Metal-Catalyzed Synthesis and Transformations of β -Haloenol Esters Metal ‐ Catalyzed Synthesis and Transformations of β ‐ Haloenol Esters

: In the last years there has been an increasing interest in the search for protocols to obtain β -haloenol esters in an e ﬃ cient and selective manner as they are versatile building blocks in synthetic organic chemistry. In this article, metal-catalyzed transformations allowing the access to both acyclic and cyclic (i.e., haloenol lactones) β -haloenol esters are reviewed. Metal-catalyzed reactions in which these molecules participate as substrates are also discussed. Enol esters are also relevant oleﬁnic derivatives with multitude of applications in modern organic chemistry [4–6]. The introduction of a halogen atom on the C = C bond of the latter leads to functionalized molecules, i.e., α -and β -haloenol esters (Figure 1), in which the reactivities of the haloalkene and enol ester functionalities can be combined and potentially exploited in numerous synthetic ways. Abstract: In the last years there has been an increasing interest in the search for protocols to obtain β ‐ haloenol esters in an efficient and selective manner as they are versatile building blocks in synthetic organic chemistry. In this article, metal ‐ catalyzed transformations allowing the access to both acyclic and cyclic (i.e., haloenol lactones) β ‐ haloenol esters are reviewed. Metal ‐ catalyzed reactions in which these molecules participate as substrates are also discussed.


Introduction
Alkenyl halides (haloalkenes) are a pivotal class of compounds in organic synthesis that can be used in a variety of carbon-carbon and carbon-heteroatom bond-forming reactions. For example, alkenyl halides are widely used as substrates in transition metal-catalyzed cross-coupling reactions [1,2] and can be easily converted, through a metal-halogen exchange, into nucleophiles for 1,2additions to carbonyl compounds [3]. Enol esters are also relevant olefinic derivatives with multitude of applications in modern organic chemistry [4][5][6]. The introduction of a halogen atom on the C=C bond of the latter leads to functionalized molecules, i.e., α-and β-haloenol esters (Figure 1), in which the reactivities of the haloalkene and enol ester functionalities can be combined and potentially exploited in numerous synthetic ways. In this context, while the utility of α-haloenol esters remains almost unexplored due to the lack of efficient and general synthetic methods [7][8][9][10], more accessible β-haloenol esters have gained significance in recent years as coupling partners in diverse chemical transformations. Several methodologies can be employed for the preparation β-haloenol esters, the most classical ones involving the acylation of haloenolate anions [11][12][13][14][15] or the haloacyloxylation of alkynes employing the elemental halogens [16][17][18][19][20], bis(pyridine)iodonium tetrafluoroborate (IPy2BF4) [21][22][23][24][25], N-halosuccinimides (NXS; X = Cl, Br, I) [26][27][28], PhI(OAc)2 [29][30][31], trihaloisocyanuric acids [32] or N,N-dibromo-p-toluenesulfonamide (TsNBr2) [33] as the electrophilic halogen source (Scheme 1). In this context, while the utility of α-haloenol esters remains almost unexplored due to the lack of efficient and general synthetic methods [7][8][9][10], more accessible β-haloenol esters have gained significance in recent years as coupling partners in diverse chemical transformations. Several methodologies can be employed for the preparation β-haloenol esters, the most classical ones involving the acylation of haloenolate anions [11][12][13][14][15] or the haloacyloxylation of alkynes employing the elemental halogens [16][17][18][19][20], bis(pyridine)iodonium tetrafluoroborate (IPy 2 BF 4 ) [21][22][23][24][25], Haloenol lactones of type A and B (see Figure 2) are also a relevant class of compounds due to their biological activity as enzymes inhibitors [34][35][36][37][38], and also because they are a common structural motif in many natural products [39]. Access to these molecules is usually achieved by halolactonization of the corresponding alkynoic acid using I2, NBS, NIS or related halogenating agents, reactions that deliver the haloenol lactone products as the E isomers exclusively (Scheme 2) [34][35][36][37][38]40,41]. We would like also to highlight here that asymmetric versions of these halolactonization processes have been recently described employing cinchona alkaloid-based organocatalysts [42][43][44]. A couple of illustrative examples are given in Scheme 3. Mechanistic investigations indicated a bifunctional behavior of the organocatalysts, activating simultaneously the halogenating agent and the carboxylic acid unit.  Access to these molecules is usually achieved by halolactonization of the corresponding alkynoic acid using I 2 , NBS, NIS or related halogenating agents, reactions that deliver the haloenol lactone products as the E isomers exclusively (Scheme 2) [34][35][36][37][38]40,41]. We would like also to highlight here that asymmetric versions of these halolactonization processes have been recently described employing cinchona alkaloid-based organocatalysts [42][43][44]. A couple of illustrative examples are given in Scheme 3. Mechanistic investigations indicated a bifunctional behavior of the organocatalysts, activating simultaneously the halogenating agent and the carboxylic acid unit. Haloenol lactones of type A and B (see Figure 2) are also a relevant class of compounds due to their biological activity as enzymes inhibitors [34][35][36][37][38], and also because they are a common structural motif in many natural products [39]. Access to these molecules is usually achieved by halolactonization of the corresponding alkynoic acid using I2, NBS, NIS or related halogenating agents, reactions that deliver the haloenol lactone products as the E isomers exclusively (Scheme 2) [34][35][36][37][38]40,41]. We would like also to highlight here that asymmetric versions of these halolactonization processes have been recently described employing cinchona alkaloid-based organocatalysts [42][43][44]. A couple of illustrative examples are given in Scheme 3. Mechanistic investigations indicated a bifunctional behavior of the organocatalysts, activating simultaneously the halogenating agent and the carboxylic acid unit. Synthetic approaches to both acyclic and cyclic β-haloenol esters have been expanded in the most recent years by the aid of metal catalysts, employing in most of the cases in situ generated or preformed haloalkynes [45][46][47] as starting materials, and are the subject of the present review article. Thus, the catalytic synthesis of β-haloenol esters will be discussed, as well as the participation of these molecules in metal-catalyzed cross-coupling processes.

