introduces the issue of selectivity between aryne-ene reaction (30) and competing nucleophilic addition (31) (Scheme [7a,b]).[23] [24] A range of trisubstituted and 1,1-disubstituted alkenes containing hydroxyl, halo, amino, carboxyl, boronate and 1,3-dienyl moieties were studied and the overall reactivity and selectivity were found to be highly substrate dependent. The geometry of the alkene donor was also important, with a cis-allylic hydrogen required for the ene reaction (note exclusive formation of nucleophilic addition product 31c). In general, 1,1-disubstituted acyclic and cyclic alkenes are mainly disposed towards ene reactions, whereas trisubstituted alkenes are slightly less reactive and also depend upon a cis-geometry of the allylic hydrogen to lead to an ene reaction. With regards to 1,3-dienes, acyclic systems favour ene reaction over Diels–Alder cycloaddition, whereas alkene-tethered cyclic dienes proceed along the Diels–Alder pathway.
Elsewhere, the groups of Minuti, Biju, Chenoweth, and Liu have reported alkene ene reactions involving larger polycyclic hydrocarbon systems.[25] [26] [27] [28] In 1999, Minuti et al. used benzyne, generated from diazotisation and subsequent thermal decomposition of anthranilic acid, to produce an arylated pentahelicene.[25] In 2014, Biju and co-workers treated a range of styrenes 32 with o-trimethylsilylaryl triflate 20, in the presence of a fluoride source, to furnish 9-aryldihydrophenanthrenes 34 through the incorporation of two equivalents of aryne (Scheme [8a]).[26] Initial Diels–Alder cycloaddition was followed by alkene ene reaction of intermediate 33 wherein the allylic hydrogen of the ene donor is also benzylic. The absence of any deuterium incorporation when the transformation was conducted in MeCN-d 3 supports a concerted process. In 2018, Chenoweth and co-workers proposed a similar aryne ene reaction involving intermediate 36 (also possessing a benzylic hydrogen as the ene donor) to account for the formation of a minor byproduct 37 in a triple aryne-tetrazine reaction sequence (Scheme [8b]).[27]
A further aryne cascade process employing an alkene ene reaction was recently reported by Liu et al. (Scheme [8c,d]).[28] Upon exposure to excess aryne, N-tosyl-2-vinylaziridines 38 undergo a sequential Diels–Alder cycloaddition, ring-opening aromatisation, ene reaction and final N-arylation to afford N-[2-(phenanthren-9-yl)ethyl]sulfonamides 40. It was found that switching reaction conditions from CsF in acetonitrile to KF and 18-crown-6 ether in 1,4-dioxane prevented the final N-arylation stage. This is particularly interestingly as it reveals that the aryne-ene reaction of intermediate 39 occurs in advance of any N-arylation, presumably driven by formation of the phenanthrene aromatic system.
Heterocycles with varying degrees of unsaturation have been reported as viable ene donors for reactions with arynes, affording both exo- and endocyclic arylation opportunities, to generate valuable functionalised heterocyclic frameworks. As part of a wider investigation into the [4+2] cycloaddition of thiophene 1,1-dioxide 41 with a range of different dienophiles, Nakayama and Yoshimura observed an unexpected alkene ene adduct 42 as the major product when 41 was exposed to benzyne, rather than the naphthalene 43 that follows Diels–Alder cycloaddition and extrusion of SO2 (Scheme [9a]).[29] Hall and co-workers also reported an isolated example of an aryne ene reaction; the Diels–Alder adduct between 4-vinylimidazole and N-phenylmaleimide was found to form a 4,5,6,7-tetrahydro-1H-benzo[d]imidazole when subsequently treated with TBAF and o-trimethylsilylphenyl triflate.[30]
He and co-workers reported an unusual inverse electron demand alkene ene reaction of exocyclic enones 44 as part of a cascade process to form 4-quinolone derivatives 47 (Scheme [9b,c]).[31] [32] A range of Morita–Baylis–Hillman adducts 44 were found to undergo a sequential nucleophilic addition, cyclisation and final aryne ene reaction upon exposure to o-trimethylsilylaryl triflates 20 under mild conditions. Higher yields and faster rates were observed with electron-rich arynes (e.g. 47b vs 47c) which offered support to the suggestion of an inverse electron demand ene reaction.
