Recent Advances in the Synthesis of Propargyl Derivatives, and Their Application as Synthetic Intermediates and Building Blocks

The propargyl group is a highly versatile moiety whose introduction into small-molecule building blocks opens up new synthetic pathways for further elaboration. The last decade has witnessed remarkable progress in both the synthesis of propargylation agents and their application in the synthesis and functionalization of more elaborate/complex building blocks and intermediates. The goal of this review is to highlight these exciting advances and to underscore their impact.


Introduction
The present review covers relevant literature published from 2010 to present. According to the consulted reports, whereas in the majority of cases the target compounds result from direct introduction of the propargyl moiety, in many examples, the propargylation reaction serves as a strategic step in a reaction sequence that results in the formation of more elaborate/complex structures. In such cases, this review emphasizes the propargylation methodologies rather than the subsequent steps en route to more complex synthetic targets. It is noteworthy that tautomerization between the propargyl (I) and allenyl (II) moieties (Scheme 1) greatly expands the scope of propargylation, since either one may function as a propargylation agent [1,2]. Indeed, in many examples discussed in this review, allenyl derivatives and propargyl derivatives can be employed interchangeably to obtain the same propargylated derivative, or be applied to different substrates, all leading to the propargylated analogs. Scheme 1. Propargyl-allenyl tautomerization process.
As depicted in Table 1, this review is organized based on the type of substrate/functional group reacting with various classes of propargylating reagents (propargyl and/or allenyl derivatives), while also highlighting the catalysts/catalytic systems employed, including complex catalytic systems formed via catalyst/ligand interactions applied to asymmetric propargylation.
A propargylation reaction in carbonyl derivatives (aldehydes and ketones) whereby the propargylation reagent acts as a nucleophile toward the C=O functionality is a convenient method for the synthesis of chiral and achiral secondary or tertiary homopropargylic alcohols from aldehydes or ketones, respectively [3]. Significant progress has been made in the development of chiral propargylation reagents and diastereoselective additions of propargylic anion equivalents to chiral aldehydes and ketones [4].
Homopropargylic alcohols are present as fundamental structural entities in many bioactive compounds [5,6], and have also attracted significant interest as useful building blocks for complex molecule synthesis [7][8][9]. In this regard, several synthetic strategies and propargylation reagents have been employed for the synthesis of this interesting family of alcohols, as summarized below.
(a) Aldehyde and ketones

With Boron-Based Propargyl Reagents
Propargyl-/allenyl-boron-based compounds are a family of propargylation reagents with easy availability and relatively low costs, and for this reason, they are widely used in the propargylation processes of diverse organic substrates, as summarized in Table 2 and Schemes 2-4.
Following the discovery of the highly enantioselective and site-selective copper alkoxide-catalyzed propargylation of aldehydes 1 (R 1 = H) with a propargyl borolane 2a ( Table 2,  Additional experiments demonstrated the proposed catalytic cycle [10]. Table 2 also summarizes several other synthetic approaches to the propargylation reaction of diverse aldehydes and ketones 1 through propargyl/allenyl borolane reagents 2, producing a variety of chiral and achiral secondary and tertiary homopropargylic alcohols 3. A simple protocol for the synthesis of homopropargyl alcohols 5, starting with isatin derivatives 4 under mild reaction conditions, was reported (Scheme 2) [22]. Reactions were performed in the presence of copper triflate as a Lewis acid catalyst, with allenylboronic acid pinacol ester 2c as a nucleophile, in aqueous media, producing excellent product 5 yields. The enantioselective synthesis of chiral propargyl alcohols 6 was also explored. The best regioselectivity was achieved when (S)-SEGPHOS was used as a chiral ligand, resulting in enantiomeric ratios up to 12:88. Gram-scale synthesis, performed to check the efficiency of the protocol, showed retention in selectivity [22].
The synthesis of tri-and tetrasubstituted allenylboronic acids was established via a versatile copper-catalyzed methodology (Scheme 3) [23]. Subsequently, the obtained allenylboronic acids 7 were subjected to propargylboration reactions with ketones 1 without any additives, producing homopropargyl alcohols 8 (Scheme 3). Additionally, catalytic asymmetric propargylboration of the ketones 1 with high stereoselectivity was achieved when (S)-Br 2 -BINOL was used as chiral ligand, allowing for the synthesis of highly enantioenriched tertiary homopropargyl alcohols 9 (Scheme 3). The reaction was suitable for the kinetic resolution of racemic allenylboronic acids, producing alkynes with adjacent quaternary stereocenters [23].
A chemo-enzymatic process was established as a useful method for the derivatization of galactose unit of spruce galactoglucomannan (GGM) and other galactose-containing polysaccharides. In this approach, a series of GGMs were selectively formylated at the C-6 position via enzymatic oxidation by galactose oxidase. The formed aldehydes 23 were further derivatized via an indium-mediated Barbier-Grignard-type reaction using propargyl bromide 19a, resulting in the formation of homoallylic alcohols 24 (Scheme 8). All the reaction steps were performed in water in a one-pot reaction. The formation of the propargylated products was identified via MALDI-TOF-MS. The polysaccharide products were isolated and further characterized via GC-MS or NMR spectroscopy. The derivatized polysaccharides 24 were considered potential platforms for further functionalization (entry 3) [50].
Another study described diastereoselective Zn-mediated propargylation for nonenolizable norbornyl α-diketones 27. In this approach, the treatment of 27 with zinc and propargyl bromide 19a in anhydrous THF, using the Barbier procedure under ultrasound, produced the corresponding norbornyl homopropargyl alcohols 28 in good yields (Scheme 8). An analysis of the crude reaction mixtures revealed that 28 was obtained in a diastereomerically pure form, along with small amounts of allene derivatives as byproducts. Moreover, the stereochemistry of 28 was confirmed via X-ray crystal structure analysis. Subsequently, homopropargyl alcohols 28 were used as precursors for an AgI-catalyzed cycloisomerization toward diversely substituted spirocyclic dihydrofuran derivatives and produced acceptable to good yields (entry 5) [53]. Based on the dual photoredox catalytic strategy [54,55], practical and effective photoredox propargylation of aldehydes 1 (R = H) promoted by [Cp 2 TiCl 2 ] was developed (Scheme 9). The reaction did not require stoichiometric metals or scavengers, and employed a catalytic amount of [Cp 2 TiCl 2 ], along with the organic dye 3DPAFIPN (as a reductant for titanium). The reaction displayed a broad scope, producing the desired homopropargylic alcohols 29 in good yields with both aromatic and aliphatic aldehydes [56]. The synthesis of homopropargyl alcohol 31 with a two-carbon extension was achieved through the propargylation of aldehydes 1, mediated by zinc(0). This reagent was generated in situ from the redox coupling of Al and ZnCl 2 in 2N HCl and THF, producing products 31 in acceptable to good yields (Scheme 10) [57]. Aldehydes 1 were transformed into their corresponding homopropargyl alcohols 32 via a reaction with propargyl bromide 19a, with CuCl and Mn powder employed in the presence of TFA in ACN solvent (Scheme 11). This method proved compatible with a variety of substrates, leading to diversely substituted products 32 in high yields. A largescale reaction was also performed, demonstrating the potential synthetic applications of this transformation [58]. Scheme 11. Cu-Catalyzed/Mn-mediated chemo-selective synthesis of homopropargyl alcohols 32.

With Organometallic Propargyl Reagents
The Barbier type nucleophilic addition of functionalized halides to carbonyls mediated by metals or metal compounds constitutes an important strategy for carbon-carbon bond formation in organic synthesis [59][60][61]. In this context, an operationally simple procedure for the propargylation of aldehydes 1 in moist solvent (distilled THF) was developed through the direct addition of propargyl bromide 19a to the aldehyde substrates 1, mediated by low-valent iron or tin (Scheme 12). The metals were prepared in situ using a bimetal redox strategy. Using different aldehydes 1 as substrates, both metals proved applicable, producing homopropargyl alcohols 34 in good yields and with high chemoselectivity in most cases. Due to its efficacy, operational simplicity, performance in moist solvent, and its use of inexpensive metal/metal salts, the procedure was claimed to be practically viable and potentially scalable [62]. Allenyl boronic acids are widely used as propargylation reagents. These compounds are usually prepared via the Hg-catalyzed magnesiation of propargyl bromide [63]. However, the use of mercury, the corrosiveness of propargyl bromide, and the pyrophoric nature of allenyl boronic acid raise environmental and safety concerns, particularly when using these reagents for large-scale applications. To circumvent these limitations, the development of a mercury-free flow chemistry process for the asymmetric propargylation of aldehydes using allene gas 35 as a reagent was reported (Scheme 13). The connected continuous processes of allene dissolution, lithiation, Li-Zn transmetalation, and the asymmetric propargylation of the chiral aldehyde 38 provided a homopropargyl β-amino alcohol 39 with high regio-and diastereoselectivity in high yield. This flow process represents a practical use for an unstable allenyllithium intermediate 36, using the commercially available and recyclable (1S,2R)-N-pyrrolidinyl norephedrine (L*) as a ligand to promote the diastereoselective propargylation of 38 [64]. The esters of 4-hydroxybut-2-ynoic acid (alkyl 4-hydroxybut-2-ynoates) 42 are promising building blocks for organic synthesis. The presence of three important functional groups, namely the acetylene bond conjugated with the ester moiety, and the hydroxyl group of the propargyl unit in the structure of these compounds, make them highly versatile and applicable to many useful synthetic transformations [65][66][67][68][69][70]. With this in mind and based on previous works on the superelectrophilic activation of acetylene compounds [71], a series of 4-aryl(or 4,4-diaryl)-4-hydroxybut-2-ynoates 42 were obtained for further studies on their transformations under the action of various acids. The treatment of propynoates 40 with a solution of BuLi in hexanes produced lithiated intermediates in situ 41. Then, carbonyl compounds 1 were added at low temperature to form the target alkyls 4-hydroxybut-2-ynoates 42 in acceptable to excellent yields (Scheme 14) [72]. Epoxides serve as both building blocks and synthetic intermediates in various organic transformations [73,74]. The conjugation of a propargyl group to an epoxide creates a highly functional small-molecule building block. A series of substituted propargyl epoxides 45 were prepared via the propargylation of α-bromoketones 43 with an organozinc reagent 44 (Scheme 15). This method complements existing synthetic methods due to the advantageous properties of the organozinc reagents, such as their availability, selectivity, operational simplicity, and low toxicity [75].

