Alkoxyallenes as building blocks for organic synthesis

Reinhold Zimmer; Hans-Ulrich Reissig

doi:10.1039/C3CS60429B

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DOI: 10.1039/C3CS60429B (Tutorial Review) Chem. Soc. Rev., 2014, 43, 2888-2903

Alkoxyallenes as building blocks for organic synthesis†

Reinhold Zimmer and Hans-Ulrich Reissig *
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany. E-mail: hans.reissig@chemie.fu-berlin.de; Fax: +49-30-838-55367; Tel: +49-30-838-55366

Received 27th November 2013

First published on 19th February 2014

Abstract

Alkoxyallenes are unusually versatile C3 building blocks in organic synthesis. Hence this tutorial review summarizes the most important transformations, including subsequent reactions and their applications in the synthesis of relevant compounds, e.g. natural products. The reactivity patterns involved and the synthons derived from alkoxyallenes are presented. Often alkoxyallenes can serve as substitutes of acrolein or acrolein acetals, utilisation of which has already led to interesting products. Most important is the use of lithiated alkoxyallenes which smoothly react with a variety of electrophiles and lead to products with unique substitution patterns. The heterocycles or carbocycles formed are intermediates for the stereoselective synthesis of natural products or for the preparation of other structurally relevant compounds. The different synthons being put into practice by the use of lithiated alkoxyallenes in these variations will be discussed.

Reinhold Zimmer (left) and Hans-Ulrich Reissig (right)

Reinhold Zimmer received his PhD degree from the Technische Universität Darmstadt in 1990 under the guidance of Prof. Hans-Ulrich Reissig. Thereafter, he did postdoctoral research as a Karl-Landsteiner fellow in the group of Dr M. A. Grassberger at the Sandoz Research Institute in Vienna, Austria. Since 1994, he has been a permanent research associate with Prof. Reissig.

Hans-Ulrich Reissig received his PhD in 1978 at the Ludwig-Maximilians-Universität München under the guidance of Prof. Rolf Huisgen. After a postdoctoral stint with Prof. Edward Piers at the University of British Columbia, Vancouver, he took academic positions at the universities in Würzburg, Darmstadt and Dresden, and since 1999 at the Freie Universität Berlin. His research interests are in the field of organic synthesis, in particular in the development of new synthetic methods and their application to synthesis of natural products and heterocycles.

Key learning points

(1) This review highlights the synthetic versatility of alkoxyallenes for the synthesis of carbocycles and heterocycles.

(2) Isomerisation of propargylic ethers to alkoxyallenes.

(3) Alkoxyallenes as tamed equivalents of acrolein.

(4) Deprotonation of alkoxyallenes affords reactive nucleophiles that add to electrophiles such as carbonyl compounds or nitriles.

(5) Cyclisation of primary adducts provides heterocycles that are precursors of natural products or other important compounds.

Introduction

The fascinating and versatile chemistry of allenes has been summarized in numerous reviews.^1,2 Due to the specific bond properties of allenes with a sp-hybridised carbon in the centre of the cumulene they display higher reactivity compared to otherwise similar alkenes, a feature that has been exploited in many useful transformations. As to be expected, functional groups at one or at both double bonds of the allene moiety strongly influence the reactivity of the compounds (Scheme 1).


	Scheme 1 Different classes of allenes (EWG: electron-withdrawing group).

Whereas alkyl and aryl groups modify the reactivity of allenes only moderately, strongly electron-withdrawing substituents such as carbonyl or sulfonyl groups lead to preferred reactions with nucleophiles or to cycloadditions. Compounds from these two major classes of allenes have frequently been used as components in transition metal-catalyzed transformations.²

The influence of electron-donating substituents such as alkoxy groups seems to be simple, because the double bond bearing this substituent preferentially reacts with electrophiles as to be expected. However many contributions in the literature show that alkoxyallenes display chameleon type reactivity.

They may also react with nucleophiles at the two terminal carbons and most importantly, they allow a smooth metalation at the carbon next to the oxygen substituent. The combination of these properties makes alkoxyallenes extremely versatile C3 building blocks³ for the synthesis of acyclic, carbocyclic and heterocyclic compounds, in part with high complexity.^4,5 As a consequence they have also been employed as crucial precursors for the preparation of a variety of natural products or their analogues. In this tutorial review we try to systematically describe the reactivity patterns of alkoxyallenes and their typical applications in organic synthesis.

1. Synthesis of alkoxyallenes

The importance of alkoxyallenes for organic synthesis is also due to the straightforward access to this product class. Alkoxyallenes are most frequently generated from propargylic ethers such as 2 by base-promoted isomerisation. The precursor propargylic derivatives are easily accessible by a Williamson ether synthesis of the adequate reaction partners, hence propargylic alcohol can smoothly be O-alkylated by an appropriate S_N2-active alkyl halide (Scheme 2, pathway a).⁶ Alternatively, a propargylic halide is treated with the corresponding alkyl alcohol or phenol derivative (Scheme 2, pathway b). The second approach has also been employed to prepare alkoxyallenes with enantiopure auxiliaries at the oxygen such as diacetone glucose (Scheme 2, pathway c).⁷


	Scheme 2 Different pathways for preparation of alkoxyallenes from propargylic precursors.

Alternative methods for the synthesis of alkoxyallenes have no general importance.³ However, C-3 substituted alkoxyallenes are simply accessible starting from unsubstituted alkoxyallenes 2 (Scheme 3). Deprotonation at C-1 (see Section 2.4) followed by C-silylation introduced a protective group that allowed a deprotonation at C-3. The generated lithiated species regioselectively reacts with alkyl halides to give trisubstituted allenes being converted into the desired C-3 substituted alkoxyallenes 9 by subsequent desilylation with fluoride. This route should also allow the preparation of C-3 disubstituted alkoxyallenes.


