1,3-Butadiynamides the Ethynylogous Ynamides: Synthesis, Properties and Applications in Heterocyclic Chemistry

Abstract

1,3-butadiynamides—the ethynylogous variants of ynamides—receive considerable attention as precursors of complex molecular scaffolds for organic and heterocyclic chemistry. The synthetic potential of these C4-building blocks reveals itself in sophisticated transition-metal catalyzed annulation reactions and in metal-free or silver-mediated HDDA (Hexa-dehydro-Diels–Alder) cycloadditions. 1,3-Butadiynamides also gain significance as optoelectronic materials and in less explored views on their unique helical twisted frontier molecular orbitals (Hel-FMOs). The present account summarizes different methodologies for the synthesis of 1,3-butadiynamides followed by the description of their molecular structure and electronic properties. Finally, the surprisingly rich chemistry of 1,3-butadiynamides as versatile C4-building blocks in heterocyclic chemistry is reviewed by compiling their exciting reactivity, specificity and opportunities for organic synthesis. Besides chemical transformations and use in synthesis, a focus is set on the mechanistic understanding of the chemistry of 1,3-butadiynamides—suggesting that 1,3-butadiynamides are not just simple alkynes. These ethynylogous variants of ynamides have their own molecular character and chemical reactivity and reflect a new class of remarkably useful compounds.

1. Introduction

Since the disclosure of a first reliable and widely applicable synthesis of ynamides (N-alkynylamides) in 1998 [1], these functionalized acetylenes combining the diverse reactivity of a carbon–carbon triple bond with one of the most important functional groups of organic chemistry—the amino function—found widespread interest within the chemical community. Ynamides distinguish from their long-time known electron-rich variants—the ynamines (N-alkynylamines)—by having at least one electron-withdrawing group (EWG) attached to the nitrogen heteroatom. This EWG is capable of serving as a protective group in further chemical manipulations—but most importantly—it guarantees a decent chemical stability of the otherwise electron-rich acetylenic unit by lowering its HOMO. As such, the nitrogen bound EWG decreases the electron density of the adjacent alkyne moiety by inducing a more or less—but significantly—polarized carbon–carbon triple bond (Figure 1). Consequently, this results in tuning reactivity and selectivity. Ynamides are habitually bench-stable functionalized acetylenes that withstand an aqueous work-up procedure as well as purification by column chromatography on silica gel—both important features that are required for being useful molecular building blocks in organic synthesis. Over the years, the chemistry of ynamides became well-recognized. Ynamides nowadays serve as multipurpose substrates in organic synthesis including transition metal, ionic, radical and photoredox-mediated processes leading to N-heterocyclic compounds, natural products and other molecular targets for life and material sciences. Their exceptional rich and diverse chemistry covers several review articles [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16].

More recently, the ethynylogous variants of ynamides—the 1,3-butadiynamides—likewise received considerable attention in organic and heterocyclic chemistry. They found interesting use in transition metal-catalyzed annulation reactions, like the Hexa-dehydro-Diels–Alder (HDDA) reaction [17,18,19,20,21], and as optoelectronic materials due to their underlying push–pull character. Notably, the intrinsic polarization of ynamides is not only preserved in 1,3-butadiynamides. It is furthermore extendable via the ethynylogous principle from a 1,2- to a formal 1,4-polarization. Therefore, 1,3-butadiynamides are appealing for nitrogen-functionalized C4-building blocks for the construction of complex structural motifs. As both triple bonds can be simultaneously or consecutively functionalized via an electrophilic and/or nucleophilic reaction step, the selective introduction of more than one substituent might be achievable selectively. Other important features of molecular 1,3-butadiynamide scaffolds are their facile synthesis and their often superb stability. This not only accounts for 1,4-diynamides, but also for the higher conjugated oligoynamides. Some chemistry associated with 1,3-butadiynamides has been briefly mentioned in reviews covering synthesis and use of ynamines and ynamides [3,4,5,12,13,14,15,16]. However, there is so far no comprehensive article focusing on the ethynylogous variant of ynamides—the 1,3-butadiynamides. Highlighting the chemistry of 1,3-butadiynamides and compiling their reactivity, specificity and miscellaneous synthetic potential is the purpose of our present review.

2. Synthesis of 1,3-Butadiynamides

The majority of described 1,3-butadiynamides are derived from arylsulfonamides (EWG = Toluenesulfonyl (Ts), Methanesulfonyl (Ms), etc.), and only a few examples rely on carbamates (EWG = CO₂Me) or oxazolidinones. Syntheses of 1,3-butadiynamides follow the basic three retrosynthesis disconnections [a–c] as shortlisted in Scheme 1.

2.1. Disconnection [a]: Cu-Catalyzed Cross-Coupling Reactions

Disconnection [a] to 1,3-butadiynamides follows common strategies for the assembly of 1,3-bisacetylenes starting from various terminal acetylenes (Glaser–Hay coupling) or cross-couplings of terminal acetylenes with 1-bromoalkynes (Cadiot–Chodkiewicz reaction). The use of terminal ynamides in copper-catalyzed cross-coupling reactions is the major strategy to access both symmetrical and unsymmetrical 1,3-butadiynamides. The required terminal ynamides are readily available by rendering the synthetic strategies outlined in Scheme 1 [13].

Application of the Glaser–Hay reaction to terminal ynamides proceeds readily affording various sets of symmetrical substituted 1,3-butadiynamides 2a–e (Scheme 2) [22,23].

The oxidative homocoupling of terminal ynamides is usually carried out in acetone at room temperature with CuI-TMEDA (tetramethylethylenediamine) as the catalyst and by exposure to atmospheric oxygen. It is also applicable to chiral amino acid-derived terminal ynamides to deliver 1,3-diynamide 2e [24].

Unsymmetrical 1,3-butadiynamides 3a–h are available via the Cadiot–Chodkiewicz cross-coupling between terminal ynamides and 1-bromoalkynes (Scheme 3) [25,26]. Reactions are usually performed in methanol at 40 °C and require copper(I) iodide as the catalyst, n-butylamine as the base and sub-stoichiometric quantities of hydroxylamine hydrochloride. The use of the latter is crucial to avoid ynamide homocoupling by reducing any copper(II) salts present in the reaction medium. Notably, the complementary approach utilizing bromine- or iodine-terminated ynamides with terminal acetylenes was unsuccessful so far. This is reasoned by the fact that bromine- or iodine-terminated ynamides are difficult to obtain and are quite unstable [27].

The Cadiot–Chodkiewicz reaction with N-ethynylated oxazolidine-2-one 4 is also suitable for the synthesis of oxazolidine-2-one-derived 1,3-butadiynamides, which, for example, delivers the chiral push–pull 1,3-butadiynamides 5 in high yields (Scheme 4, (1)) [25].

Furthermore, but limited in scope, the palladium-mediated cross-coupling of ynamide 6 with 1-bromohexyne in (i-Pr)₂NH/toluene (2:1 (v/v)) gives the corresponding 1,3-butadiynamide 7 via a Sonogashira type reaction (Scheme 4, (2)) [28].

2.2. Disconnection [b]: Amide N-Alkynylations

In analogy to related ynamide approaches, the synthesis of 1,3-butadiynamides via a copper-mediated C-N bond formation between suitable amides and 1-bromo-1,3-butadiynes was described, though only a few examples have been realized so far. Here, the stabilization of the acting copper amide complex prior to the coupling with the 1-bromo-1,3-diyne is mandatory. This is necessary to overpower the quite facile homocoupling of 1-bromodiynes (Scheme 5) [29,30]. C-N bond formation takes place at room temperature, but the drawbacks of requiring stoichiometric amounts of copper iodide and the need of high-quality pyridine should be taken into consideration. Indeed, the use of dry pyridine, freshly distilled over CaH₂ under inert atmosphere, is required. The reaction conditions are also suitable for and were applied in the synthesis of the N-methanesulfonyl 1,3-butadiynamide 9c (EWG = Ms) [31].

Ynamide syntheses relying on sub-stoichiometric amounts of copper sulfate/1,10-phenanthroline as the catalyst in toluene at 60–95 °C [32] were extended to gain access to 1,3-butadiynamides. Efficiency, however, is lower compared to the protocol leading to carbamate-derived 1,3-butadiyne 9a via stoichiometric amounts of copper salt (36 vs. 80% yield) [29]. Notably, N-alkyl N-tosylamides are better substrates, and the synthesis of N-tosyl-1,3-butadiynamide 9d proceeds with high yields under copper-catalyzed cross-coupling conditions (Scheme 6, (1)) [33].

