Allenes in Diels–Alder Cycloadditions

Dedicated to the memory of Klaus Hafner

Abstract

For a long time, allenes—and cumulenic systems in general—played a relatively minor role in Diels–Alder cycloadditions. This situation has changed, since allenes are more readily available and as their unique stereochemical features in [4+2]cycloadditions are more widely recognized. This review presents a comprehensive overview of allenes in Diels–Alder processes using selected examples. Allenes in dienes, dienophiles and cycloadducts are covered, inter- and intramolecular Diels–Alder cycloadditions are discussed, and stereochemical features of the addition process are described. Areas of emerging importance are also covered, including allenic components in dehydro-Diels–Alder processes, and dendralenic allenes in Diels–Alder sequences for the rapid generation of target-relevant molecular complexity. Preparatively useful methods for allenic precursor synthesis are also discussed.

1 Introduction

2 Allenic Dienes

2.1 Vinylallenes

2.2 Bisallenes

2.3 Cross-conjugated Allenes

3 Allenic Dienophiles

4 Intramolecular Diels–Alder Cycloadditions

5 Allenic Cycloadducts

6 Conclusions and Outlook

Introduction

The Diels–Alder addition between a conjugated diene (1) and a dienophile (2)[1] is one of the most important reactions in organic chemistry.[2] It allows the preparation of a cyclohexene (3) in a preparatively simple, one-step, stereoselective, and often high-yielding process; no wonder that its discovery and application has been rewarded by a Nobel Prize (to Diels and Alder in 1950[3]). In its standard form it requires the availability of a cisoid-conformation electron-rich diene, and an electron depleted dienophile (Scheme [1]). An oppositely polarized arrangement with an electron-poor diene and an electron-rich dienophile is, however, also well known (Diels–Alder additions with inverse electron demand). When the two starting components of a Diels–Alder addition are part of one and the same molecule, i.e., are connected by a tether (of any complexity), one speaks of an intramolecular Diels–Alder addition.[4]

Scheme [1] summarizes the four main ways in which allenes can be involved in [4+2]cycloaddition reactions. If one of the two C=C bonds of the prototypical Diels–Alder (DA) diene is replaced by an allene, vinylallene 4 is the new reactant. In this case, the cycloadduct 5 carries an exocyclic C=C bond in conjugation with the usual cyclohexene one. With bisallene 6 as the reactant DA diene, conjugated triene 7 is the cycloadduct. If allene 8 is the dienophile, then non-conjugated diene 9 is produced. Allenes can also be generated in [4+2]cycloaddition reactions, in so-called dehydro-Diels–Alder processes.[5] Thus, the reaction between vinylacetylene 10 and ethylene 2 would generate cyclohexa-1,2-diene 11, a reactive cyclic allene.

This review is structured primarily around these four subtypes of allenic Diels–Alder processes. In the case of Diels–Alder reactions involving vinylallenes and bisallenes, pertinent information on the structure and preparation of the allene-containing precursors is also presented.

One profound consequence of allenic reactants in Diels–Alder processes relates to stereochemistry. Since 1,3-disubstituted allenes are chiral, their inclusion as dienes and dienophiles is accompanied by the transformation of axially chiral precursors into cycloadducts with stereocenters.[6] Cycloadditions of substituted allenes also feature unique aspects of diastereoselection in cycloadduct alkene formation. Since the usual stereochemical features of [4+2]cycloadditions—endo/exo-selectivity and π-facial selectivity—also operate with allenic reactants, their cycloadditions are uniquely complex.

Intramolecularization of the allenic [4+2]cycloaddition, by the connection of the diene to the dienophile through a tether as in 12 (Scheme [2]), generates a product with two new rings, e.g., 13. Performing the Diels–Alder reaction intramolecularly a priori has no consequences: as long as the tether has the requisite conformational flexibility such that the reacting units may come together. If this factor holds then the intramolecular Diels–Alder (IMDA) process is entropically favored. Many IMDA processes involving allene-containing precursors have been reported and a representative selection is provided in Section 5.

An alternative [2+2]cycloaddition mode of cumulenic systems leads to the formation of four-membered rings. 1,2-Bismethylenecyclobutane (14) as the primary product from the parent allene 8.[7] In a few situations, the [2+2]cy­cloaddition pathway is preferred over the [4+2]cycloaddition but this is not a common problem with allenic precursors.

Starting from vinylallene 4 and the hybrid character of its structure (i.e., both a cumulated and a conjugated diene) many other π-systems can be designed, prepared and studied. And many of these compounds are particularly interesting­ from the perspective of their reactivity as Diels–Alder dienes and in the generation of cyclic allenes in [4+2]cycloadditions. A small selection is collected in Scheme [3].

The conjugated allenyne 15 is another (cf. 10, Scheme [1]) ‘dehydro-diene’, which offers itself to the increasingly studied dehydro variants of the Diels–Alder process (see Section 5); the aforementioned bisallene 6 formally consists of an inner buta-1,3-diene, and two outer allene systems, whereas in 2-(buta-1,3-dienyl)allene 16, two buta-1,3-diene and one allene subunits can be recognized. 1,1-Divinylallene (17) is an isomer of 16 and also contains two buta-1,3-diene moieties as well as an allenic part. As described in Section 2.3, this compound reacts as a triple Diels–Alder diene, undergoing a sequence of three [4+2]cycloadditions. Finally, structure 18 shows a hybrid of two buta-1,3-diene and also two allene building blocks. It is obvious that by incorporations of further unsaturated units—double and triple bonds, cumulenic systems, phenyl substituents and other aryl groups—countless structures can be generated, many of them unknown so far.[8]

In closing this introductory section, it should be mentioned that the transformations discussed here are the binary prototypes (compounds containing only C and H) of countless cumulenic hetero-organic systems such as ketenes or ketenimines. As far as hetero-organic dienophiles are concerned, azo-compounds,[9] [10] nitroso derivatives,[11] aldehydes[10b,12,13] and imines[14] should be mentioned, which have been used to prepare numerous heterocyclic compounds by Diels–Alder routes involving conjugated allenic systems.

Entry into the allene cycloaddition field discussed here is comparatively easy, since a comprehensive review literature exists; it extends from classical monographs[15] to more recent summaries of the literature.[16] [17] Our review differs from these earlier contributions in that we attempt to provide an overview of all aspects of allene cycloadditions in one (at the time of publication) up-to-date article.