	Scheme 3 Preparation of C-3 substituted alkoxyallenes 9via silylated allenes 8.

This approach is usually more efficient than the isomerisation of C-3 substituted propargylic ethers, however, for C-3 aryl-substituted alkoxyallenes 11, compounds 10 easily available by Sonogashira reactions of simple propargylic ethers, can be converted into their allene isomers by treatment with n-butyllithium and subsequent quenching with proton sources or other electrophiles (Scheme 4). Alkoxyallenes of type 11 are more sensitive to hydrolysis and are often used in situ for further functionalisations. 1,3-Disubstituted allenes such as 9 and 11 are axially chiral compounds and produced in racemic form using the procedures described here. They will give rise to the formation of diastereomers when added to prochiral electrophiles. The generation of axially chiral alkoxyallenes and their use in synthesis are with the exception of Nazarov cyclisations (see Section 2.4.5 and Scheme 52) so far not very broadly investigated.⁸


	Scheme 4 Preparation of 3-aryl-substituted alkoxyallenes 11 from propargylic ethers 10.

2. Reactions of alkoxyallenes

2.1 General reactivity pattern

At first glance alkoxyallenes are special enol ethers which implies that electrophiles add to the central carbon of the allene moiety. Obviously, this centre is electron-rich due to the electron-donating effect of the alkoxy group. As a consequence nucleophiles can add either to carbon C-1 or at the terminal allene carbon C-3 (Scheme 5). The additions of nucleophiles are often catalysed by Brønsted or Lewis acids. This polarisation of alkoxyallenes resembles that of α,β-unsaturated carbonyl compounds and it is also responsible for the regioselectivity of cycloadditions to alkoxyallenes.


	Scheme 5 Possible attack of electrophiles and nucleophiles on alkoxyallenes.

A dramatic change in the reactivity of alkoxyallenes 3 is achieved by the selective deprotonation at C-1.⁹ This process generates a fairly strong nucleophile being suitable to react with a variety of electrophiles. In general, lithiated alkoxyallenes 12 add electrophiles to C-1 and hence they can be regarded as an α,β-unsaturated acyl anion synthon 13 (Scheme 6). This kind of umpolung of reactivity is synthetically extremely useful and hence lithiated alkoxyallenes 12 have found numerous applications in the synthesis of compounds with unique patterns of functional groups. The remaining allene moiety can subsequently be used for further synthetic elaborations.


	Scheme 6 Deprotonation–addition sequence at C-1 of alkoxyallenes. Lithiated alkoxyallenes 12 as synthetic equivalents of an α,β-unsaturated acyl anion synthon 13.

Metalated alkoxyallenes 14 with less electropositive metals such as magnesium and titanium are accessible by transmetalation of 12 with a suitable metal halide. They may also undergo additions to the terminal C-3 carbon providing functionalised 1-alkoxyalkynes 15 as products (Scheme 7).¹⁰ After hydrolysis carboxylic acid derivatives 16 with substituents at the β-position are generated and therefore these metalated alkoxyallenes 14 serve in this mode of reactivity as an equivalent of homoenolate synthon 17.


	Scheme 7 Metalated alkoxyallenes 14 as synthetic equivalents of homoenolate synthon 17.

Another reactivity pattern of alkoxyallenes is observed when lithiated alkoxyallenes 12 are treated with nitriles and subsequently with carboxylic acids. This three component procedure delivers iminium ion intermediates 18 with an electrophilic character at the central allene carbon. The resulting polarisation is shown in Scheme 8. This kind of reactivity led to the formation of functionalised β-ketoenamides 19 that are precursors for different classes of heterocycles. In this approach the allene serves as a synthetic equivalent of zwitterionic synthon 20.


	Scheme 8 Formation of β-ketoenamides 19via iminium ion intermediates 18. Lithiated alkoxyallenes 12 as synthetic equivalents of a 1,2-zwitterionic synthon 20.

After the discussion of the most important features of general reactivity of alkoxyallenes typical and important examples of synthetic applications are presented. In all cases the three carbon atoms derived from the allene precursor are highlighted in red colour to facilitate the understanding of the ongoing reactions.

2.2 Cycloadditions to alkoxyallenes

A gold-catalysed Diels–Alder reaction with normal electron-demand has been reported employing several alkoxyallenes 3 and cyclopentadiene as a reactive 1,3-diene.¹¹ In these transformations the electron-deficient double bond of the allene is engaged in the [4+2] cycloadditions (Scheme 9).


	Scheme 9 Au-catalysed [4+2] cycloadditions of alkoxyallenes 3 and cyclopentadiene.

Two examples of hetero Diels–Alder reactions with inverse electron-demand are illustrated in Schemes 10 and 11. Methoxyallene 22 reacts with nitrosoalkenes, in situ generated from corresponding α-halogenated oximes 23, to give highly functionalised 1,2-oxazine derivatives 24 that are versatile intermediates in organic synthesis.¹² Employing alkoxyallenes with enantiopure auxiliaries at the oxygen such as 7 allows diastereoselective hetero Diels–Alder reactions with the nitrosoalkenes, which subsequently lead to enantio-enriched products.¹³


	Scheme 10 Examples for the synthesis of 5-methylene-substituted 5,6-dihydro-4H-1,2-oxazines 24.


	Scheme 11 Synthesis of 5-methylene-substituted 5,6-dihydro-4H-pyridine 26.

