enol esters: versatile substrates in synthesis of fine and … · synthetic organic chemistry...

Synthetic Organic Chemistry

Literature Research

Enol esters: Versatile substrates in synthesis of fine and specialty chemicals

by

Consuela Cambridge

May 3rd, 2016

Student number 10316035 Research institute Supervisor Van´t Hoff Institute for Molecular Sciences Prof. dr. Jan van Maarseveen Research group second supervisor Synthetic Organic Chemistry Drs. Linda Wijsman

Enol esters: versatile substrates in synthesis of fine and specialty chemicals

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I. Abbreviations AH Asymmetric hydrogenation AHF Asymmetric hydroformylation AM Anti-Markovnikov BDP Bis-3,4-diazaphospholane BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ee Enantiomeric excess EVA Ethylene-vinyl acetate (iPr)3SiH Tri-isopropyl silane M Markovnikov NBS N-bromosuccinimide NCS N-chlorosuccinimide NHC N-heterocyclic carbene PHOX Phosphinooxazolines P-OP Phosphine-phosphite ligands p-TsOH para-toluene sulfonic acid PVCA Polyvinyl chloride acetate TBDMS ether tert-butyldimethylsilyl ether TBS ether tert-butyldimethylsilyl ether TBSOTf Trimethylsilyl trifluoromethane sulfonate THF Tetrahydrofuran TIPS ether Tri-isopropylsilyl ether TMS ether Trimethylsilylether TMSCl Trimethylsilyl chloride TMSOTf Trimethylsilyl trifluoromethanesulfonate TOF Turn over frequency TON Turn over number VA Vinyl acetate VAM Vinyl acetate monomer


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II. Abstract Enol ester synthesis has gradually evolved from the mercury-catalysed transvinylation of olefinic acetates with carboxylic acids, to asymmetric ruthenium-catalysed stereoselective hydrocarboxylation of alkynes; obtaining enol esters via either Markovnikov or anti-Markovnikov addition. Optimised synthesis and ongoing research on stereo- and regioselectivity, initiated an interest in applications of enol esters. This thesis therefore provides an overview of enol and vinyl esters as substrates and intermediates, by exploring their application on small and large scale.

The asymmetric hydroformylation/Wittig olefination tandem process of Z-enol acetates yields γ-hydroxy-α,β-unsaturated carbonyl motifs present in antifungal bioactive compounds. Z-enol esters allow for asymmetric epoxidation yielding cis-epoxides, which can be converted to useful α-acyloxy ketones and α-silyloxyaldehydes. Furthermore, vinyl acetates are an opportune replacement for the synthesis of chiral alcohols when there are no suitable catalysts to hydrogenate intricate carbonyl starting material, and also function as alternative acylating agents. As for more complex applications, enol esters have been used in both substitution and addition reactions leading to α-substituted carbonyl compounds and intricate molecular scaffolds essential in synthesis of bioactive compounds. Scheme 1 provides a brief overview of enol ester applications.

Scheme 1. A brief overview of the versatility of vinyl acetate in various reactions.


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II. Table of contents I. Abbreviations ................................................................................................................................. 1

II. Abstract .......................................................................................................................................... 2

II. Table of contents ............................................................................................................................ 3

1. Introduction ................................................................................................................................... 4

2. Asymmetric hydroformylation of enol esters ................................................................................. 6

2.2. AHF/ Wittig tandem process involving enol esters ................................................................. 7

3. Asymmetric epoxidation of (Z)-enol esters ..................................................................................... 8

3.1. Enol ester epoxide derivatives: α-Acyloxy ketones ................................................................. 9

3.2. Enol ester epoxide derivatives: α-Silyloxyaldehydes .............................................................. 9

3.3. Summary and partial conclusion I ........................................................................................... 10

4. Asymmetric hydrogenation of enol ester derivatives ................................................................... 11

5. Acylation of alcohols: Transesterification using enol esters ........................................................ 12

6. Functionalisation of enol acetates at the α-position ..................................................................... 13

6.1. α-Alkyl substituted carbonyl compounds ............................................................................... 13

6.2. Michael addition of enol acetates to α,β-unsaturated ketones ............................................. 15

6.3. Heck olefination reactions ....................................................................................................... 16

6.3.1. Decarboxylative Heck olefination of enol esters ............................................................. 17

6.4. α-Arylation of enol acetates mediated by visible light........................................................... 18

6.5. Summary and partial conclusion II ......................................................................................... 19

7. Useful molecular scaffolds accessible via enol ester derivatives ................................................. 20

7.1. Oxetane synthesis: The Paternò-Büchi reaction involving enol esters ................................ 20

7.2. 4-Substituted Isocoumarins: The silver(I)-mediated annulation of enol esters ................. 21

7.3. Di-substituted cyclic ethers: The Aldol reaction of enol acetates and lactols ...................... 23

7.4. Quinolines and N-aryl lactams: Mannich-type Povarov reactions with vinyl acetates ....... 24

7.5. Synthesis of di-hydropyranones: The NHC-mediated pathway using α,β-unsaturated enol esters ................................................................................................................................................. 26

7.6. Summary and partial conclusions III ...................................................................................... 28

8. Polymers: The use of vinyl acetate in polymers ............................................................................ 29

8.1. Vinyl acetates in polymers ....................................................................................................... 29

9. Discussion and conclusion .............................................................................................................. 30

10. References ...................................................................................................................................... 32


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1. Introduction Enol esters and their derivatives are promising compounds with the potential to be utilised as substrates and intermediates in organic and pharmaceutical chemistry.1,2 They can be converted to bioactive compounds such as antibiotics, steroids, and are also promising substrates for polymer synthesis and synthesis of various molecular scaffolds. Thus far, a broad variety of reactions have been developed for the synthesis of enol esters.

Since 1940, the industry was provided with rare valuable vinyl esters via transvinylation of olefinic acetates with carboxylic acids, in presence of mercury(II), ruthenium(II), rhodium(II), platinum(II) and palladium(II) catalysts (eq. 1, Scheme 2). This method was coexistent with the thermal decomposition of vinylmercury carboxylates (eq. 2).3,4 Soon after, the application of the highly active mercury, and palladium catalysts was restricted due to toxicity of mercury and fast palladium deactivation.

Between 1960 and 1995 alternative methods to obtain alk-1-en-2-yl esters were tested. In 1995, Limat et al. isolated O-acylated enol esters in moderate to high yields when silyl enol ethers were treated with acid chlorides, and copper(I) chloride catalysts (eq. 3).5 Enolate acylation was also achieved by condensation of O-trimethylsilyl enethers with acylfluorides in presence of fluoride sources (eq. 4).6 Hitherto, the vapour-phase oxyacylation of olefins with acetic acid involving supported palladium(II) catalysts accounts for the industrial production of enol acetates (eq. 5). 2,3 Though, for researchers, a much preferred route is the hydrocarboxylation of alkynes and alkenes (eq. 6a and eq. 6b respectively), a pathway facilitated by ruthenium(II), iridium(II), rhodium(II) and palladium(II) catalyst precursors, under mild reaction conditions.2,3,7 With this straightforward synthesis, the focus in enol ester preparation shifted towards influencing their regioselectivity, by use of specific reagents and catalysts.


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Scheme 2. Schematic representation of various pathways to synthesise enol ester derivatives.