With Propargylic Ethers, Acids, and Esters
The intramolecular propargylation of aldehydes and ketones enables their entry into cyclic compounds containing a homopropargyl alcohol unit, a structural motif that is present in a variety of biologically active compounds and is highly useful for synthetic transformations [76,77]. Due to their ready availability, propargylic esters 46 [78] are logical starting points in these transformations. It has been shown that carbonyl-tethered propargylic benzoates 46 undergo intramolecular carbonyl propargylation upon treatment with Et 2 Zn in the presence of a catalytic amount of Pd 0 to form 2-alkynylcyclopentanol products 47 (Scheme 16). Diastereoselectivity for the formation of simple homopropargylcycloalkanols 47, generated through the use of Pd 0 /Et 2 Zn, was examined as a function of the palladium phosphine ligand in the absence of further structural constraints imposed by additional substituents or rings. In this approach, a ligand/solvent effect on the cis/trans selectivity (referring to the relative positions of the alkynyl and OH groups) of ring-closure was found. In a non-coordinating solvent (benzene), increasing the electron-donating ability of the phosphine ligand (while decreasing its dissociation ability) led to an increased tendency towards the trans product, while the combination of a coordinating solvent (THF) and PPh 3 resulted in the exclusive formation of cis products. The experimental and computational results were compatible with the divergent behavior of an allenyl-ethylpalladium intermediate that partitions between competitive carbonyl-addition and transmetalation pathways, each leading to a different diastereoisomers. The results also suggested that the dissociating ability of the phosphine acted as a regulating factor for this behavior [79]. Isolated in 2008 from the marine sponge Siliquariaspongia mirabilis, mirabalin [80] was found to inhibit the growth of the tumor cell line HCT-116, with an IC 50 value of 0.27 µM. This compound belongs to the chondropsin family of macrolide lactams, which comprises chondropsins A−D, 73-deoxychondropsin A, and poecillastrins A−C [81]. Alcohol 50 is a key intermediate in the convergent and flexible stereoselective synthesis of one isomer of the C44−C65 fragment of mirabalin [82]. To synthesize alcohol 50, aldehyde 48 was subjected to stereoselective Marshall allenylation [83] through the addition of a chiral allenylzinc reagent, prepared in situ via palladozincation of the (S)-propargylic mesylate 49. This method delivered propargyl alcohol 50 with good diastereoselectivity in favor of the anti,syn,anti-isomer (Scheme 17). The two diastereomers were separated via flash chromatography on silica gel. The transition metal-catalyzed carbonyl propargylation protocol is an elegant approach to the diastereo-and enantioselective construction of homopropargylic alcohols. Addition reactions of propargyl metal or metalloid to aldehydes have been widely used as general synthetic methods. Nevertheless, some limitations exist in this strategy because of its ambident nucleophile characteristics as propargyl/allenyl organometallic reagents, which open up new reaction channels and widen their synthetic scope [84,85]. To circumvent these limitations, researchers have focused on transition metal-free carbonyl propargylation for the synthesis of 1,2,4-substituted homopropargylic alcohols.
In this regard, a transition metal-free three-component process was developed by combining aldehydes 1, 3-(tributylstannyl)propargyl acetates 51 formed in situ from readily available propargyl acetates, and trialkylboranes 52, providing access to a range of 1,2,4trisubstituted homopropargylic alcohols 53 (Scheme 18). It was found that the addition of diisopropylamine played a crucial role in the selective formation of homopropargylic alcohols 53. Importantly, this methodology could be extended to a single-flask reaction sequence starting with propargyl acetates [86]. Although propargylic carbonates are readily available compounds that could potentially be used instead of the corresponding propargylic halides in the carbonyl propargylation process, they are inert under classical Barbier conditions. Whereas notable examples of the use of propargyl carbonates have been described, their applications were typically limited to aldehydes as electrophiles [78,87]. To circumvent this limitation, an efficient protocol for the synthesis of homopropargylic alcohols 55 in moderate to good yields was reported that utilized propargylic carbonates 54 as pronucleophiles (Scheme 19). This reaction is based on a combination of transition metal (palladium) and radical (titanium) chemistry, in which allenyl titanocenes and transient propargylic radicals are formed in situ as key species for the success of this multimetallic protocol. The reaction took place with excellent regioselectivity, tolerating a variety of terminal and internal alkyne functionalities of the starting propargylic carbonates 54 with different substitution patterns, as well as diverse carbonyl compounds 1 (aldehydes and ketones), thus providing a useful method for application in synthetic organic chemistry (entry 1) [88]. In a similar way, low-valent indium(I)-mediated nickel-catalyzed propargylation of aldehydes 1 with propargylic carbonates 54 was established. In this approach, the nickel/indium(I)-mediated reaction of the starting materials 54, which possessed different substitution patterns, produced syn-homopropargylic alcohols 56 in acceptable to high yields upon coupling with a variety of carbonyl compounds 1 (Scheme 19). Both the nickel catalyst and the phosphane ligands were found to play a crucial role in this transformation. Diastereoselectivity was also strongly dependent on the ligand employed. Moreover, a mechanistic sequence involving an umpolung of propargylnickel intermediates under the influence of low-valent indium was proposed, to account for the dependence of the stereochemical characteristics of the phosphane ligands (entry 2) [89].

With Methylene-Active Propargyl Compounds
Despite extensive studies on gold catalysis, σ-allenylgold species have not been invoked as catalytic intermediates and their reactivities remain to be studied. In a recent study, the formation of an in situ-generated σ-allenylgold was proposed via soft propargylic deprotonation of the methylene-active derivatives 57, mediated by the isomerization of an alkyne to an allene. The σ-allenylgold species formed from 57 underwent nucleophilic addition to the activated aldehydes 1 in bifunctional biphenyl-2-ylphosphine (L1) ligand-enabled gold catalysis. This development revealed a broad range of opportunities to achieve the propargylic C−H functionalization of 57 under catalytic and mild conditions, producing homopropargyl alcohol intermediates 58 (Scheme 20). Subsequently, the resulting homopropargyl alcohols 58 underwent ligand-enabled cycloisomerization, involving an unexpected silyl migration process, to deliver dihydrofurans 59 as isolated products [90]. Scheme 20. Gold-catalyzed synthesis of homopropargyl alcohol intermediates 58 from propargyl methylene-active derivatives 57 and aldehydes 1.

With 1,3-Enynes
While most methods for enantioselective carbonyl propargylation promote the formation of the parent α-unsubstituted homopropargylic alcohols, less attention has been devoted to the development of diastereo-and enantioselective propargylation protocols that generate useful (α-methyl)homopropargyl alcohols [91]. Under the conditions of ruthenium-catalyzed transfer hydrogenation, employing isopropanol as a source of hydrogen, unprotected isopropoxy-substituted enyne 60 and aldehydes 1 engaged in reductive coupling to provide propargylation product (α-methyl)homopropargyl alcohols 61 with good to complete levels of anti-diastereoselectivity (Scheme 21). Remarkably, it was found that the unprotected tertiary hydroxy moiety of isopropoxy enyne 60 is required in order to enforce diastereoselectivity. Moreover, deuterium-labeling studies corroborated reversible enyne hydrometalation in advance of carbonyl addition. Additionally, it was demonstrated that the isopropoxy group of products 61 could be readily cleaved upon exposure to aqueous sodium hydroxide to reveal the terminal alkyne functionality [92]. Scheme 21. Ru-catalyzed synthesis of (α-methyl)homopropargyl alcohols 61 from enyne 60 and aldehydes 1.

With Aryl-Acetylenes
The Favorskii reaction, which involves the nucleophilic addition of alkynes to aldehydes in the presence of a strong base, has been recognized as an efficient synthetic strategy to produce propargyl alcohols and α,β-unsaturated ketones [93]. Direct propargylation/alkenylation via the allenol-enone isomerization sequence through the activation of the C-H bond in terminal alkynes, without a transition metal and employing a weak base, represents a challenging research area. In response to this, a fast and efficient transition metal-free, modified Favorskii-type direct alkynylation protocol for the synthesis of propargyl alcohols 63/65 was developed using a combination of Cs 2 CO 3 and TEA as weak bases (Scheme 22). Aliphatic aldehydes 1 (R 1 = H) produced propargyl alcohols 63, while cyclic ketones 64 furnished propargyl alcohols 65. The operationally simple protocol, wide substrate scope, and gram-scale synthesis represent key aspects of this methodology. A plausible mechanism for this transformation involving the weak base-assisted propargylation of carbonyl compounds 1 was suggested [94].

Scheme 22.
Favorskii-type direct propargylation of carbonyl compounds 1 for the synthesis of propargyl alcohols 63/65 using a combination of Cs 2 CO 3 and TEA as weak bases.

(b) Hemiacetals
The development of copper(I)-catalyzed stereodivergent anomeric propargylation of unprotected aldose 66 was established as a facile synthetic pathway to a broad variety of sialic acid derivatives 69, via a key propargylation intermediate 68 (Scheme 23). The reaction proceeded with the in situ formation of a soft allenylcopper(I) species, catalytically generated from the stable allenylboronic acid pinacolate 2c. It was also observed that the addition of B(OMe) 3 facilitated the ring-opening of the non-electrophilic cyclic hemiacetal form of aldose 66 to reach its corresponding open-chain reactive aldehyde form 67, subsequently leading to the formation of the key intermediate 68. This synthetic method, which required no protecting groups, could be performed at the gram-scale, offering general and practical access to various sialic acid derivatives from unprotected-type aldoses 66 [95]. In a similar way, copper(I)-catalyzed stereodivergent nucleophilic propargylation at the anomeric carbon of unprotected N-acetyl mannosamine 70 was devised using 3substituted allenylboronates 2c as nucleophiles (Scheme 24). The homopropargylic alcohol products 71 and 72 containing two contiguous stereocenters, and two stereoisomers out of the four possible isomers, were selectively obtained in a catalyst-controlled manner by applying either basic conditions (a MesCu/(R,R,R)-Ph-SKP catalyst with a B(OiPr) 3 additive) or acidic conditions (a CuBF 4 /(S,S,S)-Ph-SKP catalyst with an MeB(OiPr) 2 additive). In the following two steps, the propargylation products 71 and 72 were transformed into C3-substituted sialic acids without the use of protecting groups [96].  The addition of organometallic reagents to imines is one of the most useful and versatile methodologies for creating both a new carbon-carbon bond and new amine functionality [97]. When a propargyl organometallic reagent is used [98], via diverse synthetic strategies, the process offers the possibility for further transformation of the unsaturation to form more carbon-carbon or carbon-heteroatom bonds [99], thus giving practical use to this synthetic approach.

With Propargyl Halide/Metal Reagents
The enantio-and/or diastereoselective version of the propargylation of imines is of additional interest because at least one new stereogenic center is created [100]. Moreover, αor γ-substitution in the imine reagent could also induce chemoselectivity in this process because the propargyl moiety could be selectively added to the structure of the product [101]. Using this approach, the diastereoselective Barbier-type addition of allyl halides to chiral sulfinylimines 73, promoted by indium metal [102], resulted in the formation of chiral N-protected homoallylic amines in good yields and % dr. More specifically, the reaction of different chiral imines 73, derived from aldehydes or ketones, with the silylated propargyl bromide 19a under sonication, in the presence of indium metal, led mainly or exclusively to the formation of protected homopropargylamines 74 in a diastereoselective manner (Scheme 25, entry 1). Of special interest in this process are the ketimine derivatives 73 (derived from ketones) because the new stereocenter has a quaternary configuration. Further, selective deprotection of the two protecting groups (TMS and sulfinyl moieties) was accomplished using conventional methods [103]. In another approach, a highly efficient method for the asymmetric synthesis of a wide range of quaternary carbon-containing homopropargylic amines 74 via the Znmediated asymmetric propargylation of N-tert-butanesulfinyl ketimines 73 was reported (Scheme 25, entry 2). In this approach, the ketimines 73 were readily prepared according to known procedures [104], producing products 74 in good yields and with high diastereoselectivities [105].
A series of enantioenriched homopropargylic amines 74 were obtained in good yields and with excellent diastereomeric ratios via the indium-mediated N-propargylation of chiral N-tert-butanesulfinyl ketimines 73 using trimethylsilylpropargyl bromide 19a, in the presence of indium metal, under sonication (Scheme 25, entry 3). Further, the chiral amines 74 were used as starting materials to obtain access to 3-substituted 1,2,3,4tetrahydroisoquinoline derivatives in their enantioenriched form [106].
A Zn-mediated propargylation/lactamization cascade reaction with chiral 2-formylbenzoate-derived N-tert-butanesulfinyl imines 73 (R = aryl, R 1 = H) was realized, as described in Scheme 26. In this strategy, sulfinyl amines 75 were obtained as intermediates, providing a practical and efficient method for the synthesis of chiral isoindolinones 76. Moreover, high diastereoselectivities and good reaction yields were observed for the majority of the examined cases [107]. An efficient approach to the synthesis of α,α-bispropargyl-substituted amines 78 in acceptable yields was achieved via Zn-promoted aza-Barbier-type reactions of N-sulfonyl imidates 77 with various propargyl reagents 19a (Scheme 27, entry 1). The synthetic utility of this approach was demonstrated via the rapid construction of pyrrolidine derivatives [108]. In a similar way, a one-pot method for the synthesis of homopropargylic N-sulfonylamines 79 from aldehydes catalyzed by zinc powder was described. The imine derivatives 77 were obtained in situ as intermediates from a reaction between the corresponding aldehydes 1 and TsNH 2 in the presence of BnBr and Zn. This procedure offers simplicity, good yields, and was shown to be applicable to a variety of aldehydes (Scheme 27, entry 2) [109]. The synthesis of 3-propargylated 3-aminooxindoles 81 was carried out via the zincmediated propargylation of isatin-derived imines 80 (Scheme 28). This approach avoided the use of catalysts, severe reaction conditions, multistep procedures, and reaction additives. To demonstrate its synthetic utility, different isatin-derived imines 80 and propargyl bromide 19a were used to obtain products 81 in good yields [110]. Scheme 28. Zinc-mediated propargylation of isatin-derived imines 80 using propargyl bromide 19a as propargylation reagent.