Allenic Dienes

Vinylallenes

The simplest allenic hydrocarbon that can participate in an intermolecular Diels–Alder reaction as a 4π component is vinylallene (4). The compound was initially prepared by Jones and co-workers[18] by treatment of unsaturated chlorides such as E-5-chloro-pent-3-en-1-yne (19, Scheme [4]) with Zn/Cu-couple in butanol. Later authors accessed this simple hydrocarbon by sodium hydroxide induced isomerization of pent-1-en-4-yne (20)[19] or Pd(0)-catalyzed Negishi cross-coupling of vinylzinc chloride (21) with propargyl bromide (22).[20] Vinylallene can be purified by distillation and is available in gram quantities.

On heating the pure hydrocarbon 4 at 170 °C in the gas phase, a complex mixture of dimeric products 23–28 is produced besides small amounts of the 4π-electrocyclization product methylenecyclobutene (29) (Scheme [5]). Formally, dimers 23–25 are [4+2]cycloaddition products, for whose formation one molecule of 4 serves as a diene component and the second one serves as the dienophile, participating either with its internal allenic C=C bond (orientational regioisomers, 23 and 24) or olefinic part (one orientational isomer, 25). Dimers 26 and 27 are formal [4+4]cycloadducts.[21]

The Pd(0)-catalyzed dimerization of 4 occurs at much lower temperature, and leads to the formal Diels–Alder adduct 30 as the main product of the reaction (81%), which is the unseen orientational regioisomer involving the vinyl group as dienophile from the pyrolysis reaction. A mixture of geometrical isomers of adducts from reaction at the terminal allenic C=C bond dienophile 31 is also seen. Treatment of the major product 30 with base led to bicycle 28 by way of through- and cross-conjugated tetraene 32.[22] Thus, we have a potential origin for 28 from the pyrolysis experiment.

Classical Diels–Alder cycloadditions of 4 with typical dienophiles have been reported by Jones and co-workers in pioneering studies that are summarized in Scheme [6].[18] Thus, the addition of tetracyanoethylene 33 to 4 provided the methylenecyclohexene adduct 34 in excellent yield at ambient temperature. With para-benzoquinone (35), adduct 36 was obtained (68%), which could be converted into 5-methyl-1,4-naphthoquinone by treatment with methanolic sodium hydroxide, then acetic acid and potassium dichromate. Diels–Alder addition of 4 and p-phenylazomaleimide (37) yielded the adduct 38 in 58% yield.

To investigate additional aspects of stereoselectivity of the Diels–Alder addition of conjugated vinylallenes with various carbon-centered dienophiles, substituted vinylallenes had to be prepared and studied.

Before discussing the corresponding [4+2]cycloadditions, we have to focus on the conformation of vinylallene (4). This simplest allene-containing buta-1,3-diene prefers the s-trans conformation, which possesses C_s molecular symmetry. This has been established by numerous physical methods from gas-phase electron diffraction,[23] Raman and IR spectroscopy,[24] photoelectron spectroscopy[25] and NMR spectroscopy.[26] These experimental results are backed up by theoretical calculations, which confirm a 2.8 kcal/mol preference for the s-trans conformer over the s-cis conformer.[27]

Does the presence of an allene in a buta-1,3-diene lead to a more or less reactive Diels–Alder diene? Scheme [7] depicts the structure of (E,E)-octa-1,2,4,6-tetraene 39, which contains both a buta-1,3-dienyl subunit and a vinylallenyl subunit and hence possesses the possibility to react in two different Diels–Alder modes. As it turns out, in the reaction with TCNE 33, only its vinylallene part undergoes the [4+2]cycloaddition.[28] This outcome is consistent with calculations of the Diels–Alder reactions of ethylene (as dienophile) with the series of dienes buta-1,3-diene 1, vinylallene 4 and bisallene 6, which indicate that activation barriers are progressively lower and reaction exothermicities are higher as allene content increases.[29] Similar results are seen in computational studies on the [4π]electrocyclizations of 1, 4 and 6.[30] Evidently, a vinylallene is a more reactive Diels–Alder diene than a buta-1,3-diene.

Considering the steric and electronic influence of substituents on the s-cis/s-trans conformational equilibrium of vinylallene 4, we would expect similar effects as observed for the classical 1,3-dienes used in the Diels–Alder process: bulky substituents, especially where more than one is present, would favor the transoid-conformation, slowing down the addition process or preventing it altogether. ‘Freezing’ a conformation in a trans-arrangement such as in 3-methylenecyclohexene would cause the same result, whereas cis-fixed structures as in 1,2-bismethylenecyclopentane would ease the cycloaddition process, so long as the C1–C4 interatomic distance is favorable for orbital overlap with the dienophile.[31]

There is, however, one decisive difference between a simple buta-1,3-diene and a vinylallene: the 90° twist caused by the sp-hybridized carbon atom in the allenic diene. Because of this, with vinylallenes carrying a terminal allene substituent, the two possible reacting sides of the buta-1,3-diene are different, with one π-diastereoface being more (and the other less) sterically hindered. This is illustrated in Scheme [8] by the vinylallene derivative 42 (shown in its cisoid-conformation), which carries a substituent (SCN) at its allene terminus. The dienophile 33 approaches the diene 42 from the sterically less shielded side, through transition state (TS) 43, yielding the E-configured adduct 44 in good yield.[32]

The other examples in Scheme [8], involving maleic anhydride (46), introduce the additional complexity of endo/exo-stereoselectivity. Further to dienophile approach to the less sterically shielded π-diastereoface of the substituted vinylallene, a strong preference for endo-mode approach of the dienophile 46 is seen in each case. Thus, reaction of 45 with 46 yields predominantly endo-adduct 48 (through preferred TS 47) over exo-adduct 49,[33] and reaction of 50 (R = H or Ph) with 46 gives 51 for similar reasons.[13] The preference for endo-mode cycloadditions has been ascribed to stabilizing secondary orbital interactions (SOIs) in the transition state.[34]

The regioselectivity of [4+2]cycloadditions to vinylallenes was reported in classical studies by Bertrand and co-workers.[35] As shown in Scheme [9], methyl vinyl ketone (52, MVK) cycloadds to vinylallene 4 to furnish the two regioisomers 53 and 54, the former being the main product (70:30 ratio). The formation of major product 53 is consistent with advanced TS bond formation between the β-carbon of the enone and to the sp carbon of the vinylallene. The generation of the major product can be understood by preferential bond formation between the more electron-deficient carbon of the dienophile and the more electron-rich carbon of the diene. Lewis acid catalysis would, most likely, lead to significantly enhanced selectivity for regioisomer 53.