The majority of the aforementioned reactions facilitate the Markovnikov (M) addition of carboxylic acids to terminal alkynes, while the anti-Markovnikov (AM) addition yields E- and Z-enol ester isomers, which as masked aldehydes, are useful in synthetic chemistry. Doucet et al. reported that ruthenium based catalysts with chelating phosphine and labile allylic ligands favour the anti-Markovnikov addition via a stereoselective trans-addition reaction, with mostly Z-enol ester products (eq.7, Scheme 3).3

In contrast, the stereoselective outcome of the acylation of silylenol ether is dependent on the conjugation of the enolate anion, since merely pure Z-isomers are obtained when the double bond is conjugated with the oxygen atom of the enolate anion, and E-isomers if the substrate has a higher conjugation.5 Access to enantioselective synthesis of enol esters was provided by Schaefer et al., when he demonstrated the catalytic asymmetric coupling of ketenes and aldehydes yielding α-arylalkanoic acids (91% enantiomeric excess (ee)), in presence of a chiral-planar DMAP iron catalyst.7

Scheme 3. Stereoselective synthesis of Z-enol esters with asymmetric ruthenium catalysts developed by Doucet et al.3

With optimised synthesis and ongoing research on stereo and regioselectivity, interest in applications of enol esters is increasing. This thesis provides background information on enol and vinyl esters as substrates and intermediates by exploring their application on large and small scale. Currently, enol and vinyl esters are involved in multicomponent8, hydroformylation9,


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epoxidation10 and acylation11,12 processes. Furthermore, variation in structural features make them eligible substrates for bio-organic and pharmaceutical synthesis. When functionalisations are made at the α-position, various α-alkylated/arylated carbonyl compounds, which are essential in natural product synthesis, can be achieved.13,14 Enol esters derivatives also serve as precursors for synthesis of molecular scaffolds such as oxetanes15, isocoumarins16, di-substituted cyclic ethers17, quinolines and N-aryl lactams. Finally, vinyl acetate derivatives, vinyl haloacetates and vinylacetates are monomers applied for production of comonomers and copolymers such as vinyl acetate/acrylic (VAA) copolymers and ethylene-vinyl acetates (EVA) copolymers used in coatings, adhesives and emulsion paints amongst others.3,4

2. Asymmetric hydroformylation of enol esters Asymmetric hydroformylation (AHF) of alkenes proceeds in one step via a one carbon homologation reaction, and is a well-known process for obtaining either a branched or linear aldehyde.9,18 This process requires an alkene substrate that is converted to an aldehyde in presence of syngas and a metal catalyst. Depending on the ligand properties two regioisomers can be obtained (see Scheme 4). The branched regioisomer contains an α-chiral centre and when enantioenriched, is very versatile in subsequent applications.

Scheme 4. Asymmetric hydroformylation of a terminal alkene obtaining branched and linear regioisomers.10

Experiments conducted by Risi and Landis et al. concluded that rhodium(I) complexes comprising of (S,S,S)/(S,S,R) bis-3,4-diazaphospholane (BDP) ligands, depicted in Figure 1, exhibit great performance on the AHF of olefins, which is expressed by the turnover number (TON) (150.000:1) and turnover frequencies (TOF) averaging 19400.9,18 Hydroformylation of vinyl acetate utilising rhodium(I) complexes with (S,S,S)-BDP ligands exhibited excellent regio- and enantioselectivity (41:1 B: L with 92-96% ee) for the chiral product, 2-(S)-acetyloxypropanal (Scheme 5).

Figure 1. Chemical structures of (S,S,S) and (S,S,R)-bis-3,4-diazaphospholane, (S,S,S)-BDP and (S,S,R)-BDP (adapted from Risi et al.).9


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Scheme 5. Asymmetric hydroformylation of vinylacetate with a rhodium catalyst yielding branched and linear regioisomers.10

Asymmetric hydroformylation reactions have several benefits. They are atom efficient, have high atom economy, are carried out under neutral pH, which suppresses isomerisation of the chiral product, and the syngas mixture is easily vented from the reaction vessel. These benefits, added to the inert catalyst, make AHF a convenient reaction for tandem processes. Tandem processes involving AHF have led to the development of pathways including: AHF/crotylation19,20, hydroformylation/ Sn1 alkylation21, AHF/ asymmetric aldol22, bidirectional hydroformylation/tandem hydrogenation-reductive bis-amination23, AHF/Wittig olefination9,24,25 and hydroformylation/asymmetric Mannich26 reactions. For the total synthesis of natural products these ensure sufficient increase in the overall yield.

2.2. AHF/ Wittig tandem process involving enol esters As far as known, the only tandem process involving enol ester derivatives is the asymmetric hydroformylation of Z-enol acetates with rhodium(I) (S,S,S)-BDP catalysts yielding α-acetoxcyaldehydes, which was first reported by both Roberto and Risi et al.9 They demonstrated that α-acetoxcyaldehydes can be converted to γ-chiral α,β-unsaturated carbonyl compounds via a stabilised ylide-mediated reaction, also known as the Wittig reaction (Scheme 6).24 Wittig olefinations with carboethoxy-substituted ylides and carbobenzyloxy- substituted ylides were both attempted and respective yields of 79% and 46% in 99 % ee were reported. Olefination with carbobenzyloxy- substituted Wittig ylides was found to undergo another AHF/Wittig olefination cycle, whereas allylic ylides yielded 1,4-dienes, which are susceptible to subsequent hydroformylation. Depending on the Wittig reagent and repetition of the AHF/Wittig process multiple stereocenters and functionalities can be introduced which have proven to be essential in the synthesis of bioactive compounds. After the AHF/Wittig olefination strategy, Risi et al. reported on a lipase-catalysed deacetylation providing a γ-hydroxy- α,β-unsaturated carbonyl motif which is in (+)-patulolide C, (+)-decarestrictine L and (-)-pyrenophorol (Figure 2).9,25

These bioactive compounds often require multiple synthetic steps, which have decreased significantly due to the AHF/Wittig olefination strategy starting from Z-enol ester intermediates. As reported, the AHF/Wittig olefination is a fruitful process, especially in total synthesis of complex compounds. Development of the aforementioned tandem processes with enol ester derivatives as substrates will ease complex synthesis.


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Scheme 6. Schematic representation of the AHF/Wittig olefination tandem process.9

Figure 2. Molecular structure of (+)-patulolide C, (+)-decarestrictine L and (-)-pyrenophorol; bioactive compounds with γ-hydroxy- α,β-unsaturated moiety

(adapted from Risi et al.).9

3. Asymmetric epoxidation of (Z)-enol esters The double bond adjacent to the ester moiety in enol esters is susceptible to asymmetric epoxidation, yielding enantioenriched epoxides.10 These products can be transformed to corresponding α-hydroxy carbonyl derivatives or rearrange to α-acyloxy ketones in a highly stereoselective manner. Matsumoto et al. have proven that asymmetric epoxidation with titanium(salalen)complexes and hydrogen peroxide, favoured the enantioselective conversion of cis-alkenes. Experiments involving mixtures of E-and Z-enol esters, such as (E)- and (Z)-Oct-1-enyl-benzoate, lead to high yields of cis-epoxide products, derived from the (Z)-enol ester, with an enantioselectivity of 99% ee (Scheme 7).