With Propargyl/Allenyl Boron Reagents
Expanding the available methods for the synthesis of homopropargylic amines, zinccatalyzed diastereoselective propargylation of tert-butanesulfinyl imines 73 using propargyl borolanes 2a was reported (Scheme 29, entry 1). This method produced both aliphatic and aryl homopropargylic amines 74 in acceptable to good yields and with good stereoselectivity. The utility of the homopropargylic amines 74 was demonstrated in the synthesis of a cis-substituted pyrido-indole through diastereoselective Pictet-Spengler cyclization [111]. Allenylborolane 2c (instead of propargyl borolane 2a) was employed in the enantioselective Ag-catalyzed propargylation of N-sulfonylketimines 82 (Scheme 29, entry 2). The reaction was compatible with a wide variety of diaryl-and alkylketimines 82, producing their respective homopropargylic sulfonamides 83 in high yields and in excellent enantiomeric ratios. It was also found that both propargyl and allenylborolane reagents (2a and 2c) could be used to obtain homopropargylic products 83, and a mechanism involving transmetalation of the borolane reagent 2c with a silver catalyst was proposed. Further, the homopropargylic products 83 were used as starting materials to elaborate diverse products of higher complexity with high stereochemical fidelity, including enyne ring-closing metathesis, Sonogashira cross-coupling, and reduction reactions [112].
The copper-catalyzed asymmetric propargylation of cyclic aldimines 86 was also reported. Asymmetric propargylation of a diverse series of N-alkyl and N-aryl aldimines 86 with propargyl borolanes 2a was achieved, producing the corresponding chiral propargylamine scaffolds 87 with good to high asymmetric induction (Scheme 29, entry 4). The utility of products 87 was further demonstrated via titanium-catalyzed hydroamination and reduction to generate the chiral indolizidines (−)-crispine A and (−)-harmicine alkaloids. Moreover, the influence of the trimers of imines 86 on inhibiting the reaction was identified, and equilibrium constants between the monomers 86 and their trimers were determined for general classes of imines [114].

With Propargyl/Allenyl-MX reagents
The diastereoselective synthesis of enantiopure homopropargylic amines 74 via the propargylation of various N-tert-butylsulfinylimines 73 with 1-trimethylsilyl allenylzinc bromides 88 was achieved (Scheme 30, entry 1). In this approach, the full conversion of imines 73 was observed when two equivalents of Zn derivatives 88 were used, giving homopropargylic amines 74 as single isomers in very good isolated yields [115].
The fluorinated analogs of tert-butanesulfinyl imines 73 were considered convenient precursors for a synthetic route to obtaining enantioenriched fluorinated monoterpenic alkaloid analogues via a Pauson-Khand cyclization reaction [116]. In this approach, diastereoselective propargylation of 73 was implemented as the key step to introducing the chiral information necessary for the rest of the synthetic sequence to be performed. In the first assay, the addition of propargyl magnesium bromide 89 to sulfinyl imine 73 (R = CF 3 ) in DCM resulted in the formation of homopropargylamine 74 (R = CF 3 ) with low diastereoselectivity. When DCM was replaced with THF, not only was the diastereoselectivity vastly improved, but the major diastereoisomer was actually the opposite of the one observed in DCM. Following the latter reaction conditions, sulfinyl amines 74 were obtained in good yields with high diastereoselectivity (Scheme 30, entry 2).
The dramatic effect of the solvent in this type of transformation was attributed to differing transition states depending on the nature of the solvent, but it was also suspected that the strong electron-withdrawing characteristics of the fluorinated groups of substrates 73 played a role in increasing the reactivity of the imines 73 and decreasing the difference in energy between the two transition states in non-coordinating solvents such as DCM [116].

With Imino-Masked Propargyl Reagents
Whereas the development of methods for the α-alkylation of carbonyl compounds has advanced tremendously in recent years, catalytic enantioselective α-propargylation is relatively less developed [117,118]. In response to this, a two-step reaction sequence for the asymmetric formal α-propargylation of ketones was introduced (Scheme 31). This approach took advantage of the amino-catalyzed conjugate addition of ketones to alkylidene isoxazol-5-ones, producing intermediates 90/91, which, through a controlled nitrosative degradation event, produced α-propargyl ketones 92/93 in moderate to good yields, with perfect diastereocontrol, good to excellent enantioselectivity, and broad structural scope [119].

With Propiolic Acids
Thermal-induced transition metal-catalyzed decarboxylative coupling reactions are recognized as a powerful tool in organic synthesis and medicinal chemistry as they require simple operation and produce CO2 as a byproduct [120][121][122]. Based on previous works in which dipropargylic amines were obtained as side products mediated by isobutylboronic acid reagents [123], the expansion of this chemistry led to the development of a more flexible approach for the synthesis of dipropargylic amines from primary amines, formaldehyde, and propiolic acids under metal-free conditions. After assaying different reaction conditions, a method in which a mixture of amine 94 (R 1 = H), formaldehyde, and propiolic acid 95 in DCE was heated in a sealed tube produced optimal yields of the target dipropargylic amines 96 (Scheme 32). The method exhibited a broad range of functional group compatibility for primary amines 94 and propiolic acids 95, and produced the corresponding products 96 in low to excellent yields [124].

With Acetylene Derivatives
A series of N-heterocyclic silylene-stabilized monocoordinated Ag(I) cationic complexes weakly bound to free arene rings (C6H6, C6Me6, and C7H8) were synthesized, and the efficacy of these electrophilic Ag(I) complexes as catalysts was investigated toward A 3coupling reactions, producing a series of propargylamines 97 in good to excellent yields in a tricomponent reaction of amines 94, acetylenes 62, and polyformaldehyde (Scheme 33). The process was accompanied by the in situ formation of an iminium species from 94 and polyformaldehyde. The best results were obtained when catalyst A was used, with low catalyst loading under solvent-free conditions [125].

With Propiolic Acids
Thermal-induced transition metal-catalyzed decarboxylative coupling reactions are recognized as a powerful tool in organic synthesis and medicinal chemistry as they require simple operation and produce CO 2 as a byproduct [120][121][122]. Based on previous works in which dipropargylic amines were obtained as side products mediated by isobutylboronic acid reagents [123], the expansion of this chemistry led to the development of a more flexible approach for the synthesis of dipropargylic amines from primary amines, formaldehyde, and propiolic acids under metal-free conditions. After assaying different reaction conditions, a method in which a mixture of amine 94 (R 1 = H), formaldehyde, and propiolic acid 95 in DCE was heated in a sealed tube produced optimal yields of the target dipropargylic amines 96 (Scheme 32). The method exhibited a broad range of functional group compatibility for primary amines 94 and propiolic acids 95, and produced the corresponding products 96 in low to excellent yields [124]. (b) Iminium Compounds

With Propiolic Acids
Thermal-induced transition metal-catalyzed decarboxylative coupling reactions are recognized as a powerful tool in organic synthesis and medicinal chemistry as they require simple operation and produce CO2 as a byproduct [120][121][122]. Based on previous works in which dipropargylic amines were obtained as side products mediated by isobutylboronic acid reagents [123], the expansion of this chemistry led to the development of a more flexible approach for the synthesis of dipropargylic amines from primary amines, formaldehyde, and propiolic acids under metal-free conditions. After assaying different reaction conditions, a method in which a mixture of amine 94 (R 1 = H), formaldehyde, and propiolic acid 95 in DCE was heated in a sealed tube produced optimal yields of the target dipropargylic amines 96 (Scheme 32). The method exhibited a broad range of functional group compatibility for primary amines 94 and propiolic acids 95, and produced the corresponding products 96 in low to excellent yields [124]. Scheme 32. Three-component synthesis of dipropargylic amines 96 mediated by a thermally induced metal-free decarboxylative transition process.

With Acetylene Derivatives
A series of N-heterocyclic silylene-stabilized monocoordinated Ag(I) cationic complexes weakly bound to free arene rings (C6H6, C6Me6, and C7H8) were synthesized, and the efficacy of these electrophilic Ag(I) complexes as catalysts was investigated toward A 3coupling reactions, producing a series of propargylamines 97 in good to excellent yields in a tricomponent reaction of amines 94, acetylenes 62, and polyformaldehyde (Scheme 33). The process was accompanied by the in situ formation of an iminium species from 94 and polyformaldehyde. The best results were obtained when catalyst A was used, with low catalyst loading under solvent-free conditions [125].