In 2017 and 2018, Jones and co-workers reported that 1,4-dihydropyridines (DHPs) 48 were effective ene donors, undergoing regioselective C-2 or C-3 arylation, when exposed to arynes under mild conditions, to generate functionalized heterocyclic frameworks 49 or 50 bearing all-carbon quaternary stereogenic centres (Scheme [9d,e]).[12] [33] The selectivity was found to be dependent upon the initial substitution pattern of the Hantzsch esters 48. No substitution at C-4 (R1 = H) favoured C-2 arylated compounds 49 via ene reaction with HA, whilst a substituent at C-4 (i.e. R1 = alkyl or aryl) caused an increase in steric interaction between the 1,4-DHP and approaching aryne, leading to an alternative ene reaction that engaged the exocyclic HB to afford C-3 arylated adducts 50. DFT calculations (B3LYP-D3/ def2-TZVP) supported experimental observations that both the C-2 and C-3 arylations proceeded by concerted ene reactions; low activation energies were calculated for the concerted processes, whereas no transition states could be computed for the alternative stepwise pathways (radical or ionic).
# 2.2
Intramolecular
Lautens and co-workers addressed the issues of chemo- and regioselectivity commonly associated with intermolecular ene reactions through the development of an intramolecular variant that proved to be a general and high-yielding method to produce a range of benzofused carbo- and heterocyclic scaffolds 52 (Scheme [10]).[11] [34] The presence of a directing group on the arene was important to access the aryne from aryl bromide 51 via ortho-deprotonation with LDA, whilst the success of the subsequent alkene ene reaction was found to be highly dependent on the geometry of the tethered alkene (trans-allylic H required). It is noteworthy that this reactivity of the trans-geometry is opposite to that observed for the intermolecular variant reported later by Lee and co-workers (see Section 2.1 and Scheme [7]).[23] DFT calculations (B3LYP/6-31G*) revealed the reaction to be concerted, with an asynchronous transition state in which C–C bond formation was more advanced. Deuterium labelling studies also supported a unimolecular process, as complete deuterium transfer onto the arene was observed from the allylic position of the alkene tether. The transformation was extended to encompass a substrate-controlled stereoselective process that afforded annulated adducts such as 52d with diastereoselectivities of >20:1 in favour of the trans-product (Scheme [10c]). Finally, the methodology was applied to the formal synthesis of an alkaloid natural product, (±)-crinine, successfully setting an all-carbon quaternary stereocentre.
Arynes generated via the HDDA cycloaddition of polyalkynyl substrates have been shown to undergo analogous intramolecular aryne ene reactions when adorned with suitable alkene-containing tethers. Hoye and co-workers first observed this transformation with triyne substrate 53 during their original disclosures of the wider HDDA reaction in 2012 (Scheme [11a]).[5] Lee and co-workers then conducted further investigations into the intramolecular alkene ene reaction with HDDA frameworks 56 and found the process to be tolerant of a range of tether chain lengths, accommodating 8- and 10-membered (57b) medium ring sizes that were unprecedented in aryne ene reactions (Scheme [11b,c]).[35] The transformation also proceeded smoothly under both thermal conditions and with the addition of a metal catalyst such as AgOTf or Grubbs 2nd generation metathesis catalyst. The greatest influence on reaction efficiency was observed through variations in the polyalkyne substrates 56, namely the heteroatom and substituent pattern in the linker between the 1,3-diynes (i.e. ‘X’ and ‘Y’) and within the alkene-containing tether (i.e. ‘Z’). For example, when the wrong alkynes engaged in the initial HDDA cycloaddition, this generated a regioisomeric aryne that underwent deleterious polymerisation, rather than aryne ene reaction, which led to poorer overall yields of the benzannulated products. The desired HDDA regioselectivity was found to be favoured with the heteroatom directly attached to the 1,3-diyne (i.e. X = CH2 and Y = NTs, see 57a–57c).
A recent report from Zi and co-workers observed similar alkene ene reactivity of HDDA-generated arynes (Scheme [12]).[36] Interestingly, the addition of a gold catalyst completely switched the reactivity of the system to favour an unprecedented carboalkoxylation of the aryne 60, via a postulated ortho-Au phenyl cation and subsequent 3,3-sigmatropic rearrangement, with no trace of the ene reaction product 59.