Scheme 7. Asymmetric epoxidation of (E) and (Z)-oct-1-enyl-benzoate with cis-epoxide as the major product (adapted from Matsumoto et al.).10

Other researchers utilised peroxides such as dimethyldioxiranes27 or fructose derived ketone catalyst with oxone10 for the epoxidation of enol esters. However, both the yield and enantiomeric excess are dependent on sterics and electronic effects of the para substituent on the Z-enol ester.10 Enol esters can be converted to cis-epoxides via asymmetric epoxidation,


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however these epoxides can also function as a substrate for subsequent conversions. The upcoming paragraphs provide an overview of several epoxide derivatives, which are accessible via reduction in presence of an (asymmetric) Lewis acid catalysts, providing α-acyloxyketones and α-silyloxyaldehydes.

3.1. Enol ester epoxide derivatives: α-Acyloxy ketones Enol ester epoxides can be rearranged to α-acyloxy ketones, a transformation often integrated in steroid synthesis.10,28 Enol ester epoxides can be transformed either thermally with intermolecular migration of the acyloxy moiety, along with inversion of configuration, or under acidic conditions with mostly retention of configuration. Both α-acyloxy ketones and their α-hydroxy ketone derivatives, are essential in synthesis of alkaloids, sugars, antibiotics, terpenes and pheromones, for they function as stereodirective groups or chiral synthons. Zhu et al. practised the rearrangement of enol ester epoxides, (R,R)-1benzoxyloxy-1,2-epoxycyclohexane, with protic and Lewis acids.29 With protic acids such as p-TsOH the ee slightly declined, while with Lewis acids the ee varied drastically depending on the acids acidity constant. For example when Yb(OTf)3 was used the R-enantiomer (4) was favoured, while the weaker acid, YbCl3, yielded the S-enantiomer (6). A schematic representation exhibited in Scheme 8 suggests that strong acids cause retention of configuration by complexation to the epoxide oxygen and cleaving the C1-O bond (pathway a), obtaining carbocation intermediate 3 and subsequent acyl rearrangement with retention of configuration yields acyloxy ketone 4. Contrary to strong acids, weak acids labilise both epoxide bonds (5) and facilitate acyloxy rearrangement with inversion of configuration yielding acyloxy ketone 6 (pathway b).

Scheme 8. Reduction of enol ester epoxides with a strong Lewis acid (pathway a) and a weak Lewis acid (pathway b) (adapted from Zhu et al.).29

3.2. Enol ester epoxide derivatives: α-Silyloxyaldehydes Generally, α-silyloxyaldehydes are synthesised following multistep processes, for instance diazotisation and partial reduction of α-amino acid derivatives or multistep differential protection and oxidation of 1,2-diols. α-Silyloxyaldehydes risk being oligomerised or tautomerised to hydroxy ketones when not protected.27 In order to limit the aforementioned setbacks, Friestad et al. designed a process which induces ring opening of Z-enol ester epoxides through application of a silyl cation.27 This experiment was carried out at room temperature and microwave irradiation, using trimethylsilyl trifluoromethanesulfonate (TBSOTf) and 2,6-lutidine in dichloromethane. These alternatives reduce the reaction time and diminish degradation pathways with yields ranging from 79% up to 97% compared to conventional methods. Though the exact mechanism has not been investigated yet, Friestad et al. suspects 2,6-lutidine to have a similar function in the silyl cation induced ring-opening of ether epoxides as in the Fujioka-Kita


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reaction involving acetals (Scheme 9).The oxycarbenium ion generated after ring opening of the epoxide moiety is stabilised by 2,6-lutidine resulting in a pyridinium salt intermediate. Scheme 9 depicts both the Fujioka-Kita reaction and the silyl-cation induced ring opening concept devised by Friestad et al. The asymmetric epoxidation of Z-enol esters eliminates the necessity of a resolution step when a particular stereoisomer of the enol ester epoxide is desired.

Scheme 9. The Fujita-Kita mechanism and a mechanistic proposal of the silyl cation-induced ring opening reaction with 2,6-lutidine by Friestad et al.27

3.3. Summary and partial conclusion I The asymmetric epoxidation of Z-enol esters results in α-acyloxy ketones and α-silyloxyaldehydes via reduction in presence of an (asymmetric) Lewis acid catalysts. Z-enol esters are, due to their configuration, ideal substrates for asymmetric epoxidation yielding cis-epoxides. And cis-epoxides can then be thermally reduced to α-acyloxy ketones by inversion of configuration or under acidic conditions wherein the configuration is retained. That aside, the acids acidity also contributes to inversion or retention of configuration. Though there is no evident explanation, strong Lewis acids promote retention, while weaker Lewis acids favour inversion.

Other cis-epoxide derivatives are α-silyloxyaldehydes which are obtained after TBSOTf-mediated epoxide ring opening and formation of a 2,6-lutidine intermediate. Deacetylation and release of 2,6-lutidine results in α-silyloxyaldehydes. However, this mechanistic proposal by Friestad et al. has not been confirmed. Though, there are numerous conventional methods to synthesise α-silyloxyaldehydes, this method reduces the amount of reaction steps, but also functional group differentiation and protecting group interchanges are reduced. Furthermore, enol ester epoxide/lutidine intermediates are easily converted to α-silyloxyaldehydes, as both the acyl moiety and 2,6-lutidine, due to their stability, are considered good leaving groups.

To summarise, the configurational features of Z-enol esters allow for asymmetric epoxidation yielding cis-epoxides, which can be readily converted to useful α-acyloxy ketones and α-silyloxyaldehydes under ambient conditions with reasonable yields. The asymmetric epoxidation of Z-enol esters also eliminates the necessity of a resolution step when a particular stereoisomer is desired.


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4. Asymmetric hydrogenation of enol ester derivatives Asymmetric hydrogenation (AH) is a thoroughly studied process which has been crucial in the synthesis of chiral amines, chiral amino acids, chiral alcohols and other essential chiral derivatives.30 Asymmetric hydrogenation of enol esters is rather novel research and is seen as an alternative pathway wherein acyl deprotection of esters (3) leads to chiral alcohols (2) (pathway b).30,31 This is contrary to the conventional AH of carbonyl compounds (1) (pathway a; Scheme 10).

Scheme 10. Hydrogenation pathways towards chiral esters (3) and chiral alcohols (2).32

Throughout the years rhodium(I) catalysts became the catalyst of choice for AH and several monodentate phosphine ligands, such as phosphonites, phosphites and phosphoramidite ligands, have been screened.32 Though AH of carbonyl compounds is facilitated by the aforementioned catalysts, AH of complex carbonyl compounds using the same catalysts, may cause a decrease in selectivity. Therefore, researchers such as Panella and Kleman et al. continued research on vinyl acetates as substrates using suitable phosphine ligands. They concluded that monodentate phosphine ligands, in most cases, are superior to bidentate derivatives.31,32 The AH of aromatic enol acetates results in chiral products with high enantioselectivity (98%) when rhodium complexes comprising of monodentate phosphine-phosphite ligands (P-OP) and its octahydro-analogue where utilised. Furthermore, substrates with alkyl moieties preferred phosphine ligands with ethane backbones and PPh2 fragments (complex 2a, c and d), whereas bulkier groups such as tert-butyl groups had higher yields and enantioselectivity when the backbone consisted of an aryl moiety (complex 1a and b, Figure 3.