With Acetylene Derivatives
A series of N-heterocyclic silylene-stabilized monocoordinated Ag(I) cationic complexes weakly bound to free arene rings (C 6 H 6 , C 6 Me 6 , and C 7 H 8 ) were synthesized, and the efficacy of these electrophilic Ag(I) complexes as catalysts was investigated toward A 3 -coupling reactions, producing a series of propargylamines 97 in good to excellent yields in a tricomponent reaction of amines 94, acetylenes 62, and polyformaldehyde (Scheme 33). The process was accompanied by the in situ formation of an iminium species from 94 and polyformaldehyde. The best results were obtained when catalyst A was used, with low catalyst loading under solvent-free conditions [125].
plexes weakly bound to free arene rings (C6H6, C6Me6, and C7H8) were synthesized, and the efficacy of these electrophilic Ag(I) complexes as catalysts was investigated toward A 3 coupling reactions, producing a series of propargylamines 97 in good to excellent yield in a tricomponent reaction of amines 94, acetylenes 62, and polyformaldehyde (Schem 33). The process was accompanied by the in situ formation of an iminium species from 9 and polyformaldehyde. The best results were obtained when catalyst A was used, with low catalyst loading under solvent-free conditions [125]. A library of N-propargyl oxazolidines and N,N-dipropargyl vicinal amino alcohols was prepared through a multicomponent reaction of formaldehyde, β-aminoalcohols 98, and acetylenes 62 using a copper-catalyzed A 3 -type-coupling process (Scheme 34). Whereas the presence of bromide and chloride ions accelerated the process toward openring alkynylation, producing dipropargylated products 99, the presence of the catalytic system Cu/I favored the formation of propargyl oxazolidines 100 [126]. A library of N-propargyl oxazolidines and N,N-dipropargyl vicinal amino alcohols was prepared through a multicomponent reaction of formaldehyde, β-aminoalcohols 98, and acetylenes 62 using a copper-catalyzed A 3 -type-coupling process (Scheme 34). Whereas the presence of bromide and chloride ions accelerated the process toward openring alkynylation, producing dipropargylated products 99, the presence of the catalytic system Cu/I favored the formation of propargyl oxazolidines 100 [126]. The addition of propargylic or allenylic metal reagents to azo compounds is a convenient method for the preparation of propargylic hydrazines [127,128]. Expanding on earlier studies, the Barbier-type propargylation of azo compounds 101 with propargylic halides 19 that utilizes reactive barium as a low-valent metal in THF as solvent was reported (Scheme 35), providing diverse propargylic hydrazines 102 regioselectively in moderate to high yields. The corresponding α-adducts 102 were exclusively formed not only from azobenzenes (diaryldiazenes) but also from dialkyl azodicarboxylates. The method was also applicable to γ-alkylated and γ-phenylated propargylic bromides 19. Notably, the ester moieties of dialkyl azodicarboxylates remained unaffected by the barium reagent, thus providing the corresponding propargylated compounds 102 as unique products [129].  Haloarenes are of great synthetic interest, since they are used as structural scaffolds of different compounds employed in catalytic chemistry, medical chemistry, and agrochemistry. Due to this, new strategies have emerged to obtain various halogenated aromatics, for example, the insertion of a substituent in the ortho-position with respect to a pre-existing halogen group. In this context, the synthesis of ortho-propargyl iodobenzenes 104 represents a desirable goal. A viable procedure to synthesize these derivatives involves reacting (diacetoxyiodo)arenes 103, previously activated with BF3, with a propar- The addition of propargylic or allenylic metal reagents to azo compounds is a convenient method for the preparation of propargylic hydrazines [127,128]. Expanding on earlier studies, the Barbier-type propargylation of azo compounds 101 with propargylic halides 19 that utilizes reactive barium as a low-valent metal in THF as solvent was reported (Scheme 35), providing diverse propargylic hydrazines 102 regioselectively in moderate to high yields. The corresponding α-adducts 102 were exclusively formed not only from azobenzenes (diaryldiazenes) but also from dialkyl azodicarboxylates. The method was also applicable to γ-alkylated and γ-phenylated propargylic bromides 19. Notably, the ester moieties of dialkyl azodicarboxylates remained unaffected by the barium reagent, thus providing the corresponding propargylated compounds 102 as unique products [129]. A library of N-propargyl oxazolidines and N,N-dipropargyl vicinal amino alcohols was prepared through a multicomponent reaction of formaldehyde, β-aminoalcohols 98, and acetylenes 62 using a copper-catalyzed A 3 -type-coupling process (Scheme 34). Whereas the presence of bromide and chloride ions accelerated the process toward openring alkynylation, producing dipropargylated products 99, the presence of the catalytic system Cu/I favored the formation of propargyl oxazolidines 100 [126]. The addition of propargylic or allenylic metal reagents to azo compounds is a convenient method for the preparation of propargylic hydrazines [127,128]. Expanding on earlier studies, the Barbier-type propargylation of azo compounds 101 with propargylic halides 19 that utilizes reactive barium as a low-valent metal in THF as solvent was reported (Scheme 35), providing diverse propargylic hydrazines 102 regioselectively in moderate to high yields. The corresponding α-adducts 102 were exclusively formed not only from azobenzenes (diaryldiazenes) but also from dialkyl azodicarboxylates. The method was also applicable to γ-alkylated and γ-phenylated propargylic bromides 19. Notably, the ester moieties of dialkyl azodicarboxylates remained unaffected by the barium reagent, thus providing the corresponding propargylated compounds 102 as unique products [129].  Haloarenes are of great synthetic interest, since they are used as structural scaffolds of different compounds employed in catalytic chemistry, medical chemistry, and agrochemistry. Due to this, new strategies have emerged to obtain various halogenated aromatics, for example, the insertion of a substituent in the ortho-position with respect to a pre-existing halogen group. In this context, the synthesis of ortho-propargyl iodobenzenes 104 represents a desirable goal. A viable procedure to synthesize these derivatives involves reacting (diacetoxyiodo)arenes 103, previously activated with BF3, with a propargyl metalate 12 using an ACN/DCM mixture as solvent, to furnish ortho-propargyl iodo-  Haloarenes are of great synthetic interest, since they are used as structural scaffolds of different compounds employed in catalytic chemistry, medical chemistry, and agrochemistry. Due to this, new strategies have emerged to obtain various halogenated aromatics, for example, the insertion of a substituent in the ortho-position with respect to a pre-existing halogen group. In this context, the synthesis of ortho-propargyl iodobenzenes 104 represents a desirable goal. A viable procedure to synthesize these derivatives involves reacting (diacetoxyiodo)arenes 103, previously activated with BF 3 , with a propargyl metalate 12 using an ACN/DCM mixture as solvent, to furnish ortho-propargyl iodobenzenes 104 in moderate to high yields (Scheme 36), as described in [130]. A striking feature of this protocol is that it generates a singly propargylated product 104 for each substrate 103 bearing a single type of ortho-CH site. The regioselectivity is affected by the electronic environment of the iodoarene nucleus 103, and the method is applicable to electron-deficient iodoarenes 103. Synthetic access to ortho-propargylated arylsulfides, as in compounds 106, is also of great interest, since a variety of synthetic derivatives with a wide catalog of applications can be produced from these types of structures. Compounds 106 have been synthesized in good to excellent yields via a cross-coupling reaction between aryl-sulfoxide 105 and propargylsilanes 17, using Tf2O as an electrophilic activator and 2,6-lutidine as base in ACN (Scheme 37). The addition of 2,6-lutidine improved their reaction yields and prevented the formation of undesirable products via acid-mediated cyclization. A plausible mechanism for this metal-free cross-coupling process involves an interrupted Pummerer/allenyl thio-Claisen rearrangement, where the formation of classic Pummerer products did not occur, even in the presence of electron-scavenging alkyl chains on sulfur. Hence, this methodology allows for the formation of sp 2 -sp 3 C-C bonds in products 106 in an efficient and regioselective manner [131].

With Propargyl Alcohols
The nucleophilic substitution of the -OH group in propargyl alcohols is an efficient methodology for the preparation of synthetic precursors, which, due to its versatility, could be further implemented in synthetic schemes via alkyne functionality and the possible addition of acetylides to different carbonyls. However, this type of substitution is challenging in aryl-propargyl alcohols due to the low reactivity of the hydroxyl as a leaving group and the formation of unwanted side products, as well as polymers originating from unstable/highly reactive carbocationic intermediates. The viable alternative methods for the preparation of propargyl derivatives, such as 108, via the nucleophilic substitution of aryl-propargyl alcohols 63 are highlighted in Scheme 38. Synthetic access to ortho-propargylated arylsulfides, as in compounds 106, is also of great interest, since a variety of synthetic derivatives with a wide catalog of applications can be produced from these types of structures. Compounds 106 have been synthesized in good to excellent yields via a cross-coupling reaction between aryl-sulfoxide 105 and propargylsilanes 17, using Tf 2 O as an electrophilic activator and 2,6-lutidine as base in ACN (Scheme 37). The addition of 2,6-lutidine improved their reaction yields and prevented the formation of undesirable products via acid-mediated cyclization. A plausible mechanism for this metal-free cross-coupling process involves an interrupted Pummerer/allenyl thio-Claisen rearrangement, where the formation of classic Pummerer products did not occur, even in the presence of electron-scavenging alkyl chains on sulfur. Hence, this methodology allows for the formation of sp 2 -sp 3 C-C bonds in products 106 in an efficient and regioselective manner [131]. Synthetic access to ortho-propargylated arylsulfides, as in compounds 106, is also of great interest, since a variety of synthetic derivatives with a wide catalog of applications can be produced from these types of structures. Compounds 106 have been synthesized in good to excellent yields via a cross-coupling reaction between aryl-sulfoxide 105 and propargylsilanes 17, using Tf2O as an electrophilic activator and 2,6-lutidine as base in ACN (Scheme 37). The addition of 2,6-lutidine improved their reaction yields and prevented the formation of undesirable products via acid-mediated cyclization. A plausible mechanism for this metal-free cross-coupling process involves an interrupted Pummerer/allenyl thio-Claisen rearrangement, where the formation of classic Pummerer products did not occur, even in the presence of electron-scavenging alkyl chains on sulfur. Hence, this methodology allows for the formation of sp 2 -sp 3 C-C bonds in products 106 in an efficient and regioselective manner [131].

With Propargyl Alcohols
The nucleophilic substitution of the -OH group in propargyl alcohols is an efficient methodology for the preparation of synthetic precursors, which, due to its versatility, could be further implemented in synthetic schemes via alkyne functionality and the possible addition of acetylides to different carbonyls. However, this type of substitution is challenging in aryl-propargyl alcohols due to the low reactivity of the hydroxyl as a leaving group and the formation of unwanted side products, as well as polymers originating from unstable/highly reactive carbocationic intermediates. The viable alternative methods for the preparation of propargyl derivatives, such as 108, via the nucleophilic substitution of aryl-propargyl alcohols 63 are highlighted in Scheme 38.

With Propargyl Alcohols
The nucleophilic substitution of the -OH group in propargyl alcohols is an efficient methodology for the preparation of synthetic precursors, which, due to its versatility, could be further implemented in synthetic schemes via alkyne functionality and the possible addition of acetylides to different carbonyls. However, this type of substitution is challenging in aryl-propargyl alcohols due to the low reactivity of the hydroxyl as a leaving group and the formation of unwanted side products, as well as polymers originating from unstable/highly reactive carbocationic intermediates. The viable alternative methods for the preparation of propargyl derivatives, such as 108, via the nucleophilic substitution of aryl-propargyl alcohols 63 are highlighted in Scheme 38. There is currently considerable interest in multi-metallic catalysis since it allows for the design of specifically homogeneous hetero-bimetallic catalysts that can facilitate the activation of different electrophiles through the stereoelectronic characteristics of two metals present in a single compound, thus promoting selective binding to a substrate. In this sense, the use of hetero-bimetallic catalysts constitutes an alternative method for the functionalization of propargyl alcohols. For example, using an Ir III -SnI V catalyst in 1,2-dichloroethane (DCE) as a solvent enabled the activation of propargyl alcohols 63 (electrophiles), which reacted with a series of aromatic nucleophiles (Nu-H) 107 regioselectively, to furnish aryl-propargylated derivatives 108 with high turnover frequency (TOF) and with moderate to good yields (Scheme 38, entry 1) [132]. Furthermore, the direct propargylation of arenes 107 with propargyl alcohols 63 was promoted by SnCl2 or Ce(OTf)3 in MeNO2 as a solvent. These transformations resulted in high selectivity toward the propargylated products 108 (Scheme 38, entry 2 and entry 3) [133,134].

With Propargyl Fluorides
The Nicholas reaction has been employed as an alternative to circumvent the challenges involved in the propargylation of arenes, but this method has drawbacks because it uses Co2(CO6), requires several steps, and gives low yields with electron-poor arenes. The ionization of propargyl fluorides 19 (X = F) in trifluoroacetic acid (TFA) in a mixture of DCM/HFIP as solvents produced products 108 in acceptable to excellent yields (Scheme 39), thus providing a viable method to directly obtain a variety of substituted aryl-propargyl derivatives 108 in a Friedel-Crafts-type propargylation reaction [135].