The presence of a methyl substituent at the vinyl terminus of vinyl allene enhances the orientational regioselectivity of the reaction (compare the regioselectivities of the two reactions in Scheme [9]). The preferential formation of endo-adduct 57 over its exo-stereoisomer 58 from the disubstituted vinylallene 56 and MVK 52 is due to SOIs in the TS leading to the former. The endo-preference of the dienophile MVK 52 is generally not as strong as that for MA 46 (cf. Scheme [8]). The Z-diastereomer 55 did not add under the reaction conditions, presumably because the cisoid conformation of this particular vinylallene is disfavored.[36]

That the reactions between vinylallenes and appropriate dienophiles display the typical characteristics of a Diels–Alder process (i.e., concerted, suprafacial addition with respect to both diene and dienophile) is also emphasized by preservation of dienophile geometry in the reaction between substituted vinylallene 59 and dimethyl fumarate (60), leading to a mixture of adducts 61 and 62 in good yield (Scheme [10]).[37] The interesting preference for diastereomer 61 could be the result of a shorter developing bond at the sp carbon in TS 63, which might give rise to stronger stabilizing SOI interactions with the endo-oriented –CO₂Me group. Alternatively, destabilizing steric clashes in TS 64 between the endo-oriented –CO₂Me group and the proximate n-Pr substituent on the vinylallene might disfavor the formation of adduct 62.

Vinylallenes are versatile Diels–Alder dienes, permitting polycycle construction in short order. Schemes 11 and 12 summarize a small selection of the vast literature describing precursors with pre-existing rings.

Pure hydrocarbon systems including polyalkylated, alkenyl and arylated vinylallenes,[12c] [38] and vinylallenes in a fixed cisoid orientation (65), provide the expected Diels–Alder­ adducts (such as 66) with common dienophiles such as MA 46, in usually good to excellent yields.[39] The retention of enantiopurity during the conversion of axially chiral vinylallenes into cycloadducts with stereocenters is also shown in Scheme [11]. Highly enantiomerically enriched precursors 70 and 72 were subjected to Diels–Alder addition with dienophiles 46 and 73, respectively. In the former case, the adduct 71 was obtained with high stereoselectivity (er 98:2, dr > 20:1) from relatively simple precursors 67 and 68.[40] An enantioselective Pd(0) catalyzed cross-coupling process, brought about by an in situ generated catalyst deploying chiral ligand 69, generated the vinylallene 70, which underwent cycloaddition with added dienophile 46 in a one-flask operation. In the latter case, vinylallene 72 was isolated then subjected to an ‘on water’ Diels–Alder reaction with maleimide 73 to give adduct 74 with no loss in enantiopurity.[10d] [41]

Turning to functionalized vinylallene components next, the selection summarized in Scheme [12] is typical. The formal Diels–Alder transformation of substituted vinylallene 75 into adduct 76 demonstrates that even hydrocarbons like buta-1,3-diene (1) can be brought about to serve as a dienophile under Pd(0)-catalysis (c.f. Scheme [5]).[22c] [33] [42]

The example 77 + 46 → 78 [43] demonstrates that polycyclic ring systems related to terpenoid natural products can be rapidly constructed. The last example in Scheme [12] depicts, firstly, an operationally simple preparation of vinylallene 81 from Barbier-type addition of an organoindium species derived from bromide 80 to benzaldehyde 79. Next, addition of the dienophile TCNE 33 gives Diels–Alder adduct 82.[44]

Bisallenes

For the preparation of the parent compound of the conjugated acyclic bisallenes, hexa-1,2,4,5-tetraene (6, biallenyl),[45] propargyl bromide (22) was first converted into its Grignard reagent 83, which has an allenic structure (Scheme [13]). Subsequently CuCl is added, which very likely generates an organocuprate intermediate, which is then coupled with a second equivalent of 22 to yield the desired 6 and its propargylic isomer, hexa-1,2-dien-5-yne (84, propargylallene).

The two C₆H₆-isomers 6 and 84 are produced in ca. 40:60 ratio and the total yield varies between 40 and 70% depending largely on the work-up conditions.[46] Separation of the two hydrocarbons by distillation suffers from their instability and similar physical properties. Analytically pure isomers 6 and 84 have been obtained by preparative gas chromatography as well as selective removal of 6 by Diels–Alder additions with dienophiles (see below). Solutions of 6/84 in ether containing up to 50 g of the former can be readily prepared.[46]

One of the most general routes to (alkylated) bisallenes consists of the formal insertion of carbon into the C=C double bonds of a conjugated diene. This is illustrated by the conversion of the tetramethyl derivative 85 into its bisallenic counterpart 87 (Scheme [13]).[47] In the first step, the starting diene 85 is dibromocyclopropanated to the tetrabromobicyclopropyl derivative 86. On treatment with an alkyllithium reagent, each dibromocyclopropane is dehalogenated to generate a carbene, which undergoes an electrocyclic ring opening to the allene (Doering–Moore–Skattebøl route[48]).

Another general protocol to conjugated bisallenes is reminiscent of the route to conjugated vinylallenes described above in Scheme [4]; it will be illustrated here for the synthesis of deuterated derivatives of hydrocarbon 87 (Scheme [13]).[49] In its first step, the bromoallene building block 90 was prepared from substituted propargyl alcohol 88 via the deuterio-derivative 89 by standard methods of acetylene/allene chemistry. The organozinc reagent 91 was subsequently prepared by first treating 90 with n-butyl lithium in ether to form the organolithium species, then transmetallating with ZnCl₂. Negishi coupling in the presence of [Pd(PPh₃)₄] with either 90 or 93 finally furnished the deuterio derivatives 92 and 94.

Among the many other routes to conjugated bisallenes (which are often represented in the literature through only one or two examples), noteworthy methods include those in which all the required atoms of the target molecule are already present in the starting material. A case in point is the thermal [3,3]sigmatropic rearrangement of hexa-1,5-diyne 95 to the bisallene 6. While some highly substituted examples have preparative value for bisallene synthesis,[50] less substituted molecules—such as the parent system 6—undergo facile [4π]electrocyclic ring closure to 3,4-dimethylenecyclobutene 96.[45] [51] Since the preparation of numerous substituted and/or functionalized bisallenes was reviewed relatively recently (in 2012)[16] we stop our summary of preparative methods providing these compounds here.