Figure 3. Structures of phosphines-phosphite (PO-P) ligands and hydrogenated products (Kleman et al.)33

Altogether, the substrate scope and corresponding suitable catalysts for the AH of vinyl esters is comprehensive and AH of vinyl acetates is mainly regarded as an auspicious replacement for the


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synthesis of chiral alcohols when there are no suitable catalysts to hydrogenate (complex) carbonyl starting materials.

5. Acylation of alcohols: Transesterification using enol esters Acylation of hydroxyl- or amine-groups is often applied in multistep organic synthesis and is useful due to the resistance of the acyl moiety to a variety of reagents.11 (Acetic) anhydrides, 3-acetylthiazolidine, hindered amines and acid halides are few of the generally applied acylating agents. Acylation is often facilitated in the presence of protic or Lewis acids such as Sn(OTf)3, TiCl4/AgClO4, CoCl2, Sc(NTf2)3, TMSCl, TMSOTf and Sc(OTf)3.11 In acylation with anhydrides, the use of bases, such as pyridine, triethylamine and 4-(dimethylamino) pyridine, is recurrent (Scheme 11). Moreover, a combination of Lewis acid/base systems (MgBr2/R3N) is also considered in some cases.

For the past twenty years researchers have been exploring alternative methods in order to replace aforesaid traditional systems, as these pose several inconveniences. For example, (basic) catalysts can be air-sensitive and flammable. Also, in polyhydroxy natural product synthesis some acylating agents lack selectivity for either primary or secondary hydroxyl groups. Additionally, functional groups, namely dienes, epoxides, acetals and tert-butyldimetylsilyl ethers (TBDMS ether) are susceptible to cleavage when acidic acylation catalysts are used. To prevent these from occurring, transesterification with esters was attempted. This method however had a high reversibility rate, urging scientists to consider enol esters. The advantage of enol esters is that the enolate ion can interconvert to an aldehyde or ketone (Scheme 11). Catalyst used in acylation reactions with enol esters/vinyl acetates include PdCl2/CuCl systems 34, Sm(Cp*)2(thf)2 or SmI2 in cross coupling reactions of aldehydes and vinyl acetates 12, and iminophosphiranes11.

Scheme 11. An overview of enol acetates and anhydrides as acylating agents.


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As several conventional methods pose inconveniences ranging from stability to lack of selectivity, vinyl acetates would provide a plausible solution, as upon release the enol moiety is resonance stabilised and ceases the reverse reaction from occurring. Studies assessing vinyl acetate selectivities between hydroxides and amine groups are limited, however insight on this topic would promote utilisation of vinyl acetates as acylating agents.

6. Functionalisation of enol acetates at the α-position Researchers are genuinely interested in enol acetates as these substrates fulfil an important role in carbon-carbon bond formation. The catalytic arylation or alkylation of carbonyl compounds is therefore a subject of interest. In the following paragraphs an overview of a variety of enol acetates functionalisation is provided.

6.1. α-Alkyl substituted carbonyl compounds Alkylation of carbonyl compounds at the α-position has been attempted several times.13 Previous attempts include a ruthenium catalysed reaction, coupling of 1-arylpropargylic alcohol with an excess of ketone compounds, like acetone (eq. 14a), direct alkylation of 1,3-dicarbonyl compounds (eq. 14b) and hydrogenation transfer method involving ketones and primary alcohols (eq.14c), which require strong base for enolate generation (Scheme 12).13

Scheme 12. A brief overview of previously attempted α-alkylation reactions.


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Reactions with tosylates and mesylate alcohol derivatives, organometallic compounds, enolates and enamines with electrophiles, and organic halides are conventional methods for C-C bond formation. However, direct use of alcohols is preferred, mainly because they are readily accessible. Unfortunately, their application still poses a problem due to poor leaving group ability of the hydroxyl moiety and their tendency to decompose catalysts and active intermediates.13,35 Intensive investigation by amongst others Nishimoto et al. provided novel Lewis acid catalysts, namely InCl3, Hf(OTf)3, FeBr3, GaBr3 and La(OTf)3 for effective carbon-carbon bond formation between diverse alcohols and enol acetates, with either ketone or aldehyde products13(Scheme 13). The reaction requires Lewis acids with moderate oxophilicity and proceeds under ambient conditions (83ᵒC, 1 atm).

Scheme 13. Schematic representation of carbon-carbon bond formation between diverse alcohols and enol acetates, with either ketone or aldehyde products.

In 2011, Onishi et al. considered using silylethers to couple alkyl groups to enol acetates/enol esters, while retaining the ketone/aldehyde functionality (Scheme 14).36 Their stability against nucleophilic substitution makes them eligible coupling reagents. In synthesis of α-alkylated carbonyl compounds, silyl ethers where coupled to enol acetates in presence of a combined Lewis acid system, InCl3 and Me3SiBr. A variety of silylethers were tested, and secondary benzylic ethers bearing electron-withdrawing and donating groups had yields up to 99%, while high yields were also obtained when enol acetates derived from aromatic or aliphatic ketones were used. Advantages to this pioneering method include the absence of deprotection steps and the occurrence of the coupling reaction at room temperature within approximately two hours. The best solvent for this synthesis is dichloromethane, which is neither a coordinating nor non-coordinating solvent.

Scheme 14. Synthesis of α-substituted ketones/aldehydes from silylethers and enol acetates (adapted from Onishi et al.)36

The previously mentioned catalysts enable the reaction between alcohols and enol acetates, but remain toxic and expensive alternatives. Their pyrophoric properties and the use of excessive amounts of reagents urged scientists to explore for other catalysts. Umeda et al. discovered that ReX(CO)5 complexes (X=Cl or Br), which are both less toxic and less expensive, also facilitate


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coupling of alcohols and enol acetates under ambient conditions with ketones or aldehydes as products.35

6.2. Michael addition of enol acetates to α,β-unsaturated ketones The synthesis of 1,5-dicarbonyl compounds is an essential preliminary step in preparation of many natural products such as terpenoids.37 Extensive studies have provided several conventional pathways of which the Michael addition of metal or ester enolates (metal =Li, Sn, K, Si) to α-β-unsaturated ketones is most conventional (Scheme 15).38,39

Scheme 15. Reaction of a metal ester enolate with an α-β-unsaturated ketone yielding a 1,5-dicarbonyl compound.

In 2012, Onishi et al. reported the Michael addition of enol acetates instead of metal enolates to α,β-unsaturated carbonyl compounds.39 This method facilitates isolation and usage of enol-form products, contrary to when metal enolates are used. They screened various Lewis acid catalysts in a reaction between crotonophenone ((E)-1-phenyl-2-buten-1-one) and isopropenyl acetate, and concluded that InBr3, InCl3, InI3 with additive, Me3SiCl, had consecutive yields of 53%, 69% and 72% respectively (Scheme 16). Reactions were carried out in dichloromethane at room temperature and took approximately five hours to complete. The yield increased when a five-fold amount of isopropenyl acetate was utilised. Enol acetates derived from aliphatic or aromatic ketones along with enol acetates carrying a substituent at the olefinic moiety all had yields ranging between 60% and 95%. In all isolated products the enol acetate moiety had the Z-configuration.

Scheme 16. Reaction of crotonophenone and isopropenyl acetate, yielding the enol form of 1,5-dicarbonyl compounds.


