Introduction {#sec1}
============

Propargylamines are a diverse family of organic compounds possessing unique properties, which has been the subject of wide research with continually increasing intensity.^[@ref1],[@ref2]^ The soaring scientific interest surrounding these compounds is partly because of the bioactive nature exhibited by certain members of their family, rendering them intrinsically valuable because of their potential use in drug development, pharmacology, and medicine.^[@ref1]−[@ref3]^ Additionally, propargylic amines are versatile intermediates in organic synthesis, providing facile access to a multitude of structurally complex organic scaffolds.^[@ref1],[@ref2]^ Because of their highly functionalized character, they can be easily transformed in various manners and rapidly lead to the generation of molecular complexity, hence their utilization in diversity-oriented synthesis and natural product synthesis.^[@ref1],[@ref2],[@ref4]−[@ref6]^ Moreover, they serve as precursors to a wide variety of heterocyclic molecules,^[@ref1]^ including oxazolidinones,^[@cit7a],[@cit7b]^ through the incorporation of carbon dioxide in a similar manner to propargylic alcohols.^[@cit7c]^ Their value as organic synthons is complemented by the fact that they can frequently be accessed through catalytic, multicomponent reaction systems based on the C--H activation of terminal alkynes,^[@ref1],[@ref2],[@ref8]^ thus, obviating the generation of waste, stemming from the synthesis and purification of imine and alkyne-derived intermediates.^[@ref9]^ Importantly, these systems often involve the use of sustainable metal-based catalysts,^[@ref10]^ which, in combination with the atom and step economy associated with multicomponent synthesis and C--H activation,^[@ref11]^ is an aspect giving them increased potential from the standpoint of green methodology development.^[@ref9]^ The most widely known reaction of this type is the A^3^ coupling (aldehyde, amine, alkyne).^[@ref2],[@ref12],[@ref13]^ This three-component coupling reaction has been thoroughly studied during the past two decades, leading to the development of very efficient and sustainable catalytic protocols for the synthesis of trisubstituted propargylamines.^[@ref12]−[@ref15]^ Notably, enantioselective versions of this metal-catalyzed reaction were elegantly designed, not long after its formal discovery, with the employment of appropriate chiral ligands.^[@ref16]^