A similar Diels–Alder reaction proceeds with the α,β-unsaturated imine 25 which combines with methoxyallene 22 to furnish pyridine derivative 26 (Scheme 11).¹⁴ In the examples of Schemes 10 and 11 the electron-rich double bond of the allene undergoes the cycloaddition with the electron-deficient diene.

A unique [2+1] cycloaddition of a silylene using silacyclopropane 27 as the precursor was reported by Woerpel.¹⁵ The resulting methylene silacyclopropane 28 undergoes palladium-catalysed cycloadditions to alkenes to afford silacyclopentanes 29 that are useful vinylsilane derivatives suitable for subsequent transformations (Scheme 12).


	Scheme 12 Synthesis of silacyclopentane derivatives 29 starting from methoxyallene 22.

Although other cycloadditions with alkoxyallenes are known, e.g. [3+2] cycloadditions, they are often not regio- and stereoselective and therefore synthetically not particularly important.

2.3 Additions of nucleophiles to C-1

Assisted by electrophilic catalysts, O-, N- or C-nucleophiles generally add to C-1 of alkoxyallenes furnishing allylic acetals, allylic O,N-semiaminals or allylic ethers. The resulting products are versatile precursors for further transformations, e.g. for olefin metathesis. Scheme 13 depicts one of many examples of hydroalkoxylations to benzyloxyallenes 30 providing under gold-catalysis allylic acetals 31 in good to excellent yields.¹⁶


	Scheme 13 Au-catalysed hydroalkoxylation of benzyloxyallenes 30.

For nitrogen nucleophiles palladium(II) seems to be an efficient catalyst as shown by the examples of Scheme 14. By using palladium acetate and the chiral ligand 34 a very high degree of enantiopurity of the intermediates 35 can be achieved.¹⁷ These products are efficiently converted into dihydropyrrole derivatives 36 employing the Grubbs II catalyst.


	Scheme 14 Enantioselective synthesis of dihydropyrroles 36 employing palladium-catalysed additions of amines 33 to alkoxyallene 32 and olefin metathesis as crucial steps.

An alternative subsequent reaction is achieved with a compound incorporating an allyl silane substructure (Scheme 15). Palladium(II)-catalysed addition of enantiopure nosyl-protected amine 37 to benzyloxyallene 38 affords addition product 39 in good yield as a mixture of diastereomers. This O,N-semiaminal is a suitable precursor for a Lewis acid promoted ring closure to 40, a precursor of the alkaloid Quinolizidine 233A.¹⁸


	Scheme 15 Crucial steps in the synthesis of Quinolizidine 233A employing benzyloxyallene 38 as a building block.

Benzyloxyallene 38 and azalactones 41 combine in the presence of hippuric acid, palladium(II) trifluoroacetate and chiral ligand 34 to form a new carbon–carbon bond between C-1 of the allene and the CH-acidic component (Scheme 16).¹⁹ The resulting allylic ethers 42 are formed in good yields and with high enantio- and diastereoselectivities.


	Scheme 16 Enantioselective hydrocarbonation of benzyloxyallene 38 with CH-acidic compounds in the presence of ligand 34.

With nucleophiles containing aryl halide moieties these palladium-catalyzed processes lead to simultaneous formation of new C–C bonds (by carbopalladation) and of C–O or C–N bonds. As an example, Scheme 17 illustrates the addition of ortho-iodo phenol or aniline derivatives 43 and alkoxyallenes 44 that afford bicyclic products 45 with an exo-alkylidene group.²⁰


	Scheme 17 Example of palladium-catalysed benzannulation reactions using alkoxyallenes 44 and iodo aryl compounds 43.

All the examples in this section demonstrate the excellent capability of alkoxyallenes to serve as C3 building blocks for the synthesis of functionalised allylic ether derivatives that are very versatile intermediates for the synthesis of all kinds of heterocycles.

2.4 Deprotonation of alkoxyallenes and reactions with electrophiles

The generation of lithiated alkoxyallenes and their first reactions with electrophiles were reported shortly after the discovery of the standard route to alkoxyallenes by the Arens group.⁹ In general, n-butyllithium in ethereal solvents such as THF or diethyl ether is used to abstract the proton at C-1 of the alkoxyallene 3. The resulting lithiated species is depicted with simplified formula 12 (Scheme 18) that is sufficient to understand most of its reactions with electrophiles. It should also be noted here that lithiated compounds such as 12 are carbenoids since they bear a potential leaving group OR at the metalated centre and hence their thermal stability is limited. Their subsequent reactions should occur at temperatures below −20 °C otherwise decomposition to unknown products complicates the outcome of the transformations.


	Scheme 18 Generation of lithiated alkoxyallenes 12 and subsequent additions to various electrophiles leading to C-1-substituted alkoxyallenes 46–52.

Whereas additions of alkyl halides have been reported they did not become as important as additions of carbonyl compounds and their equivalents such as imines and nitrones (see Scheme 40). Nitriles, aziridines or epoxides are also suitable electrophiles; the strained small ring compounds are generally attacked at the less substituted carbon by lithiated alkoxyallenes 12 and undergo ring opening. Reactions with electrophiles such as chlorotrialkylsilanes or chlorotrialkylstannanes are also possible.