With Propargyl Phosphates
The copper-catalyzed direct propargylation of polyfluoroarenes 107 (n = 4 and 5) with secondary propargyl phosphates 109 that uses a strong base, such as, tBuOLi or THF, as a solvent has been described. Using this method, a series of propargylated polyfluoroarenes 108 were synthesized in moderate to good yields, with high chemo-and There is currently considerable interest in multi-metallic catalysis since it allows for the design of specifically homogeneous hetero-bimetallic catalysts that can facilitate the activation of different electrophiles through the stereoelectronic characteristics of two metals present in a single compound, thus promoting selective binding to a substrate. In this sense, the use of hetero-bimetallic catalysts constitutes an alternative method for the functionalization of propargyl alcohols. For example, using an Ir III -SnI V catalyst in 1,2-dichloroethane (DCE) as a solvent enabled the activation of propargyl alcohols 63 (electrophiles), which reacted with a series of aromatic nucleophiles (Nu-H) 107 regioselectively, to furnish arylpropargylated derivatives 108 with high turnover frequency (TOF) and with moderate to good yields (Scheme 38, entry 1) [132]. Furthermore, the direct propargylation of arenes 107 with propargyl alcohols 63 was promoted by SnCl 2 or Ce(OTf) 3 in MeNO 2 as a solvent. These transformations resulted in high selectivity toward the propargylated products 108 (Scheme 38, entry 2 and entry 3) [133,134].

With Propargyl Fluorides
The Nicholas reaction has been employed as an alternative to circumvent the challenges involved in the propargylation of arenes, but this method has drawbacks because it uses Co 2 (CO 6 ), requires several steps, and gives low yields with electron-poor arenes. The ionization of propargyl fluorides 19 (X = F) in trifluoroacetic acid (TFA) in a mixture of DCM/HFIP as solvents produced products 108 in acceptable to excellent yields (Scheme 39), thus providing a viable method to directly obtain a variety of substituted aryl-propargyl derivatives 108 in a Friedel-Crafts-type propargylation reaction [135]. There is currently considerable interest in multi-metallic catalysis since it allows for the design of specifically homogeneous hetero-bimetallic catalysts that can facilitate the activation of different electrophiles through the stereoelectronic characteristics of two metals present in a single compound, thus promoting selective binding to a substrate. In this sense, the use of hetero-bimetallic catalysts constitutes an alternative method for the functionalization of propargyl alcohols. For example, using an Ir III -SnI V catalyst in 1,2-dichloroethane (DCE) as a solvent enabled the activation of propargyl alcohols 63 (electrophiles), which reacted with a series of aromatic nucleophiles (Nu-H) 107 regioselectively, to furnish aryl-propargylated derivatives 108 with high turnover frequency (TOF) and with moderate to good yields (Scheme 38, entry 1) [132]. Furthermore, the direct propargylation of arenes 107 with propargyl alcohols 63 was promoted by SnCl2 or Ce(OTf)3 in MeNO2 as a solvent. These transformations resulted in high selectivity toward the propargylated products 108 (Scheme 38, entry 2 and entry 3) [133,134].

With Propargyl Fluorides
The Nicholas reaction has been employed as an alternative to circumvent the challenges involved in the propargylation of arenes, but this method has drawbacks because it uses Co2(CO6), requires several steps, and gives low yields with electron-poor arenes. The ionization of propargyl fluorides 19 (X = F) in trifluoroacetic acid (TFA) in a mixture of DCM/HFIP as solvents produced products 108 in acceptable to excellent yields (Scheme 39), thus providing a viable method to directly obtain a variety of substituted aryl-propargyl derivatives 108 in a Friedel-Crafts-type propargylation reaction [135].

With Propargyl Phosphates
The copper-catalyzed direct propargylation of polyfluoroarenes 107 (n = 4 and 5) with secondary propargyl phosphates 109 that uses a strong base, such as, tBuOLi or THF, as a solvent has been described. Using this method, a series of propargylated polyfluoroarenes 108 were synthesized in moderate to good yields, with high chemo-and

With Propargyl Phosphates
The copper-catalyzed direct propargylation of polyfluoroarenes 107 (n = 4 and 5) with secondary propargyl phosphates 109 that uses a strong base, such as, tBuOLi or THF, as a solvent has been described. Using this method, a series of propargylated polyfluoroarenes 108 were synthesized in moderate to good yields, with high chemo-and regioselectivity (Scheme 40). Furthermore, this reaction could also be extended to triethylsilyl-and tertbutyl substituted alkynes [136].

With Propargyl Cation Equivalents
Given the prevalence of the phenol motif in bioactive molecules, phar and functional materials [137], a series of ortho-propargyl phenols 111 were via a boron-catalyzed sequential procedure through the addition of termina (R 2 = Aryl) to substituted phenols 110, bearing congested quaternary carbons Control experiments combined with DFT calculations suggested that the r ceeds via a sequential phenol alkenylation/hydroalkynylation process [138]. (b) Heterocyclic derivatives (i) Indoles

With Propargyl Alcohols, Ethers, and Esters
N-Heterocyclic systems are important as building blocks of natural prod and functional organic materials, and the development of mild and selective the direct introduction of propargyl groups into heterocyclic rings is highly order to access important and novel organic precursors.

With Propargyl Cation Equivalents
Given the prevalence of the phenol motif in bioactive molecules, pharmaceuticals, and functional materials [137], a series of ortho-propargyl phenols 111 were synthesized via a boron-catalyzed sequential procedure through the addition of terminal alkynes 62 (R 2 = Aryl) to substituted phenols 110, bearing congested quaternary carbons (Scheme 41). Control experiments combined with DFT calculations suggested that the reaction proceeds via a sequential phenol alkenylation/hydroalkynylation process [138].

With Propargyl Cation Equivalents
Given the prevalence of the phenol motif in bioactive molecules, p and functional materials [137], a series of ortho-propargyl phenols 111 w via a boron-catalyzed sequential procedure through the addition of term (R 2 = Aryl) to substituted phenols 110, bearing congested quaternary carbo Control experiments combined with DFT calculations suggested that th ceeds via a sequential phenol alkenylation/hydroalkynylation process [13 Scheme 41. Boron-catalyzed sequential procedure for the synthesis of congested nols 111.
(b) Heterocyclic derivatives (i) Indoles 2.3.6. With Propargyl Alcohols, Ethers, and Esters N-Heterocyclic systems are important as building blocks of natural p and functional organic materials, and the development of mild and select the direct introduction of propargyl groups into heterocyclic rings is hig order to access important and novel organic precursors.
Focusing on indoles, Table 4 provides a summary of available metho thesis of propargyl-indole hybrids 113 via the reaction of indole derivativ versely substituted propargyl derivatives 54/63, employing various Lewis and superacids, in molecular solvents, as well in ionic liquids (entries 1-7) Enantioselective propargylation between indoles 112 and propargyl lyzed by the transition metal CuOTf•1/2C6H6, was reported in the pres ligand ((4S,5R)-diPh-Pybox) in 4-methylmorpholine and MeOH, leading in moderate to high yields, ( Table 4, entry 8) [145]. Likewise, an asymm was described, consisting of Friedel-Crafts alkylation between substitu and propargyl carbonates 54, in the presence of Ni(cod)2 and the chiral lig and a base, in toluene, forming propargyl-indole derivatives 113 with hig tivity and regioselectively and in moderate to good yields (entry 9) [146]. N-Heterocyclic systems are important as building blocks of natural products, drugs, and functional organic materials, and the development of mild and selective methods for the direct introduction of propargyl groups into heterocyclic rings is highly desirable in order to access important and novel organic precursors.

With Allenyl Bromides
A direct method for a C-H propargylation reaction of indole derivatives 112 using bromoallenes 19c (X = Br) was reported, which employed Mn(I)/Lewis acid as cocatalyst [147]. The presence of BPh 3 not only promoted reactivity, but also enhanced selectivity. Using this method, secondary, tertiary, and even quaternary carbon centers in the propargylic position could be directly constructed, leading to diversely substituted propargyl-indoles 114 in moderate to high yields (Scheme 42) [147].

With Allenyl Bromides
A direct method for a C-H propargylation reaction of indole derivatives 112 using bromoallenes 19c (X = Br) was reported, which employed Mn(I)/Lewis acid as cocatalyst [147]. The presence of BPh3 not only promoted reactivity, but also enhanced selectivity. Using this method, secondary, tertiary, and even quaternary carbon centers in the propargylic position could be directly constructed, leading to diversely substituted propargylindoles 114 in moderate to high yields (Scheme 42) [147]. The same approach as that described in Scheme 37 was adopted for the direct metalfree ortho-propargylation of heteroaromatics 115 to produce o-propargylated heteroaromatic sulfides 116. Thus, mixtures of thiophenyl or furanyl sulfoxide 115, propargyl-TMS derivatives 17, and Tf2O were reacted in ACN as a solvent to produce products 116 regioselectively and in good to excellent yields (Scheme 43) [131]. Following the approach described in Scheme 36, a method for the synthesis of orthopropargyl iodothiophenes 119/120 was described [130]. In this case, a mixture of propargyl-TMS derivative 12, thiophenyliodine diacetates 117/118, and BF3•OEt2 in ACN/DCM as a solvent was allowed to react at low temperature to produce products 119/120 regioselectively, and in good yields (Scheme 44) [130].

With Allenyl Bromide
Following the procedure described in Scheme 42, propargylated pyrrole and thiphene derivatives 125-128 were obtained in acceptable to good yields from bromoallenes 19c (X = Br), and the corresponding heteroaromatic precursors 121-124 are shown in Scheme 45 [147]. Following the approach described in Scheme 36, a method for the synthesis of orthopropargyl iodothiophenes 119/120 was described [130]. In this case, a mixture of propargyl-TMS derivative 12, thiophenyliodine diacetates 117/118, and BF 3 •OEt 2 in ACN/DCM as a solvent was allowed to react at low temperature to produce products 119/120 regioselectively, and in good yields (Scheme 44) [130].
(ii) Other heterocyclic substrates 2.3.8. With Propargyl-TMS The same approach as that described in Scheme 37 was adopted for the direct metalfree ortho-propargylation of heteroaromatics 115 to produce o-propargylated heteroaromatic sulfides 116. Thus, mixtures of thiophenyl or furanyl sulfoxide 115, propargyl-TMS derivatives 17, and Tf2O were reacted in ACN as a solvent to produce products 116 regioselectively and in good to excellent yields (Scheme 43) [131]. Following the approach described in Scheme 36, a method for the synthesis of orthopropargyl iodothiophenes 119/120 was described [130]. In this case, a mixture of propargyl-TMS derivative 12, thiophenyliodine diacetates 117/118, and BF3•OEt2 in ACN/DCM as a solvent was allowed to react at low temperature to produce products 119/120 regioselectively, and in good yields (Scheme 44) [130].

With Allenyl Bromide
Following the procedure described in Scheme 42, propargylated pyrrole and thiphene derivatives 125-128 were obtained in acceptable to good yields from bromoallenes 19c (X = Br), and the corresponding heteroaromatic precursors 121-124 are shown in Scheme 45 [147].

With Allenyl Bromide
Following the procedure described in Scheme 42, propargylated pyrrole and thiphene derivatives 125-128 were obtained in acceptable to good yields from bromoallenes 19c (X = Br), and the corresponding heteroaromatic precursors 121-124 are shown in Scheme 45 [147].

Acyl Halides With Propargyl-Organolithium Reagent
Homopropargyl and bis-homopropargyl alcohols are convenient intermediates in organic synthesis [152]. Previous studies have established that the controlled lithiation of allenes forms operational equivalents of propargyl dianions (C 3 H 2 Li 2 , 1,3-dilithiopropyne) 143 [153,154]. In this vein, controlled dilithiation of propargyl bromide with two equivalents of n-butyllithium, in the presence of TMEDA, was reported to be a productive method for the synthesis of bis-homopropargylic alcohols 142 (Scheme 47). In this approach, dianion 141 underwent in situ reactions with acid chlorides 140 to produce alcohols 142 in moderate yields with high regioselectivity [155].