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Experiments with a variety of α-β-unsaturated ketones showed that increased substitution with phenyl rings increases the overall yield. To further demonstrate the utility of stable enol-acetate products, they were submitted for hydrogenation reactions, radical coupling reactions, nitroso-aldol reactions and transesterification reactions visible in Scheme 17 all which had moderate to high yields.39

Scheme 17. Possible follow-up reactions with the enol form of 1,5-dicarbonyl compounds (adapted from Onishi et al.)39

6.3. Heck olefination reactions The Mizoroki-Heck reaction, also known as Heck-reaction, enables one to do reactions at the sp2-hybridised carbon atoms.40,41 The most approachable Heck reactions involve triflates, diazonium salts, and aryl, aroyl- and arylsulfonyl halides with an electron deficient alkene containing at least one hydrogen atom. Formation of a carbon-carbon double bond is mediated in presence of palladium acetates, preformed triarylphosphine palladium complexes or palladium chlorides; other ligands include BINAP and PHOX.42 A special feature of this reaction is the high selectivity for trans-products (Scheme 18).

Scheme 18. Schematic representation of a readily accessible Heck olefination reaction.


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The mechanism depicted in Figure 4 reveals that the halide and hydrogen atom, released upon β-hydrogen elimination, form a strong acid, therefore stoichiometric amounts of base, usually potassium carbonate, and triethylamine and sodium acetate, are necessary for Pd0 regeneration and neutralisation of acidic waste. The aforementioned is also the downside of the reaction, because separation and disposal of precipitates are a subject of concern, especially in industrial processes.

Figure 4. The Palladium-catalysed Heck olefination mechanism between an aryl halide and activated alkene.

6.3.1. Decarboxylative Heck olefination of enol esters In order to reduce the salt load, different approaches to the Heck olefination have been designed by Gooßen and de Vries et al.41 Dams et al. suggested to upgrade previous attempts by Gooßen and de Vries et al. which include utilising p-nitrophenyl esters and aryl carboxylic anhydrides, regenerable nonhalogenated aryl substrates, by direct coupling of arenes to alkenes wherein the palladium catalyst is reoxidised by oxygen (Scheme 19).40,43,44 Contrary to conventional methods, this method proceeds under ambient conditions (90ᵒC, 0.8 MPa) and no solvent is required, no halide promoter is needed, and instead of carbon monoxide, water is the only by-product. Although these reactions allow for waste reduction, they remain small scale alternatives, as isolation and recyclability of the by-products still pose difficulties.


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Scheme 19. Previous attempts by Gooßen and de Vries et al. to waste free Heck olefination reactions.

Nevertheless, enol esters could offer a solution following a decarboxylative Heck olefination pathway introduced by Lukas et al..41 They generated an enol ester intermediate by reacting aromatic carboxylic acids with allenes or propynes. The enol ester intermediate is then left to react with an olefinic compound to give vinyl arenes with carbon monoxide and acetone as by-products, which can be burned to carbon dioxide and water. Unfortunately, the trail reaction which involved the conversion of isopropenyl benzoate with styrene in order to obtain trans-stilbene, depicted in Scheme 20, had poor yield with conventional palladium catalysts, Pd(OAc)2

and (dba)3Pb2. Hence, a combination of palladium bromide and tetra-alkyl phosphoniumbromides or tetra-alkylammonium, provided sufficient yields (<80%). This reaction reduces waste and does not require stoichiometric amounts of base. However, catalyst stabilizing agents, namely N-dodecyl-N-methylephedriniumbromide and tri n-butyl (2-hydroxyethyl) ammonium bromide, are required.

Scheme 20. Decarboxylative Heck olefination of isopropenyl benzoate.

6.4. α-Arylation of enol acetates mediated by visible light Arylation of (unsaturated) compounds has led to reactions involving aromatic haloethylation, arylation of olefins, aromatic allylation and arylation of allylic alcohols.45 Many arylation reactions have been developed and involved nickel, palladium, copper, iron or mercury catalysts, palladium being the most frequently used. In 1968, Heck et al. first reported the palladium-catalysed arylation of enol esters, unfortunately with poor selectivity.45 One of the most recent developments in enol ester applications is the arylation of enol acetates with aryl diazonium salts, mediated by visible light.14 The arylated species can be valuable in ibuprofen and β-blocker atenolol synthesis. Heterocycles accessible via 1,2-diarylated ethanones are essential in a broad spectrum of drugs including indoles, pyrazoles, oxazoles and diazepines. All these substrates can be acquired starting from a procedure designed by Hering et al.14 Through


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photoinduced electron transfer, a reaction of aryl diazonium salt, p-nitrobenzenediazonium tetrafluoroborate, with isopropenyl acetate irradiated with 440 nm light in presence of [Ru(bpy)3]Cl2 or photocatalytic active organic dyes yielded α-arylated ketones (Scheme 21).14 The ruthenium catalysts had best results with yields ranging from 40% to 90% depending on the reactants. The reaction was carried out at 20ᵒC in DMSO for two hours. Hering et al. proved the reaction could be followed up by a reductive cyclisation reaction with iron powder and acetic acid, obtaining substituted indoles (Scheme 22).

Scheme 21. Schematic representation of the photoinduced electron transfer reaction of aryl diazonium tetrafluoroborate salt with enol acetate.

Scheme 22. Reductive cyclisation reaction of α-arylated product mediated by iron powder and acetic acid, obtaining substituted indoles.

6.5. Summary and partial conclusion II Conventional pathways to functionalise carbonyl compounds at the α-position often involve reacting an excess of ketones with 1-arylpropargylic alcohol or primary alcohols. These reactions require strong base for enolate generation, and are often catalysed by oxophilic transition metal catalysts leading to fast catalyst deactivation. To reduce side reactions, Lewis acids such as InCl3, Hf(OTf)3, FeBr3, GaBr3 and La(OTf)3 with moderate oxophilicity are applied in reactions involving alcohols and vinyl acetate reagents. Additionally, combined Lewis acid systems, such as InCl3 and Me3SiBr, exhibited great selectivity in synthesis of α-alkylated carbonyl compounds in which silyl ethers where coupled to enol acetates.

The reaction of α,β-unsaturated ketones with enol acetates catalysed by InBr3, InCl3, InI3 with additive, Me3SiCl, yielded the enolised form of 1,5-dicarbonyl compounds in the Z-configuration. Increased substitution with phenyl rings at the α-β-unsaturated ketones showed an increase in the overall yield ranging from 60% to 95%. The partly enolised 1,5-dicarbonyl product is susceptible to subsequent hydrogenation, radical coupling, nitroso-aldol and transesterification


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reactions. Inspired by the Heck olefination reaction, researchers developed the decarboxylative Heck olefination reaction with enol ester substrates. The enol ester reacts with an olefinic compound to give vinyl arenes with carbon monoxide and acetone as by-products, which can be burned to carbon dioxide and water. Palladium bromide and tetra-alkyl phosphoniumbromides or tetra-alkylammonium, along with catalyst stabilizing agents, namely N-dodecyl-N-methylephedriniumbromide and tri-n-butyl(2hydroxyethyl)ammonium provided sufficient yields (<80%). This reaction reduces waste and does not require stoichiometric amounts of base.

Probably the most recent development in enol ester applications, is the α-arylation of enol acetates with aryl diazonium tetrafluoroborate salts mediated by light in presence of [Ru(bpy)3]Cl2 or photocatalytic active organic dyes. This reaction yielded α-arylated ketones with potential application in ibuprofen and β-blocker atenolol synthesis. With mediocre yields depending on the substrate properties, optimisation is necessary. Nevertheless this method can be followed up by a reductive cyclisation reaction with iron powder and acetic acid, obtaining substituted indoles.