The primary addition products still contain alkoxyallene moieties that can be exploited in various reaction modes. The alkoxyallene unit may be just hydrolysed by aqueous acid to afford α,β-unsaturated carbonyl compounds 53 with a heteroatom-substituted carbon adjacent to the carbonyl group (Scheme 19). These enones 53 are good substrates for cycloadditions or Michael additions. More importantly, cyclisation to dihydrofuran derivatives 54 leads to heterocycles with considerable synthetic potential. This cyclisation either occurs under basic conditions or under the influence of soft Lewis acids. Alternatively, the alkoxyallene unit can also be oxidatively degraded by ozonolysis to furnish functionalised alkyl esters 56.⁴ In these three sequences the lithiated alkoxyallenes serve as synthetic equivalents of an α,β-unsaturated acyl anion synthon 13, of a 1,3-zwitterionic synthon 55 or of an alkoxycarbonyl anion synthon 57. The synthetic value of this type of transformations is evident and has been exploited in numerous applications.^3,4


	Scheme 19 Hydrolysis, cyclisation and ozonolysis of α-hydroxy-substituted alkoxyallenes 47 leading to enones 53, to dihydrofurans 54 or to alkyl esters 56. Lithiated alkoxyallene 12 is a synthetic equivalent to synthons 13, 55 and 57 in these transformations.

Although there are quite a number of useful applications employing lithiated alkoxyallenes as synthons 13, 55 and 57, the primary products are most often used as precursors for cyclisations to provide heterocyclic compounds such as 54. The reaction of lithiated alkoxyallenes 12 with imines or with nitrones as electrophiles leads to primary adducts 48 and 59. The heterocyclic products, dihydropyrroles 58 or 1,2-oxazine derivatives 60, are formed by spontaneous cyclisations or by application of suitable catalysts (for details, see the following subsections) (Scheme 20).⁴


	Scheme 20 Additions of lithiated alkoxyallenes 12 to imines and nitrones and subsequent cyclisations leading to dihydropyrroles 58 and 1,2-oxazine derivatives 60.

Primary products derived from lithiated alkoxyallenes and α,β-unsaturated aldehydes or ketones as electrophiles may also undergo cyclisation or rearrangement reactions to deliver products with unique structures not fitting in a general scheme. They will be discussed in a separate section (see Section 2.4.5).

2.4.1 Examples of additions to carbonyl compounds and transformations into dihydrofurans. Arens et al. already demonstrated that lithiated alkoxyallenes smoothly add to carbonyl compounds and that the primary products, e.g.61, can be cyclised under rather specific, strongly basic conditions into dihydrofurans, such as 62 (Scheme 21).⁹ Subsequent acidic hydrolysis of 62 affords the corresponding furanone derivatives 63.


	Scheme 21 Conversion of methoxyallene 22 and carbonyl compounds into furanones 63 by an addition–cyclisation–hydrolysis sequence.

The exact mechanism of this seemingly simple cyclisation is still unclear in its details and an electron-transfer mechanism has been proposed by Magnus.²¹ Despite this uncertainty this approach to dihydrofuran derivatives has been used in stereoselective synthesis, e.g. for the preparation of an enantiopure primarily helical compound 64 by repetitive additions of lithiated methoxyallene to carbonyl groups (Scheme 22).²²


	Scheme 22 Synthesis of enantiopure primarily helical compound 64 starting from methoxyallene 22 and enantiopure dibenzyl-protected alaninal.

Dihydrofurans of type 66 are prone to undergo an oxidative ring-opening delivering enediones 67 (Scheme 23) which have been used for the synthesis of the rare carbohydrate L-Cymarose and its stereoisomers starting from L-lactic acid as a chiral pool compound.²³ Other enediones 68 bearing a CH group next to the internal carbonyl group could be converted into cyclopentenone derivatives 69 (Scheme 24).²⁴


	Scheme 23 Oxidative transformation of dihydrofurans 66 into enediones 67 as crucial intermediates for the synthesis of a series of rare methoxy-substituted carbohydrates.


	Scheme 24 Intramolecular aldol reaction of enediones 68 to cyclopentenone derivatives 69.

In the course of these studies, it was discovered that gold-catalysis – well known for other allene cyclisations²⁵ – smoothly converts many of the primary addition products 47 (Scheme 19), obtained from lithiated alkoxyallenes and carbonyl compounds into the corresponding dihydrofuran derivatives 54. Starting from diacetone glucose-derived allene 7 (Scheme 2) the addition to pentadecanal provides allenyl alcohol 70 with low diastereoselectivity, which after gold-catalysed cyclisation affords dihydrofuran derivative 71 in good yield (Scheme 25). Due to the sensitive carbohydrate substituent this transformation was not efficient under the standard basic cyclisation conditions. Compound 71 was converted into the cytotoxic natural product Jaspine B in enantiopure form and three of its stereoisomers.²⁶


	Scheme 25 Synthesis of enantiopure Jaspine B via dihydrofuran derivative 71.

Addition of lithiated methoxyallene 65 to functionalised aryl aldehydes such as 72 and subsequent hydrolysis give enones of type 73 that can be employed either in Heck reactions (Scheme 26) or in cuprate additions. This allows the synthesis of precursors like 74 that are highly suitable for the synthesis of benzannulated spiroketals (e.g.75), a class of compounds important for the synthesis of rubromycin natural products.²⁷


	Scheme 26 Synthesis of benzannulated spiroketal 75 with the alkoxyallene-derived enone 73 as a crucial intermediate.

2.4.2 Examples of additions to imines and transformation into dihydropyrroles or other heterocycles. Analogously to the additions to carbonyl compounds, imines derived from aldehydes are excellent electrophiles, smoothly reacting with lithiated alkoxyallenes 12 (Scheme 27). The primary allenyl amines 48 with N-alkyl substituents undergo spontaneous cyclisation to give dihydropyrrole derivatives 58. In contrast, allenyl amines 48 with electron-withdrawing substituents at the nitrogen (aryl, tosyl, and BOC) had to be treated with silver- or gold-catalysts to give the desired heterocycles.²⁸ This approach is suitable for the synthesis of natural products such as Detoxinine, Anisomycin, Preussin, Codonopsinine and analogues containing highly substituted pyrrolidine rings. With a ketimine as an electrophile the tricyclic compound 76 is available,²⁹ which is considered to be a possible precursor for the alkaloid FR 901483.³⁰ The enol ether double bond of the dihydropyrroles of type 58 is suitable for further functionalisations.