In 2019 Lee and co-workers extended their studies into the intramolecular ene reaction of HDDA systems by preparing a range of benzocyclobutenes 63 (Scheme [13]).[37] Careful design of the polyalkyne substrate 61 was key to overcoming the high kinetic energy barrier associated with constructing a benzo-fused 4-membered ring. A bulky substituent occupies the position on the aryne intermediate 62 ortho to the ene-donor tether, which gears the associated alkene-containing chain, via bond angle distortion, to attain an appropriate transition state for the ene reaction. The gearing effect is maximised by the introduction of a second steric feature at the benzylic position of the tether (e.g. R = OTBS). An isopropanol moiety was the preferred gearing element as it participates in an internal hydrogen bond with a carbonyl acceptor in the polyalkyne tether. Further to the steric demands, this H-bonding was also found to accelerate the initial HDDA cycloaddition. DFT calculations revealed that H-bonding promotes a conformation whereby the isopropanol gem-dimethyl group exerts a strong steric pressure on the donor tether, thereby lowering the activation barrier for the ene reaction (by ~11 kcal mol–1 vs no ortho-substituent). DFT analysis also explained the high levels of cis-selectivity observed in the cyclobutene formation, with a higher transition state energy (~1.2 kcal mol–1) calculated for the trans-isomer due to slightly lower angle distortion.
This general strategy of accessing benzofused scaffolds via intramolecular aryne ene reactions was elegantly extended by Li and co-workers in 2018 through the employment of 1,2-benzdiyne equivalents 64 (Scheme [14]).[13] This approach enables the creation of three new bonds to the arene (C–C, C–N, and C–H) during the same transformation and operates via a domino nucleophilic-ene process. Initial addition of the sulfonamide 65 to the first aryne equivalent generates the tethered ene donor in situ which then engages with the second aryne to afford benzofused N-heterocycles 66. Choosing a tosylate leaving group for the second aryne equivalent, to slow the rate of aryne generation, was found to be key to achieving the nucleophilic-ene cascade. A range of bi- and tricyclic N-heterocycles were furnished via this methodology, including the spirocyclic indoline core of ibutamoren mesylate 66d, a growth hormone agonist.
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# 3
Alkyne Ene Reactions
3.1Intermolecular
Aryne ene reactions involving alkyne coupling partners provide opportunities to access arylallenes. In 1968, Wasserman and Fernandez first identified an allenyl species 69 as a minor byproduct from the reaction between benzyne and 1-ethoxypropyne (67) (Scheme [15a]).[38] Usieli and Sarel also identified trace amounts of an arylallene when treating benzyne with ethynylcyclopropane.[39] In both cases, benzenediazonium-carboxylate 6 was used as the source of benzyne. However, in 2006 the use of milder conditions to generate arynes enabled Cheng and co-workers to utilize the alkyne-ene reaction to isolate arylallenes in good yields (Scheme [15b,c]).[10] Treatment of different 2-(trimethylsilyl)aryl triflates 20 with KF and 18-crown-6 in the presence of a range of terminal alkynes 70 (R = H) gave the corresponding arylallenes 71. Internal alkynes (R ≠ H) were also tolerated; symmetrical hex-3-yne afforded a single product 71b, whereas unsymmetrical hex-2-yne led to the two possible allene regioisomers 71c and 71c′ in a 1:1 ratio. Experimental and computational evidence was presented to support a concerted mechanism. DFT calculations revealed an exothermic process (92.7 kcal mol–1) with a small 2.4 kcal mol–1 activation energy barrier, whilst deuterium incorporation in the products 71d and 71e, obtained from reactions with 1-deuteriohex-1-yne (70d) and α,α-dideuteriobenzylethyne (70e) respectively, matched that expected for a concerted process (Scheme [15d]).
# 3.2
Intramolecular
In 2014, Yuan and Ma utilized an intramolecular aryne ene reaction during a Pd(0)-catalysed cascade process for the synthesis of 2,3-disubstituted benzofurans 78 (Scheme [16]).[40] Aryl propargyl ethers 72, bearing an adjacent o-silylaryl triflate, underwent an alkyne ene reaction when exposed to CsF. The resulting arylallene intermediate 75 was then intercepted by the arylpalladium species 76 arising from oxidative addition of Pd(0) and aryl iodide 73. An insertion afforded π-allyl Pd 77 and subsequent β-hydride elimination furnished benzofurans 78 in moderate yields. The reaction tolerated both electron-donating and -withdrawing groups on the aryl iodide 73, as well different substituents at both propargylic positions on the alkyne 72.