With Propargyl Bromide
Among the nitrogen-containing fused heterocycles, quinoline, azepine, and triazole moieties are considered privileged scaffolds, are present in numerous natural products, and are among the most widely exploited heterocyclic rings for the development of bioactive molecules [157][158][159]. The propargylation of secondary amines 149, prepared via the

With Propargyl Bromide
Among the nitrogen-containing fused heterocycles, quinoline, azepine, and triazole moieties are considered privileged scaffolds, are present in numerous natural products, and are among the most widely exploited heterocyclic rings for the development of bioactive molecules [157][158][159]. The propargylation of secondary amines 149, prepared via the

With Propargyl Bromide
Among the nitrogen-containing fused heterocycles, quinoline, azepine, and triazole moieties are considered privileged scaffolds, are present in numerous natural products, and are among the most widely exploited heterocyclic rings for the development of bioactive molecules [157][158][159]. The propargylation of secondary amines 149, prepared via the reductive amination of 2-chloro-3-formylquinolines 148, produced tertiary propargylamines 150 as key intermediates for the synthesis of fused-heterocyclic products 151, incorporating three active pharmacophores (quinoline, azepine and triazole) in a single molecular framework [160]; this illustrates the potential of the N-propargyl moiety in heterocyclic synthesis (Scheme 50).
Molecules 2023, 28, x FOR PEER REVIEW 29 of 65 reductive amination of 2-chloro-3-formylquinolines 148, produced tertiary propargylamines 150 as key intermediates for the synthesis of fused-heterocyclic products 151, incorporating three active pharmacophores (quinoline, azepine and triazole) in a single molecular framework [160]; this illustrates the potential of the N-propargyl moiety in heterocyclic synthesis (Scheme 50). Chiral N-tert-butanesulfinyl imines are important for the stereoselective synthesis of nitrogen-containing heterocyclic systems [161]. With the goal of synthesizing 3-substituted 1,2,3,4-tetrahydroisoquinolines 153 in an enantioenriched form, the N-propargylation of enantioenriched homopropargylic amines 74 was performed under basic conditions to give the corresponding 4-azaocta-1,7-diyne intermediates 152 in fair to good yields (Scheme 51). An oxidation step, followed by [2+2+2] cyclotrimerization promoted by a Wilkinson catalyst, produced the target structure 153 which contained substituents at the 3-, 6-and 7-positions in high yields [106]. This illustrative example highlights the efficacy of bis-homopropargylamine in heterocyclic synthesis. Chiral N-tert-butanesulfinyl imines are important for the stereoselective synthesis of nitrogen-containing heterocyclic systems [161]. With the goal of synthesizing 3-substituted 1,2,3,4-tetrahydroisoquinolines 153 in an enantioenriched form, the N-propargylation of enantioenriched homopropargylic amines 74 was performed under basic conditions to give the corresponding 4-azaocta-1,7-diyne intermediates 152 in fair to good yields (Scheme 51). An oxidation step, followed by [2+2+2] cyclotrimerization promoted by a Wilkinson catalyst, produced the target structure 153 which contained substituents at the 3-, 6-and 7-positions in high yields [106]. This illustrative example highlights the efficacy of bishomopropargylamine in heterocyclic synthesis. ondary amines 149 with propargyl bromide 19a in the presence of calcium carbonate. Chiral N-tert-butanesulfinyl imines are important for the stereoselective synthesis of nitrogen-containing heterocyclic systems [161]. With the goal of synthesizing 3-substituted 1,2,3,4-tetrahydroisoquinolines 153 in an enantioenriched form, the N-propargylation of enantioenriched homopropargylic amines 74 was performed under basic conditions to give the corresponding 4-azaocta-1,7-diyne intermediates 152 in fair to good yields (Scheme 51). An oxidation step, followed by [2+2+2] cyclotrimerization promoted by a Wilkinson catalyst, produced the target structure 153 which contained substituents at the 3-, 6-and 7-positions in high yields [106]. This illustrative example highlights the efficacy of bis-homopropargylamine in heterocyclic synthesis. The N-propargylation of substituted isatins 4 (R = H) was accomplished via a microwave-assisted reaction using anhydrous K2CO3 as base in DMF solvent, according to Scheme 53, to produce a set of diversely substituted N-propargyl isatins 156 in good to excellent yields [163]. The N-propargylation of vinyl sulfoximines 154 with propargyl bromide 19a produced N-propargyl-sulfoximines 155 as highly functionalized biologically promising small molecules (Scheme 52) [162]. ondary amines 149 with propargyl bromide 19a in the presence of calcium carbonate. Chiral N-tert-butanesulfinyl imines are important for the stereoselective synthesis of nitrogen-containing heterocyclic systems [161]. With the goal of synthesizing 3-substituted 1,2,3,4-tetrahydroisoquinolines 153 in an enantioenriched form, the N-propargylation of enantioenriched homopropargylic amines 74 was performed under basic conditions to give the corresponding 4-azaocta-1,7-diyne intermediates 152 in fair to good yields (Scheme 51). An oxidation step, followed by [2+2+2] cyclotrimerization promoted by a Wilkinson catalyst, produced the target structure 153 which contained substituents at the 3-, 6-and 7-positions in high yields [106]. This illustrative example highlights the efficacy of bis-homopropargylamine in heterocyclic synthesis. The N-propargylation of substituted isatins 4 (R = H) was accomplished via a microwave-assisted reaction using anhydrous K2CO3 as base in DMF solvent, according to Scheme 53, to produce a set of diversely substituted N-propargyl isatins 156 in good to excellent yields [163]. The N-propargylation of substituted isatins 4 (R = H) was accomplished via a microwaveassisted reaction using anhydrous K 2 CO 3 as base in DMF solvent, according to Scheme 53, to produce a set of diversely substituted N-propargyl isatins 156 in good to excellent yields [163].

With Propargylic Cation Intermediates
The nucleophilic addition of the primary amino-ester 169 to cobalt-stabilized propargylic carbocation 170-initially in the presence of BF3•OEt2, followed by CAN, as catalytic systems-generated the corresponding dipropargylamino-ester 171 according to Scheme 57 [167].

With Propargylic Cation Intermediates
The nucleophilic addition of the primary amino-ester 169 to cobalt-stabilized propargylic carbocation 170-initially in the presence of BF3•OEt2, followed by CAN, as catalytic systems-generated the corresponding dipropargylamino-ester 171 according to Scheme 57 [167]. Scheme 57. Synthesis of dipropargylamino-ester 171 using co-stabilized propargylic carbocation 170 as a propargylating agent, in the presence of BF3•OEt2/CAN as a catalytic system.

Vinylstananes
With Propargyl Bromide A methodology involving the coupling of vinyl-stannanes (β-trifluoromethyl (Z)-αand (Z)-β-stannylacrylates) 172 to propargylic bromides 19a catalyzed by copper(I) provided access to the corresponding propargylated products 173 without allenic transposition (Scheme 58). This Pd-free cross-coupling process tolerated various R-groups, and occurred with retention of the configuration at the double bond; furthermore, homocoupling and allenic products were not detected [168]. Scheme 57. Synthesis of dipropargylamino-ester 171 using co-stabilized propargylic carbocation 170 as a propargylating agent, in the presence of BF 3 •OEt 2 /CAN as a catalytic system.

Vinylstananes With Propargyl Bromide
A methodology involving the coupling of vinyl-stannanes (β-trifluoromethyl (Z)-αand (Z)-β-stannylacrylates) 172 to propargylic bromides 19a catalyzed by copper(I) provided access to the corresponding propargylated products 173 without allenic transposition (Scheme 58). This Pd-free cross-coupling process tolerated various R-groups, and occurred with retention of the configuration at the double bond; furthermore, homocoupling and allenic products were not detected [168].
Expanding on the strategy for the synthesis of quinoline/azepine pharmacophores fused to a triazole moiety (see Scheme 50), hetero-polycyclic products 179 were obtained from (2-chloroquinolin-3-yl)methanol derivatives 177 via the O-propargylation of 177 to give the key propargyl intermediates 178, followed by a click reaction and Pd-catalyzed C-H functionalization (Scheme 60) [160]. The O-Propargylation of oxime 180 with propargyl bromide 19a, according to Scheme 61, provided facile access to the perylenediimide compound 181, whose main characteristic was its capability to detect Cu 2+ and Pd +2 ions in water [174]. The O-Propargylation of oxime 180 with propargyl bromide 19a, according to Scheme 61, provided facile access to the perylenediimide compound 181, whose main characteristic was its capability to detect Cu 2+ and Pd +2 ions in water [174]. Scheme 62 highlights two synthetic strategies for access to propargylated ethers 183 and 186. The first process involves the cyclization of L-glutamic acid to obtain the lactone 182, which was reacted with propargyl bromide 19a in alkaline medium in a mixture of polar aprotic solvents to obtain the propargylated lactone 183 in moderate yields [175]. Compound 183 was then used as a starting point for multistep synthesis, leading to polycyclic compound 184. The goal of the second etherification process was to generate propargylated disaccharides. In this case, glycoside 185 was reacted with propargyl bromide 19a to produce the tetra-propargylated arabino-3,6-galactane 186 in good yields [176]. Scheme 62 highlights two synthetic strategies for access to propargylated ethers 183 and 186. The first process involves the cyclization of L-glutamic acid to obtain the lactone 182, which was reacted with propargyl bromide 19a in alkaline medium in a mixture of polar aprotic solvents to obtain the propargylated lactone 183 in moderate yields [175]. Compound 183 was then used as a starting point for multistep synthesis, leading to polycyclic compound 184. The goal of the second etherification process was to generate propargylated disaccharides. In this case, glycoside 185 was reacted with propargyl bromide 19a to produce the tetra-propargylated arabino-3,6-galactane 186 in good yields [176]. Scheme 62 highlights two synthetic strategies for access to propargylated ethers 183 and 186. The first process involves the cyclization of L-glutamic acid to obtain the lactone 182, which was reacted with propargyl bromide 19a in alkaline medium in a mixture of polar aprotic solvents to obtain the propargylated lactone 183 in moderate yields [175]. Compound 183 was then used as a starting point for multistep synthesis, leading to polycyclic compound 184. The goal of the second etherification process was to generate propargylated disaccharides. In this case, glycoside 185 was reacted with propargyl bromide 19a to produce the tetra-propargylated arabino-3,6-galactane 186 in good yields [176].

With Propargyl Alcohol/Ethers
An efficient method for the synthesis of end-functionalized oligosaccharides from unprotected monosaccharides using a one-pot/two-step approach was developed (Scheme 66) [180]. In the first step, mannose 197 was functionalized with propargyl alcohol 63 (R = R 1 = H) at the anomeric position through Fisher glycosylation using Amberlyst-15, producing a propargyl monosaccharide 198. In a second step, the reaction mixture was heated under vacuum at 100 °C in order to increase the degree of polymerization of 198, Implementing the strategy outlined in Scheme 55, a series of O-propargylated compounds 191a-d bearing one or two propargyl groups in their structures were synthesized using 3-methyl-9H-carbazol-1-ol (187a), 4-hydroxycoumarin (187b), and α-mangostin (187c) as substrates (Scheme 64). These compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines, the HepG2, LU-1, and Hela cell lines. Compound 191c proved most active, showing IC50 values of 1.02, 2.19, and 2.55 µg/mL, respectively [165].