Though the reaction conditions for functionalisation of enol esters at the α-position are ambient, an excess of reagents is often necessary, also most catalysts are toxic, pyrophoric, expensive or require promoting additives for optimal activity. Vinyl acetates are, due to their nucleophilicity at the β-carbon and easy release of the acyl group, ideal starting materials. As the application of vinyl acetates in these reactions is novel, extensive research is necessary to enlarge substrate scopes and develop optimal catalytic systems while enhancing yields.

7. Useful molecular scaffolds accessible via enol ester derivatives In many experiments simple vinyl acetates are either functionalised, used as a masked acylating agent or masked carbonyl compound. Nonetheless, the enol ester scaffold can also be (partly) incorporated in intricate molecular structures essential in bio-inspired synthetic pathways. In the following paragraphs a brief overview is given on the incorporation of enol esters in synthesis of oxetanes, 4-substituted isocoumarins, cyclic ether quinolines, N-aryl lactams and di-hydropyranones.

7.1. Oxetane synthesis: The Paternò-Büchi reaction involving enol esters The Paternò-Büchi reaction involves a photochemical addition of an olefin to a carbonyl compound with an oxetane as product.15,46 According to the Woodward-Hoffmann rules, the reaction has to proceed photochemically and is valuable in stereoselective intermolecular [2+2] photocycloaddition reactions, which are crucial reactions in synthesis of bio-inspired compounds such as taxols (Figure 5).15 Taxols contain a 3-acetoxyoxetane-subunit which is accessible via a Paternò-Büchi reaction of enol acetates and benzaldehydes.


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Figure 5. Taxol molecular structure with oxetane subunits.

Vasudevan et al. has executed these intermolecular photocycloadditions of enol acetates, by reacting isopropenyl acetates, 1-acetoxycylododecenes or 4-tert-butyl-1-acetoxycyclohexenes with various benzaldehydes at room temperature in benzene (Scheme 23).15 An excess of enol acetate was used and the product consisted of 2-aryl-3-acetoxyoxetanes. Reaction times varied from 20 up to 72 hours with increasing moderate yields (6%-28%) and the regio- and stereochemistry of the reaction products mainly depend on the starting materials used.

Scheme 23. Schematic representation of the Paternò-Büchi reaction involving enol acetates and benzaldehydes.

Oxetanes are also readily available via dehydration of 1,3-diols, cyclisation of aryl sulfonate esters on polystyrene and PEG-polymeric supports, reactions with potassiumhydroxide and 3-chloropropyl acetate or decarboxylation of cyclic six-membered carbonates.46 However, the Paternò-Büchi reaction enables more stereo- and regioflexibility and preserves the acetoxy-subunit essential in natural product synthesis. Furthermore, most of the reactions mentioned above are multistep processes, which require high reaction temperatures and/or harsh chemicals.

7.2. 4-Substituted Isocoumarins: The silver(I)-mediated annulation of enol esters Isocoumarins are often incorporated into pharmaceuticals with the purpose of treating antifungal, anti-inflammatory, antiallergic, anticancer, inhibitory activities, antimicrobial and anti-diabetic disorders.47 Due to their importance, their synthesis has been thoroughly investigated and includes (for example) the ruthenium, rhodium and iridium-catalysed annulation of carboxylic acids with alkynes. This Sonogashira type coupling of terminal alkynes with halo-carboxylic acids, is mediated by transition metal catalysts.

More recent research resulted in the copper(I)-catalysed cross-coupling of various 2-halobenzoic acids and 1,3-dicarbonyl compounds, and also the copper(I)-catalysed tandem C-C/C-O coupling reactions involving 2-bromobenzoates with acyclic 1,3-diones succeeded by annulation.47 However, in general these methods are less favourable, since they involve multistep synthesis at high temperatures in order to obtain the required starting materials, and require of highly toxic transition metal catalysts. The products of aforesaid procedures often


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yield 3- or 3,4-disubstituted isocoumarins, while procedures for 4-substituted isocoumarins are scarce. Apart from the palladium-catalysed preparation of 4-alkyl/aryl-substituted isocoumarins, more pathways need to be developed in order to synthesise equally important 4-substituted isocoumarins. A short overview of reactions, developed to synthesise substituted isocoumarins, is given in Scheme 24.

Scheme 24. Various synthetic pathways toward the synthesis of substituted isocoumarins.

In 2015, Panda et al. explored the selective intramolecular silver(I)-mediated C-arylation reaction yielding 4-substituted isocoumarins (Scheme 25).16 Their approach involved intramolecular annulation of 2-(ethoxycarbonyl)-vinyl 2-iodobenzoate derivatives, a product of alkyl propiolates and o-iodobenzoic acids. Several copper- and silver-catalysts were tested, and yields of 95% and 79% were obtained using respectively AgOAc and Ag2O at room temperature.


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Optimal results were reported when promoting oxidants (K2S2O8), bases (preferably 4-dimethylaminopyridine) and acetonitrile as solvent were used. The substrate scope of the reaction is promising, albeit reaction conditions require adjustments. Moreover, deacetylation is supressed resulting in higher product yields.

Scheme 25. Selective intramolecular silver(1)-mediated C-arylation of 2-(ethoxycarbonyl)vinyl 2-iodobenzoate yielding 4-substituted isocoumarins.

Enol ester derivatives are often selected in reactions due to the ease of the acyl moiety. Contrary to this, in the intramolecular silver(I)-mediated C-arylation reaction yielding 4-substituted isocoumarins, the entire enol ester moiety is embedded. The 2-(ethoxycarbonyl)vinyl 2-iodobenzoate derivatives are easily accessible via alkyne hydrocarboxylation, making the approach developed by Panda et al. a promising contribution to existing methods for the synthesis of 4-alkyl/aryl-substituted isocoumarins

7.3. Di-substituted cyclic ethers: The Aldol reaction of enol acetates and lactols Enol acetates have also proven to be promising substrates in aldol reactions with lactols (hemiacetals) from which cyclic di-substituted ethers result.17 Enol acetates were applied in a peculiar diastereoselective reaction reported by Masuyama et al.17 By combining 2-hydroxy-5-pentyl-tetrahydrofuran and isopropenyl acetate with SnX2 (X= Cl, Br, F) and N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) the product, 2-acetonyl-5-pentyl-tetrahydrofuran, was obtained with yields ranging from 80% to 88%, and a diastereomer ratio of 60:40 (Scheme 26). Using SnCl2 and NCS in dichloromethane at -30-5ᵒC were found to be optimal reaction conditions. The reaction is believed to proceed by primary formation of a tin lactol alkoxide intermediate succeeded by cyclic tin oxy-carbenium ion formation that further reacts with vinyl acetate. The Lewis acid facilitates the formation of the oxy-carbenium intermediate. The preference for vinyl esters is due to the stability of the leaving group (acyl moiety).


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Scheme 26. Formation of di-substituted cyclic ether by reacting a lactol with enol acetate.