Hg-Catalyzed Synthesis of β-Haloenol Esters
Extending previous studies with non-halogenated molecules [49], Krafft and Katzenellenbogen described in 1981 a synthetic route to haloenol lactones through the mercury-catalyzed cyclization of halogen-substituted alkynoic acids [50]. In particular, they were able to generate compounds 8 and 9 in moderate yield (40%-69%) by treatment of dichloromethane solutions of 5-chloro-4-pentynoic acid (6) and 5-bromo-4-pentynoic acid (7), respectively, with 10 mol % of Hg(OAc)2 or Hg(OCOCF3)2 (Scheme 5). The reactions proceed through the anti addition of the carboxylate group to the C≡C bond activated by π-coordination to mercury and, contrary to the halolactonization methods commented above (see Scheme 2), they delivered the haloenol lactone products as the Z isomers exclusively. In an independent study, Krantz and co-workers extended this cyclization reaction to 5-iodo-4-pentynoic acid (10). However, the use of an excess of mercury(II) trifluoroacetate was in this case needed, and the (Z)-iodoenol lactone 11 could only be obtained in low yield (Scheme 6) [51]. In an independent study, Krantz and co-workers extended this cyclization reaction to 5-iodo-4-pentynoic acid (10). However, the use of an excess of mercury(II) trifluoroacetate was in this case needed, and the (Z)-iodoenol lactone 11 could only be obtained in low yield (Scheme 6) [51]. Barluenga and co-workers achieved also the stereoselective synthesis of the acyclic (Z)-β-iodoenol acetates 12 through a difunctionalization reaction of the corresponding internal alkynes by means of the Hg(OAc)2/I2 combination (Scheme 7) [52]. The formation of a cationic intermediate of type C, which undergoes the attack of the acetate anion, was proposed by the authors as the most likely reaction pathway. Barluenga and co-workers achieved also the stereoselective synthesis of the acyclic (Z)-β-iodoenol acetates 12 through a difunctionalization reaction of the corresponding internal alkynes by means of the Hg(OAc) 2 /I 2 combination (Scheme 7) [52]. The formation of a cationic intermediate of type C, which undergoes the attack of the acetate anion, was proposed by the authors as the most likely reaction pathway. Scheme 6. Mercury-mediated cyclization of 5-iodo-4-pentynoic acid.
Barluenga and co-workers achieved also the stereoselective synthesis of the acyclic (Z)-β-iodoenol acetates 12 through a difunctionalization reaction of the corresponding internal alkynes by means of the Hg(OAc)2/I2 combination (Scheme 7) [52]. The formation of a cationic intermediate of type C, which undergoes the attack of the acetate anion, was proposed by the authors as the most likely reaction pathway. Scheme 7. Synthesis of acyclic (E)-β-iodoenol acetates by bifunctionalization of internal alkynes.

Ag-Catalyzed Synthesis of β-Haloenol Esters
In 1991, the group of Katzenellenbogen described a two-steps protocol for the selective Z-bromoenol lactonization of akynoic acids employing stoichiometric amounts of AgNO3 and Br2 (Scheme 8) [53]. The process involves the initial silver-mediated cyclization of the substrates to generate the metallated lactones D, which subsequently undergo an Ag/Br exchange upon treatment with Br2. Both 5-and 6-membered ring lactones could be synthesized employing this methodology, whose efficiency was found to be conditioned by the substitution pattern of the starting alkynoic acids. In particular, the presence of substituents in α and β position with respect to the carboxylate group (R 1 and R 2 ) was key to obtain the products in high yields, those substrates unsubstituted in these positions leading to very poor results (2%-5% yield). Additionally, of note is the fact that the lactonization process resulted ineffective with akynoic acids featuring an internal C≡C bond or when I2 was employed as the electrophile.