With Propargyl Alcohol/Ethers
An efficient method for the synthesis of end-functionalized oligosaccharides from unprotected monosaccharides using a one-pot/two-step approach was developed (Scheme 66) [180]. In the first step, mannose 197 was functionalized with propargyl alcohol 63 (R = R 1 = H) at the anomeric position through Fisher glycosylation using Amberlyst-15, producing a propargyl monosaccharide 198. In a second step, the reaction mixture was heated under vacuum at 100 °C in order to increase the degree of polymerization of 198, leading to a fully functionalized propargylated glycoside 199, with a degree of polymeri-

With Propargyl Alcohol/Ethers
An efficient method for the synthesis of end-functionalized oligosaccharides from unprotected monosaccharides using a one-pot/two-step approach was developed (Scheme 66) [180]. In the first step, mannose 197 was functionalized with propargyl alcohol 63 (R = R 1 = H) at the anomeric position through Fisher glycosylation using Amberlyst-15, producing a propargyl monosaccharide 198. In a second step, the reaction mixture was heated under vacuum at 100 • C in order to increase the degree of polymerization of 198, leading to a fully functionalized propargylated glycoside 199, with a degree of polymerization (n) up to 8 [180]. The reaction of difluoropropargyl-bromide-dicobalt complexes 188 with enolizable ketones and aldehydes 204, in the presence of AgNTf2 and with iPr2NEt or DTBMP as a base, led to the synthesis of difluoropropargyl vinyl ether-dicobalt complexes 205 bearing diverse substituents (Scheme 69). These compounds were then utilized as convenient precursors for the synthesis of difluorodienone and difluoroallene derivatives [182].  The reaction of difluoropropargyl-bromide-dicobalt complexes 188 with enolizable ketones and aldehydes 204, in the presence of AgNTf 2 and with iPr 2 NEt or DTBMP as a base, led to the synthesis of difluoropropargyl vinyl ether-dicobalt complexes 205 bearing diverse substituents (Scheme 69). These compounds were then utilized as convenient precursors for the synthesis of difluorodienone and difluoroallene derivatives [182]. The propargylation of phenolic hydroxyl groups is important because of its potential as starting material for the preparation of high-molecular-weight synthetic and natural polymers. The reaction of propargyl bromide 19a with the phenolic OHs of the lignin derivative 206, in the presence of an aqueous base, yielded a propargylated-lignin product 210 (entry 1) [183]. In other studies, the propargylation of phenols 207, 208, and 209, in the presence of K2CO3 as catalysts in acetone or DMF and under MW irradiation, produced the corresponding propargylated ethers 211 (entry 2) [184], 212 (entry 3) [185], and 213 (entry 4) [186] (Scheme 70). These compounds were further functionalized via "click" chemistry.

With Propargyl Alcohols/Ethers
Following the procedure described in Scheme 57, propargylated tyrosine derivatives 215, were prepared starting from with dicobalt complexes 202 as propargylating agents, according to Scheme 71, and employing BF3•OEt2 and CAN as catalytic systems [167].

With Propargyl Alcohols/Ethers
Following the procedure described in Scheme 57, propargylated tyrosine derivatives 215, were prepared starting from with dicobalt complexes 202 as propargylating agents, according to Scheme 71, and employing BF 3 •OEt 2 and CAN as catalytic systems [167]. The propargylation of phenolic hydroxyl groups is important because of its potential as starting material for the preparation of high-molecular-weight synthetic and natural polymers. The reaction of propargyl bromide 19a with the phenolic OHs of the lignin derivative 206, in the presence of an aqueous base, yielded a propargylated-lignin product 210 (entry 1) [183]. In other studies, the propargylation of phenols 207, 208, and 209, in the presence of K2CO3 as catalysts in acetone or DMF and under MW irradiation, produced the corresponding propargylated ethers 211 (entry 2) [184], 212 (entry 3) [185], and 213 (entry 4) [186] (Scheme 70). These compounds were further functionalized via "click" chemistry.
The preparation of C-propargylic esters 228 was carried out via a reaction between N-protected amino acids 227 and propargyl bromide 19a (R = Br) in DMF in the presence of anhydrous potassium carbonate (Scheme 74, entry 3) [191].

With O-Propargylated Hydroxylamine
A novel bio-orthogonal prodrug 231 of the HDACi panobinostat was developed that was harmless to cells and could be converted back into the cytotoxic panobinostat via Au catalysis. The key propargylated product 231 was obtained from O-propargylated hydroxylamine 230 with β-substituted-acrylic acid 229 using N-(3-dimethylaminopropyl)-N′ethylcarbodiimide hydrochloride (EDC) in H2O, according to Scheme 75 [192]. The preparation of C-propargylic esters 228 was carried out via a reaction between N-protected amino acids 227 and propargyl bromide 19a (R = Br) in DMF in the presence of anhydrous potassium carbonate (Scheme 74, entry 3) [191].

With O-Propargylated Hydroxylamine
A novel bio-orthogonal prodrug 231 of the HDACi panobinostat was developed that was harmless to cells and could be converted back into the cytotoxic panobinostat via Au catalysis. The key propargylated product 231 was obtained from O-propargylated hydroxylamine 230 with β-substituted-acrylic acid 229 using N-(3-dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride (EDC) in H 2 O, according to Scheme 75 [192]. Scheme 74. Propargylation of the hydroxyl groups in carboxylic acids 223, 225, and 227 using propargyl bromide 19a and propargylamine 222.

With O-Propargylated Hydroxylamine
A novel bio-orthogonal prodrug 231 of the HDACi panobinostat was developed that was harmless to cells and could be converted back into the cytotoxic panobinostat via Au catalysis. The key propargylated product 231 was obtained from O-propargylated hydroxylamine 230 with β-substituted-acrylic acid 229 using N-(3-dimethylaminopropyl)-N′ethylcarbodiimide hydrochloride (EDC) in H2O, according to Scheme 75 [192].

With Propargylic Cation Intermediates
Following a similar procedure to that described in Scheme 57, the propargylated N-Bz-D-phenylalanine 232 was synthesized through its carboxyl-CO2H functionality, by reacting the propargyl-dicobalt complex 170 with a phenylalanine derivative 227 (R 1 = Bn) in the presence of BF3•OEt2 and CAN (Scheme 76) [167].

With Propargylic Cation Intermediates
Following a similar procedure to that described in Scheme 57, the propargylated N-Bz-D-phenylalanine 232 was synthesized through its carboxyl-CO 2 H functionality, by reacting the propargyl-dicobalt complex 170 with a phenylalanine derivative 227 (R 1 = Bn) in the presence of BF 3 •OEt 2 and CAN (Scheme 76) [167]. Scheme 74. Propargylation of the hydroxyl groups in carboxylic acids 223, 225, and 227 using propargyl bromide 19a and propargylamine 222.

With O-Propargylated Hydroxylamine
A novel bio-orthogonal prodrug 231 of the HDACi panobinostat was developed that was harmless to cells and could be converted back into the cytotoxic panobinostat via Au catalysis. The key propargylated product 231 was obtained from O-propargylated hydroxylamine 230 with β-substituted-acrylic acid 229 using N-(3-dimethylaminopropyl)-N′ethylcarbodiimide hydrochloride (EDC) in H2O, according to Scheme 75 [192].

With Propargylic Cation Intermediates
Following a similar procedure to that described in Scheme 57, the propargylated N-Bz-D-phenylalanine 232 was synthesized through its carboxyl-CO2H functionality, by reacting the propargyl-dicobalt complex 170 with a phenylalanine derivative 227 (R 1 = Bn) in the presence of BF3•OEt2 and CAN (Scheme 76) [167].  Catalytic enantioselective allylic substitution is a widely used strategy in organic synthesis, because it transforms an alkenyl substrate into a new unsaturated compound bearing an allylic stereogenic center [193].
Transformations of acyclic, or aryl-, heteroaryl-, and alkyl-substituted penta-2,4-dienyl phosphates 233, as well as cyclic dienyl phosphates 234, were carried out in the presence of commercially available allenyl-B-(pinacolato) 2c, mediated by a sulfonate-containing NHC-Cu complex (NHC = imidazolyl carbene). Products 235/236 were obtained that contained, in addition to a 1,3-dienyl group, a readily functionalizable propargyl moiety (Scheme 77). The positive attributes of this reaction were high yields, high E:Z ratios, and impressive enantiomeric ratios (er). Kinetic isotope effect measurements and DFT computations provided mechanistic insights into this catalytic process [194]. Catalytic enantioselective allylic substitution is a widely used strategy in organic synthesis, because it transforms an alkenyl substrate into a new unsaturated compound bearing an allylic stereogenic center [193].
Focusing on allylic substitution, in another study, 1,5-enynes 238 were synthesized via a silver-catalyzed allylic substitution by reacting a propargylic organoboron compound 2a with allylic phosphates 237, using a chiral N-heterocyclic carbene (NHC) ligand and a silver catalyst complexed to a copper chloride salt (Scheme 78) [195]. In all cases, the incorporation of the propargylic group was favored over allenyl addition. . The reaction exhibited a broad substrate scope, with the possibility for the recovery/reuse of the IL solvent with a minimal decrease in isolated yields, after six cycles [196]. . The reaction exhibited a broad substrate scope, with the possibility for the recovery/reuse of the IL solvent with a minimal decrease in isolated yields, after six cycles [196]. Focusing on allylic substitution, in another study, 1,5-enynes 238 were synthesized via a silver-catalyzed allylic substitution by reacting a propargylic organoboron compound 2a with allylic phosphates 237, using a chiral N-heterocyclic carbene (NHC) ligand and a silver catalyst complexed to a copper chloride salt (Scheme 78) [195]. In all cases, the incorporation of the propargylic group was favored over allenyl addition. . The reaction exhibited a broad substrate scope, with the possibility for the recovery/reuse of the IL solvent with a minimal decrease in isolated yields, after six cycles [196]. In another approach, diarylalkenyl propargylic frameworks 242 were synthesized via an Fe-catalyzed reaction of propargylic alcohols 63 with various symmetric and asymmetric 1,1-diarylethylenes 241 (Scheme 80). The reaction worked well for a wide range of ethylenes 241 bearing electron-donating or electron-withdrawing groups (as R 2 or R 3 substituents) [197]. In another approach, diarylalkenyl propargylic frameworks 242 were synthesized via an Fe-catalyzed reaction of propargylic alcohols 63 with various symmetric and asymmetric 1,1-diarylethylenes 241 (Scheme 80). The reaction worked well for a wide range of ethylenes 241 bearing electron-donating or electron-withdrawing groups (as R 2 or R 3 substituents) [197]. An efficient catalytic method for the propargylation of quinones 243 that benefits from the cooperative effect of Sc(OTf)3 and Hantzsch ester (HE) has been reported, yielding the corresponding propargylated quinone derivatives 244 (Scheme 81). Using this approach, a broad range of propargylic alcohols 63 were converted into the appropriate propargyl derivatives 244 in acceptable to excellent yields [198]. An efficient catalytic method for the propargylation of quinones 243 that benefits from the cooperative effect of Sc(OTf) 3 and Hantzsch ester (HE) has been reported, yielding the corresponding propargylated quinone derivatives 244 (Scheme 81). Using this approach, a broad range of propargylic alcohols 63 were converted into the appropriate propargyl derivatives 244 in acceptable to excellent yields [198]. Scheme 81. Cooperative catalytic propargylation of quinones 243 mediated by Sc(OTf) 3 and Hantzsch ester (HE).