From a structural viewpoint, the most thoroughly investigated conjugated bisallene is the parent compound 6. Not only has its vibrational spectrum been measured and interpreted,[52] but its most stable conformation in the gas phase has been determined by electron diffraction (GED).[53] Both of these methods support the C _2h -symmetry of 6, i.e., a transoid conformation as the most stable conformation. This is supported by NMR measurements in a nematic solvent at room temperature[54] and its photoelectron spectrum (PES).[25] [55] Although no X-ray analysis of 6 has been reported (the compound is a liquid at room temperature), X-ray structural analyses of about 4 dozen solid derivatives of 6 have been reported in the Cambridge Crystallographic Database.[16]

Turning to Diels–Alder cycloadditions now, while we have been unable to locate a publication describing the experimental or computed conformational dynamics of the molecule, it is clear that 6 has no difficulties acquiring the cisoid conformation required for the reaction to take place. As mentioned earlier, calculations point to a faster and more thermodynamically favorable Diels–Alder reaction with 6 as a diene than with vinylallene 4.[29] Addition of MA 46 to 6 affords the expected Diels–Alder adduct 97 in good yield, which can be aromatized to the dimethylphthalic anhydride 98 in good yield (83%) by treatment with a weak base such as pyridine in dioxane (Scheme [14]).[9]

Likewise, the addition of N-phenylmaleimide (99, NPM) provides 100 (60%) which can be isomerized to 101. When the dienophile lacks hydrogen atoms, as in 102 (DDQ), the addition process stops after the primary process (quantitative formation of 103). Many additions of substituted bisallenes have been reported and Scheme [15] shows a small but representative selection.

Azetidinones (β-lactams) 104 were reacted with different double bond dienophiles, of which dimethyl fumarate 60 is representative, to provide the [4+2]cycloadducts such as 105, which subsequently were aromatized to 106 in a similar manner to the previous Scheme.[56]

To investigate aspects of the stereochemistry of the addition process, both hepta-1,2,4,5-tetraene (107)[9] and the two diastereomeric bisallenes 110 and 113 were trapped by MA (46) and NPM (99), respectively.[57] As shown in Scheme [15] for all three dienes, the addition of the dienophiles takes place from the less hindered π-diastereoface (TSs 108, 111 and 114), furnishing adducts 109, 112 and 115, in which the more bulky substituent points away from the heterocycle. As expected, the addition to 110, in which one of the π-diastereofaces of the diene component is ‘free’, occurs faster than in the diastereomeric case 113, in which both π-diastereofaces are hindered.

Turning to symmetrically disubstituted triple bond dienophiles 116 (Scheme [16], EWG = CHO, COMe, CO₂Me, CN, CF₃) next, 6 reacts readily to provide tetrasubstituted, anti-configured [2.2]paracyclophanes 118 in 25–50% yields. Presumably, this surprisingly short preparative route to functionalized paracyclophanes involves the formation of a p-xylylene intermediate 117 in its first (Diels–Alder) step, followed by a dimerization of this highly reactive species.[46] [58] Parenthetically, the dimerization proceeds most likely through a stepwise mechanism involving a biradical intermediate.[59] The substituted [2.2]paracyclophane synthesis is restricted to activated dienophiles 116, with compounds such as tolane, but-2-yne and cyclooctyne showing no tendency to cycloadd.

Replacing 116 by an unsymmetrically substituted dienophile such as propiolic aldehyde (119) leads to the generation of a monosubstituted p-xylylene intermediate 120, which has four different options to dimerize, as shown in Scheme [16]. Experimentally, a mixture of all four possible disubstituted dialdehydes 121–124 was generated, without a pronounced preference for either one, in up to 45% yield.[60] The different isomers 121–124, which can be separated easily by column chromatography, are interesting starting materials in cyclophane chemistry.[61] Other monosubstituted triple bond dienophiles such as cyanoacetylene and methyl propiolate react correspondingly.

A few examples have been reported in which the cisoid-conformation of 6 is fixed by the introduction of bridging structural elements (Scheme [17]). Thus, the cyclobutane carrying two semicyclic allene groups 125 furnishes the [2.2]paracyclophane derivative 128 in 7.5% yield when treated with dimethyl acetylenedicarboxylate (126, DMAD) in benzene at 50 °C; again, the most reasonable intermediate being the bridged p-xylylene 127.[62]

Analogously, the rigid bisallenes 129 and 131 react with TCNE 33 to furnish Diels–Alder adducts 130 [63] and 132.[64]

Closing this section on Diels–Alder additions of conjugated bisallenes, it might be mentioned that other pericyclic reactions of this compound class have been studied also, including the addition of N-sulfinylaniline, various carbenes and their higher molecular weight analogues (silylenes, germylenes), sulfur dioxide etc.[16] In most of these cases the heterocyclic adducts produced are formed by routes in accordance of the Woodward–Hoffmann rules.

Cross-conjugated Allenes

We elected to summarize the Diels–Alder chemistry of cross-conjugated allenic systems in a separate section since this chemistry is uniquely powerful for rapid structure complexity generation. The simplest cross-conjugated hydrocarbon molecule, [3]dendralene 133, reacts as a double diene, undergoing a sequence of two Diels–Alder reactions with two separate dienophiles. Shown in Scheme [18] is the simplest incarnation of this sequence, in which the two hypothetical dienophiles are ethylene (2) molecules.

Cycloaddition of the first ethylene dienophile 2 to either one of the two equivalent dienes of the [3]dendralene 133 generates vinylcyclohexene 134, which can next react with the second ethylene dienophile molecule 2 to form bicyclic octalin product 135. This double cycloaddition process has been long known[65] as a diene-transmissive Diels–Alder sequence:[66] the first cycloaddition brings about transmission of C=C bond character to the C2–C3 site of the first reacting diene, bringing it into conjugation with the bystander vinyl group from the first cycloaddition event, thereby generating a second buta-1,3-diene moiety.

When the central C=C bond of [3]dendralene is ‘stretched’ into an allene, a diene-transmissive sequence of three Diels–Alder reactions is permitted. Scheme [19] depicts the imaginary, stripped back scenario with no substituents on 1,1-divinylallene 17 and ethylene 2 as the hypothetical dienophile for all three cycloadditions. The first dienophile can cycloadd to either of the two equivalent vinylallene ends of the molecule, through which it generates 2,3′-cyclo[3]dendralene 136. The second cycloaddition of the C=C dienophile is constrained to occur at the semicyclic diene site of 136, since this is the only one that can adopt the cisoid diene conformation. A third ethylene dienophile addition to bicycle 137 completes the trio of cycloadditions in sequence, resulting in the formation of a decahydro-phen­alene­ tricyclic ring system 138.

A cross-conjugated hydrocarbon with n × C=C bonds can react, in a diene-transmissive manner, through an optimal sequence of (n–1) [4+2]cycloadditions. Not every cross-conjugated system can behave this way, however, since the correct arrangement of π-bonds is needed. Thus, the allene positional isomer of 1,1-divinyl allene 17, namely (buta-1,3-dien-2-yl)allene 16 (Scheme [20]) can undergo a maximum of only two cycloadditions, since the two double adducts 140 and 142 carry dienes that are not reactive in Diels–Alder additions. These two regioisomeric double adducts result from the two possible sites for the first ethylene dienophile to react, either at the vinylallene part of hydrocarbon 16 to give through-conjugated triene 139 (which has only one cisoid diene portion for a second addition) or the buta-1,3-diene part of 16 to give cyclohexenyl-allene 141.