Ag-Catalyzed Synthesis of β-Haloenol Esters
In 1991, the group of Katzenellenbogen described a two-steps protocol for the selective Z-bromoenol lactonization of akynoic acids employing stoichiometric amounts of AgNO 3 and Br 2 (Scheme 8) [53]. The process involves the initial silver-mediated cyclization of the substrates to generate the metallated lactones D, which subsequently undergo an Ag/Br exchange upon treatment with Br 2 . Both 5-and 6-membered ring lactones could be synthesized employing this methodology, whose efficiency was found to be conditioned by the substitution pattern of the starting alkynoic acids. In particular, the presence of substituents in α and β position with respect to the carboxylate group (R 1 and R 2 ) was key to obtain the products in high yields, those substrates unsubstituted in these positions leading to very poor results (2-5% yield). Additionally, of note is the fact that the lactonization process resulted ineffective with akynoic acids featuring an internal C≡C bond or when I 2 was employed as the electrophile. The first general and truly catalytic protocol to obtain acyclic β-haloenol esters came to light only in 2010 and it was developed by Jiang´s group [54]. As shown in Scheme 9, they were able to synthesize a large variety of (Z)-haloenol acetates 13 through an AgBF4-catalyzed difunctionalization reaction of terminal alkynes with N-halosuccinimides (NXS) and acetic anhydride. In the reactions, which were performed at 120 °C with 5 mol % of AgBF4 and employing directly Ac2O as the solvent, the silver(I) cation plays a dual role. Thus, it first acts a σ-activator allowing the in situ generation of the corresponding haloalkynes RC≡CX, and subsequently as a π-activator facilitating the nucleophilic attack of the acetate anion to the C≡C bond. The process featured an exquisite regioand stereoselectivity, and tolerated the presence of common functional groups in the alkyne Scheme 8. Silver-mediated Z-bromoenol lactonization of alkynoic acids.
The first general and truly catalytic protocol to obtain acyclic β-haloenol esters came to light only in 2010 and it was developed by Jiang's group [54]. As shown in Scheme 9, they were able to synthesize a large variety of (Z)-haloenol acetates 13 through an AgBF 4 -catalyzed difunctionalization reaction of terminal alkynes with N-halosuccinimides (NXS) and acetic anhydride. In the reactions, which were performed at 120 • C with 5 mol % of AgBF 4 and employing directly Ac 2 O as the solvent, the silver(I) cation plays a dual role. Thus, it first acts a σ-activator allowing the in situ generation of the corresponding haloalkynes RC≡CX, and subsequently as a π-activator facilitating the nucleophilic attack of the acetate anion to the C≡C bond. The process featured an exquisite regio-and stereoselectivity, and tolerated the presence of common functional groups in the alkyne substrates. Scheme 8. Silver-mediated Z-bromoenol lactonization of alkynoic acids.
The first general and truly catalytic protocol to obtain acyclic β-haloenol esters came to light only in 2010 and it was developed by Jiang´s group [54]. As shown in Scheme 9, they were able to synthesize a large variety of (Z)-haloenol acetates 13 through an AgBF4-catalyzed difunctionalization reaction of terminal alkynes with N-halosuccinimides (NXS) and acetic anhydride. In the reactions, which were performed at 120 °C with 5 mol % of AgBF4 and employing directly Ac2O as the solvent, the silver(I) cation plays a dual role. Thus, it first acts a σ-activator allowing the in situ generation of the corresponding haloalkynes RC≡CX, and subsequently as a π-activator facilitating the nucleophilic attack of the acetate anion to the C≡C bond. The process featured an exquisite regioand stereoselectivity, and tolerated the presence of common functional groups in the alkyne substrates. Scheme 9. Silver-catalyzed synthesis of (Z)-β-haloenol acetates from terminal alkynes.

Au-Catalyzed Synthesis of β-Haloenol Esters
In 2006, and almost simultaneously, the groups of Michelet and Pale demonstrated that both terminal and internal alkynoic acids could be efficiently cyclized under mild conditions employing AuCl as a catalyst [55,56]. 5-Bromo-4-pentynoic acid (7) and 6-bromo-5-hexynoic acid (14) made part of the substrates studied by Pale and, from them, the Z-bromoenol lactones 9 and 15, respectively, could be synthesized in excellent yield (Scheme 10) [56,57]. The cycloisomerization reactions, which were performed at room temperature with 10 mol % of AuCl in combination with K 2 CO 3 (10 mol %), involve the intramolecular exo-dig anti-addition of the carboxylate anion generated by deprotonation with the K 2 CO 3 base to the C≡C bond, which is activated by π-coordination to the Au + cation. Final protonolysis of the gold-carbon bond in the metallated intermediate E liberates the enol-lactone products.
More recently, Nolan and coworkers reported the regio-and stereoselective cyclization of 6-bromo-5-hexynoic acid (14) and 7-bromo-6-heptynoic acid (16) into lactones 15 and 17 employing catalytic amounts of the hydroxo-bridged dinuclear gold( [58]. The addition of an external base was in this case not needed, the bridging OH ligand facilitating the generation of the carboxylate anion. It is also worthy of note that, while the conversion of 14 into 15 proceeded rapidly at r.t. with only 0.1 mol % of 18, the generation of the ε-alkylidene-lactone 17 from 16 resulted in being more demanding and an increase of the Au loading, temperature and reaction time was required. could be synthesized in excellent yield (Scheme 10) [56,57]. The cycloisomerization reactions, which were performed at room temperature with 10 mol % of AuCl in combination with K2CO3 (10 mol %), involve the intramolecular exo-dig anti-addition of the carboxylate anion generated by deprotonation with the K2CO3 base to the C≡C bond, which is activated by π-coordination to the Au + cation. Final protonolysis of the gold-carbon bond in the metallated intermediate E liberates the enol-lactone products.