During Lee and co-workers’ study of the intramolecular aryne ene reaction of 1,3-bisdiynes operating via the HDDA cyclisation, an example was reported using a propargylic tether (Scheme [17]).[35] Allene 80 was obtained in the highest yield upon heating 79 in acetonitrile and in the absence of a Ag catalyst.
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# 4
Allene Ene Reactions
Allenes can operate as ene donors via two competing modes: the aryne overlaps with an allylic C(sp3)–H bond (cf. alkene ene) to afford the aryl-1,3-diene motif 82, or it intercepts an allenyl C(sp2)–H bond to furnish an alkyne 83 (Scheme [18a]). As part of a wider study into the ene reaction of allenes, Lee and co-workers reported an intermolecular aryne ene reaction between linear silylallene 81a and o-silylaryl triflate 20 to afford TMS-alkyne 83a (Scheme [18b]).[41] The silyl group significantly weakens the α-allenic C(sp2)–H bond, which was found to be key to accessing this mode of reactivity in preference to engaging the allylic C(sp3)–H bond, as observed in cases of non-silylated substrates with alternative enophiles.
In 2021 Lee and co-workers expanded their investigations by developing an intramolecular allene ene reaction of tethered arynes, accessed by the HDDA reaction of suitable polyalkyne substrates such as bis-sulfonamides 84 (Scheme [19]).[42] Modifications to the allene substituents (chain length and allene substitution pattern) revealed competing aryne reactivity modes, with selectivity dependent on the precise nature of the allene tether. For example, the allenic aryne ene reaction (86) was found to be favoured with 1,3-disubstituted allenes, whereas 1,1,3-trisubstituted allenes engaged in the allylic ene process (87). Conversely, a [2+2] cycloaddition was observed (88) between the aryne and terminal double bond of a 1,1-disubstituted allene.
# 5
Aromatic Ene Reactions
Arenes possessing a benzylic C–H bond can act as ene donors; however, the inherent disruption to aromaticity during the pericyclic process means that this is a particularly challenging transformation. Furthermore, aromatic rings can also function as viable dienes for competitive Diels–Alder cycloadditions between the aryne and aromatic coupling partner. As such, very few examples of the aromatic ene reaction have been reported and typically afforded products in extremely low yields (≤6%).[43] [44]
In contrast, Hoye and co-workers described an efficient intramolecular process in 2014 that exploited the thermal HDDA cyclisation of triyne precursors 89, bearing appropriate arenes with meta-alkyl substituents as ene donors, to form intermediate isotoluene species 91 that rearomatize to tricyclic products 92 (Scheme [20]).[45] Excellent control of the reaction outcome was achieved by simply altering the length of the arene tether: shorter tethers (n = 0 or 1) preferred the ene reaction whilst the more flexible system (n = 2) operated via an intramolecular Diels–Alder (IMDA). This selectivity was also supported by computational calculations. Interestingly, similar DFT studies of a model bimolecular process revealed comparable activation energies between the competing ene and Diels–Alder reactions. This aromatic ene transformation was amenable to variation of both the triyne linker and the arene tether, whilst secondary benzylic C–H bonds are also viable ene donors, albeit slower than primary. Mechanistic studies suggested that the final rearomatization of the isotoluene intermediate 91 to toluene 92 was promoted by adventitious water in the reaction; note that thermal 1,3-sigmatropic rearrangement is either symmetry forbidden (suprafacial) or unfavourable (antarafacial). Finally, as an alternative to rearomatization with water, the isotoluene intermediates 94 were intercepted by a range of exogenous enophiles 95 to furnish more highly functionalized products 96 via an HDDA/aromatic ene/alkene ene cascade process (Scheme [20c]).