It is worth noting that, even if a cross-conjugated hydrocarbon system can behave in a diene-transmissive way, diene site selection is often needed in order for the maximum number of cycloadditions to be realized. A case in point is [4]dendralene 143 (Scheme [21]): An initial addition to one of the two equivalent terminal diene sites gives the 1,2-cy­clo[3]dendralene mono-adduct 145, which can react on through two separate diene-transmissive Diels–Alder pathways to form triple adducts 147 and 148. In contrast, an initial addition to the central diene site of [4]dendralene 143 forms monoadduct 144, which can only undergo one further cycloaddition to yield double adduct 146.

Returning to cross-conjugated allenes, the synthetic generation of both of the two simplest hydrocarbons, 1,1-divinyl allene 17 and (buta-1,3-dien-2-yl)allene 16, have been reported. The successful route to (buta-1,3-dien-2-yl)allene 16 involves the S_N2′-like substitution of allenol-derived phosphate 149 with allenyl magnesium bromide 83 under CuBr catalysis (Scheme [22]).[67] The compound is generated in this manner in ca. 60% yield, but the majority of the material decomposes upon attempted purification. The so-far unreported Diels–Alder reaction of this hydrocarbon with a dienophile would reveal its selectivity towards competing buta-1,3-diene and vinylallene sites, which would complement the previously described study in the through conjugated series (Scheme [7]).

The synthesis of the parent 1,1-divinylallene 17 (Scheme [23]) involves the Grieco–Sharpless elimination of the selenoxide derivative of precursor 150.[68] The volatile hydrocarbon 17 is co-distilled from the reaction mixture with the CDCl₃ solvent, as a simple method of separation from the byproducts of the reaction and generation of an NMR-ready solution. 1,1-Divinylallene 17 polymerizes too rapidly to be handled in neat form at ambient temperature, so it is best generated and characterized in solution. The hydrocarbon undergoes a diene-transmissive, triple Diels–Alder sequence with NPM 99 to form hexacyclic product 153. The sequence was discussed above for the case of a hypothetical dienophile ethylene 2 (Scheme [19]). With the NPM dienophile, issues of endo/exo-diastereoselectivity and π-diastereofacial selectivity exist, hence the situation is considerably more complex. Nonetheless, the first two cycloadditions occur with (within the limits of detection) complete endo-diastereoselection, with the second dienophile molecule approaching the less sterically encumbered diene face of the mono-adduct 151 to form bis-adduct 152. Uncommonly for this type of dienophile, the third cycloaddition is exo-selective, presumably on account of both of the possible endo-approaches of the dienophile to the diene 152 being sterically blocked.

The generation and Diels–Alder reaction of the methyl substituted 1,1-divinylallene 153 were reported more than two decades earlier than the preparation of the parent 1,1-divinyl allene 17.[67] As shown in Scheme [24], the compound was prepared through regioselective substitution of methyl ether 154, which has three potential sites for S_N2′-type reaction, specifically the termini of the two vinyl groups or the one ethynyl substituent. Reaction occurs selectively at the alkyne terminus to generate allene 155, high quality spectra for which were unobtainable due to its instability. The TCNE Diels–Alder adduct 156 was isolated from a reaction in pentane at ambient temperature, albeit in low yield.

The first chiral 1,1-divinylallene reported in the literature was trimethyl analogue 159,[69] which was prepared through a Kumada-type cross coupling between propargylic mesylate 157 and Grignard reagent 158, during which the now familiar propargyl- to allenyl-transposition ensued (Scheme [25]). This compound can be prepared on scales over several grams but, once again, is best generated in solution and used in situ, due to its propensity to polymerize when neat at ambient temperature. Uncatalyzed Diels–Alder reaction with dienophile 160 furnished mainly the 2,3′-cyclo[3]dendralene 161, in a ca. 5:1 ratio with other isomers. An essentially complete retention of enantiopurity was seen on switching from central (157) to axial (159) chirality, and back to central (161) chirality once again. Reaction of the mono-cycloadduct 161 in two further Diels–Alder­ reactions led ultimately to natural product 162.

The first synthesis of 1,1-diallenylethylene 164 involved the base-catalyzed twofold propargyl- to allenyl-isomerization from 1,1-dipropargylethylene 163 (Scheme [26]).[67] The reaction is high yielding but, once again, the susceptibility of bis-allene 164 to polymerization thwarted attempts to purify and fully characterize the hydrocarbon. A Diels–Alder­ addition with TCNE 33 at ambient temperature gave mono-adduct 165 in modest yield. A second dienophile addition to the newly created vinylallene portion of mono-adduct 165 would give putative double adduct 166. This as yet unexplored sequence offers significant potential in synthesis.

Finally in this section, tetravinylallene 170 was recently prepared, along with several substituted analogues (Scheme [27]).[70] Hydrocarbon 170 was prepared reproducibly, albeit in low yield along with regiosiomer 171, through a challenging Negishi cross-coupling with transposition, between the sensitive methanesulfonate derivative 168 of trienol 167 with vinylzinc bromide 169. Tetravinylallene 170 is a little more kinetically stable (and less volatile) than the previous unsubstituted molecules described in this section, being amenable to purification by flash column chromatography. The hydrocarbon 170 undergoes a spectacular sequence of three Diels–Alder reactions with NPM 99, with a highly torquoselective 6π electrocyclization punctuating the second and third cycloadditions. The first dienophile molecule has four equivalent vinylallene sites to which it may react, generating mono-adduct 172. The second addition occurs at the transmitted diene site, forming bisadduct 173, which undergoes the electrocyclization to 174. The final cycloaddition occurs to the semicyclic diene site of the 1,3′-cyclo[3]dendralene 174 to give heptacyclic product 175, with seven C–C bonds and four rings formed about the tetravinylallene core.

Thus, cross-conjugated allenic systems serve as a central hub for the generation of polycyclic systems by way of diene-transmissive Diels–Alder sequences, which can also involve electrocyclization events. The allenes in these molecules, akin to all allenic systems covered thus far, react as a part of a Diels–Alder diene. In the next section, we move onto the dienophile reactivity of allenic molecules.

Allenic Dienophiles

Compared to allenic dienes (Section 2), the number and particularly the structural variety of acyclic allenic dienophiles which have been studied or used in synthesis is comparatively small. The simplest dienophile of this type is allene (8) itself. As shown in Scheme [28], it reacts with cyclopentadiene (176) under drastic conditions to provide adduct 177 in moderate yield.[71]

Other unactivated allenes such as 1,1-dimethylallene (3-methylbuta-1,2-diene) react similarly.[72] Much more often, though, electron-deficient allenes are employed. Introducing an electron-withdrawing (and generally conjugating) substituent lowers the LUMO energy of the allene. The C=C bond of the allene in conjugation with the electron-withdrawing substituent is the one that is activated for reaction in a normal electron-demand cycloaddition with an electron-rich diene. This fact is borne out by numerous examples using allenic esters such as 178 and 182, ketones (179), sulfonyl allenes (180), fluoroallenes (183), allenyl phosphine oxides (181) to name but a few.[73]

Insights into the stereochemical course of the addition of allenic dienophiles to various dienes can be gleaned through the reactions summarized in Scheme [29].