Scheme 10. AuCl-catalyzed cycloisomerization of bromo-substituted alkynoic acids.
More recently, Nolan and coworkers reported the regio-and stereoselective cyclization of 6-bromo-5-hexynoic acid (14) and 7-bromo-6-heptynoic acid (16) into lactones 15 and 17 employing catalytic amounts of the hydroxo-bridged dinuclear gold( [58]. The addition of an external base was in this case not needed, the bridging OH ligand facilitating the generation of the carboxylate anion. It is also worthy of note that, while the conversion of 14 into 15 proceeded rapidly at r.t. with only 0.1 mol % of 18, the generation of the ε-alkylidene-lactone 17 from 16 resulted in being more demanding and an increase of the Au loading, temperature and reaction time was required. Making use of a catalytic system composed of the gold(I) complex [AuCl(PPh3)] and the chloride abstractor AgPF6, a broad scope procedure for the preparation of acyclic (Z)-β-iodoenol esters was also recently developed by Cadierno and co-workers (Scheme 12) [59][60][61]. The process, which proceeds under mild conditions and tolerates the presence of several functional groups in the substrates, involves the intermolecular addition of carboxylic acids to iodoalkynes, the latter being activated towards the carboxylate anion attack by π-coordination to the in situ generated gold(I) cation [Au(PPh3)] + . As expected, the carboxylate anion adds selectively to the more electrophilic C-2 carbon of the iodoalkyne [45][46][47] and, as usually observed in the chemistry of π-alkyne-gold complexes [62], the addition takes places in an anti fashion, thus affording the olefinic products 19 in a complete regio-and stereoselective manner. With a couple of representative examples, i.e., the addition of acetic acid to 1-(chloroethynyl)-4-methylbenzene and 1-bromooct-1-yne, the authors also demonstrated the applicability of this procedure for the synthesis of related (Z)-β-chloroenol and Making use of a catalytic system composed of the gold(I) complex [AuCl(PPh 3 )] and the chloride abstractor AgPF 6 , a broad scope procedure for the preparation of acyclic (Z)-β-iodoenol esters was also recently developed by Cadierno and co-workers (Scheme 12) [59][60][61]. The process, which proceeds under mild conditions and tolerates the presence of several functional groups in the substrates, involves the intermolecular addition of carboxylic acids to iodoalkynes, the latter being activated towards the carboxylate anion attack by π-coordination to the in situ generated gold(I) cation [Au(PPh 3 )] + . As expected, the carboxylate anion adds selectively to the more electrophilic C-2 carbon of the iodoalkyne [45][46][47] and, as usually observed in the chemistry of π-alkyne-gold complexes [62], the addition takes places in an anti fashion, thus affording the olefinic products 19 in a complete regioand stereoselective manner. With a couple of representative examples, i.e., the addition of acetic acid to 1-(chloroethynyl)-4-methylbenzene and 1-bromooct-1-yne, the authors also demonstrated the applicability of this procedure for the synthesis of related (Z)-β-chloroenol and (Z)-β-bromoenol esters [60].
Making use of a catalytic system composed of the gold(I) complex [AuCl(PPh3)] and the chloride abstractor AgPF6, a broad scope procedure for the preparation of acyclic (Z)-β-iodoenol esters was also recently developed by Cadierno and co-workers (Scheme 12) [59][60][61]. The process, which proceeds under mild conditions and tolerates the presence of several functional groups in the substrates, involves the intermolecular addition of carboxylic acids to iodoalkynes, the latter being activated towards the carboxylate anion attack by π-coordination to the in situ generated gold(I) cation [Au(PPh3)] + . As expected, the carboxylate anion adds selectively to the more electrophilic C-2 carbon of the iodoalkyne [45][46][47] and, as usually observed in the chemistry of π-alkyne-gold complexes [62], the addition takes places in an anti fashion, thus affording the olefinic products 19 in a complete regio-and stereoselective manner. With a couple of representative examples, i.e., the addition of acetic acid to 1-(chloroethynyl)-4-methylbenzene and 1-bromooct-1-yne, the authors also demonstrated the applicability of this procedure for the synthesis of related (Z)-β-chloroenol and (Z)-β-bromoenol esters [60]. Scheme 12. Gold-catalyzed intermolecular addition of carboxylic acids to iodoalkynes. Scheme 12. Gold-catalyzed intermolecular addition of carboxylic acids to iodoalkynes.
Following the same gold-catalyzed protocol, Muthusamy and Pansare synthesized later a large family of (Z)-β-iodoenol cinnamates 20 starting from the corresponding aromatic or aliphatic iodoalkyne and cinnamic acid ( Figure 3) [63].   [64,65]. The allyl cation H thus generated evolves into the final products 22 by deprotonation and protodeauration. It is important to note that the use of rigorously anhydrous conditions is mandatory for the rearrangement process to proceed selectively since, in the presence of water, hydrolysis of intermediate G readily takes place leading to the corresponding α-halomethyl ketones 23 [64,66,67]. In line with this, we would like to mention that efficient protocols for the hydration of haloalkynes RC≡CX into α-halomethyl ketones RC(=O)CH2X employing catalytic systems composed of AgF/CF3CO2H [68], In(OTf)3/CH3CO2H [69] and Cu(OAc)2•H2O/CF3CO2H [70] have been described, in which hydrolysis of a β-haloenol acetate or trifluoroacetate intermediate (RC(O2CR´)=CHX; R´ = CH3 or CF3) has been proposed as the most likely reaction pathway.  [64,65]. The allyl cation H thus generated evolves into the final products 22 by deprotonation and protodeauration. It is important to note that the use of rigorously anhydrous conditions is mandatory for the rearrangement process to proceed selectively since, in the presence of water, hydrolysis of intermediate G readily takes place leading to the corresponding α-halomethyl ketones 23 [64,66,67]. In line with this, we would like to mention that efficient protocols for the hydration of haloalkynes RC≡CX into α-halomethyl ketones RC(=O)CH 2 X employing catalytic systems composed of AgF/CF 3  to proceed selectively since, in the presence of water, hydrolysis of intermediate G readily takes place leading to the corresponding α-halomethyl ketones 23 [64,66,67]. In line with this, we would like to mention that efficient protocols for the hydration of haloalkynes RC≡CX into α-halomethyl ketones RC(=O)CH2X employing catalytic systems composed of AgF/CF3CO2H [68], In(OTf)3/CH3CO2H [69] and Cu(OAc)2•H2O/CF3CO2H [70] have been described, in which hydrolysis of a β-haloenol acetate or trifluoroacetate intermediate (RC(O2CR´)=CHX; R´ = CH3 or CF3) has been proposed as the most likely reaction pathway.