# 6
Hetero Ene Reactions
6.1Enols
The aryne ene reaction of enol equivalents offers a metal-free approach to either the α-arylation of ketones or, when using phenol starting materials, o-hydroxylated biaryls. The phenol ene reaction was first reported by Hoye and co-workers in 2012, employing arynes generated under neutral conditions via the HDDA reaction.[5] The authors subsequently published a full investigation in 2016 involving the cycloisomerisation of polyalkynyl substrates 97 (Scheme [21]).[46] A range of phenol derivatives and HDDA precursors were amendable to the transformation, with more electron-rich phenols trapping the arynes most efficiently. Interestingly, phenols lacking a para-substituent were found to afford a small amount of the corresponding [4+2] cycloaddition adduct 101. The reaction was completely regioselective towards biaryl formation at C-6 of the intermediate aryne 98; consistent with the greater internal bond angle (138° vs 117°) and therefore electrophilic character of the aryne at C-6 compared to C-7. Mechanistic support for the ene reaction was provided by experimental observations and DFT calculations. Finally, when the reaction was conducted in the presence of base (Cs2CO3), no phenol-ene product was observed; instead the diaryl ether arising from O-arylation was isolated in good yield.
In related studies, Daugulis and co-workers have shown that under strongly basic conditions the reactivity of phenoxide with benzyne can be tuned towards either C- or O-arylation, through counterion and solvent selection, to afford analogous biaryl products albeit via non-ene pathways.[47]
In 2011, Okuma et al. proposed an aryne-mediated α-arylation of a ketone intermediate in the synthesis of 2-arylindolin-3-ones 105 from amino acid methyl esters 102 and benzyne (Scheme [22]).[48] Using 2-(trimethylsilyl)aryl triflate 20 in the presence of CsF, a variety of amino acids bearing alkyl and aryl residues were found to be amenable to the reaction. Initial cycloaddition furnished the 5-membered indolinone 103, with α-arylation of the ketone proposed to proceed via a keto-enol tautomerisation and subsequent enol ene reaction of 104 with a second equivalent of aryne.
# 6.2
Enamines
In an analogous manner to enol equivalents, the enamine ene reaction presents opportunities to effect either the α-arylation of imines or the preparation of o-amino biaryls. To this end, in 2012 Greaney and co-workers reported a highly regioselective metal-free o-arylation of aniline derivatives 106 using 2-(trimethylsilyl)aryl triflate 20 and CsF (Scheme [23]).[49] A bulky N-trityl protecting group was required to prevent competitive N-arylation under the neutral conditions, but this was easily cleaved with TFA during work-up to reveal the free aniline. The transformation was amenable to a wide range of m/p-substituted anilines, both electron-rich and -poor, with electron-donating groups particularly effective. Interestingly, further arylation of the o-substituted products 109 did not occur, which aligns with the overall lack of reactivity displayed by o-substituted aniline starting materials. These observations provided support for a concerted mechanism, as the required ene reaction conformation (108) places the bulky N-trityl group and any ortho-substituent in close proximity. A lack of o/p product mixtures and no deuterium incorporation when the reaction was conducted in acetonitrile-d 3 provided additional evidence for a concerted process. Elsewhere, Daugulis and co-workers have described the o-arylation of anilines under strongly basic conditions,[50] analogous to the investigations into phenoxides,[47] which again operates via a non-ene pathway.
Aly and Shaker proposed the existence of a transient enamine in the transformation of 1-aryl-5-methyl-1H-tetrazoles 110 to the corresponding 5-benzyltetrazoles 112 (Scheme [24]).[51] Under the neutral reaction conditions, an N/C-tautomerisation involving the 5-methyl group was invoked in order to form exocyclic enamine 111, which then underwent a hetero ene reaction with benzyne generated from the thermal decomposition of benzenediazonium-carboxylate 6.
# 6.3
Imines
In 1999, Aly and co-workers reported the C-arylation of 1,1′-(1,4-phenylene)bis(N-cyclohexylmethanimine) 113 upon treatment with benzenediazonium-carboxylate 6 (Scheme [25]).[52] It was proposed that the reaction proceeded via an initial aryne ene reaction involving the imine and adjacent methine proton of the cyclohexyl group, followed by a dehydrogenation of intermediate 114 to form ketimine 115 in 32% yield.