It is worth noting that the synthesis of N-aryl N-toluenesulfonyl ynamides (R¹ = Ar) via copper-catalyzed C-N bond-forming protocols with 1-bromo alkynes does not proceed at all, or proceeds in very low yields after several days of heating [34]. Probably, this is due to the weaker nucleophilicity of N-aryl N-toluenesulfonylamides. Therefore, the Cadiot–Chodkiewicz reaction with terminal ynamides remains the state of the art to obtain 1,3-diynamides having an N-aryl group. However, more recently, a copper-catalyzed electrophilic N-1,3-diynylation with triisopropylsilyl 1,3-diynyl benziodoxolone (10) was described to give straightforward TIPS protected 1,3-butadiynamides 11 including examples with N-aryl tosylamides (Scheme 6, (2)) [35].

2.3. Disconnection [c]: Functional Group Interconversion (FGI) at the C-Terminus

Chemical modifications of ynamides without affecting the triple bond have been scarcely explored until recently [13]. In the case of 1,3-butadiynamides, examples of modifications of the C-terminus are even fewer.

The synthesis of a terminal 1,3-butadiynamide through desilylation of the corresponding trimethylsilyl protected precursor with tributylammonium fluoride (TBAF) at −78 °C in dry THF proceeds in high yield (Scheme 7, (1)) [36]. Alternatively, access to terminal 1,3-butadiynamides is provided under basic conditions starting from the parent 1,3-butadiynamide terminated by the acetone adduct (Scheme 7, (2)) [25].

1,3-Butadiynamide synthesis followed by transformation to a terminal 1,3-butadiynamide via protective group strategies allows for the development of iterative Cadiot–Chodkiewicz couplings to higher order ethynylogous ynamides. Such iterative cross-couplings offer a straightforward entry to conjugated tri- and tetraynamides 13 and 14 using as coupling partners diynamide 12e and a 1-bromoalkyne or a 1-bromo-1,3-diyne, respectively (Scheme 7, (3) and (4)) [25].

3. Molecular Structure and Electronic Properties

1,3-Butadiynamides and their higher homologues not only gain interest as molecular building blocks in organic synthesis, but they also receive considerable attention for their unique conformation on basis of principal helical twisted molecular orbitals delocalized over the entire conjugated carbon rod, with their optoelectronic properties including NLO performance, and their possible function as molecular wire or as monomer in solid-state topo-chemical polymerizations.

Whilst axial chirality in certain odd numbered cumulenes like allenes is well-documented, the understanding of chirality based on helical twisted frontier molecular orbitals (Hel-FMO) and its impact on chemical, optical and physical properties is still in its early infancy. Markedly, it is mainly limited to the theoretical and computational description of conjugated cumulenes [37,38], spiroconjugated systems [39] and suitable extended conjugated oligoynes (ECOs) [40,41,42,43]. The latter favor a twisted near orthogonal conformation caused by the combination of repulsive interactions between the terminating functional groups and the constructive orbital overlap upon twisting. Nitrogen atom-terminated oligoynes are predicted of being important members of the ECO family because of both being stable and having helical molecular orbitals delocalized over the entire conjugated polyyne carbon rod (Figure 2).

For example, the high-level density functional theory (DFT) calculation of the still unknown—but synthetically feasible—diynamide 15 predict helical twisted molecular frontier orbitals with axial chiral geometry [41]. For the 1,3-diynamide 15, a torsion angle (TA) of TA = 66.74° was calculated together with a right-handed helical HOMO (Figure 2). Notably, similar values of TAs can be found in the single crystal structure data of the ynamine 16 (TA = 78.5°) [44], the 1,3-diynamines 17a (TA = 60.2°) [45] and 17b (TA = 85.2°) [46], the 1,3-diynamide 2d (TA = 76.6°) [23] and the 1,3,5-triynamide 14 (TA = 65.8°) [25]. Although these data are taken from solid-state structures, and conformational changes due to crystal structure-packing effects cannot be neglected, all TAs are of similar magnitudes and underline the influence of helical twisted molecular orbitals on the conformational output of 1,3-diynamides and their higher homologues.

A set of donor-π-spacer-acceptor “push–pull” ynamides end-capped with nitrogen donor and 4-nitro or 4-cyanophenyl acceptor units was investigated by the electro-optical absorption method (EOAM). The aim of the study was to examine their intramolecular charge transfer (ICT) properties in relation to the extent of the spacing-conjugated oligoyne units [25]. Dipole moments in solution of the ground (μ_g), the Franck–Condon excited state (μ_ε^FC) and their respective change of dipole moment (Δ^aμ) were obtained. Values of dipole moments for measurements in 1,4-dioxane of selected para-nitro-phenyl substituted ynamide derivatives are compiled in

Table 1. Electrooptical absorption measurement (EOAM) of selected “push–pull” ynamides end-capped with a nitrogen donor and a 4-nitro-phenyl acceptor unit [25].

Ynamide	μg	Δaμ	μaFC
	[10−30 Cm] in 1,4-dioxane
	9.7	74.6	84.3
	9.5	92.3	101.8
	10.9	30.8	41.7
	11.8	69.7	81.5

. The observed very high values for the change of dipole moments after transition from the ground to the Franck–Condon excited state show effective ICTs and consequently potential non-linear optical properties for these electronically tunable, extended, conjugated oligoynamides. Notably, the increase of change of dipole moments reaches a maximum for push–pull 1,3-diynamides with two spacing-conjugated alkyne units. Elongation of the conjugated alkyne units from one to two triple bonds results in an increase of the Δ^aμ values, while the ground-state dipole moments μ_g are almost unaffected. Increasing to three conjugated alkyne units, however, leads to a decrease of Δ^aμ (Figure 3).

Topochemical solid-state polymerization of 1,3-diacetylenes in single crystals gives conjugated polymers that have attracted attention on their physical properties such as conductivity, optical nonlinearity and mechanical strength. Consequently, 1,3-butadiynamides that are often crystalline materials were also investigated in topochemical polymerizations [23,47,48].

4. Addition, Cycloaddition and Oxidation Reactions

Non-symmetrical 1,3-butadiynamides—unlike their symmetrical counterparts—often act as internal ynamides. In many examples of addition and cycloaddition reactions, the 1,2-activation of the 1,3-diyne is superior to the 1,4-activation, and the second triple bond remains unaffected in the underlying transformation. However, in view of the richness of acetylene chemistry, the obtained products can often undergo further chemical transformations, broadening the array of available molecular and heterocyclic structures.

4.1. Addition Reactions

Stereodefined 1,3-dienes bearing N-substituents are important building blocks in organic synthesis. Simple access to versatile 1,4-dihalogenated E,E-1,4-dienamides was achieved from readily available symmetrical 1,3-butadiynamides 2a–b in regio- and stereoselective hydrohalogenations (Scheme 8, (1)) [49].

Hydrogen halides are generated in situ from halotrimethylsilane (Br, I) and water─or chlorotrimethylsilane and saturated ammonium chloride. Under these conditions, the perfect syn-addition of H-X (X = Cl, Br) across the ynamide triple bond occurs. The hydrobromination of non-symmetrical 1,3-butadiynamides 3f,j ensues only on the triple bond linked to the nitrogen atom, i.e., the more electron-rich carbon-carbon triple bond, affording the 1-en-3-ynamides 19a–b (Scheme 8, (2)). Notably, the hydrobromination of 1,4-diphenyl-butadiyne does not occur under similar reaction conditions. Germylzincation of 1,3-butadiynamide 20 was achieved with excellent regio- and stereoselectivity using a combination of hydrogermanes and ZnEt₂ (Scheme 9) [50].

Addition of germanium did not occur in the absence of Et₂Zn. The proposed mechanism involves the addition of a germanium-centered radical across the triple bond on β-position to the N-atom in agreement with the underlying polarization of the 1,3-butadiynamide. The resulting α-heteroatom-substituted vinyl radical undergoes ethylzinc group transfer to give the β-zincated vinylgermane 21 along with an ethyl radical keeping the radical chain propagation. The (E)-form of the vinylgermane radical is favored. Retention of the double bond geometry of the vinylzinc intermediate 21 is observed upon hydrolysis or Cu(I)-mediated C-C bond formation with 1-bromophenylacetylene. The resulting stereodefined tri- and tetrasubstituted ynenamides 22a–b and 23 can be further functionalized through displacement of germanium. Vinylgermanes gain increasing attention as alternatives to vinylsilanes and vinylstannanes for the preparation of stereodefined alkenes because of their low toxicity, increased stability towards protonolysis and facile transformation into vinyl halides.