Pd-Catalyzed Synthesis of β-Haloenol Esters
In 2011, an efficient approach to (Z)-β-haloenol acetates 24 was developed by Zhu and coworkers by coupling haloalkynes with allyl acetate, employing a catalytic system composed of Pd(OAc) 2 and the bidentate ligand 4,4'-dimethoxy-2,2'-bipyridine (Scheme 14) [71]. The regio-and stereoselectivity of the process was exquisite, the formation of byproducts being in no case observed. A reaction pathway involving the initial acetoxypalladation of the alkyne, followed by insertion of the allyl acetate molecule into the Pd-C bond of the resulting alkenyl-palladium intermediate I, was proposed by the authors. A final β-elimination step in the alkyl-palladium species J furnished the (Z)-β-haloenol acetate products 24. Both chloro-and bromoalkynes participated in the reaction, but the process resulted inoperative with iodoalkynes due to their decomposition under the reaction conditions employed. Negative results were also obtained when substituted allyl acetates, such as 1-phenylallyl acetate, 2-methylallyl acetate or cinnamyl acetate, were used as the olefinic coupling partners.
On the other hand, in the context of their studies on the cycloisomerization of alkynoic acids with indenediide-based palladium pincer catalysts, the group of Martin-Vaca and Bourissou also reported the efficient and selective conversion of 6-bromo-5-hexynoic acid (14) into the corresponding lactone 15 (see Scheme 11) employing complexes 25 and 26 (5 mol % of Pd at 90 • C; see Figure 4) [72,73]. Analogously to the case of hydroxo-gold complex [{Au(IPr)} 2 (µ-OH)][BF 4 ] (18), a reaction mechanism involving the intramolecular exo-dig anti-addition of the carboxylate anion on the π-activated C≡C bond of substrate was proposed, with the electron-rich indenediide ligand being in this case responsible for the deprotonation of the carboxylic acid unit. the allyl acetate molecule into the Pd-C bond of the resulting alkenyl-palladium intermediate I, was proposed by the authors. A final β-elimination step in the alkyl-palladium species J furnished the (Z)-β-haloenol acetate products 24. Both chloro-and bromoalkynes participated in the reaction, but the process resulted inoperative with iodoalkynes due to their decomposition under the reaction conditions employed. Negative results were also obtained when substituted allyl acetates, such as 1-phenylallyl acetate, 2-methylallyl acetate or cinnamyl acetate, were used as the olefinic coupling partners.

Metal-Catalyzed Transformations of β-Haloenol Esters
As commented in the introduction of this article, haloalkenes are widely employed in synthetic organic chemistry for the construction of polysubstituted olefins through transition-metal catalyzed cross-coupling reactions [1,2]. In this section, the participation of β-haloenol esters in metal-catalyzed transformations is discussed.