The reaction between allenic ester 178 and cyclopentadiene 176 leads to a mixture of endo- and exo-cycloadducts 184 and 185, under conditions significantly milder than those required for the parent allene. When carried out thermally, the Diels–Alder addition is mildly endo-selective but a Lewis acid promoter gives a significant rate enhancement and improved endo-preference.[74]

The more complex case of the cycloaddition of the (chiral, racemic) allene ester 187 to furan 186 yielded endo-adduct 189 via transition state 188 and exo-adduct 191 via the competing transition state 190. In both cases, approach from the less hindered face of allene 187 occurs (i.e., the π-diastereofacial selectivity of the reaction is due to the diene avoiding the allenic dienophile’s methyl substituent). The geometry of the exocyclic alkene is determined by the twisting that occurs during the cycloaddition, resulting from the change in hybridization at four carbon atoms of the diene and dienophile. In an uncatalyzed cycloaddition with furan as solvent at reflux temperature (40 °C), the total yield amounts to 40% and the endo/exo ratio is 75:25. In the catalyzed (1 mol% Eu(fod)₃) reaction performed at ambient temperature, endo-adduct 189 is produced exclusively and in better total yield (70%).[75] Furan diene cycloadditions can be reversible on account of the molecule’s aromaticity, with kinetic endo-adducts favored from shorter reactions at lower temperatures and thermodynamic exo-adducts from longer reactions. While the improvement in endo-selectivity with Eu(fod)₃ is most likely due to an enhancement in SOIs, a LUMO-lowering rate enhancement (hence lower reaction temperature and time) would also reduce the prospect of reversibility, hence channeling towards the exo-adduct.

The reactivity of the allene component in these cycloadditions may not only be increased by electron-withdrawing substituents, but also by incorporating the allene unit into six or seven-membered ring. Two examples are shown in Scheme [30]. When 1-bromo-cyclohex-1-ene (193) is treated with potassium tert-butoxide in DMSO, cyclohexa-1,2-diene (11) is generated as a reactive intermediate, which can be trapped by diphenylisobenzofuran (192) as the diene component to furnish endo- and exo-adducts, 194 and 195, respectively, as the main products as well as the deoxygenated adduct 196 as a trace compound.[76]

The generation of cyclic strained allene dienophiles has seen a resurgence of late, with the mild Kobayashi method (originally devised for 1,2-didehydrobenzyne formation[77]) being extended to the generation of six-membered carbocyclic,[78] azacyclic[79] and oxacyclic allenes.[80] A representative example of a strain-driven Diels–Alder cycloaddition involves oxacyclic allene 198, generated upon treatment of silyl triflate 197 with CsF. Heterocyclic allene 198 reacts in a [4+2]cycloaddition with diphenylisobenzofuran 192 to form endo-adduct 199 as the major product. A recent publication explains the endo-stereoselectivity of Diels–Alder reactions of cyclohexa-1,2-diene and heterocyclic analogues.[81]

So far, the Diels–Alder reactions of allenes described in this review have been limited to those involving separate diene and dienophile molecules. In the next section we describe representative examples of intramolecular processes.

Intramolecular Diels–Alder Additions Involving Allenes

Connecting a diene and dienophile by a molecular linker or spacer (of any complexity) as in 12 (Scheme [2]) results in a reduction of pathways by which these two components of a Diels–Alder process can approach each other in three-dimensional space. It hence comes as no surprise that this pre-orientation has often been applied to influence or control the regio- and stereochemistry of a [4+2]cycloaddition. This is also the case for the reaction between allenic dienophiles and dienes. Typical examples are reproduced in Scheme [31].[82]

When the acyclic precursor 200, in which the two moieties of a Diels–Alder addition are connected by a (flexible) trimethylene chain, is heated in toluene at reflux temperature, a mixture of the endo- and exo-adducts 201 and 202 is produced in 87% yield in a 35:65 ratio. These are the products to be expected for an allene-dienophile reacting at its more reactive double bond (see above), although in the acyclic pendant we would have expected the endo-adduct (formed through TS 203) to predominate. If the reaction is carried out in the presence of a Lewis acid (Et₂AlCl), a slight reduction in total yield is noted (65%), the reaction temperature is drastically reduced and the endo-isomer 201 predominates (87:13 ratio). Evidently, complexation of the ester group to the Lewis acid has a LUMO-lowering effect, which also enhances SOIs in the endo-TS.

In the less flexible compound 204, it is the terminal allene double bond that reacts preferentially, furnishing adduct 205 in 76% yield.[83] Approach of the allene to the bottom face of the semicyclic diene is controlled by the configuration of the pre-existing stereocenter. The dienophile site selectivity was ascribed to the preference of the ester group in the tether to adopt a transoid conformation.

In certain cases, even a benzene ring can be induced to participate as a 4π-component in an intramolecular Diels–Alder addition, a case in point being provided by the cy­cloaddition of the allene amide 206 to the tricyclic adduct 207 (Scheme [32]).[84] These so-called Himbert cycloadditions were originally performed only on amide-tethered precursors. More recently, they have been shown to proceed through concerted mechanisms and with a broader range of tethers.[85] The broadened scope of Himbert-type cycloadditions has resulted in renewed synthetic interest in this well-established process.[86] [87]

Occasionally the linker unit can be quite complex and provide additional stereochemical information, as in the conversion of 208 into 209, which took place at room temperature on concentrating HPLC fractions.[88] The electronically less activated C=C bond is the one that reacts. The lack of reaction at the more activated site was explained in terms of developing steric repulsion between a terminal methylene H and the furan diene in this alternative IMDA TS.

It is not necessary for the allenic dienophile to be present in the substrate: it can be generated as a reaction intermediate. This is demonstrated by the initial conversion of the propargyl ether 210 into its allenic isomer 211 by base treatment. Subsequently cycloaddition to the terminal C=C bond of allene 211 generates tricyclic enol ether 212.[89]

Another pericyclic reaction cascade starts from the nitrile 213 and subjects its toluene solution to longer reaction times under reflux conditions (Scheme [33]). In the first step of the transformation, an intramolecular Alder ene (perhaps a tetradehydro-ene) reaction takes place to provide a cyclized vinylallene 214. This is subsequently trapped by an intramolecular dehydro-Diels–Alder addition of a nitrile function to yield, after 1,5-H shift of initial adduct 215, the pyridine derivative 216 in excellent yield.[90]

Not surprisingly, the butadiene section of vinylallenes has also been shown to participate in intramolecular allene Diels–Alder reactions.[91] [92] [93] [94] Typical examples are summarized in Scheme [34].