Gold-catalyzed double hydroaminations of symmetrical substituted 1,3-butadiynamides 2a,c,f with anilines readily proceed at room temperature and deliver the corresponding 2,5-diamido-N-arylpyrroles 24a–d (Scheme 10) [51].

Moreover, the 1,2,5-trisubstituted pyrrole 25 is accessible by using phenylhydrazine as the hydroamination reagent. In this case, thermal activation is required, as well as the use of the more reactive Echavarren’s gold catalyst derived from the bulky and electron-rich di-t-butylphosphinobiphenyl ligand (Scheme 11) [51].

Copper catalysis in the presence of a zinc additive is also effective in the pyrrole series and proceeds with excellent functional group tolerance [52]. In comparison to the gold-catalyzed protocol, the scope of 2,5-diamidopyrroles available from 1,3-butadiynamides is considerably broadened as primary aliphatic amines, and sterically hindered anilines are now suitable hydroamination reagents (Scheme 12).

Interestingly, the copper-catalyzed reaction of 1,3-butadiynamide 26 with 2-amino (benzo)thiazoles as nucleophiles does not deliver pyrrole derivatives. Now, fused diazepines 28a–f are formed via a formal [4+3] annulation sequence (Scheme 13) [52].

Symmetrical substituted 1,3-butadiynamides also serve as substrates in gold catalyzed hydration leading to the 2,5-diamidofurans 29a–c (Scheme 14, (1)) [51]. Interestingly, the dimethanesulfonyl analogue of 29b—the 2,5-diamidofuran 30—was obtained in a better yield using a copper(II) catalyst in the presence of a zinc additive (Scheme 14, (2)) [52].

The metal-catalyst-free synthesis of 2,5-diamido-thiophenes 31a–d using 1,3-butadiynamides 2a–d and Na₂S•9H₂O as the sulfur-providing source proceeds under very mild conditions (Scheme 15, Conditions A) [26]. Both symmetrical as well as the non-symmetrical 1,3-diynamides undergo a formal 1,4-functionalization of the parent 1,3-diyne unit. In the case of diynamide 2a (R¹ = Ph), whose electrophilicity is enhanced by conjugation of the ynamide unit with the N-phenyl group, these reaction conditions were not suitable. This is probably because of side reactions resulting from the addition of ethanol across the triple bond. Switching to acetonitrile as the solvent was the key for success (Conditions B). Now, the corresponding thiophene 31a is obtained in 62% yield. Importantly, the method is likewise effective with unsymmetrical 1,3-butadiynamides 3a–c,e–h giving a straightforward entry to variously functionalized 2-amidothiophenes 32a–g (Scheme 15).

This new approach to 2-amido- or 2,5-diamidothiophenes is extendable to the synthesis of terthiophenes (Scheme 16). The required tetrayne 33 bearing two linked 1,3-diynamide units is accessible via a double Cadiot–Chodkiewicz coupling between a terminal ynamide and bis(bromoalkynyl)thiophene. Application of the developed reaction conditions to substrate 33 delivers the diamido-capped terthiophene 34 having a string of N,S heteroatoms embedded in a highly π-conjugated molecular scaffold. Electron-rich terthiophenes are interesting as active materials in organic electronics such as organic transistors or organic photovoltaic cells.

4.2. Cycloaddition Reactions

Intramolecular [4+2] cycloadditions of 1,3-butadiynamides 35a–d tethered to an enyne moiety furnish functionalized 7-alkynyl indolines 37a–d (Scheme 17) [53]. Yields improve in the presence of BHT, which not only suppresses the polymerization of enyne substrates, but also facilitates the isomerization of the cyclic allene intermediate 36 into indoline 37 via proton/hydrogen atom transfer. As alkyl-substituted ynamides with only one C–C triple bond give low yields in related [4+2] cycloadditions, the hydrogenation of the triple bond of indolines 37a–d is an alternative and offers a valuable entry to the parent alkyl-substituted indolines. In these Didehydro–Diels–Alder (DHDA) reactions the 1,3-butadiynamide serves as the formal dienophile. Notably, this has to be distinguished from its use in Hexa-Dehydro-Diels–Alder (HDDA) reactions that will be discussed in Chapter 6, where the 1,3-butadiynamide unit functions as the formal 4π cycloaddition partner.

Azide-alkyne [3+2] cycloadditions of 1,3-butadiynamide 3c using rhodium catalysis afford 4-alkynyl 5-amino-triazole 38 [54], whereas the copper-catalyzed addition of azides to terminal 1,3-butadiynamides provide alternative ynamide-derived azide-alkyne click-products 39 (Scheme 18) [35]. Click reactions with 1,3-diynamides are exclusively chemo- and regioselective with stoichiometric amounts of azides. The exclusion of air and moisture is unnecessary in the case of the rhodium catalysis, whereas high yields in copper-mediated azide-alkyne [3+2] cycloadditions are obtained only under strict anhydrous conditions.

The gold-catalyzed cycloaddition of 1,3-butadiynamide 3k with aminide 40 as N-acyl nitrene equivalent gives 5-alkynyloxazole 41 as a single regioisomer in 83% yield (Scheme 19) [55]. This formal [3+2] cycloaddition is based on the use of the robust and air-stable dichloro(pyridine-2-carboxylato)gold(III) complex as a pre-catalyst.

4.3. Oxidation Reactions

The catalytic oxidation of aryl 1,3-butadiynamides 42 with 8-methylquinoline oxide (43) using a cationic gold catalyst in the presence of a silver salt delivers the 1,4-oxidation products 46 (Scheme 20) [56].

In agreement with other gold-catalyzed oxidations of ynamides with pyridine N-oxides, a striking chemoselectivity for C(1) oxidations is observed leading to the α-carbonyl gold carbene intermediate 44, which, in the case of the ethynylogous ynamide, undergoes a 1,3-carbene migration affording intermediate 45 [57]. The 1,3-migration tautomer 45 is then further oxidized to give the double oxidation products 46. Finally, this oxidative process results in a 1,4-functionalization of the 1,3-diynamide moiety.

Interestingly, a different chemical outcome is observed with 5-hydroxy-1,3-butadiynamides 47a–b, which refrain from C(1) oxidation. Here, an atypical C(3) oxidation and a further gold-mediated oxidative cyclization lead to either furan-3-ones 48a–e or to pyran-4-ones 49a–e with AuCl₃ and CyJohnPhosAuCl/AgSbF₆, respectively (Scheme 21) [56]. The formation of pyran-4-ones 49 from the less basic N-phenyl N-toluenesulfonylamide-derived substrates 47 (R¹ = Ph) is more efficient with 8-iso-propylquinoline oxide, which is illustrated in the synthesis of product 49b with 78 vs. 33% yield. Importantly no exchange between the two cyclic ketones occurs in the presence of the gold catalysts.

DFT calculations support a mechanism for the chemoselective conversion of 47a (R¹ = Ph, R² = H) into cyclic ketones 48b or 49b (Scheme 22).

The gold π-complexed alkynes 50 and 51 in Scheme 22 are interconvertible. The 1,4-functionalization through the oxidation at C(3) relies on an energetically favored complex 51 in comparison to 50 because the energy barrier of the oxidation of 51 with 8-methylquinoline oxide (43) is calculated as lower. The resulting α-oxo gold carbene 52 undergoes 1,2-hydride migration leading to intermediate 53, which evolves to the 3-oxo-5-enol intermediate 54 by releasing a gold species. Complexation of the triple bond of 54 with less alkynophilic (more Lewis acidic) Au(III)Cl₃ induces an intramolecular carbonyl addition to the alkyne moiety via a 5-exo-dig cyclization. The latter affords intermediate 56, whereas the formation of a keteniminium species 57 in the case of the cationic gold catalyst facilitates 6-endo-dig cyclization to give intermediate 58. A mechanism for the transformation of the 1,3-diynamide 47b bearing an aryl-substituted hydroxy moiety was unfortunately not provided by the authors. The structure of the corresponding products 48c–e and 49c–e, however, suggests that a less often observed 1,2-aryl migration takes place [58]. This might also explain the net result with substrate 47 bearing an alkyl-substituted hydroxy moiety. The migratory aptitude of an alkyl group to an electron deficient center typically follows the order H > Ph > alkyl.

5. Metal-Catalyzed Cascade-Type Cyclization and Annulation Reactions

5.1. Intramolecular Processes

The activation of 1,3-butadiynamides with transition metal π-acids to form keteniminium ions provide superb opportunities of cascade-type cyclization and annulation reactions. For intramolecular processes, only gold catalysts have been used so far [59]. The involved gold catalysts often vary according to the 1,3-butadiynamides or to the reaction conditions applied.