Acyclic β-Haloenol Esters
In the context of their studies on the palladium-catalyzed coupling of haloalkenes with organoboron compounds, Suzuki and Miyaura reported in 1992 the first cross-coupling reactions involving a β-haloenol ester [74]. Thus, as shown in Scheme 15, the treatment of the bromoenol acetate 27 with different alkyl-, aryl-and alkenyl-boron reagents in the presence of catalytic amounts of [Pd(PPh 3 ) 4 ] and a base cleanly afforded the corresponding trisubstituted olefins, which were isolated in high yields (73-89%) and with complete retention of the stereochemistry of the starting C=C bond. organoboron compounds, Suzuki and Miyaura reported in 1992 the first cross-coupling reactions involving a β-haloenol ester [74]. Thus, as shown in Scheme 15, the treatment of the bromoenol acetate 27 with different alkyl-, aryl-and alkenyl-boron reagents in the presence of catalytic amounts of [Pd(PPh3)4] and a base cleanly afforded the corresponding trisubstituted olefins, which were isolated in high yields (73%-89%) and with complete retention of the stereochemistry of the starting C=C bond. In a wider scope study, Cadierno, Pizzano and coworkers employed the (Z)-β-iodoenol acetates 30 as starting materials for the synthesis of several (Z)-1-substituted-2-arylvinyl acetates 31, via [Pd(PPh3)4]-catalyzed coupling of 30 with aromatic boronic acids (Scheme 17) [59,61]. Remarkably, the asymmetric hydrogenation of compounds 31 to afford the corresponding chiral homobenzylic esters 32, of interest as precursors of synthetically useful chiral alcohols by deacylation, could be successfully accomplished by the same authors employing rhodium(I) catalysts containing optically pure bidentate phosphine-phosphite ligands (ee up to 98%) [59,61]. In a wider scope study, Cadierno, Pizzano and coworkers employed the (Z)-β-iodoenol acetates 30 as starting materials for the synthesis of several (Z)-1-substituted-2-arylvinyl acetates 31, via [Pd(PPh3)4]-catalyzed coupling of 30 with aromatic boronic acids (Scheme 17) [59,61]. Remarkably, the asymmetric hydrogenation of compounds 31 to afford the corresponding chiral homobenzylic esters 32, of interest as precursors of synthetically useful chiral alcohols by deacylation, could be successfully accomplished by the same authors employing rhodium(I) catalysts containing optically pure bidentate phosphine-phosphite ligands (ee up to 98%) [59,61].
In addition, the tetrasubstituted olefins 37-40 (see Figure 5) were also synthesized in high yields (72%-99%) by Suzuki-Miyaura coupling of the corresponding β-haloenol acetates with boronic acids (the C-C bond formed is highlighted in bold) [28,31,71]. Probably, the reactions of β-haloenol esters most widely studied to date are the palladium-catalyzed Sonogashira-type couplings with terminal alkynes [30,54,60,71,[76][77][78]. In this regard, a large number of (Z)-and (E)-β-haloenol esters (both chlorides, bromides and iodides) have been successfully coupled with alipahic and aromatic alkynes, 1,3-enynes or propargylic alcohols to generate the corresponding enynyl ester products in high yields and with complete preservation of the C=C bond stereochemistry of the starting olefins (the results obtained in references [60], [76] and [77] are depicted in Scheme 19). Probably, the reactions of β-haloenol esters most widely studied to date are the palladium-catalyzed Sonogashira-type couplings with terminal alkynes [30,54,60,71,[76][77][78]. In this regard, a large number of (Z)-and (E)-β-haloenol esters (both chlorides, bromides and iodides) have been successfully coupled with alipahic and aromatic alkynes, 1,3-enynes or propargylic alcohols to generate the corresponding enynyl ester products in high yields and with complete preservation of the C=C bond stereochemistry of the starting olefins (the results obtained in references [60,76,77] are depicted in Scheme 19). The main interest in these Sonogashira-type reactions is that the enynyl ester products can be employed as starting materials for the generation of polysubstituted furans via metal-catalyzed [76,77] or halogen-induced electrophilic cyclization reactions [30,[79][80][81]. Illustrative examples are shown in Scheme 20.  The main interest in these Sonogashira-type reactions is that the enynyl ester products can be employed as starting materials for the generation of polysubstituted furans via metal-catalyzed [76,77] or halogen-induced electrophilic cyclization reactions [30,[79][80][81]. Illustrative examples are shown in Scheme 20. Contrary to the case of the Suzuki-Miyaura and Sonogashira reactions, the participation of β-haloenol esters in Negishi-and Kumada-Corriu-type cross-coupling processes remains almost unexplored. In fact, only the examples depicted in Scheme 21 can be currently found in the literature [61,64]. Scheme 20. Some furan-ring formation reactions employing enynyl acetates as precursors.
Contrary to the case of the Suzuki-Miyaura and Sonogashira reactions, the participation of β-haloenol esters in Negishi-and Kumada-Corriu-type cross-coupling processes remains almost unexplored. In fact, only the examples depicted in Scheme 21 can be currently found in the literature [61,64].
On the other hand, homocoupling reactions of alkenyl halides have been extensively studied during the last decades since they provide a straightforward access to conjugated 1,3-dienes and polyenes [82]. In this context, taking advantage of previous works by Takagi and coworkers with non-functionalized alkenyl halides [83][84][85], an efficient and broad scope protocol for the homocoupling of (Z)-β-iodoenol esters 41 was developed by Francos and Cadierno (Scheme 22) [86]. The process, which is catalyzed by nickel(0) species generated in situ by combining [NiCl 2 (PPh 3 ) 2 ] with NaI and Zn dust, afforded the buta-1,3-diene-1,4-diyl diester products 42 as the corresponding ZZ-isomers exclusively. It is also worth noting that 1,3-dienes 42 proved to be useful precursors for the preparation of synthetically relevant C 2 symmetric 1,4-diols 43, through a rhodium-catalyzed asymmetric hydrogenation of the two C=C bonds of 42 and a subsequent base-promoted deacylation reaction [87]. Scheme 20. Some furan-ring formation reactions employing enynyl acetates as precursors.
Contrary to the case of the Suzuki-Miyaura and Sonogashira reactions, the participation of β-haloenol esters in Negishi-and Kumada-Corriu-type cross-coupling processes remains almost unexplored. In fact, only the examples depicted in Scheme 21 can be currently found in the literature [61,64]. On the other hand, homocoupling reactions of alkenyl halides have been extensively studied during the last decades since they provide a straightforward access to conjugated 1,3-dienes and polyenes [82]. In this context, taking advantage of previous works by Takagi and coworkers with non-functionalized alkenyl halides [83][84][85], an efficient and broad scope protocol for the homocoupling of (Z)-β-iodoenol esters 41 was developed by Francos and Cadierno (Scheme 22) [86]. The process, which is catalyzed by nickel(0) species generated in situ by combining [NiCl2(PPh3)2] with NaI and Zn dust, afforded the buta-1,3-diene-1,4-diyl diester products 42 as the corresponding ZZ-isomers exclusively. It is also worth noting that 1,3-dienes 42 proved to be useful precursors for the preparation of synthetically relevant C2 symmetric 1,4-diols 43, through a rhodium-catalyzed asymmetric hydrogenation of the two C=C bonds of 42 and a subsequent base-promoted deacylation reaction [87].
A broad scope protocol for the synthesis of 3-substituted isocoumarins 46 by coupling of bromoalkynes with benzoic acids, catalyzed by palladium(II) trifluoroacetate in combination with the diphosphine ligand DPEPhos (bis [2-(diphenylphosphino)phenyl] ether) and K2CO3, was described by Wu, Jiang and co-workers (Scheme 24) [88]. A reaction pathway involving the initial anti addition of the acid to the alkyne, and subsequent oxidative annulation of the resulting β-bromoenol benzoates 45, was proposed by the authors. Acyclic β-haloenol esters have also been employed as starting materials for the generation of heterocyclic systems. In this context, the intramolecular palladium-catalyzed Mizoroki-Heck coupling of the (Z)-β-iodoenol cinnamates 20 allowed the preparation of furanones 44 in moderate to high yields (Scheme 23) [63]. On the other hand, homocoupling reactions of alkenyl halides have been extensively studied during the last decades since they provide a straightforward access to conjugated 1,3-dienes and polyenes [82]. In this context, taking advantage of previous works by Takagi and coworkers with non-functionalized alkenyl halides [83][84][85], an efficient and broad scope protocol for the homocoupling of (Z)-β-iodoenol esters 41 was developed by Francos and Cadierno (Scheme 22) [86]. The process, which is catalyzed by nickel(0) species generated in situ by combining [NiCl2(PPh3)2] with NaI and Zn dust, afforded the buta-1,3-diene-1,4-diyl diester products 42 as the corresponding ZZ-isomers exclusively. It is also worth noting that 1,3-dienes 42 proved to be useful precursors for the preparation of synthetically relevant C2 symmetric 1,4-diols 43, through a rhodium-catalyzed asymmetric hydrogenation of the two C=C bonds of 42 and a subsequent base-promoted deacylation reaction [87].
A broad scope protocol for the synthesis of 3-substituted isocoumarins 46 by coupling of bromoalkynes with benzoic acids, catalyzed by palladium(II) trifluoroacetate in combination with the diphosphine ligand DPEPhos (bis [2-(diphenylphosphino)phenyl] ether) and K2CO3, was described by Wu, Jiang and co-workers (Scheme 24) [88]. A reaction pathway involving the initial anti addition of the acid to the alkyne, and subsequent oxidative annulation of the resulting β-bromoenol benzoates 45, was proposed by the authors. A broad scope protocol for the synthesis of 3-substituted isocoumarins 46 by coupling of bromoalkynes with benzoic acids, catalyzed by palladium(II) trifluoroacetate in combination with the diphosphine ligand DPEPhos (bis [2-(diphenylphosphino)phenyl] ether) and K 2 CO 3 , was described by Wu, Jiang and co-workers (Scheme 24) [88]. A reaction pathway involving the initial anti addition of the acid to the alkyne, and subsequent oxidative annulation of the resulting β-bromoenol benzoates 45, was proposed by the authors. (Z)-β-Halenol acetates proved to be also useful starting materials for the preparation of symmetrical 2,5-disubstituted pyrazines 47 (Scheme 25) [89]. Although the formation of compounds 47 was initially observed in the reactions of the haloenol acetates with an ammonia solution under palladium/copper-catalyzed conditions, a more detailed investigation showed that no metal sources are really needed for the reaction to proceed, and that any source of ammonia can be employed. In this regard, employing ammonium formate, and performing the reaction in DMF at 120 °C, a wide range of 2,5-disubstituted pyrazines could be accessed in moderate to excellent yields starting from both aromatic and aliphatic (Z)-β-iodoenol or (Z)-β-bromoenol acetates (Scheme 25). The regioselectivity of the process was excellent, the formation of the corresponding 2,6-disubtituted regioisomers being not observed under these optimized conditions. According to the authors, α-halomethyl ketones could be involved as intermediates. Scheme 25. Synthesis of 2,5-disubstituted pyrazines from (Z)-β-haloenol acetates.