	Scheme 27 Synthesis of dihydropyrroles 58 as key intermediates for a series of natural products containing functionalised pyrrolidine rings.

Imines may also be generated in situ from aldehydes and lithium bis(hexamethylsilazide) and subsequently treated with lithiated alkoxyallenes. This three-component one-pot protocol efficiently affords the allenyl amines that can be cyclised to give the corresponding dihydropyrrole derivatives 77 in reasonable overall yields (Scheme 28).³¹ These heterocycles can be oxidised to electron-rich and fairly sensitive pyrroles such as 78 if stabilised by an electron-withdrawing group at the nitrogen.


	Scheme 28 Formation of dihydropyrroles 77 and subsequent oxidation to pyrrole 78.

After cyclisation either under basic conditions or – in general with better reliability – by gold catalysis, the resulting N-tosyl-substituted dihydropyrroles 80 undergo a base-promoted elimination of potassium sulfinate to provide the electron-rich pyrroles 81 that are not easily accessible by alternative methods (Scheme 29). They have recently been used to prepare BODIPYs such as 82 bearing alkoxy groups. These dye molecules may be useful for new applications, e.g. fluorescent marker compounds for biomolecules.


	Scheme 29 Access to novel BODIPYs of type 82 from alkoxyallene-derived electron-rich pyrroles 81.

An alternative subsequent reaction involves the treatment of the allenyl amines 83 with iodine in nitriles as solvent. The addition of the electrophilic iodine to the central carbon atom of the allene generates a stabilised allyl cation which is trapped by the nitrile followed by a cyclisation to dihydroimidazole derivative 84. They undergo an acid-promoted elimination to specifically substituted imidazole derivatives in moderate to good overall yield (Scheme 30).³² The iodovinyl-substituted imidazole derivatives 85 may be used for subsequent reactions such as palladium-catalysed couplings or as starting materials for Grignard intermediates.


	Scheme 30 Synthesis of iodovinyl-substituted imidazole derivatives 85 from allenyl imines 83 and nitriles.

Thioisocyanates may also be regarded as special imine derivatives. Fairly early, Brandsma and Nedolya recognized the potential of this type of electrophile for the synthesis of heterocycles from lithiated alkoxyallenes.³³ The addition provides an alkoxy-substituted imino allene 86 which after S-alkylation with methyl iodide and subsequent treatment with copper(I) bromide furnishes the 2-thiomethyl-3-alkoxy-substituted pyrrole derivative 87 (Scheme 31). The cyclisation reaction is strongly dependent on the substitution pattern and may also provide pyridine derivatives instead of pyrroles.


	Scheme 31 Synthesis of 2-thiomethyl-3-alkoxy-substituted pyrrole derivative 87 by addition of a lithiated alkoxyallene to methyl thioisocyanate and subsequent reactions.

2.4.3 Examples of additions to nitriles. The addition of lithiated alkoxyallenes 12 to nitriles was executed in order to directly access electron-rich pyrroles such as 88 (Scheme 32). However, the cyclisation to the sensitive products 48 turned out to be quite capricious, but it could be achieved in several examples employing silver(I) salts. By serendipity, it was discovered that treatment of the primary addition products of lithiated alkoxyallenes 12 and nitriles with trifluoroacetic acid established a new approach to synthesise functionalised β-ketoenamides 89 and as subsequent products pyridines 90 or other heterocycles.³⁴


	Scheme 32 Formation of allenyl imines 48 and their silver-catalysed transformation into pyrroles 88 and the three-component reaction with acids to pyridines 90.

A mechanistic scenario for the formation of the β-ketoenamides 89 and the pyridines 90 is depicted in Scheme 33. It involves protonation of the primarily formed allenyl imines 48 at the nitrogen and addition of the carboxylate to the central allene carbon atom. Subsequent acyl migration to the nitrogen leads to the β-ketoenamides 89 and an intramolecular aldol-type condensation reaction provides pyridinones 91 which are in equilibrium with the corresponding 4-pyridinol derivatives 90. For the full conversion of 89 to 90 trimethylsilyl triflate and base are suitable condensation reagents. This fairly efficient protocol enables the new three-component synthesis of a variety of highly functionalised pyridine derivatives 89.³⁵


	Scheme 33 Proposed mechanism for the formation of β-ketoenamides 89 and pyridines 90.

The functional groups in compounds 90 can be employed for subsequent reactions, e.g. all kinds of palladium-catalysed coupling reactions.³⁵ Sonogashira reactions and subsequent cyclisations led to new furopyridine derivatives. Depending on the position of the coupling either furo[2,3-c]pyridines (92) or furo[3,2-c]pyridines (93) were prepared (Scheme 34).


	Scheme 34 Synthesis of furo[2,3-c]-pyridine (93) and furo[3,2-c]pyridine (93) from 4-pyridinol derivative 90 by a suitable activation/coupling strategy and subsequent cyclisations. Nf = C₄F₉SO₂.

As an example of the synthesis of a drug intermediate, the preparation of the Glenvastatin precursor 95 is described (Scheme 35).³⁶ Here lithiated methoxyallene 65, isobutyronitrile and benzoic acid serve as simple starting materials for the synthesis of the crucial β-ketoenamide 96. Cyclisation and subsequent coupling provide 95 in moderate overall yield.


	Scheme 35 A formal synthesis of Glenvastatin. Nf = C₄F₉SO₂.