7.4. Quinolines and N-aryl lactams: Mannich-type Povarov reactions with vinyl acetates Carbon-carbon bond formation is facilitated according to several reactions, of which one is the Mannich reaction (Scheme 27).48 The Mannich reaction is a multi-component reaction wherein a carbonyl compound reacts with an iminium-compound. The iminium-compound is obtained via a reaction of a primary or secondary amine with an aldehyde. The three components yield a β-amino-carbonyl compound, also known as the Mannich-base, which upon variation of each component provides access to various molecular scaffolds.

Scheme 27. Schematic representation of the Mannich reaction: A reaction between a non-enolisable aldehyde, a primary or secondary amine and an enolisable carbonyl

compound.

On the other hand, the Povarov reaction requires an aniline, aldehyde and an activated olefin which usually results in tetrahydroquinolines.48 Isambert et al. aspired to increase the synthetic versatility of this multicomponent reaction by using (cyclic) enol esters as the necessary activated alkene.8 Contrary to their expectations, the reaction of 2,4-dihydro-6-methyl-2H-pyran-2-one (1), p-toluidine (2) and ethyl glyoxalate (3) yielded not the desired lactone product A, but an N-aryl lactam C (25%). In order to obtain N–aryl lactam C, the expected Friedel-Crafts termination in the Povarov reaction should be less dominant than the heterocyclic ring formation involving deacetylation, when the nucleophilic nitrogen reacts with the carbonyl group as can be seen in Scheme 28. However, this can only be achieved if the three components react according to the Mannich reaction resulting in intermediate B.


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Scheme 28. Proposed mechanism of the Mannich reaction of 2,4-dihydro-6-methyl-2H-pyran-2-one (1), p-toluidine (2) and ethyl glyoxalate (3).

The synthesis was carried out at room temperature in acetonitrile with Sc(OTf)3 as catalyst. The kinetic product, C, has a cis/trans ratio of 3:1 which after refluxing for 24 hours with trifluoroacetic acid (20%) epimerised to a 1:9 cis/trans mixture, D. The highest yield reported was 65%, however many additional catalysts and additives including Yb(OTf)3, TMSCl, anhydrous Na2SO4, molecular sieves (4Å) and SOCl2 were used. The low yield of the reaction is caused by hydrolysis of intermediate B with an acyclic amino acid byproduct. When isopropenyl acetate was utilised, simple Mannich products were obtained while vinyl acetate substrates yielded quinoline scaffolds (Scheme 29 and Scheme 30 respectively).

Scheme 29. The Mannich reaction with isopropenyl acetate yielding simple Mannich products.


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Scheme 30. The Mannich reaction with vinyl acetate affording a quinoline product.

Most importantly, Isambert et al. succeeded in designing N-arylated lactams via a multi-component reaction which has never been attempted. These lactams are important scaffolds for herbicides, integrin antagonists and other bioactive derivatives.8,49 Though promising, the aforementioned reactions still have meagre yields and need to be optimised.

7.5. Synthesis of di-hydropyranones: The NHC-mediated pathway using α,β-unsaturated enol esters Between 1950 and 1965, N-Heterocyclic carbenes (NHC) have been used in inorganic and organometallic reactions.50 Nowadays, NHCs are known for their utility as organocatalysts and are often derived from thiazoles, imidazolines, imidazoles and triazoles. Due to their nucleophilicity, NHCs are often used in reactions requiring carbonyl coupling, including benzoin and Stetter reactions.51 This organocatalysts is often combined with other molecular structures gaining useful intermediates for organic synthesis. One of these intermediates is α,β-unsaturated acyl azolium (4) which is created when an aldehyde or ketene is added via oxidation, redox or addition mechanisms (Scheme 31).52,51 Because of their potential, Ryan et al. explored conjugate addition reactions involving α,β-unsaturated acyl azolium.51 They discovered that when choosing an α,β-unsaturated enol esters 2, an enolate ion 3 is released upon generation of α,β-unsaturated carboxylate 4 under Lewis basic conditions. Recombination of 3 and 4 provides enolate intermediate 5, which followed by proton transfer and acylation results in pyranone 7. The NHC catalysts 1 is regenerated after every cycle. Tetra-methyl carbenes and carbenes with both aromatic and aliphatic substituents resulted in the highest yields, 40% and 79-86% respectively. The reaction was carried out under reflux or at low temperature (-78ᵒC) in toluene, for approximately sixteen hours in presence of potassium tert-butoxide, which is responsible for deprotonation of α,β-unsaturated acyl azolium prior to the cyclisation step yielding the di-hydropyranone product.


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Scheme 31. The proposed catalytic pathway for formation of di-hydropyranones adapted from Ryan et al.51

The importance of the aforementioned approach was illustrated by Candish et al., who demonstrated the 18-step synthesis of bicyclic cyclopenta[c]pyran, the core structure of iridoids, that belong to a class of monoterpenoids that exhibit medicinal activity.53 In general, the H5 of the cyclopenta[c]pyran core 2, depicted in Scheme 32, is positioned cis to the H9.53 In this diastereoselective synthesis, this orientation was achieved when the α,β-unsaturated enol ester 1, was reacted with diastereoselective NHC, A, in tetrahydrofuran (THF) at temperatures ranging from -78ᵒC to room temperature. The yield was 83% with a d:r ratio of 3.4 to 1. Further trails to optimise the process by use of different solvents, chiral carbenes and temperatures were less successful. The final product, (-)-7-deoxyloganin 3, was isolated after β-glycosylation.


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Scheme 32. Synthesis of (-)-7-deoxyloganin involving the reaction of α-β-unsaturated enol ester with diastereoselective NHC, adapted from Candish et al.53

7.6. Summary and partial conclusions III In many experiments simple vinyl acetates are either functionalised, or used as a masked acylating agent or masked carbonyl compound. Nonetheless, the enol ester scaffold can be (partly) incorporated in intricate molecular structures essential in bio-inspired synthetic pathways.

Some of these have been listed above and include the intermolecular photocycloaddition of enol acetates with benzaldehydes forming oxetane units known to be present in taxols. In contrast to conventional multistep synthesis that require high reaction temperatures and/or harsh chemicals, the Paternò-Büchi reaction enables more stereo- and regioflexibility and preserves the acetoxy-subunit essential in taxols.

Furthermore, the synthesis of 4-substituted isocoumarins involving intramolecular annulation of enol ester containing scaffolds such as 2-(ethoxycarbonyl)vinyl 2-iodobenzoate derivatives (a product of alkyl propiolates and o-iodobenzoic acids) was investigated. Silver catalysts, such as AgOAc and Ag2O resulted in yields of 95% and 79% respectively at room temperature. Optimal results were reported when promoting oxidant (K2S2O8) and base (4-dimethylaminopyridine) were used.

Enol acetates have also proven to be promising substrates in aldol reactions with lactols (hemiacetals) from which cyclic di-substituted ethers result. In this reaction the Lewis acid catalyst facilitates the formation of the oxy-carbenium intermediate.

Contrary to oxetane and isocoumarin synthesis, vinyl acetate was chosen due to the stability of the leaving group (acyl moiety). Enol ester derivatives were also applied in multicomponent reactions in which their cyclic derivatives yielded N-aryl lactams while vinyl acetate substrates yielded quinoline scaffolds. Simple Mannich products were acquired when isopropenyl acetate was used as the activated alkene. This multicomponent Mannich-type Povarov reaction still needs catalyst optimisation to increase yields. However, it gives insight on how the molecular structure of enol esters affects the mechanism and therefore the reaction products.