Cyclic β-Haloenol Esters
Although to a much lesser extent, the participation of haloenol lactones in metal-catalyzed cross-coupling reactions has also been described. In this regard, several 5-and 6-membered ring ynenol lactones, including some optically pure representatives, could be accessed from the corresponding iodoenol lactones via classical Pd-catalyzed Sonogashira coupling reactions ( Figure  6) [41,44,90,91]. Interestingly, these compounds featured biological activity as enzymes inhibitors [44,90,91]. (Z)-β-Halenol acetates proved to be also useful starting materials for the preparation of symmetrical 2,5-disubstituted pyrazines 47 (Scheme 25) [89]. Although the formation of compounds 47 was initially observed in the reactions of the haloenol acetates with an ammonia solution under palladium/copper-catalyzed conditions, a more detailed investigation showed that no metal sources are really needed for the reaction to proceed, and that any source of ammonia can be employed. In this regard, employing ammonium formate, and performing the reaction in DMF at 120 • C, a wide range of 2,5-disubstituted pyrazines could be accessed in moderate to excellent yields starting from both aromatic and aliphatic (Z)-β-iodoenol or (Z)-β-bromoenol acetates (Scheme 25). The regioselectivity of the process was excellent, the formation of the corresponding 2,6-disubtituted regioisomers being not observed under these optimized conditions. According to the authors, α-halomethyl ketones could be involved as intermediates. (Z)-β-Halenol acetates proved to be also useful starting materials for the preparation of symmetrical 2,5-disubstituted pyrazines 47 (Scheme 25) [89]. Although the formation of compounds 47 was initially observed in the reactions of the haloenol acetates with an ammonia solution under palladium/copper-catalyzed conditions, a more detailed investigation showed that no metal sources are really needed for the reaction to proceed, and that any source of ammonia can be employed. In this regard, employing ammonium formate, and performing the reaction in DMF at 120 °C, a wide range of 2,5-disubstituted pyrazines could be accessed in moderate to excellent yields starting from both aromatic and aliphatic (Z)-β-iodoenol or (Z)-β-bromoenol acetates (Scheme 25). The regioselectivity of the process was excellent, the formation of the corresponding 2,6-disubtituted regioisomers being not observed under these optimized conditions. According to the authors, α-halomethyl ketones could be involved as intermediates. Scheme 25. Synthesis of 2,5-disubstituted pyrazines from (Z)-β-haloenol acetates.