With Propargyl Bromides
The development of enantioselective alkyl-alkyl cross-couplings with the formation of a stereogenic center is significant and highly desirable. In this context, the regio-and enantioselective Ni-catalyzed hydropropargylation of acrylamides 245 yielded propargylamides 246 bearing a tertiary stereogenic carbon center (Scheme 82). This protocol was carried out using propargyl bromides with alkyl, aryl, and silyl substituents 19a in the presence of a NiBr 2 glyme, an (R,R)-L12 chiral ligand, trimethoxylsilane, potassium phosphate monohydrate, and tert-butanol in diethyl ether, producing Csp 3 -Csp 3 cross-coupling products 246 in good yields and with excellent enantioselectivities [199].

With Propargyl Ethers/Esters
Allenamides have received increasing attention in recent decades due to their diverse reactivity. In this context, highly diastereoselective oxy-propargylamination of allenamides 248 with C-alkynyl N-Boc-acetals as difunctionalization reagents 247 has been described, which employs XPhosAu-(MeCN)PF 6 as a catalyst. This methodology provided highly functionalized propargyl-1,3-amino alcohol derivatives 249 in acceptable to good yields and with good to excellent diastereoselectivities (Scheme 83) [200].
Propargylic alcohols can be activated towards S N 1-type reactions with nucleophiles using a variety of Lewis acids or Brønsted acids as catalysts [206]. In this process, the highly stereoselective organocatalytic alkylation of internal propargylic alcohols with aldehydes has been described, with water used as a solvent, using a mixture of In(OTf) 3 and the MacMillan organocatalyst L*; these worked in a cooperative manner to produce propargyl aldehydes 270 regioselectively (Scheme 88). The reported method is versatile and tolerates diverse functional groups, allowing for the use of highly functionalized internal alkynes 63 and aldehydes 269 as precursors. According to the reaction conditions, the formation of 270 proceeds via an S N 1-type reaction involving a stabilized propargylic cation species formed via the ionization of propargylic alcohols 63 [207].  [211].
Scheme 91 illustrates the reported synthesis of γ-ketoacetylene 284 via a condensation reaction between propargyl chloride 282 and β-keto ester 283 in the presence of sodium hydride [213]. This compound is a key intermediate in the biomimetic synthesis of plumarellide, a polycyclic diterpene [214]. 1,4-Diynes are valuable and versatile synthons for natural products, organometallic complexes, and the synthesis of novel molecules [215]. Scheme 92 illustrates a reported method for the catalytic synthesis of difluorinated compounds 286, difluoromethylene (CF 2 )-skipped 1,4-diynes, via palladium-catalyzed cross-coupling between terminal alkynes 62 and gem-difluoropropargyl bromide 285 in toluene. The method exhibited high functional group tolerance and a broad substrate scope [216]. Compounds bearing a quaternary carbon stereocenter are important building blocks in medicinal chemistry, and are found in biologically active compounds such as pharmaceuticals and agrochemicals. Scheme 93 illustrates an efficient enantioselective method for the asymmetric α-alkylation of α-branched aldehydes 204 with propargyl bromide 19a to generate products 287 bearing a chiral quaternary carbon stereocenter. The reaction proceeds through enamine-based organocatalysis using a chiral primary amino acid as a catalyst [217]. Propargylated products 289 were synthesized via the Suzuki-type coupling of propargylic electrophiles 19d/109 with diborylmethane 288, using CuI/PPh 3 as the catalytic system and tBuOLi as a base, under mild conditions with good functional group tolerance (Scheme 94) [218]. Scheme 94. CuI/PPh 3 -mediated Suzuki-Miyaura-type cross-coupling reaction for the synthesis of propargylated products 289 from propargyl electrophiles 19d/109 and diborylmethane 288.

With Propargyl Ethers or Esters
The diastereo-and enantioselective synthesis of 2,2-disubstituted benzofuran-3(2H)ones 291 was achieved via a "copper-pybox"-catalyzed reaction between 2-substituted benzofuran-3(2H)-ones 290 and propargyl acetates 200 (R = Ac), as outlined in Scheme 95, entry 1. The positive attributes of the method were good functional group tolerance and broad substrate scope. The utility of the method was demonstrated by further transformation of the terminal alkyne of 291 into a methyl ketone without loss of enantiomeric purity [219]. Using a similar approach, propargyl tricarboxylate derivatives 293 were synthesized via the copper-catalyzed enantioselective propargylation of triethylmethanetricarboxylate 292 with propargylic alcohol derivatives 200. The active catalyst "copperpybox" was generated by combining the copper complex Cu(CH 3 CN) 4 BF 4 with (S)-secbutyl-Pybox (Ligand L1*) at low temperatures in methanol, with DIPEA as base, as outlined in Scheme 95, entry 2. The scope of the methodology was demonstrated using phenyl-substituted propargylic substrates 200 bearing electron-donating as well as electronwithdrawing groups at the para-position of the phenyl ring [220].  (vi) Enantioselective copper-catalyzed vinylogous propargylic substitution with coumarin derivatives. In this approach, aromatic and aliphatic propargylic esters 200 reacted with substituted coumarins 306 under mild conditions to yield propargylated coumarin derivatives 307 with impressive enantioselectivities (Scheme 98). Further, biological studies on the compounds 307 led to the discovery of a novel class of autophagy inhibitors [226].
A series of substituted pyrrole derivatives 310 were synthesized via a zinc(II) chloridecatalyzed regioselective propargylation/amination/cycloisomerization process by reacting enoxysilanes 309 with propargylic acetates 200 and primary amines 94. This method was applicable to a variety of aromatic and aliphatic propargylic acetates 200 without the necessity of isolating intermediates such as 258 (Scheme 100) [228]. A series of diversely substituted propargyl ethers 311 were obtained via a Re(I)catalyzed hydropropargylation reaction between silyl enol ethers 309 and propargyl ether 191 (Scheme 101). Mechanistic studies suggested that the reaction proceeded via the intermediacy of vinylidene-alkenyl metal intermediates undergoing a 1,5-hydride transfer to generate the isolated products 311 [229]. Fully substituted pyrroles are important bioactive motifs, and are widely presented in many biologically active compounds and natural products [230]. In this context, a coppercatalyzed and microwave-assisted tandem propargylation/alkyne azacyclization/isomerization sequence between propargyl acetates 200 and β-enamino compounds 312 was established (Scheme 102). Through this process, a series of pentasubstituted pyrroles 314 were synthesized. This transformation was characterized by a broad substrate scope that tolerated diverse substituents in its starting materials 200 and 312, and could be scaled up for further biomedical research. A mechanistic sequence in which an enyne-like structure 313 acts as a key intermediate in the catalytic cycle was proposed [231].

With 1,3-Diarylpropynes
Direct C-C coupling from Csp 3 -H bonds with molecular oxygen as the terminal oxidant continues to be a challenging task. In this context, diversely substituted propargyl adducts 318 were synthesized via a coupling reaction between 1,3-dicarbonyl compounds 257/259 and 1,3-diarylpropynes 57 in the presence of molecular oxygen, DDQ, and sodium nitrite (Scheme 104). The addition of HCO 2 H dramatically increased the speed of the process [233]. Scheme 104. Synthesis of propargyl adducts 318 from a coupling reaction between 1,3-dicarbonyl compounds 257/259 and 1,3-diarylpropynes 57 in the presence of molecular oxygen, DDQ, and sodium nitrite.

With Propargyl Aldehydes
The metal-free, amino acid-catalyzed, three-component reductive coupling of propargyl aldehydes 319 and cyclic/acyclic methylene-active compounds 320/321, in the presence of Hantzsch ester and (S)-proline as catalysts, produced diversely substituted and gramscalable propargylated cyclic/acyclic systems 322/323 (Scheme 105). To demonstrate the synthetic value of this protocol, in selected cases, adducts 322/323 were further transformed into dihydropyran derivatives through an annulative etherification reaction using AgOTf as a catalyst [234]. The propargylated alcohol 325 was synthesized via catalytic asymmetric propargylation of the highly enolizable β-keto-lactone 324 with propargyl aldehyde 319 (Scheme 106). The reaction was mediated by an Evans aldol type reaction [235], promoted by rigorously acid-free Sn(OTf) 2 . Notably, the synthesis of this compound was a key step in the total synthesis of leiodermatolide, a natural product derived from a deep-sea sponge with potent cytotoxic activity (Scheme 106) [236].

Carbocationic Electrophiles With Propargyl Organometallic-Based Reagents
A series of diversely substituted o-propargylated phenols 327 were obtained through the transition metal-free alkynylation of substituted 2-(tosylmethyl)phenols 326 with bromo(alkynyl)zinc reagents 89, generated from the corresponding terminal alkyne with BuLi and ZnBr 2 , under N 2 at room temperature. This efficient strategy exhibited good functional group compatibility (Scheme 107). The products were further used as intermediates for the synthesis of 2,3-disubstituted benzofurans [237]. A method for the synthesis of spiroketals 329 bearing a five-membered and a sevenor eight-membered ring was described. In this approach, initially, the alkyne 328 was treated with Co 2 (CO) 8 in DCM at room temperature to form the corresponding alkyne-Co 2 (CO) 6 complex intermediates, which were subsequently exposed to BF 3 •OEt 2 at low temperature to produce the desired dioxaspiro [4.7]-compounds 329 (Scheme 108). This method was applicable to cyclopropanes possessing gem-disubstituents, as well as monoaryl substituents [238]. Among the metal catalysts that promote alcohol C-H functionalization via C-X bond reductive cleavage pathways, rhodium-based catalysts were shown to be promising candidates [240]. In this sense, the carbinol C-propargylation of alcohols 187 with propargyl chlorides 19d in basic media, under rhodium-catalyzed transfer hydrogenation, enabled the direct conversion of primary alcohols 187 into propargylated alcohols 13. Interestingly, this methodology tolerated benzylic and heteroaromatic benzylic alcohols, as well as aliphatic and allylic alcohols 187, producing the expected homopropargyl alcohols 13 in good yields (Scheme 110) [241]. A radical hydrodifluoropropargylation method in which alkenes 241 are reacted with silyl-protected bromodifluoropropyne 285 in DMF, at room temperature and under irradiation with blue LEDs, has been described [242]. The method employed diphenyldisulfide and benzothiazoline 333 as reductants, yielding silyl-protected difluoropropargylated products 334 in acceptable to good yields, with wide functional group tolerance (Scheme 111) [242]. Scheme 111. Blue LED-catalyzed synthesis of difluoropropargylated products 334 from alkenes 241 and silyl-protected bromodifluoropropyne 285 as propargylating agent.

Nitrones With Propargyl Bromide
The propargylation of chiral nonracemic mono-and poly-hydroxylated cyclic nitrone derivatives 338-340 with Grignard reagents (generated in situ) was established as an efficient method for preparing building blocks containing an alkyne moiety 341-343. These compounds were then employed in copper-catalyzed azide alkyne cycloaddition click chemistry [247]. The synthesis of 341-343 was accompanied, in most cases, by the formation of diastereomeric mixtures, and also required the use of (trimethylsilyl)propargyl bromide 19a as a precursor for the formation of the Grignard reagent, in order to avoid the formation of undesired allene derivatives (Scheme 114).

Conclusions and Outlook
This review has underscored the importance of the propargyl moiety as a highly versatile and powerful building block in organic synthesis. Propargylic and homopropargylic reagents have been synthesized from a variety of precursors and applied to a highly diverse array of substrates to synthesize propargylated derivatives. Judicious selections of catalysts, co-catalysts, and chiral ligands have resulted in the development the stereo-and enantioselective synthesis of numerous functional small molecules, with applications in natural products and medicinal chemistry. The progress in this area during the last decade has been nothing short of astonishing. Clearly, this is a highly dynamic and continuously evolving research area, and we are confident that it will continue to advance in the coming decade.