A series of 2-thienyl-substituted pyridine derivatives such as 97 and 100 is also accessible. Again lithiated methoxyallene 65, thiophene-2-carbonitrile and 2-thiophenecarboxylic acid are the ingredients to deliver the corresponding β-ketoenamide. After cyclisation to the pyridinol 97 and further activation by iodination the resulting pentasubstituted pyridine derivative 98 is used to prepare triflate 99 after several coupling steps (Scheme 36).³⁷ The resulting final products 100 and 101 (bearing nine thiophene rings!) are interesting due to their photophysical and electrochemical properties.


	Scheme 36 Synthesis of poly(2-thienyl)-substituted pyridine derivatives.

Intermediate β-ketoenamides 19 are also very versatile starting materials for the synthesis of highly substituted pyrimidines 102 and pyrimidine N-oxides 103 (Scheme 37). The condensation with ammonia sources or with hydroxylamine hydrochloride leads to these heterocycles that can be further transformed into a variety of other derivatives due to the functional groups present (OR group and methyl group).³⁵


	Scheme 37 β-Ketoenamides 19 as starting materials for the synthesis of pyrimidines 102 and pyrimidine N-oxides 103.

On the other hand, β-ketoenamides 19 with an acid sensitive OR group undergo a smooth cyclisation to functionalised oxazole derivatives 104.³⁸ These heterocycles contain a methyl ketone moiety that can also be employed in subsequent reactions, e.g. in a Fischer indole synthesis providing compound 106 or the transformation into an alkyne 107 serving as the precursor for the star-shaped compound 108 (Scheme 38). The intriguing self-assembly of compounds of this type on highly oriented pyrolytic graphite has been investigated by scanning tunneling microscopy.


	Scheme 38 Synthesis of 5-acetyl-substituted oxazole derivatives 104 and transformation of oxazole 105 into subsequent products.

All these examples demonstrate that β-ketoenamides 19 obtained by the novel three-component reaction are extremely versatile intermediates for the synthesis of a broad range of functionalised heterocycles (Scheme 39). The lithiated alkoxyallenes 12 trigger the formation of the β-ketoenamides 19 and provide a functionalised C3-unit allowing all subsequent transformations into highly substituted products.³⁵


	Scheme 39 Heterocycles accessible by alkoxyallene-derived β-keto-enamides 19.

2.4.4 Examples of additions to nitrones. Nitrones are versatile components of 1,3-dipolar cycloadditions leading to isoxazole derivatives, but they also react with nucleophiles at their electrophilic carbon atom. We found that a variety of nitrones smoothly combine with lithiated alkoxyallenes 12 providing hydroxylamine derivatives that can be isolated only in rare cases, but rather undergo a fast cyclisation to 1,2-oxazine derivatives.³⁹ The stereodivergent behaviour of this [3+3] cyclisation is shown by the addition of lithiated alkoxyallenes to glyceraldehyde derived nitrone 112 (Scheme 40). The standard conditions provide the syn-configured 1,2-oxazines 113 in excellent yields and diastereoselectivities, whereas pre-complexation of the nitrone with diethylaluminium chloride allows a perfect switch to the corresponding anti-configured 1,2-oxazines 113. A similar stereodivergent performance of this nitrone with simple organometallics has earlier been reported and mechanistically interpreted by the Dondoni group.⁴⁰


	Scheme 40 Stereodivergent preparation of syn- and anti-configured 1,2-oxazines 113 by addition of lithiated alkoxyallenes 12 to glyceraldehyde-derived nitrone 112.

Since glyceraldehyde is easily available in both enantiomeric forms, the enantiomers of syn- and anti-1,2-oxazines 113 are also accessible. From these four stereoisomers a variety of enantiopure subsequent products are easily prepared as summarised for the transformations of syn-1,2-oxazine 114 in Scheme 41.⁴


	Scheme 41 Acyclic and cyclic products derived from methoxyallene-derived syn-1,2-oxazine 114.

Many of the products depicted in Scheme 41 still contain the methoxy group that in general cannot be converted into a hydroxyl group under mild conditions. Alternatively, (2-trimethylsilyl)ethoxy- (TMSEO) or benzyloxy-substituted 1,2-oxazine derivatives are also available with similar selectivities and efficacy. They allow the removal of the O-protective group under mild and specific conditions. As an example the synthesis of N-acetyl neuraminic acid 116 is shown in Scheme 42 employing benzyloxyallene 38 as key C3-building block.⁴¹ In this case methoxyallene 22 is additionally employed in the late stage of the synthesis to introduce the methoxycarbonyl group as a nucleophile. Hence in this sequence lithiated alkoxyallenes are used as 1,3-zwitterionic synthon 55 and as alkoxycarbonyl anion synthon 57.


	Scheme 42 Synthesis of a N-acetyl neuraminic acid derivative 116 from anti-configured benzyloxy-substituted 1,2-oxazine derivative 115 using lithiated alkoxyallenes as 1,3-zwitterionic synthon 55 and alkoxycarbonyl anion synthon 57.

A general feature of the 1,2-oxazine intermediates is that the enol ether double bond undergoes highly stereoselective addition reactions. The stereoselective hydroboration is an example and was the key step for the preparation of enantiopure pyrrolidine, pyrrolizidine and azetidine derivatives with high selectivity.⁴² A collaboration with the Goti group established a short, efficient and stereodivergent synthesis of the pyrrolizidine alkaloids Australine and Casuarine. Lithiated benzyloxyallene 117 was employed as the crucial C3 building block (Scheme 43). Its addition to D-arabinose derived nitrone 118 provided bicyclic 1,2-oxazine 119 in essentially quantitative yield. Depending on the subsequent steps different sides of the intermediates were attacked either leading to Australine in a few steps or to Casuarine.⁴³


	Scheme 43 Stereoselective synthesis of the pyrrolizidine alkaloids Casuarine and Australine starting from benzyloxyallene as a C3 building block and D-arabinose derived nitrone 118.