The intramolecular Diels–Alder addition of 217 took place at 140 °C, and the resulting 1:1 mixture of diastereomeric ketone adducts were reduced to the alcohols 218 and 219, valuable intermediates in the total synthesis of the natural product (+)-compactin and a diastereomer.[95] [96] Precursor 217 was used as a 1:1 mixture of diastereomers about the allene moiety, and the two products 218 and 219 have opposite configurations at the four stereocenters generated in the IMDA-reduction sequence.

The diene partner in these processes can also be prepared en route, as shown by the dehydrobromination of 220 to the cyclohexene derivative 221, which, on base-catalyzed isomerization, yielded the vinylallene intermediate 222 first, which subsequently underwent the cycloaddition to 223 under mild conditions in high yield.[97]

Other pericyclic processes may compete with a desired intramolecular Diels–Alder addition if the tether does not permit the diene and dienophile to dock in the required manner. An example involving lactone 224 is shown in Scheme [35].

Rather than adding in a [4+2] mode to the vinylallenic part of 224, an alternate pathway is followed, presumably due to the short vinylallene-alkene tether.[98] To explain the formation of the cyclooctatriene product 225, a sequence of no less than three pericyclic steps have been proposed: [2+2]cycloaddition of 224 to 226, which isomerizes to 227 by a thermal 1,5-hydrogen shift. Formally the latter is a 1,2-divinylcyclobutane derivative which, driven by a release in ring-strain, undergoes electrocyclic ring opening to the isolated product 225.

An interesting final example from the heterocyclic field (Scheme [36]) involves the thermal isomerization/cyclization of the triazamacrocyclic compound 228 to the vinylallene intermediate 229, which is subsequently trapped by the opposing triple bond in a transannular cycloaddition. The initial tetracyclic product 230 tautomerizes to the heteroaromatic product 231 in very good overall yield, considering the molecular transformation that has taken place from starting material 228 to product 231.[99]

It should be noted that all the intramolecular Diels–Alder­ additions presented here have been reported for suitable vinylallene systems, no bisallenic compounds containing a hexa-1,2,4,5-tetraene subunit having been described. Although for example cyclic, conjugated bisallenes have been postulated as reaction intermediates,[100] none have been trapped–either by an added or tethered dienophile.

As illustrated in Scheme [37], intramolecular [4+2]cy­cloadditions of double and triple bond dienophilic moieties to bisallene units could lead to useful and interesting aromatic systems. For example, 232 could provide the Diels–Alder adduct 233 as in the case of the intermolecular addition of double bond dienophiles to hexa-1,2,4,5-tetraene (see Scheme [16]) which, in turn might tautomerize to the fused aromatic system 234. Likewise, 235 would yield the reactive p-xylylene intermediate 236 initially, which could dimerize to the [2.2]paracyclophane 237 (see Scheme [17]). The preferred mode of dimerization to form compounds akin to 237 will depend on the activating groups present in the starting materials, the length and composition of the spacers, and the relative orientations of the two intermediates 236 with respect to each other (cf. Scheme [16]).

Allenic Cycloadducts

Traditionally, strained cycloallenes have been generated either by elimination reaction as shown by the examples summarized in Scheme [30] or by using the Doering–Moore–Skattebøl procedure (see Scheme [13]), starting from the next lower-membered cycloalkene.

Recently, however, strained cyclohexa-1,2-dienes (11) and related systems such as cyclohexa-1,2,3-triene (242), a cyclic [3]cumulene, have become available by routes that formally resemble Diels–Alder additions and have been termed dehydro-Diels–Alder additions; Scheme [38] summarizes the presently known processes of this novel type of cycloaddition, which preparatively has resulted in an enormous extension of the classical [4+2]process.[101] [102]

Starting from the classical ‘diene reaction’ in which buta-1,3-diene 1, for example, reacts with a dienophile of general structure 2 to provide a cyclohexene derivative 3, the replacement of 2 by a triple bond dienophile 238 is a didehydro-Diels–Alder process;[103] the product now being a cyclohexa-1,4-diene (239). Another variant of the didehydro-Diels–Alder reaction involves a triple bond as part of the diene, in its simplest form vinylacetylene (10). When this cycloadds to ethylene 2, cyclohexa-1,2-diene (11) results, whose actual existence was already proven by the trapping experiment in Scheme [30].

Replacement of ethylene 2 by acetylene 238 and carrying out the cycloaddition with 10 leads to the next higher level of oxidation, i.e., a tetradehydro-Diels–Alder addition, and furnishes a cycloadduct (240) which has been termed ‘isobenzene’ (see below). Again, there exists a second alternative: employing diacetylene (241, 1,4-butadiyne) and 2 leads to the cyclocumulene 242. Finally, when all hydrogen atoms of both components are removed, a hexadehydro-process results and generates 1,2-didehydrobenzene (243) as an intermediate.[104] [105]

As shown in Scheme [38], these cycloadditions are not restricted to ‘diene components’ involving four carbon atoms. With penta-1,2-dien-4-yne (15) and a triple bond dienophile (238), the [4+2]cycloaddition mode furnishes an α,3-dehydrotoluene 244 as a reactive intermediate in a pentadehydro-Diels–Alder cycloaddition.[106]

Before we discuss several examples of these dehydro-Diels–Alder additions in more detail, we want look at the reaction of 10 with either a double (2) or a triple bond dienophile (238) in greater detail (Scheme [39]). We do not intend to present a comprehensive discussion of these ‘dehydro-processes’ here, the main reason being that the cy­cloadditions summarized in the rest of this review display more or less complex allenic starting materials (as dienes and dienophiles), not intermediately generated allenic and/or cumulenic species whose existence is inferred from their subsequent chemical behavior.

The highly reactive 1,2-cyclohexadiene 11 formed from 10 and 2 has two pathways to react further. In the presence of a trapping agent such as diphenylisobenzofuran (192) it can provide either the trapping products 194 and 195 (see Scheme [30]), or self-trap (dimerize) to the tricyclic hydrocarbon 245.[107]

When 2 is replaced by 238, isobenzene 240 results, which by a 1,3-hydrogen shift isomerizes to the most stable C₆H₆ hydrocarbon, benzene 249. That 240 is indeed generated as the first step of this aromatization reaction was shown by intercepting it with added styrene 246 in a [2+2]cycloaddition to give adduct 247.[108] Heating the acyclic precursor 248 in the gas phase brings about cycloaromatization to benzene 249, the so-called Hopf cyclization,[109] which also proceeds through cyclic vinylallene 240.