Lastly, dihydropyranones are easily formed when substituted α,β-unsaturated enol esters were combined with N-heterocyclic carbenes under basic conditions and low temperatures in presence of a Lewis acid catalyst. In a mechanism involving addition, C-C bond formation, proton transfer and acylation, dihydropyranones were formed in moderate yields.


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In conclusion, incorporation of enol ester scaffolds in the synthesis of the structures mentioned above, results in valuable structures. Both the oxetane and 4-substituted isocoumarins units incorporated all of the enol ester moiety, while the multicomponent Mannich-type Povarov reaction excluded the acyl moiety via a deacetylation reaction. When N-heterocyclic carbenes were applied, α,β-unsaturated enol esters would undergo recombination in order to facilitate dihydropyranone formation. Although, enol esters have been utilised only upon recently, they make good substrates for addition of carbonyl, aldehyde or olefin functional groups to molecular structures. This is facilitated by the nucleophilicity at the β-carbon and facile release of the acyl group.

8. Polymers: The use of vinyl acetate in polymers Apart from utilisation in organic and pharmaceutical synthesis, enol esters have been commercially exploited in the form of polymers.4 In 2007, the annual production of vinyl acetate monomer (VAM) was estimated at 6,154,000 tonnes/annum. Vinyl acetate monomers find their use in non-woven binders, paper coatings, textile sewing thread, paper coating, emulsion paints, caulks and adhesives. They are often combined with other monomers forming copolymers such as vinyl acetate/acrylic (VA/AA) copolymers, ethylene-vinyl acetate (EVA) copolymers, poly-vinyl (butyral/formal) and polyvinyl chloride acetate (PVCA) copolymers.

8.1. Vinyl acetates in polymers Polyvinyl acetate is the simplest polymer produced, however its poor hydrolytic stability expressed by the acetate hydrolysis of ester moieties make it a less desired product for outdoor use. Therefore higher vinyl ester monomers (RC(O)O-CH=CH2, R>CH3) are preferred.4,54 Higher vinyl ester monomers are less susceptible to hydrolysis as aliphatic branches shield the ester moieties from hydrolysis (Figure 6).

In the 60s, chemists from Shell in collaboration with Dr .H. Koch and the Max-Planck institute, developed copolymers of vinyl esters of C9 or C10 versatic acid (commercially known as VeoVA9™ and VeoVa10™) and vinyl acetate (Figure 7).54 VeoVA9™ monomers provide rigidity and VeoVa10™ monomers flexibilize the copolymer.

Figure 6. Higher vinyl esters increase hydrophobicity of the polymer.


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Figure 7. Molecular structure of VeoVa9™ and VeoVa10™ monomer. R1 and R2 are alkyl groups containing a total of six carbon atoms for VeoVa9™ and seven carbon

atoms for VeoVa10™.

In the early 1990s, R.E. Murray of Union Carbide applied the transvinylation method on vinyl esters and numerous carboxylic acids in polymer synthesis to obtain new hard and soft monomers such as vinyl pivalate and vinyl-2-ethylhexanoate, also known commercially as Vynate™.4,54 All these monomers can be combined with a variety of vinyl acetates to form comonomers necessary to produce polymers with high tensile strength, varying glass transition temperatures, water resistance and other performance properties.

9. Discussion and conclusion Over the years, enol esters have been applied in various chemical reactions. In this thesis many have been discussed, starting with the asymmetric hydroformylation of Z-enol acetates, which yields linear and branched α-acetoxcyaldehydes. Due to its efficiency and high atom economy, asymmetric hydroformylation can be combined in several tandem processes of which the asymmetric hydroformylation/Wittig olefination process has been explored in synthesis of γ-hydroxy-α,β-unsaturated carbonyl motifs present in bioactive compounds, such as (+)-patulolide C, (+)-decarestrictine L and (-)-pyrenophorol.

Apart from asymmetric hydroformylation, Z-enol acetates are also asymmetrically epoxidised to cis-epoxides, which can be readily converted to useful α-acyloxy ketones and α-silyloxyaldehydes under ambient conditions with reasonable yields. The asymmetric epoxidation of Z-enol esters also eliminates the necessity of a resolution step when a particular stereoisomer is desired.

Both asymmetric hydroformylation and epoxidation provide valuable compounds. However, when it comes to the synthesis of chiral alcohols, asymmetric hydrogenation of vinyl esters is regarded as an auspicious method. Especially when there are no suitable catalysts to hydrogenate intricate carbonyl substrates. As several conventional acylating methods pose inconveniences ranging from instability to lack of selectivity, vinyl acetates would provide a plausible solution, as upon release, the enol moiety is stabilised by resonance, which ceases the reverse reaction from occurring. Functionalisation of vinyl acetates in the α-position via substitution, Michael additions, decarboxylative Heck olefinations and α-arylation mediated by visible light gave rise to a variety of α-alkylated/arylated ketones and aldehydes. Additionally, enol ester scaffolds can be incorporated in intricate molecular structures essential in bio-inspired synthetic pathways of oxetanes and isocoumarins. In Mannich-type Povarov reactions, parts of vinyl acetates are incorporated in N-aryl lactams and quinoline derivatives. When combined with N-heterocyclic carbenes, α,β-unsaturated enol esters form di-hydropyranones after a recombination step.


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In general, enol ester derivatives are versatile and therefore applicable in numerous reactions ranging from simple acylation and asymmetric hydrogenation/hydroformylation reactions, to more complex α-functionalisation reactions. Few researchers have also applied them in oxetane, 4-substituted isocoumarin, cyclic ether quinoline, N-aryl lactam and di-hydropyranone synthesis.

Vinyl acetates are ideal starting materials due to their nucleophilicity at the β-carbon, and easy release of the acyl group generating ketones and aldehydes. They have been utilised only upon recently, and make good substrates for addition of carbonyl, aldehyde or olefin functional groups to molecular structures. In most cases when conventional reagents were replaced by vinyl acetates, reaction conditions remained ambient, however different catalysts had to be tested.

Enol ester synthesis has gradually evolved and asymmetric ruthenium-catalysed stereoselective hydrocarboxylation of alkynes and alkenes is currently the most accessible pathway in obtaining enol esters via either Markovnikov or anti-Markovnikov addition. These reactions can be applied in bio-organic and pharmaceutical chemistry for synthesis of a variety of scaffolds essential in bioactive compounds, such as terpenes, alkaloids and steroids with antifungal, anti-inflammatory, antiallergic, anticancer, inhibitory activities, antimicrobial and anti-diabetic properties. Also vinyl acetate monomers combined with other monomers are used in commercially available copolymers.

Further research is necessary in order to explore possible tandem processes which are initiated with (asymmetric) hydroformylation. The asymmetric hydroformylation/Wittig olefination tandem process is a predecessor while AHF/crotylation, hydroformylation/ SN1 alkylation, AHF/ asymmetric aldol, bidirectional hydroformylation/tandem hydrogenation-reductive bis-amination, and hydroformylation/asymmetric Mannich reactions remain unexplored. In order to optimise reactions concerning vinyl acetates as acylating agents, the selectivity between amines and alcohols has to be tuned. As the application of vinyl acetates in functionalisation reactions and bio-inspired organic synthesis is novel, extensive research is necessary to enlarge substrate scopes and to develop optimal catalytic systems for enhancing yields and selectivity. Nonetheless, enol esters and their derivatives remain promising substrates in chemical and pharmaceutical chemistry.


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