Whereas many transformations of the enantiopure 1,2-oxazines proceed in a straightforward and foreseeable manner, a serendipitous discovery led to a new scenario. During the attempt to convert TMSEO-substituted 1,2-oxazine 120 into the corresponding 1,2-oxazinone by treatment with Lewis acids we discovered that a novel process occurred. It incorporates the “protective group” into the isolated product generating bicyclic 1,2-oxazinones 121 in good to excellent yields (Scheme 44).⁴²


	Scheme 44 Lewis acid-promoted transformation of TMSEO-substituted 1,2-oxazines 120 into bicyclic 1,2-oxazinones 121. TMSEO = (2-trimethylsilyl)ethoxy.

The mechanism of this rearrangement involves coordination of the Lewis acid (LA) to the dioxolane oxygen, ring-opening to provide a stabilized carbenium ion 122 that attacks the enol ether moiety of the 1,2-oxazine ring (Scheme 45). The resulting new carbenium ion 123 undergoes a fast fragmentation into the corresponding ketone 121, ethylene and a trimethylsilyl-X species. The carbon–carbon bond forming step can be considered as a Lewis acid-promoted aldol-type addition of an acetal to an enol ether or as Prins reaction. The fast fragmentation of the TMSEO group is a prerequisite for a smooth course of this kind of transformation. With simple alkyl groups side reactions leading to different products are observed.


	Scheme 45 Proposed mechanism for the Lewis acid-promoted transformation of TMSEO-substituted 1,2-oxazines 120 into bicyclic 1,2-oxazinones 121. TMSEO = (2-trimethylsilyl)ethoxy.

A variety of bicyclic 1,2-oxazines 121 were accessible by this method. Due to their high degree of functionalisation they are excellent starting materials for the synthesis of enantiopure polyhydroxylated aminopyran and aminooxepane derivatives that can be considered as analogues of carbohydrates (Scheme 46).⁴² These carbohydrate mimetics, e.g.124 and 125, have found application as crucial components of multivalent conjugates showing extremely high affinities to L- and P-selectins, carbohydrate recognising proteins involved in inflammation processes.⁴⁴


	Scheme 46 Synthesis of carbohydrate mimetics 124 and 125.

By introduction of a thiophenyl group into the dioxolane moiety bicyclic 1,2-oxazine derivatives such as 126 can be generated in an analogous manner. They are equivalents of pyrans containing an anomeric centre (Scheme 47) and they allowed the straightforward preparation of branched carbohydrate derivatives and the corresponding di- and trisaccharides of types 129 and 130.⁴²


	Scheme 47 Thiophenyl-substituted 1,2-oxazine derivative 126 as a precursor for the synthesis of bicyclic 1,2-oxazine 127 and aminopyran 128 as well as di- and trisaccharide 129 and 130. TMSEO = (2-trimethylsilyl)ethoxy.

2.4.5 Examples of rearrangements involving alkoxyallene adducts. Alkoxyallenes with a hydroxyalkyl group adjacent to C1 of the allene moiety are very easily accessible by adding the lithiated species to carbonyl compounds (see above, e.g.Scheme 21). The primary products such as 131 obtained from cyclobutanones as electrophiles undergo a smooth palladium-catalysed ring-expansion to 2-vinyl-substituted cyclopentanone derivatives 132.⁴⁵ If this pinacol-type rearrangement is executed in the presence of enantiopure ligands (R,R)-133 and (R,R)-134, respectively, the resulting cyclopentanones 132 are formed with up to 95% ee (Scheme 48). In this process the alkoxyallenes deliver a vinyl carbene synthon 135 formally inserting into the carbon–carbon bond next to the carbonyl group of the starting cyclobutanone.


	Scheme 48 Synthesis of enantio-enriched cyclopentanones 132 by rearrangement of alkoxyallene–cyclobutanone adducts 131.

Similar benzannulated compounds 136 lead to ring-expanded bicyclic products of type 137 employing tetrakis(triphenylphosphine) palladium as a catalyst (Scheme 49).⁴⁶


	Scheme 49 Palladium-catalysed ring expansion of methoxyallene adducts 136.

A gold(III)-catalysed process starts from TMS-protected allenyl alcohols 138 and provides cyclic enol ethers 139 as different type of rearrangement product (Scheme 50).⁴⁷ As a crucial intermediate the vinyl gold species is assumed to undergo [3+2] cycloaddition to siloxycyclopropane 140 which ring-opens to give the final product.


	Scheme 50 Au(III)-catalysed cyclisation of TMS-protected alkoxyallene adducts 138 to cyclopentene derivatives 139.

A different method generates benzene rings from alkoxyallenes and α,β-unsaturated aldehydes (Scheme 51). Addition of the lithiated alkoxyallene to the carbonyl group provides the corresponding allenyl alcohols that were subsequently converted into the aromatic unit by gold(I)-catalysis.⁴⁸ Among the carbazole derivatives prepared from the corresponding 2-formyl-substituted indole was the natural product Clausine V.⁴⁹


	Scheme 51 Formation of benzene rings 142 and 144 from alkoxyallenes and α,β-unsaturated aldehydes 141 and indole-2-carbaldehydes 143.