1,3-Butadiynamides 59 that are linked via the ynamide nitrogen by a two carbon tether to electron-rich benzenes or electron excess heteroaromatics readily undergo a gold-catalyzed cascade reaction with IPrAuNTf₂ (IPr = 1,3-bis(diisopropylphenyl)imidazole-2-ylidene), leading to sulfone-containing pyrrolo[2,1-a]tetrahydroisoquinolines 60a–g (Scheme 23) [60]. The cationic nature of the gold catalyst is crucial. The counter anion NTf₂⁻ acts as a proton transfer shuttle and facilitates the overall process, which notably involves a formal 1,4-sulfonyl migration. No reaction takes place in the absence of an electron-donating group on the phenyl ring (see 60h). This stands for the electrophilic aromatic substitution step within the reaction cascade. Further functional groups susceptible to react with the gold catalyst, such as alkyne, hydroxy or acetate groups, are tolerated (see 60e–g). Remarkably, other structural motifs are also accessible through this process, such as the pyrrolo-azepine 61 or the heterocyclic systems 62 and 63.

The main intermediates involved in this cascade reaction find support from DFT calculations (Scheme 24). The gold keteniminium species 64 resulting from a regioselective attack of the electrophilic gold catalyst to the 1,3-diynamide moiety undergoes an intramolecular arylation (Vilsmeier–Haack-type reaction) followed by re-aromatization through a 1,3-H shift mediated by the counter anion NTf₂⁻ to deliver intermediate 66. The isomerization of cis-66 to trans-67 required for the second annulation process is the proposed rate-determining step. This second cyclization takes place via a concerted C-N bond formation and includes a 1,2-methanesulfonyl-(Ms) migration to give intermediate 68. A second 1,2-Ms shift followed by a 1,2-H shift, which is greatly facilitated by the counter anion NTf₂⁻, delivers intermediate 70, which finally furnishes product 60a after demetallation.

A related gold(I)-catalyzed para-toluenesulfonic acid (PTSA) promoted cycloisomerization of 1,3-diynamides 71 gives access to α,β-unsaturated ketones 72 together with minor amounts of the 1,3-diynamide hydration product 73 (Scheme 25) [61]. The studied transformation was limited to 1,3-diynamides terminated with a phenyl group, and the other substitution pattern was incompatible mismatched with the desired reactivity.

C-terminal-functionalized 1,3-butadiynamides 74 linked to a terminal alkyne and an allylic ether were used in a reaction cascade involving a dual gold-catalyzed process. The reaction cascade includes an intramolecular carboalkoxylation and a subsequent charge-accelerated [3,3] sigmatropic rearrangement to deliver carbazoles 75 as the major products (Scheme 26) [62]. Compound 76, resulting from a [1,3] sigmatropic rearrangement, was formed as the minor side product in most cases. However, reversal of regioselectivity took place when the latter process was electronically favored (see 76h).

Triynes bearing an internal instead of a terminal alkyne moiety are unsuitable for this reaction cascade in agreement with the proposed mechanism that is being initiated by a σ,π dual activation of triyne 74a to give intermediate 77 (Scheme 27). The latter undergoes a 5-exo-dig cyclization to give the gold vinylidene carbenoid 78, which then cyclizes to furnish the ortho-Au phenyl cation 79. The gold-complexed aryne 79 is trapped by the ether group leading to the oxonium species 80. A charge-accelerated [3,3] sigmatropic rearrangement of 80 gives intermediate 81 followed by re-aromatization delivering 82 along the release of the gold ion. The final step of the proposed mechanism is the protodeauration of 82 to furnish product 75a by releasing the active gold catalyst.

5.2. Intermolecular Processes

As highlighted in chapter 4, the metal-catalyzed double hydroaminations of symmetrical 1,3-butadiynamides with anilines gives 2,5-diamido-N-arylpyrroles. Surprisingly, in related transformations, ortho-substituted anilines as hydroamination reagent trigger a cationic driven reaction cascade after the first hydroamination step. For example, silver(I)-catalyzed transformations of 1,3-butadiynamides 83a–f with ortho-substituted anilines 84 bearing electron-donating substituents give 2-amidoquinolines 85a–h (Scheme 28) [63]. The combination of steric and electronic factors is crucial to gain preference for the formation of quinoline over pyrrole-derived products. One purpose of the electron-donating group in ortho position of the aniline is to facilitate the sequential electrophilic aromatic substitution step that rationalizes product formation. Symmetrical substituted 1,3-butadiynamides are also suitable substrates as shown in the example of bis-amido quinoline 85g (96% yield).

The proposed mechanism is depicted in Scheme 29. Silver-catalyzed intermolecular hydroamination of 1,3-butadiynamide 83 with aniline 84 delivers the enyne intermediate 86, which, after proton transfer and protodeargentation, leads to 87. Silver complexation of the remaining triple bond in 87 facilitates intramolecular hydroarylation via an electrophilic aromatic substitution process to give 89. Subsequent proton transfer and re-aromatization results in the final quinoline 85.

The synthesis of 2-aminopyrrolo[1,2-b]pyridazines 92a–g from non-symmetrical 1,3-butadiynamides 83a–f and 1-aminopyroles 91 via a related strategy is also reported (Scheme 30) [64]. The overall reaction cascade proceeds through Au(I)/Ag(I)-mediated C-N/C-C bond formations to end up with readily substituted 2-aminopyrrolo[1,2-b]pyridazines 92.

The reaction of symmetrical substituted 1,3-butadiynamides 93a–c with ortho-cyano anilines 94 provides aryl-fused 1H-pyrrolo[3,2-c]quinolines 95a–g within a single step via a dual catalyst process (Scheme 31) [65]. Heteroaryl-fused 1H-pyrrolo[3,2-c]quinolines 96a–b are also accessible using 2-amino-3-cyano thiophenes as nucleophiles. Both catalysts—copper(II) acetate and zinc(II) triflate—are necessary for the cascade reaction to be effective. Finally, the overall sequence realizes the formation of one C-C and two new C-N bonds.

Activation of 1,3-butadiynamides via metal–π coordination of a π-acidic copper(II)-species to form the metal keteniminium 97 is the initiating step of the proposed mechanism (Scheme 32). This facilitates the intermolecular hydroamination to give enamine 98 followed by activation of the cyano group in 98 through coordination with the Zn catalyst. The resulting Zn-complexed 99 can undergo a 6-exo-dig cyclization via intramolecular nucleophilic attack of the enamine moiety producing 100. Activation of the remaining carbon–carbon triple bond by Cu(II) facilitates a 5-endo-dig cyclization providing 101, which upon protodemetallation leads to the 1H-pyrrolo [3,2-c]quinoline product 95. In the case of non-symmetrical 1,3-butadiynamides 102 (R = Ph), tautomerization of intermediate 100 leads to the monocyclization product 103, which is a major side product in the reaction. Quinoline 103 is unable to provide 104 through a second annulation sequence, as shown in a separate control experiment. Therefore, an equimolar mixture of products 103 and 104 resulting from both pathways is observed starting from 1,3-butadiynamide 102 even after prolongation of the reaction time. Notably, diphenyl-1,3-diacetylene did not undergo any reaction under these reaction conditions. This one more time underlines the differences in reactivity between 1,3-diynamides and other 1,3-butadiynes.

The outcome of gold-catalyzed reactions of 1,3-butadiynamides 102 with anthranils 105 is substrate-dependent, preferentially affording the formal [5+2] annulation products 106 in the case of 1,3-butadiynamides bearing an electron-deficient N-aryl group, while in contrast, [3+2] annulation products 107 are preferentially formed with more electron-rich N-alkyl 1,3-butadiynamides (Scheme 33) [66].

DFT calculations rationalize the observed chemoselectivity. Gold activation of the 1,3-butadiynamide followed by N-attack of anthranils leads to intermediate 109, which evolves into the energetically more favorable α-imino gold carbene 110 (Scheme 34). The latter undergoes carbonyl addition to give 111 bearing a seven-membered cycle (path a). Although intermediate 111 is higher in energy than intermediate 112, resulting from carbene arylation (path b), the free energy barrier for the formation of 111 is smaller than the one of 112. Moreover, the conversion of 111 into quinoline oxide 106 is highly exothermic and expected to be almost barrierless. The preference for path a relies on the presence of the alkynyl substituent, which brings favorable steric and electronic effects to facilitate the formation of seven-membered ring intermediate 111. These results are specific to 1,3-butadiynamides [67].