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# 7
Conclusions
The past 60 years have witnessed significant developments in the aryne ene reaction. From initial reports that described generally low yielding and poorly selective processes (competing [4+2] and [2+2] cycloadditions, as well as regioselectivity), recent years have afforded a wealth of novel transformations that incorporate a broad range of ene donors with generally much higher reactivity and selectivity. These advancements can be attributed to the milder reaction conditions facilitated by contemporary methods of aryne generation, in addition to an increased understanding of the reaction mechanism and structural requirements of the systems. To this end, more recent reports have presented detailed structure-reactivity relationships in addition to probing the mechanisms (via experimental isotope studies and/or computational calculations) of the novel transformations described. These investigations generally support a concerted mechanism with an asynchronous transition state in which C–C single bond formation is slightly more advanced. With regards to substrate viability, various alkenes, alkynes, allenes, toluenes and heteroatom-containing donors have successfully engaged arynes in ene reactions. Overall, the intermolecular transformations give rise to metal-free hydrocarbon arylations that are complementary to more typical transition-metal-mediated methods, whilst intramolecular processes afford benzofused carbo- and heterocyclic frameworks in a single step. Furthermore, these unimolecular systems have overcome regioselectivity issues commonly associated with the bimolecular processes and also exhibited high levels of diastereoselectivity. The significant advancements made in aryne ene methodologies over the past decade attest to the synthetic utility of this reaction and exciting opportunities exist for further developments. For example, employing more complex substrates, such as heterocyclic donors containing multiple heteroatoms, or as part of cascade processes that enable rapid access to valuable complex molecular frameworks.
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Conflict of Interest
The authors declare no conflict of interest.
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References
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- 31 Reddy RS, Lagishetti C, Chaithanya Kiran IN, You H, He Y. Org. Lett. 2016; 18: 3818
- 32 Liu L.-L, Li Z.-J, Gu C.-Z, He L, Dai B. J. Saudi Chem. Soc. 2017; 21: 458
- 33 Sun W, Trinchera P, Kurdi N, Palomas D, Crespo-Otero R, Afshinjavid S, Javid F, Jones CR. Synthesis 2018; 50: 4591
- 34 Candito DA, Dobrovolsky D, Lautens M. J. Am. Chem. Soc. 2012; 134: 15572
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- 36 Wang H.-F, Guo L.-N, Fan Z.-B, Tang T.-H, Zi W. Org. Lett. 2021; 23: 2676
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- 39 Usieli V, Sarel S. Tetrahedron Lett. 1973; 14: 1349
- 40 Yuan W, Ma S. Org. Lett. 2014; 16: 193
- 41 Sabbasani VR, Huang G, Xia Y, Lee D. Chem. Eur. J. 2015; 21: 17210
- 42 Sabbasani VR, Huang G, Xia Y, Lee D. Org. Chem. Front. 2021; 8: 3390
- 43 Brinkley YJ, Friedman L. Tetrahedron Lett. 1972; 13: 4141