Nazarov-type cyclisations involving alkoxyallenes have systematically been studied by the Tius group and also summarized in reviews.⁸ Two examples are depicted in Scheme 52. In the first case, addition of the lithiated alkoxyallene 146 to an α,β-unsaturated ketone furnished intermediate 147 in excellent yield. Its treatment with trifluoroacetic acid anhydride induces the formation of a stabilised carbenium ion 148 which undergoes the Nazarov cyclisation to 149 finally giving exo-methylene cyclopentenone 150.⁵⁰ The MOM group is essential for achieving smooth transformations. In a different variation, the carbohydrate-derived lithiated allene 151 and amide 152 combine to give the α,β-unsaturated ketone 153. Treatment with acid in hexafluoroisopropanol converts 153 into cyclisation product 154 bearing a hydroxyl group at C2.⁵¹ In these applications the alkoxyallene served as a dianionic synthon 155.


	Scheme 52 Nazarov-type cyclisations of alkoxyallene intermediates 147 and 153 leading to cyclopentenone derivatives 150 and 154. Equivalence of alkoxyallenes with a dianionic synthon 155.

A related method to generate cyclopentenone derivatives from highly substituted alkoxyallenes involves the oxidation of the allenes either with dimethyldioxirane or with meta-chloroperbenzoic acid (Scheme 53). The alkoxyallenes 157 were prepared from the corresponding propargylic ethers 156 by a deprotonation–protonation-sequence and then treated with dimethyldioxirane (DMDO) as the oxidising reagent.⁵² The resulting species is a 2-oxoallyl cation that undergoes the Nazarov cyclisation to the products 158. This elegant method has been employed to the synthesis of the natural product Rocaglamide in its racemic form.⁵³


	Scheme 53 Oxidation of alkoxyallene derivatives 157 and oxidative Nazarov-type cyclisation of 159.

2.5 Examples of other reaction types

Simple addition reactions to one of the two bonds of alkoxyallenes may also provide useful products for further synthetic endeavours. For example, addition of simple electrophiles such as fluorinated sulfinyl chlorides to alkoxyallenes furnishes the alkenyl sulfoxides 161 under mild conditions (Scheme 54).⁵⁴ This process is likely to occur via a reasonably stabilised allylic cation. The product 161 still contains an enol ether moiety suitable for further transformations. The second example of Scheme 54 is a related process, but due to a different substitution pattern of the allene the product 162 contains two electron-withdrawing groups at the double bond. Compounds of this type should be excellent Michael acceptors.


	Scheme 54 Addition of perfluoroalkanesulfinyl chlorides to alkoxyallenes providing α,β-unsaturated sulfoxides of type 161 or type 162.

The nucleophilic samarium ketyls, generated from carbonyl compounds and samarium diiodide, add to the terminal carbon of alkoxyallenes generating vinyl radicals. They trap either a hydrogen atom from THF or HMPA or they are further reduced by samarium diiodide and protonated to give enol ethers of type 163 (Scheme 55).⁵⁵ These compounds are valuable intermediates and enable the synthesis of a variety of γ-lactones 164. The regioselective additions of the ketyls demonstrate that alkoxyallenes react preferentially at the terminal carbon with nucleophilic species. Other allenes, e.g. phenylallene are usually attacked by radicals at the central carbon.


	Scheme 55 Synthesis of γ-lactones 164via a samarium diiodide induced coupling reaction of methoxyallene 22 and carbonyl compounds.

3. Conclusions

This tutorial review summarises synthetically important examples which impressively demonstrate the broad applicability of alkoxyallenes in organic synthesis. There are many addition reactions and cycloadditions where alkoxyallenes play the role of acrolein or acrolein acetal substitutes. Although these examples of use seem simple they are nevertheless synthetically very valuable.

The most versatile use of alkoxyallenes involves their deprotonation at C1 followed by reactions with electrophiles. Often a cyclisation is the (spontaneous) subsequent step, leading to a series of highly functionalised five-membered and six-membered heterocycles. Here the deprotonated alkoxyallenes serve as building blocks operating as 1,3-zwitterionic C3 synthon 55 (Scheme 56). The functional groups installed in the heterocycles allow many transformations, in particular by exploiting the remaining enol ether double bond. The addition of lithiated alkoxyallenes to nitriles followed by treatment with carboxylic acids establishes a 1,2-zwitterionic C3 synthon 20 that also allowed syntheses of a series of unusually functionalised heterocycles.


	Scheme 56 C3 synthons derived from alkoxyallenes as discussed in this tutorial review.

The alkoxy group of the allenes can easily be varied and thus allows modulation according to the synthetic problem in the subsequent products, including selective deprotection in complex products. Use of enantiopure alcohols from the pool of chiral compounds allows the preparation of alkoxyallenes with auxiliaries and as a consequence the stereoselective preparation of enantiopure products, including a series of natural products.

Another important use of specifically substituted alkoxyallenes concerns Nazarov-type cyclisations to cyclopentenone derivatives. These and other metal-promoted transformations illustrate the potential of alkoxyallenes to be incorporated into carbocyclic compounds serving as synthons 135 and 155.

The use of axially chiral alkoxyallenes is still a field to be fully explored. Finally, it should be noted that heteroatom analogues of alkoxyallenes, such as allenyl thioethers or allenyl amides, are also valuable building blocks in organic synthesis. Their reactivity shows many similarities, but also shows distinct differences compared to alkoxyallenes and thus nicely complements the rich chemistry of this type of allenes.²

Acknowledgements

We would like to thank all group members who have been involved over the years in the alkoxyallene projects for their significant intellectual and experimental contributions. Their names are (in part) listed in the references below. The generous support by the Deutsche Forschungsgemeinschaft, the Alexander von Humboldt-Foundation, and Bayer HealthCare is most gratefully acknowledged.

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Footnote

† Dedicated to Professor Helmut Schwarz on the occasion of his 70th birthday.