Gold-catalyzed oxidative cascade reactions of (het)aryl-tethered 1,3-butadiynamides, using pyridine N-oxide as the oxidant, encompass efficient protocols to access complex polycyclic heteroaromatics within a single step. Here, the active gold species is an α-carbonyl gold carbene, whose obviously faster reaction with the proximal electron-rich aromatic group overrides the otherwise typical 1,4-dicarbonyl formation (Section 4.3, Scheme 20).

The reaction of 3-methoxyphenyl-tethered 1,3-butadiynamides 113a–b with pyridine N-oxide (114), using catalytic amounts of IPrAuCl in the presence of NaBAr^F₄, leads to furo [2,3-c]isoquinolines 115a–h (Scheme 35) [68]. The nature of the substituent at the terminal 1,3-diynamide end—alkyl or phenyl—for the outcome of the reaction cascade is negligible, but the presence of the 3-methoxy group on the tethered aryl ring is mandatory for the reaction cascade to occur. In the absence of the 3-methoxy group, in the case of substrates N-benzyl 1,3-butadiynamide 120 (Ar = Ph, Scheme 36), the double oxidation product 122 is the only product formed under the reaction conditions (Path b, Scheme 36).

According to the proposed mechanism, the gold-activated 1,3-butadiynamide 113 is oxidized by pyridine N-oxide (114) to give α-carbonyl gold carbenoid 116, which is in situ trapped by the aryl group through CH insertion delivering intermediate 117 (path a, Scheme 36). Carbonyl addition on the activated second triple bond of 117 leads to the fused tricyclic intermediate 118, which undergoes protodeauration to 119. The transformation of intermediate 119 into the final polycyclic heteroaromatic product 115 via release of sulfonic acid is highly favorable and might be the driving force of the total transformation according to the authors. The involvement of 119a (R² = Ph) was evidenced by conducting the reaction at room temperature that provided 119a (25% isolated yield) along with unreacted 1,3-butadiynamide 113a. Full conversion of 119a into product 115a was achieved upon heating at 80 °C.

Accordingly, as extension, the assembly of fused tetracyclic heteroaromatics 125a–g was achieved via the same strategy using N-methyl indolyl-tethered 1,3-butadiynamides 123 as the substrates and 2-chloropyridine N-oxide (124) as the oxidant (Scheme 37).

Strikingly, the outcome of the gold-catalyzed oxidative cascade cyclization of methoxyphenyl-tethered 1,3-butadiynamides is tunable by modifying the position of the methoxy group [69]. Indeed, the gold-catalyzed reaction of 2-methoxyphenyl-tethered 1,3-butadiynamides 126 with pyridine N-oxide (114) selectively delivers the polycyclic compounds 127a–i with a barbalan-type carbon skeleton along with the byproduct 128, resulting from hydrolysis and saponification of 126 (Scheme 38).

Arene CH insertion from in situ generated α-carbonyl gold carbenoids is not involved here in comparison to the case of the parent α-carbonyl gold carbenoid 116 depicted in Scheme 36. The preferential mechanistic path now is the intramolecular cyclopropanation of the arene unit by the carbenoid 129 to give norcaradiene 130 (Scheme 39). [3,3] Sigmatropic enyne cycloisomerization between the vinyl methoxy ether and the gold-activated alkynyl moiety leads to the formation of oxocarbenium ion 131, which after hydrolysis delivers the polycycle 127.

A different set of polycycles now having an eight-membered ring moiety is available through a related gold-catalyzed dearomatization/cycloisomerization process by placing an additional methoxy group and varying the substitution pattern of dimethoxyphenyl-tethered 1,3-butadiynamides substrates. For example, 2,4-dimethoxyphenyl-tethered 1,3-butadiynamides 132 are selectively converted into the polycyclic products 133a–f upon reaction with pyridine N-oxide (114) using Cy₃AuCl/AgF as the catalyst (Scheme 40). In this case, the 2-methoxy group remains intact, whereas the additional 4-methoxy group is involved in the formal [3,3] sigmatropic enyne rearrangement.

Using 2,5-dimethoxyphenyl-tethered 1,3-butadiynamides 136 as substrates makes the two fused N-heterocyclic structures 137a–d and 138a–d available, depending on whether the reaction is carried out in the presence of water or under anhydrous conditions, respectively (Scheme 41).

The proposed mechanism involves the generation of a reactive α-carbonyl gold carbene species 139, which undergoes a formal [2+1] cycloaddition with the adjacent arene moiety to give norcaradiene intermediate 140 (Scheme 42). The methoxy-substituted cyclopropane unit facilitates norcaradiene to cycloheptatriene ring expansion, leading to 141. Subsequent intramolecular enyne cycloisomerization delivers intermediate 142, whose hydrolysis furnishes the tricyclic products 137. Under anhydrous conditions, intermediate 142 converts into product 143 via deprotonation and protodeauration. Acidic treatment of 143 induces the cleavage of one carbocycle, delivering the bicyclic compounds 138. Importantly, such a pathway is supported by the isolation of compound 143a (R² = Ph) and its conversion into the corresponding product 138a by treatment with PTSA.

Whereas the majority of the so far reviewed transformations of 1,3-butadiynamides rely on activation of one or two of its carbon–carbon triple bonds by either Brønsted or Lewis acids, or by transition metal catalysts acting both as π-acid and Lewis acid, or Au catalysts transforming 1,3-diynamides into metal carbenoid intermediates, other principles of ynamide activation might result from transforming 1,3-butadiynamides into [4]cumulenimines or related highly unsaturated π-conjugated molecular scaffolds.

Recently, divergent palladium-catalyzed reaction cascades for the selective synthesis of either 2-amino-3-alkynyl-indoles 145a–d or 2-amino-4-alkenylquinolines 146a–f from 1,3-butadiynamides 144 and primary or secondary amines were established (Scheme 43) [70]. Starting from identical or similar substrates, the outcome of the reaction giving either indole or quinoline motifs is switchable, respectively, by the absence of presence of TBAF.

Under similar reaction conditions than those applied for the synthesis of 2-aminoindoles through Pd-catalyzed heteroannulation reaction from N-alkynyl-2-haloanilides [71], the 1,3-butadiynamides 144 behave like internal ynamides. The second triple bond remains unaffected through the transformation, whose key intermediate is the σ,π-chelated palladium species 147 (Scheme 44, path a). The latter results from the initial oxidative addition of the Pd(0) catalyst to the iodophenyl moiety of 1,3-butadiynamides 144. Metal–π complexation of the ynamide triple bond in 147 facilitates intermolecular amine addition delivering the 3-alkynyl indoles 145 selectively. Strikingly, in the presence of TBAF, both triple bonds are engaged to convert 1,3-butadiynamides 144 in 2-aminoquinolines 146a–f in one pot (Scheme 44, path b). The combination TBAF/KOH is believed to induce cleavage of the tosyl group either as the first step or after the oxidative addition of the palladium catalyst to the iodophenyl moiety. Now, the key intermediate is the palladium-chelated [4]cumulenimine 148. The intermolecular amine addition to 148 selectively occurs at the α-carbon delivering the allene-derived intermediate 149. Subsequent intramolecular Heck-type reaction furnishes the annulated π-allyl palladium species 150, which undergoes β-hydrogen elimination to produce 4-alkenyl quinolines 146.

The [4]cumulenimine structure in 148 is unprecedented. However, the deuterium labeling experiment shows the selective deuterium incorporation into the C3 and C11 positions of the quinoline products 146 in agreement with the formation of the transient species 148.

6. HDDA Cascade Reactions

The hexa-dehydro-Diels–Alder (HDDA) reaction of 1,3-diynamides tethered to 1,3-butadiynes delivers highly reactive arynes (dehydrobenzenes) after a formal intramolecular [4π + 2π] cycloaddition process [17]. They are subsequently trapped by in situ intra- or inter-molecular additions to the dehydrobenzene carbon–carbon triple bond, leading to a variety of new heterocyclic structures and useful products. The HDDA reaction itself was discovered in 1997 [72,73] and further developed. However, since 2012, it has received considerable attention, and the underlying process was coined with the term HDDA [18]. The field of HDDA reactions is rapidly expanding, including substrate variations and development of new aryne-trapping modes. The latter takes vast advantage of the fact that typical reagents necessary for generating arynes are absent and therefore cannot interfere [19,20,21]. Studies have shown that reagent-free HDDA reactions proceed through a stepwise mechanism via diradical intermediates. Significant acceleration of the process is observed when the formal 2π cycloaddition partner in the underlying [4π + 2π] cycloaddition process bears an alkynyl substituent (1,3-butadiynyl unit) [33,74]. This is why tetraynes rather than triynes are frequently used in HDDA cascade reactions.