- 44 Tabushi L, Yamada H, Yoshida Z, Oda R. Bull. Chem. Soc. Jpn. 1977; 50: 285
- 45 Niu D, Hoye TR. Nat. Chem. 2014; 6: 34
- 46 Zhang J, Niu D, Brinker VA, Hoye TR. Org. Lett. 2016; 18: 5596
- 47 Truong T, Daugulis O. Chem. Sci. 2013; 4: 531
- 48 Okuma K, Matsunaga N, Nagahora N, Shioji K, Yokomori Y. Chem. Commun. 2011; 47: 5822
- 49 Pirali T, Zhang F, Miller AH, Head JL, McAusland D, Greaney MF. Angew. Chem. Int. Ed. 2012; 51: 1006
- 50 Truong T, Daugulis O. Org. Lett. 2012; 14: 5964
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- 52 Aly AA, Mohamed NK, Hassan AA, Mourad A.-FE. Tetrahedron 1999; 55: 1111
Selected general reviews on ene reactions:
Selected reviews on aryne chemistry:
Corresponding Author
Publication History
Received: 31 March 2022
Accepted after revision: 14 April 2022
Accepted Manuscript online:
14 April 2022
Article published online:
31 May 2022
© 2022. Thieme. All rights reserved
Georg Thieme Verlag KG
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References
- 1 Alder K, Pascher F, Schmitz A. Ber. Dtsch. Chem. Ges. 1943; 76: 27
- 2a Hoffman HM. R. Angew. Chem. Int. Ed. Engl. 1969; 8: 556
- 2b Snider BB. Acc. Chem. Res. 1980; 13: 426
- 2c Oppolzer W. Angew. Chem. Int. Ed. Engl. 1984; 23: 876
- 2d Baird MS. Top. Curr. Chem. 1988; 144
- 2e Mikami K, Shimizu M. Chem. Rev. 1992; 92: 1021
- 2f Dias LC. Curr. Org. Chem. 2000; 4: 305
- 2g Adam W, Krebs O. Chem. Rev. 2003; 103: 4131
- 3a Sanz R. Org. Prep. Proced. Int. 2008; 40: 215
- 3b Tadross PM, Stoltz BM. Chem. Rev. 2012; 112: 3550
- 3c Dubrovskiy AV, Markina NA, Larock RC. Org. Biomol. Chem. 2013; 11: 191
- 3d Hoffmann RW, Suzuki K. Angew. Chem. Int. Ed. 2013; 52: 2655
- 3e Pérez D, Peña D, Guitían E. Eur. J. Org. Chem. 2013; 5981
- 3f Holden C, Greaney MF. Angew. Chem. Int. Ed. 2014; 53: 5746
- 3g Yoshida S, Hosoya T. Chem. Lett. 2015; 44: 1450
- 3h García-López J.-A, Greaney MF. Chem. Soc. Rev. 2016; 45: 6766
- 3i Bhojgude SS, Bhunia A, Biju AT. Acc. Chem. Res. 2016; 49: 1658
- 3j Shi J, Li Y, Li Y. Chem. Soc. Rev. 2017; 46: 1707
- 3k Diamond OJ, Marder TJ. Org. Chem. Front. 2017; 4: 891
- 3l Idiris FI. M, Jones CR. Org. Biomol. Chem. 2017; 15: 9044
- 3m Roy T, Biju AT. Chem. Commun. 2018; 54: 2580
- 3n Shi J, Li L, Li Y. Chem. Rev. 2021; 121: 3892
- 4 Himeshima Y, Sonoda T, Kobayashi H. Chem. Lett. 1983; 12: 1211
- 5 Hoye TR, Baire B, Niu D, Willoughby PH, Woods BP. Nature 2012; 490: 208
- 6 Arnett EM. J. Org. Chem. 1960; 25: 324
- 7 Simmons HE. J. Am. Chem. Soc. 1961; 83: 1657
- 8 Wittig G, Durr H. Justus Liebigs Ann. Chem. 1964; 672: 55
- 9 Wasserman HH, Solodar AJ, Keller LS. Tetrahedron Lett. 1968; 5597
- 10 Janath TT, Jeganmohan M, Cheng M.-J, Chu A.-Y, Cheng C.-H. J. Am. Chem. Soc. 2006; 128: 2232
- 11 Candito DA, Panteleev J, Lautens M. J. Am. Chem. Soc. 2011; 133: 14200
- 12 Trinchera P, Sun W, Smith JE, Palomas D, Crespo-Otero R, Jones CR. Org. Lett. 2017; 19: 4644
- 13 Xu H, He J, Shi J, Tan L, Qiu D, Luo X, Li Y. J. Am. Chem. Soc. 2018; 140: 3555
- 14 Tabushi I, Okazaki K, Oda R. Tetrahedron 1969; 25: 4401
- 15 Friedman L, Osiewicz RJ, Rabideau PW. Tetrahedron Lett. 1968; 5735
- 16 Wasserman HH, Keller LS. Tetrahedron Lett. 1974; 15: 4355