Many thermal dehydro-Diels–Alder reactions involve enyne components in which the double bond is part of an aromatic system. In one of the earliest reactions of this type—observed more than 100 years ago—phenylpropiolic acid (250) was heated in a sealed tube in the presence of acetic anhydride (Scheme [40]). The cyclized anhydride 252 was presumably formed via the isobenzene intermediate 251.[110]

Often in these cycloaromatizations, mixtures of isomers are produced. A case in point is the intramolecular tetra­dehydro Diels–Alder reaction of the ether 253, which provides a mixture of 256 and 257 in a 75:25 ratio when heated in xylene.[111] The initial [4+2]cycloadduct is the isobenzene derivative 254. It has been suggested[112] that this highly reactive intermediate displays diradical character, resulting from uncoupling of the allene unit to better accommodate the inherent strain of the intermediate. This is indicated by resonance structure 255 in Scheme [40]. When this undergoes a 1,3-hydrogen shift reaction, the main isomer 256 is produced, whereas a 1,3-carbon shift leads to side product 257. The macrocyclic substrate 258 allows for a twofold transannular dehydro-cyclization process and furnishes the fused perylene derivatives 259.[113]

The still higher oxidized form of a dehydro Diels–Alder addition is provided by the hexadehydro process summarized in Scheme 41.[105]

When the tetrayne alcohol 260 is oxidized with MnO₂ at room temperature in dichloromethane a deep-seated transformation takes place to provide dihydrobenzofuran 261 in acceptable yield. To rationalize this amazing transformation, the authors have proposed an initial oxidation to the ketone derived from 260. In the subsequent step the hexadehydro addition takes place to furnish intermediate 262, a cyclic cumulene which looks more familiar when displayed in its resonance form 263, a 1,2-didehydrobenzene. Ring closure by the pending substituent then leads to the zwitterion 264, which can undergo a retro-Brook rearrangement to the isolated product. There are direct hints that 262/263 is passed en route, since this intermediate can be trapped by benzene (used as a solvent), norbornene and other trapping reagents.

Conclusions and Outlook

Allenic dienes and dienophiles played no significant role as components of the Diels–Alder reaction for a long time. This review demonstrates that allenes are becoming well established in Diels–Alder chemistry, and it is appropriate to speculate on reasons for this change.

The broader use of allenes in [4+2]cycloadditions has to do with several factors, the first one being availability. Traditionally, allenes were prepared by the classical routes of preparative chemistry for unsaturated molecules, namely elimination and isomerization. Base-catalyzed isomerizations of propargylic systems were commonly employed, since the high energy content of acetylenic bonds provides a thermodynamic driving force for allene formation: But-1-yne, for example, is thermodynamically less stable than its isomer buta-1,2-diene.

The second traditional approach for allene synthesis involved the formal insertion of a single carbon atom between the two carbon atoms of a C=C bond. In the laboratory this has been accomplished over two steps, the first of which is an addition of a dihalocarbene to an alkene. The resulting dihalocyclopropane is subsequently dehalogenated by treatment with an alkyllithium reagent at low temperature, leading to a ‘carbenacyclopropane’, which, because of its high strain energy, undergoes electrocyclic ring opening to the allene.

These two classical approaches for allene synthesis involve the deployment of either alkenes or alkynes as precursors. Strategically, they are functional group interconversions which require harsh reagents, and base-sensitive functionality in particular are not tolerated. In contrast, the present-day preferred methods of allene synthesis involve metal-catalyzed C–C bond-forming cross-coupling reactions. Not only do they generally take place under mild conditions, they can also be used constructively, to generate the C–C bond that connects the vinyl group with the allenyl group in a vinylallene, for example. Thus, the cross-coupling methods promote the invention of convergent synthetic pathways to precursors for Diels–Alder reactions. Moreover, they permit the generation of allenic precursors in enantiomerically enriched form.

Another reason for the slow uptake of allenic precursors in Diels–Alder reactions relates to their undeserved reputation for being capricious. A consequence of concentrating a maximum number of π-electrons over a comparatively small number of carbon atoms is the generation of reactive species. Allenes, vinylallenes and the related through- and cross-conjugated molecules have, as this review has shown, an abundance of reactivity. Nonetheless, even the most reactive of the allenic substrates described in this review are, based upon our own experience, manageable compounds. The majority can be worked with in the same way as any other compound in synthesis. The challenging reputation concerning the handling of an allene, vinylallene and bisallene in the laboratory, is, in our opinion, erroneous.

Presently, the majority of reported Diels–Alder reactions involving allenes are focused on methodological contributions. Applications in total synthesis, materials and biology are comparatively rare. Looking forward, we feel that there are many valuable and thus far unexplored possibilities for allenic [4+2]cycloadditions in these and other fields. The high reactivity of allenes permits their participation in types of Diels–Alder additions that are either difficult to achieve—perhaps even unachievable, when using the corresponding alkenes and alkynes. The bourgeoning field of bioorthogonal reactions, of which uncatalyzed cycloadditions already play an important role, would benefit significantly from utilizing certain allenic precursors and their Diels–Alder processes.[114]

Of the methodological contributions made so far, most of the reported examples are of the electron-deficient dienophile/electron-rich diene-type. Inverse electron demand allenic Diels–Alder reactions should be investigated more thoroughly.

In terms of mechanistic and physical organic studies, experimental investigations involving ‘hard’ physical methods (e.g., gas-phase electron diffraction for conformational information on dienes) are being gradually replaced by computational approaches. Nonetheless, a strong case can be made for more experimental studies into structure and reactivity (e.g., kinetics studies), since such data is both scarce and of great value.

We predict that the interest in allenic components in dehydro-Diels–Alder processes will continue to expand, as will the use of arenes as diene and dienophile components in allenic Diels–Alder reactions. The absence of target synthesis applications of these processes—arguably the ultimate test of any synthetic methodology—is an obvious opportunity for creative researchers in the field.

The authors believe that the concept of blending the chemical and structural properties of different π-systems, as shown with cross-conjugated systems, has a particularly bright preparative future. When both its constructive potential and scope are considered, the Diels–Alder reaction is the most powerful molecule-building reaction. In the era of synthetic efficiency and practicality, endeavors focusing on the invention of molecules that can rapidly build complex, target-relevant structures through domino sequences of this most powerful reaction are worthy of greater consideration.

Conflict of Interest

The authors declare no conflict of interest.

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Corresponding Author

Publication History

Received: 18 May 2021

Accepted after revision: 16 June 2021

Article published online:
04 August 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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