1,3-Butadiynamides tethered to monoalkynes or 1,3-butadiyne moieties are privileged substrates for HDDA reactions because aryne formation proceeds chemo- and regioselectively due to the intrinsic polarization of the 1,3-diynamide unit. Notably, intramolecular HDDA reactions with 1,3-diynamides belong to transformations relying on a 1,4-functionalization of 1,3-diynamides, although the underlying process is step-wise. The follow-up reaction of those 1,3-diynamide-originated arynes continues being highly regioselective, i.e., for the addition of nucleophiles to the aryne. For example, the thermal reaction of tetrayne 152 with triethylamine or trifluoroethanol regioselectively furnishes indolines 153 and 154, respectively (Scheme 45, (1)) [75]. A novel entry to functionalized carbazoles 157a–d from triyne substrates 155 is accessible through perfectly regioselective nucleophilic addition to HDDA-generated carbazolynes 156 (Scheme 45, (2)) [76].

The discriminating reactivity of HDDA-generated arynes from 1,3-butadiynamides was further highlighted by chemo- and regioselective transformations using structurally complex multifunctionalized “aryne-trapping agents” taken from the nature pool. For example, the reaction of tetrayne 158 with the cinchona alkaloid quinidine, which displays several potential reacting sites and/or reacting modes, delivers the single indoline product 159 (Scheme 46) [77].

Experimental results of intramolecular HDDA reactions with 1,3-diynamide were rationalized by DFT calculations (Scheme 47) [78]. Amongst possible diradical intermediates formed in the principal first step of the HDDA reaction of tetrayne 158, the aza-cycloheptynes 163 and 164 can be ruled out, because they are higher in energy by 35.9 and 41.7 kcal/mol, respectively, compared to the pyrrolidine species 160. This largely originates from the twofold propynyl stabilization inherent in biradical 160 and the high triple bond strain energy in arynes 163 and 164. The formation of intermediate 160 is the rate-determining step. Steric factors govern the selective formation of aryne 161 in the second step. The activation barrier to aryne 161 and 162 is 4.3 and 6.6 kcal/mol, respectively, and relates to differences in product stability. Aryne 162 is less stable than 161 by 3.4 kcal/mol because of the steric hindrance between the methanesulfonyl group and the propynyl moiety.

Computational studies, moreover, explain why nucleophilic additions to indoline aryne 161 take place selectively on the C-6 rather than the C-7 position (Scheme 47) [79]. Transition state distortion energies determine regioselectivity. In other words, the aryne 161 displays unsymmetrical bending distortion, and the nucleophilic addition occurs at its flatter and more electropositive end.

The silver-catalyzed HDDA reaction is an interesting alternative to the sole thermal version, eventually affording different reaction outcomes [80]. Ag(I) complexation of the aryne allows for its stabilization while retaining high reactivity. The reactive intermediate resulting from the interaction of aryne with silver salts is described as the silver-bound aryl cations 165, 166 or by its mesomeric 1,2-carbene-silver carbenoid 167 (Scheme 48).

6.1. Sole Thermally Induced HDDA Cascade Reactions

Aryne trapping via C-C bond formation: The HDDA-generated benzyne 161 reacts selectively with phenols and delivers 2-hydroxybiaryl compounds 169a–f, and not the expected diaryl ethers, which are archetypal products of arynes generated by elimination reactions (Scheme 49, (1)) [81]. Indeed, sole thermal HDDA reactions proceed under neutral conditions, without the presence of any base or metal reagent, in contrast to classical methods of benzyne generation. The biaryl junction occurs at the ortho-position to the hydroxyl group via a “concerted phenol-ene-type” reaction. On the other hand, in the presence of cesium carbonate, the thermal reaction of tetrayne 158 with 4-methoxyphenol gives diaryl ether 170 as a single product (Scheme 49, (2)) [81].

Inter- and intramolecular Alder-ene reactions with HDDA-generated arynes lead to a variety of differently substituted indolines. The reaction between 1,3-butadiynamides 171a–c with methyl methacrylate regioselectively delivers the ortho-isomers of indolines ortho-172a–c (Scheme 50) [82].

However, the steric bulk of the R² substituent has an influence on the Alder-ene reaction outcome. The conversion of 1,3-butadiynamide 171c substituted with a bulky silyl group (R² = SiEt₃) preferentially gives indoline meta-173 with 2-methyl-hepten-3-one.

Intramolecular HDDA reactions followed by intramolecular Alder-ene sequences were realized with 1,3-diynamides 174a–d to deliver the linear annulated indolines 176a–d (Scheme 51, (1)) [83]. The chemoselective formation of aryne 175 makes the Alder-ene reaction the most favorable pathway amongst all other possible aryne reacting modes. Extending the tether from three to four atoms delivers eight-membered ring products like compound 176d. Tetrayne 177 bearing a shorter two-atom tether with a methyl-substituted alkene also undergoes an Alder-ene reaction to deliver tricyclic compound 178 (Scheme 51, (2)) [84]. Isoprenyl-tethered tetrayne 179a displaying an even shorter one-atom link fails to produce the corresponding Alder-ene product 181a (R¹ = 1-hexynyl) even under more drastic conditions [85]. However, increase of steric pressure with the rather bulky isopropanol group in triyne 179b (R¹ = C(Me)₂OH) facilitates the formation of the corresponding benzocyclobutene 181b (Scheme 51, (3)).

Thermal HDDA reactions of allene-tethered 1,3-butadiynamides 182 deliver the corresponding aryne intermediates 183, whose reactivity and selectivity are divergent. The outcome of the intramolecular reaction of the allene with the aryne moiety depends on the substitution pattern of the allene and on the length of the tether (Scheme 52) [86]. The Alder-ene reaction involving an allylic C-H bond is favored with trisubstituted allenes (path a) leading to the eight-membered ring containing product 184. In contrast, the allenic C-H bond is preferentially involved with mono- and 1,3-disubstituted allenes affording the seven-membered Alder-ene product 185 (path b). Finally, [2+2] cycloaddition is the preferred path of intramolecular aryne reactions with a 1,1-disubstituted terminal allene furnishing the tetracyclic compound 186 (path c).

The sole thermal reaction of N-arenesulfonyl 1,3-butadiynamides 187, spacing a terminal alkene moiety by a two-atom tether, leads to the pentacyclic structures 189 or 190 via an unprecedented aryne-mediated dearomatization of the phenyl connected to the sulfonyl moiety (Scheme 53) [84]. This transformation reveals the 1,2-dicarbene character of HDDA-generated arynes (intermediate 188). The efficiency of the reaction increases with cation-stabilizing substituents on the alkene (R²) and electron-withdrawing substituents on the arenesulfonyl group (R³). Interestingly, compounds 189a–c, bearing a haloalkene moiety (R² = halogen), do not undergo subsequent acetic acid elimination to give the corresponding aromatization products 190. It is also worth noting that a ketone-containing triyne is a suitable substrate delivering the corresponding pentacyclic product 191 at a slightly higher reaction temperature of 120 °C.

A plausible mechanism, underlined by DFT calculations carried out on the simplified aryne structure 192, is given in Scheme 54. Alkene cyclopropanation is feasible due to the 1,2-dicarbene character of the HDDA-generated aryne and gives carbene 193. The latter undergoes nucleophilic addition onto the electron-deficient phenylsulfonyl moiety delivering 1,3-zwittterion 194. Subsequent ring expansion of the cyclopropane generates the 1,6-zwitterion 195, which leads to the final product 196 via intramolecular proton transfer.

Acenes with indolylnaphthalene or indolylanthracene units are accessible through iterative intramolecular HDDA reaction cascades starting from 1,3-butadiynamide 197 (Scheme 55) [87]. A first intramolecular HDDA cycloaddition gives aryne 198 consecutively undergoing a second intramolecular HDDA reaction to provide the new aryne 199 as the reactive intermediate. The latter is trapped either by [4+2] cycloaddition with α-pyrone to give indolylanthracene 200 or by dichlorination with dilithium tetrachlorocuprate, leading to indolylnaphthalene 201, respectively, as the sole products.

Aryne trapping via C-N bond formation: In situ trapping of HDDA-generated aryne 202 with simple tertiary amines such as triethylamine leads to the zwitterionic species 203, which delivers the same product 204 as being provided from 152 with diethylamine. Disproportionation of the zwitterion 203 by release of ethylene delivers the final product 204 (Scheme 56, (1)) [75]. This olefin elimination sequence was confirmed in the case of tertiary amines bearing activated β-protons such as β-aminoester 205 (Scheme 56, (2)) [88].