- 17 Ahlgren G, Åkermark B. Tetrahedron Lett. 1970; 11: 3047
- 18 Garsky V, Koster DF, Arnold RT. J. Am. Chem. Soc. 1974; 96: 4207
- 19 Crews P, Beard J. J. Org. Chem. 1973; 38: 522
- 20 Chen Z, Liang J, Yin J, Yu G.-A, Liu SH. Tetrahedron Lett. 2013; 54: 5785
- 21 Dubrovskiy AV, Larock RC. Tetrahedron 2013; 69: 2789
- 22 Pérez P, Domingo LR. Eur. J. Org. Chem. 2015; 2826
- 23 Gupta S, Xie P, Xia Y, Lee D. Org. Lett. 2017; 19: 5162
- 24 Gupta S, Xie P, Xia Y, Lee D. Org. Chem. Front. 2018; 5: 2208
- 25 Minuti L, Taticchi A, Marrocchi A, Gacs-Baitz E, Galeazzi R. Eur. J. Org. Chem. 1999; 3155
- 26 Bhojgude SS, Bhunia A, Gonnade RG, Biju AT. Org. Lett. 2014; 16: 676
- 27 Suh S.-E, Chen S, Houk KN, Chenoweth DM. Chem. Sci. 2018; 9: 7688
- 28 Liu J, Li J, Ren B, Zhang Y, Xue L, Wang Y, Zhao J, Zhang P, Xu X, Li P. Adv. Synth. Catal. 2021; 363: 4734
- 29 Nakayama J, Yoshimura K. Tetrahedron Lett. 1994; 35: 2709
- 30 Watson LJ, Harrington RW, Clegg W, Hall MJ. Org. Biomol. Chem. 2012; 10: 6649
- 31 Reddy RS, Lagishetti C, Chaithanya Kiran IN, You H, He Y. Org. Lett. 2016; 18: 3818
- 32 Liu L.-L, Li Z.-J, Gu C.-Z, He L, Dai B. J. Saudi Chem. Soc. 2017; 21: 458
- 33 Sun W, Trinchera P, Kurdi N, Palomas D, Crespo-Otero R, Afshinjavid S, Javid F, Jones CR. Synthesis 2018; 50: 4591
- 34 Candito DA, Dobrovolsky D, Lautens M. J. Am. Chem. Soc. 2012; 134: 15572
- 35 Karmaker R, Mamidipalli P, Yun SY, Lee D. Org. Lett. 2013; 15: 1938
- 36 Wang H.-F, Guo L.-N, Fan Z.-B, Tang T.-H, Zi W. Org. Lett. 2021; 23: 2676
- 37 Gupta S, Lin Y, Xia Y, Wink DJ, Lee D. Chem. Sci. 2019; 10: 2212
- 38 Wasserman HH, Fernandez JM. J. Am. Chem. Soc. 1968; 90: 5322
- 39 Usieli V, Sarel S. Tetrahedron Lett. 1973; 14: 1349
- 40 Yuan W, Ma S. Org. Lett. 2014; 16: 193
- 41 Sabbasani VR, Huang G, Xia Y, Lee D. Chem. Eur. J. 2015; 21: 17210
- 42 Sabbasani VR, Huang G, Xia Y, Lee D. Org. Chem. Front. 2021; 8: 3390
- 43 Brinkley YJ, Friedman L. Tetrahedron Lett. 1972; 13: 4141
- 44 Tabushi L, Yamada H, Yoshida Z, Oda R. Bull. Chem. Soc. Jpn. 1977; 50: 285
- 45 Niu D, Hoye TR. Nat. Chem. 2014; 6: 34
- 46 Zhang J, Niu D, Brinker VA, Hoye TR. Org. Lett. 2016; 18: 5596
- 47 Truong T, Daugulis O. Chem. Sci. 2013; 4: 531
- 48 Okuma K, Matsunaga N, Nagahora N, Shioji K, Yokomori Y. Chem. Commun. 2011; 47: 5822
- 49 Pirali T, Zhang F, Miller AH, Head JL, McAusland D, Greaney MF. Angew. Chem. Int. Ed. 2012; 51: 1006
- 50 Truong T, Daugulis O. Org. Lett. 2012; 14: 5964
- 51 Aly AA, Shaker RM. Tetrahedron Lett. 2005; 46: 2679
- 52 Aly AA, Mohamed NK, Hassan AA, Mourad A.-FE. Tetrahedron 1999; 55: 1111
Selected general reviews on ene reactions:
Selected reviews on aryne chemistry:
Christopher R. Jones (right) read Natural Sciences at the University of Cambridge (MSci Hons, 2005), where he later joined the group of Professor Martin D. Smith and received his Ph.D. in 2009. He then moved to the University of Oxford as a Junior Research Fellow to work with Professor Timothy J. Donohoe. In 2013 Chris joined Queen Mary University of London where he is currently a Senior Lecturer in Chemistry. His research interests are based on the development of new synthetic methodologies, with a particular focus on aryne chemistry.