Cyclic β-Haloenol Esters
Although to a much lesser extent, the participation of haloenol lactones in metal-catalyzed cross-coupling reactions has also been described. In this regard, several 5-and 6-membered ring ynenol lactones, including some optically pure representatives, could be accessed from the corresponding iodoenol lactones via classical Pd-catalyzed Sonogashira coupling reactions ( Figure 6) [41,44,90,91]. Interestingly, these compounds featured biological activity as enzymes inhibitors [44,90,91]. Catalysts 2020, 10, x FOR PEER REVIEW 18 of 23 Additionally, Hennecke and coworkers reported the synthesis of the arylenol lactones 49 by Negishi coupling of the iodoenol derivative 48 with the corresponding arylzinc chloride catalyzed by [PdCl2(dppf)] (dppf = 1,1´-bis(diphenylphosphino)ferrocene) (Scheme 26) [44]. The use of [PdCl2(dppf)] as catalyst proved to be crucial, since other palladium sources, i.e., PEPPSI-type catalysts or the [Pd2(dba)3]/trisfurylphosphine combination, led to the extensive dehalogenation of 48. Additionally, of note is the fact that attempts to generate compounds 49 through Pd-catalyzed Suzuki-Miyaura coupling of 48 with aryl boronic acids failed, due to the incompatibility of the iodoenol moiety with the basic conditions required in this particular cross-coupling process [44].

Conclusions
In this contribution we summarized the catalytic protocols currently known for the preparation of β-haloenol esters and haloenol lactones, a particular class of haloalkenes, which are gaining significance as coupling partners in diverse chemical transformations of synthetic interest. Metal-catalyzed reactions in which these functionalized olefins participate as substrates, mainly palladium-catalyzed C-C cross-coupling processes, were also discussed. Most of the works herein presented have been published during the last decade, demonstrating the current interest on the use of these molecules as building blocks in organic synthesis. Although there is already a body of work Additionally, Hennecke and coworkers reported the synthesis of the arylenol lactones 49 by Negishi coupling of the iodoenol derivative 48 with the corresponding arylzinc chloride catalyzed by [PdCl 2 (dppf)] (dppf = 1,1'-bis(diphenylphosphino)ferrocene) (Scheme 26) [44]. The use of [PdCl 2 (dppf)] as catalyst proved to be crucial, since other palladium sources, i.e., PEPPSI-type catalysts or the [Pd 2 (dba) 3 ]/trisfurylphosphine combination, led to the extensive dehalogenation of 48. Additionally, of note is the fact that attempts to generate compounds 49 through Pd-catalyzed Suzuki-Miyaura coupling of 48 with aryl boronic acids failed, due to the incompatibility of the iodoenol moiety with the basic conditions required in this particular cross-coupling process [44]. Additionally, Hennecke and coworkers reported the synthesis of the arylenol lactones 49 by Negishi coupling of the iodoenol derivative 48 with the corresponding arylzinc chloride catalyzed by [PdCl2(dppf)] (dppf = 1,1´-bis(diphenylphosphino)ferrocene) (Scheme 26) [44]. The use of [PdCl2(dppf)] as catalyst proved to be crucial, since other palladium sources, i.e., PEPPSI-type catalysts or the [Pd2(dba)3]/trisfurylphosphine combination, led to the extensive dehalogenation of 48. Additionally, of note is the fact that attempts to generate compounds 49 through Pd-catalyzed Suzuki-Miyaura coupling of 48 with aryl boronic acids failed, due to the incompatibility of the iodoenol moiety with the basic conditions required in this particular cross-coupling process [44].

Conclusions
In this contribution we summarized the catalytic protocols currently known for the preparation of β-haloenol esters and haloenol lactones, a particular class of haloalkenes, which are gaining significance as coupling partners in diverse chemical transformations of synthetic interest. Metal-catalyzed reactions in which these functionalized olefins participate as substrates, mainly palladium-catalyzed C-C cross-coupling processes, were also discussed. Most of the works herein presented have been published during the last decade, demonstrating the current interest on the use of these molecules as building blocks in organic synthesis. Although there is already a body of work Scheme 26. Access to arylenol lactones by Negishi coupling.

Conclusions
In this contribution we summarized the catalytic protocols currently known for the preparation of β-haloenol esters and haloenol lactones, a particular class of haloalkenes, which are gaining significance as coupling partners in diverse chemical transformations of synthetic interest. Metal-catalyzed reactions in which these functionalized olefins participate as substrates, mainly palladium-catalyzed C-C cross-coupling processes, were also discussed. Most of the works herein presented have been published during the last decade, demonstrating the current interest on the use of these molecules as building blocks in organic synthesis. Although there is already a body of work in the field, it still remains open and new synthetic approaches to these compounds and applications can be expected in the near future.