However, in protic solvents, the preferential pathway does not involve intra- but intermolecular protonation of the zwitterionic species (209 → 210). Now, a quaternary ammonium center is formed following ring opening by a nucleophile in the case of cyclic tertiary amines (210 → 211) [88]. This reaction sequence also delivers poly-heterocyclic structures 211a–d based on three-component reactions (TCR) with HDDA-generated arynes 209 (Scheme 57) [31]. The addition of the amine onto benzyne 209 must be faster than that of the protic nucleophile. In some cases, such as acetic acid, the expected TCR product 211b (54%) was formed along with the direct benzyne–acetate addition product (27%). Thus, a two-step sequence based on the addition of triflic acid to generate ammonium triflates and their subsequent nucleophilic ring opening by nucleophilic displacement of the triflate in the second step broadens the scope of suitable nucleophiles.

The TCR strategy is applicable to six-membered N-heteroaromatics as the nitrogen nucleophile. For instance, the reaction of 1,3-butadiynamide 158 with quinoline in chloroform provides the addition product 213 via betaine 212 (Scheme 58, (1)) [89]. Catching the aryne generated from 158 with triflic acid and N-heteroaromatics like quinoline or quinazolines delivers isolable N-arylinium triflates 214a–b, which undergo nucleophilic addition of Grignard reagents in a second reaction to give the heterocyclic products 215a–b (Scheme 58, (2)).

The reaction of HDDA-generated benzyne starting from 1,3-butadiynamide 158 and diaziridines 216a–b delivers N-arylhydrazones 217a–b (Scheme 59, (1)) [90]. The more nucleophilic but also more hindered N-benzyl nitrogen atom in 216a–b adds to the aryne moiety. This reasons the formation of meta-isomer of 217a–b along with the expected major ortho-isomer.

Arylhydrazines are ambident nucleophiles, but in the case of para-nitro-phenylhydrazine 219, only the β-nitrogen atom (NH₂) engages in the trapping of arynes thermally generated from tetraynes 158 (EWG = Ms) or 218 (EWG = Ts) (Scheme 59, (2)) [91]. The reaction is highly regioselective and subsequent oxidation of the resulting 1,2-diarylhydrazines 220a–b with MnO₂ delivers azoarene products 221a–b.

The reaction of HDDA-generated arynes with C,N-diarylimine 222 proceeds efficiently, whereas this reaction is known to be poor yielding with o-benzynes generated by classical methods, i.e., by ortho-elimination of arene compounds (Scheme 60) [92]. Aromatization of the resulting dihydroacridine 223 by oxidation with MnO₂ gives acridine 224. The conversion of 158 to 223 probably involves a formal [2+2] cycloaddition of an imine to a highly reactive aryne species. Initial imine addition on benzyne 161 provides betaine 225, which cyclizes to benzazetidine intermediate 226 to provide azo-quinomethide 227 after electrocyclic ring opening. Finally, a 6π electrocyclization followed by a proton shift gives dihydroacridine 223.

Aryne trapping via C-O bond formation: Intramolecular HDDA reactions generated with 1,3-butadiynamide 228, linked via two carbons to a silyl ether unit, result in fully substituted benzene derivatives via formal aryne insertion into the O-silicon bond. For example, furanyl-annulated indoline 229 and carbazole 230 are products from aryne reactions involving C-O bond formation (Scheme 61) [18,76].

Intermolecular trapping of HDDA-generated benzynes from tetrayne 158 with hydroxy-containing cyclic ethers such as glycidol 231a is also possible (Scheme 62, (1)) [93]. The reaction preferentially proceeds via the addition of the cyclic ether oxygen to the aryne. The resulting betaine 232 is protonated followed by ring opening of the cyclic oxonium ion delivering aryl ether 233a. Addition of the alcohol hydroxy of 231a to the aryne becomes a competitive pathway when a large excess of glycidol (100 equiv) is used. In the case of trisubstituted epoxide 231b, another concurrent pathway based on C–C-bond cleavage and aldehyde liberation is observed leading to aryl enol derivative 234 (Scheme 62, (2)). The use of the cyclopropanol derivative 236 as the nucleophile readily delivered the cyclobutanone compound 238 via a cationic-driven cyclopropanol to the cyclobutanone ring-enlargement reaction (Scheme 62, (3)).

HDDA reaction-generated arynes trapped by 3,3-disubstituted enals 240 offer a new entry to benzopyran motifs, in particular to the pyranocarbazole skeleton, as found in the products 241a–b (Scheme 63) [76]. Betaine 242 is the primary addition product and undergoes a formal [2+2] cycloaddition to the benzoxetene 243. Subsequent 4π-electrocyclic ring opening gives (Z)-dienone 244, which finally undergoes 6π-electrocyclic ring closure to restore the aromaticity and gives the pyran moiety. The use of exocyclic conjugated enals delivered a variety of fused spirocyclic benzopyran structures like 241c [94].

With di(4-methoxy)phenyl sulfoxide (246) as an aryne-trapping agent, dimeric dibenzofuran S-shaped helicene 247 is obtained as major product along with carbazoles 248 and 249 starting from triyne 245 (Scheme 64) [95]. Remarkably, five new fused rings assemble within a single step under sole thermal activation.

Mechanistically, the reaction of HDDA-generated benzyne 250 with sulfoxide 246 first leads to adduct 251 (Scheme 65). The latter interacts with a second benzyne molecule 250 to give tetracarbo-ligated σ-sulfurane 252. The hypervalent S(IV) species 252 is the key intermediate of this novel process. Reductive elimination of diarylsulfide 253 delivers the helicene product 247. The 1:1 adduct carbazole 248 is the S_NAr reaction product of 251 via the Meisenheimer intermediate 254 (Scheme 65).

Aryne trapping via C-S bond formation: HDDA reactions of tetrayne 218 with its 1,3-butadiynamide moiety in the presence of either thiirane (255a) or tetrahydrothiophene 255b both furnish vinyl sulfide 258 (Scheme 66, (1)) [96]. The initial formation of a betaine 256 (o-sulfonium/arylcarbanion) is followed by intramolecular proton transfer leading to a more stable S-aryl sulfur ylide 257, which undergoes ring cleavage. Moreover, in the presence of a protic nucleophile, a three-component reaction takes place (Scheme 66, (2)). This becomes possible when the sulfide reacts faster with the aryne than the protic nucleophile. Intermolecular protonation of the resulting aryl carbanion leads to sulfonium 259. Subsequent ring opening by nucleophile addition affords the final products 260a–c. It is worthy of note that thiirane (255a) is not a suitable component for such a process because fragmentation to the vinyl sulfide is faster than nucleophile addition.

The HDDA reaction of tetraynes 158 (EWG = Ms) or 218 (EWG = Ts) with aryl thioamides 261 affords the dihydrobenzothiazine-derived molecules 262a–c in a regio- and diastereoselective fashion (Scheme 67) [97]. Notably, these are the first examples of the use of thioamides as aryne-trapping agents. The proposed mechanism involves the formation of benzothietene 263 and its ring opening to give intermediate 264 or its resonance form o-thiolatoaryliminium 265. Intramolecular 1,3-hydrogen atom migration delivers the iminium zwitterion 267, whose cyclization leads to products 262a–c. The analogous product 268 was also obtained using a thiourea as reaction partner.

Aryne trapping via C-B bond formation: The hydroboration of the aryne that was generated by an HDDA reaction with tetrayne 269, with the N-heterocyclic carbene borane (NHC-borane) 270, provides the highly functionalized arylborane compound 271 as a single isomer (Scheme 68) [98]. The feasibility of the reaction relies on the fact that NHC-boranes are deactivated and do not hydroborate the starting tetrayne unlike most other borane reagents.

6.2. Silver-Catalyzed HDDA Reactions

Ag(I)-bound aryne trapping via C-C bond formation: Alkane C-H bonds can be activated by 1,3-butadiyne-HDDA-reaction generated arynes in the presence of silver(I) salts (Scheme 69) [99]. Importantly, under Ag(I)-free reaction conditions, the alkane C-H insertion fails to appear. According to mechanistic studies, the C(sp³)-H bond-breaking and C(sp²)-H bond-forming processes are concerted and induced via the silver-carbenoid intermediate 273.

The fact that Ag(I) salts drive the character of the aryne reactivity from an alkyne towards a carbene character was nicely shown with the silyl-substituted substrates 275 bearing a primary C-H bond (Scheme 70, (1)) [100]. In the presence of a secondary or tertiary C-H bond on the β-carbon of the silyl group, hydride transfer occurs instead of C-H insertion (Scheme 70, (2)). This result is plausible considering a favorable hyperconjugation of the β-silicon stabilized carbocation 280, whose reaction with water delivers the formal aryne hydrogenation products 281a–b.

Silver-catalyzed reactions of non-activated benzenes 283 with 1,3-butadiynamide-282–HDDA reaction-generated arynes lead to the hydroarylation products 284a–c (Scheme 71) [101]. Diels–Alder reaction products of arynes with arenes, as usually found with “free arynes”, stay out and are not formed. The chemical outcome of this transformation is rationalized by an electrophilic aromatic substitution through the formation of a Wheland-type intermediate 286 (arenium ion) and subsequent water-catalyzed proton transfer.

Ag(I)-bound aryne trapping via C-N bond formation: Nitriles are too weak nucleophiles to react with arynes. However, in the presence of a silver catalyst, the trapping of HDDA-generated aryne is taking place with nitriles readily via the formation of nitrilium ion intermediates 291a–b. The latter can react with water or with acetic acid under anhydrous conditions to give indolinyl amide 292 or imide 293, respectively, starting from tetrayne 288 (Scheme 72, (1)) [102].

Under anhydrous conditions and in the absence of carboxylic acids, tetrayne 288 converts into quinazoline 296 by incorporation of two benzonitrile molecules (289c) (Scheme 72, (2)) [103]. Now, the nitrilium ion 291c interacts with a second nitrile molecule to give the resonance-stabilized complex 294. Transformation of 294 into bis-nitrile adduct 295 and the subsequent ring closure finally delivers quinazoline 296.

Ag(I)-bound aryne trapping via C-O bond formation: Water, unlike alcohols or carboxylic acids, is a less suitable aryne-trapping agent to deliver subsequent phenols. This is probably because of the immiscibility of water in organic solvents where transient arynes are generated. Silver trifluoroacetate (AgO₂CCF₃) turned out to be a suitable water surrogate to obtain phenol-related compounds [75,104]. Indeed, the reaction of 1,3-butadiynes 152 or 297 with AgO₂CCF₃ leads via transient HDDA reaction-generated arynes 298 to trifluoroacetoxy organosilver arenes 299, whose hydrolysis on silica gel furnishes the phenolic compounds 300a–b (Scheme 73).

Ag(I)-bound aryne trapping with fluorine-containing reagents: Fluorination, trifluoromethylation and trifluoromethylthiolation of HDDA-generated arynes from 1,3-butadiynes 301 were successfully achieved by using AgBF₄, AgCF₃ (in situ generated from AgF and TMSCF₃) and AgSCF₃ in stoichiometric quantities, respectively (Scheme 74) [105]. The trifluoromethylation reaction is not proceeding with terminal (R = H) or tertiary alkyl-substituted 1,3-butadiynamides as starting materials (see 303b, 303d). A catalytic protocol for aryne fluorination appeared. It relies on the use of AgBF₄ (10 mol%) as the catalyst and the BF₄•pyridinium salt (1.5 equiv) as the fluoride source. Importantly, fluorination fails in the absence of silver salts.

6.3. HDDA Reactions Catalyzed by Other Metals Than Silver

The hydrohalogenative aromatization of ynamide-derived tetraynes 305 readily proceeds in halogenated hydrocarbons CH₂X₂ (X = Cl, Br, I) as the solvent in the presence of Grubbs-type ruthenium alkylidene complex 306 and delivers novel halogenated indoline derivatives 308a–e (Scheme 75) [106]. The proposed mechanism involves the activation of CH_{2 × 2} by the ruthenium catalyst for the HX transfer to ruthenium-complexed aryne intermediate 307.

The addition of 1-bromoalkynes 309 or terminal alkynes 311 to 1,3-butadiyne-218-HDDA-reaction generated aryne proceeds efficiently under copper catalysis (Scheme 76) [107]. Interestingly, the insertion of the alkynyl moiety into the aryne carbon–carbon triple bond to give either indolines 310a–e or 312a–e, respectively, takes place at complementary positions.

Two different catalytic cycles A and B are proposed to rationalize the outcome of these reactions (Scheme 77). In the case of the bromoalkynylation, CuBr adds to in situ generated aryne 313 (from 1,3-diynamide 218) to give aryl copper (I) species 314. Oxidative addition of this Cu(I) species to 1-bromoalkyne 309 gives the aryl copper(III) intermediate 315. Subsequent reductive elimination produces the 4,7-diethynyldihydroindole 310 and regenerates the copper(I) catalyst. In the case of the catalytic hydroalkynylation reaction (catalytic cycle B), aryne 313 undergoes carbocupration with in situ generated copper acetylide 316 from terminal alkyne 311, providing aryl copper species 317. Proton exchange with terminal alkyne 311 delivers compound 312 and closes the catalytic cycle.

The catalytic reaction of tetrayne 218 with homopropargyl alcohol (318) selectively gives the hydroalkynylation product 319, whereas compound 320 resulting from the addition of the alcohol moiety on the transient aryne 313 is the major compound in the absence of copper catalyst (Scheme 78).

7. Conclusions and Perspectives

The present review covers the synthesis, molecular properties and use of 1,3-butadiynamides in heterocyclic chemistry. Based on this comprehensive summary and its compiled reactions, which not only focused on applications in organic synthesis, but also on mechanistic aspects, it becomes obvious that 1,3-butadiynamides—the ethynylogous variant of ynamides—are more than just simple alkynes: they should be considered as a new class of compounds showing its own specific reactivity.

Their potential as building blocks for the construction of complex molecular scaffolds has emerged only recently, although the synthesis of symmetrical and unsymmetrical 1,3-butadiynamides was described more than 15 years ago. Terminal ynamides are useful precursors of 1,3-butadiynamides for their use in the Glaser–Hay coupling reaction or the Cadiot–Chodkiewicz cross-coupling reaction with 1-bromoalkynes. The latter emerged to a broadly used and indispensable synthetic method to access various highly functionalized non-symmetrical 1,3-butadiynamides. Alternative protocols based on the direct N-buta-1,3-diynylation of amides appeared just recently and will find further attention.

The extended conjugation and polarized character of 1,3-butadiynamides facilitate their use in addition and cycloaddition reactions with predictable regioselectivity. Many of them involve gold catalysis along with the successful use of other metal salts (Pd, Ag, Cu/Zn). Moreover, 1,3-butadiynamides are easily derivatized by introducing judicious functional groups tethered to the N-atom and/or to the C-terminal of the 1,3-diynyl moiety. Such diversely functionalized 1,3-butadiynamides serve as highly useful molecular scaffolds in the development of new reaction cascades.

Intensive studies have been dedicated to thermal or metal-catalyzed reactions with 1,3-butadiynamides tethered to a monoalkyne or 1,3-butadiyne moiety. These tetra- or triynes having a 1,3-butadiynamide unit are privileged substrates for the HDDA reaction because they lead to the in situ formation of a single aryne isomer, and its intermolecular trapping takes place regioselectively. Reagent-free, highly chemo- and regioselective aryne formation with regioselective follow-up reactions by inter- or intramolecular aryne trapping not only enhanced the chemistry of 1,3-butadiynamides, but also boosted the understanding of different reaction channels available for in situ generated aryne species. HDDA reactions with 1,3-butadiynamide units can be performed solely thermally or in the presence of sub-stoichiometric amounts of Ag(I)-salts. The latter often changes the mode of reactivity towards a more carbenoid character of the aryne intermediate and opens new alternative reaction channels.

Most described 1,3-butadiynamides are derived from sulfonamides. It is conceivable that the synthesis of carbamate- or oxazolidinone-related 1,3-butadiynamides will be further explored and that new reaction sequences will be discovered, as the strength of the nitrogen bound EWG group will alter the 1,3-butadiynamide reactivity.

The more classical activation of 1,3-butadiynamides relies on the in situ generation of a keteniminium species to accelerate follow-up transformations. Recently, a new reaction mode—the in situ liberation of [4]cumulenenimines from 1,3-butadiynamides—was revealed. This finding will probably initiate the development of novel reaction cascades and broaden the array of available structurally complex molecules.

Finally, the examples of optically active 1,3-butadiynamides are scarce, and the possibility of chirality transfer during reaction cascades has not been investigated yet. Asymmetric or enantioselective synthesis relying on the transformation of 1,3-butadiynamides will certainly be a future topic to gain access to the chiral world of heterocycles. Surely, the chemistry of 1,3-butadiynamides is still at its infancy and more new reactions and more sophisticated applications, especially in the field of heterocyclic chemistry, will appear in near future.