Ketimines exhibit substantially lower reactivity than aldimines because of both their stereochemical and electronic characteristics.^[@ref17]^ Therefore, addition of nucleophiles to ketimines is usually challenging, with the exception of cyclohexanone-derived ketimines, which react favorably because of the release of torsional strain.^[@ref18]^ As a result, the incorporation of ketones instead of aldehydes in the A^3^ coupling represented a nontrivial challenge until quite recently. Gaining access to ketone-derived, tetrasubstituted (or α-tertiary) propargylamines through a catalytic, multicomponent coupling is a worthy goal, considering the wide array of natural products that possess α-tertiary amine moieties,^[@ref19]^ the intrinsic value of propargylamines and the inherently limited scope of other strategies used to access such molecules.^[@ref20]^ The difficulty of this task was demonstrated by Ramón and co-workers in 2010, when a maximum of 38% yield was achieved after 7 days of reaction between piperidine, 3-pentanone and phenylacetylene, catalyzed by the otherwise efficient Cu(OH)~*x*~--Fe~3~O~4~ catalyst.^[@ref21]^ The first breakthrough was made by Van der Eycken and co-workers, who exploited the enhanced reactivity of cyclohexanones to construct propargylamines derived from cyclohexanones, benzylamines, and phenylacetylene under homogeneous, solvent-less CuI catalysis, and microwave irradiation, also coining the term "KA^2^ coupling" (ketone, amine, alkyne---[Scheme [1](#sch1){ref-type="scheme"}](#sch1){ref-type="scheme"}).^[@ref22]^ Later on, the same research group-coupled azoles instead of alkynes, with secondary amines and cyclic ketones, under copper catalysis and microwave irradiation.^[@ref23]^ Subsequently, AuBr~3~ in 4.0 mol % loading was used as the catalyst to couple mostly secondary amines, cyclohexanones, and phenylacetylene.^[@ref24]^ In a frequently overlooked work, a homogeneous N-heterocyclic carbene--Au(I)-based system was used to facilitate the coupling of alkynes with *N*,*N*′-disubstituted hydrazines and aldehydes/ketones, followed by intramolecular hydroamination.^[@ref25]^ Prompted by the observation that Cu(OTf)~2~ catalyzes the reaction between benzylamine, cyclohexanone, and an aliphatic alkyne,^[@ref26]^ Larsen and co-workers developed a green, efficient system for the KA^2^ coupling, based on CuCl~2~.^[@ref27],[@ref28]^ The already wide scope of this system was expanded to include prochiral ketones when Ti(OEt)~4~ was used as an additive.^[@ref29]^ Ma and co-workers found that CuBr in toluene, along with molecular sieves, was a very efficient and scalable catalytic system for the KA^2^ coupling of secondary amines, various ketones, and terminal alkynes.^[@ref30]^ The first and only system to incorporate aromatic ketones in the KA^2^ coupling was reported by the same group and relied on the cooperative action of CuBr~2~, Ti(OEt)~4~, and sodium ascorbate.^[@ref31]^ Only by using a different approach, in combination with Cu~2~O catalysis, ω-chloro ketones, primary amines, and alkynes could be coupled to furnish 2-alkynyl heterocycles.^[@ref32]^ As expected, the rapidly increasing interest in this reaction has also given rise to various heterogeneous catalytic systems focusing on catalyst recyclability, such as those based on Cu~2~O nanoparticles on titania,^[@cit33a]^ nano Cu~2~O--ZnO,^[@cit33b]^ Cu~2~O/nano-CuFe~2~O~4~,^[@cit33c]^ CuO/Fe~2~O~3~ nanoparticles,^[@cit33d]^ Cu(II)-hydromagnesite,^[@cit33e]^ polystyrene-supported, *N*-phenylpiperazine-CuBr~2~,^[@cit33f]^ Ag-doped nanomagnetic γ-Fe~2~O~3~\@DA core--shell hollow spheres,^[@cit33g]^ Cu(II)\@furfural imine-decorated Halloysite,^[@cit33h]^ CuI on Amberlyst A-21,^[@cit33i]^ Fe~2~O~3~\@SiO~2~-IL/Ag hollow spheres,^[@cit33j]^ semi-heterogeneous, magnetically recoverable graphene oxide-supported CuCl~2~,^[@cit33k]^ and polystyrene-supported N-heterocyclic carbene--Au(III).^[@cit33l]^

![The KA^2^ Coupling Reaction](ao-2019-01387d_0002){#sch1}

The well-established field of homogeneous zinc catalysis includes the unique chemistry of in situ-generated zinc acetylides,^[@ref34],[@ref35]^ which has witnessed a rapid evolution since the seminal discoveries of Carreira and co-workers.^[@ref11],[@ref35]^ Catalytic zinc acetylide addition has proven to be an effective strategy for the synthesis of various types of propargylic amines.^[@ref6],[@ref11],[@ref36]^ Specifically, addition to preformed aldimines in the presence of TMSCl is catalyzed by ZnCl~2~,^[@ref37]^ while Zn(OTf)~2~ in toluene is an efficient catalyst for the alkynylation of unactivated, preformed aldimines and ketimines.^[@ref38]^ The addition of cyclopropylacetylene to cyclic, trifluoromethylated *N*-acyl imines has been achieved using stoichiometric amounts of Zn(OTf)~2~,^[@ref39]^ while ZnMe~2~ has been employed to mediate an enantioselective version of A^3^ coupling and also the enantioselective alkynylation of preformed, activated ketimines.^[@ref40],[@ref41]^ Recently, ZnEt~2~ in 5.0 mol % in the presence of an acid co-catalyst was used to synthesize N-unprotected, tetrasubstituted propargylamines from N-unprotected, trifluoromethyl-substituted ketimines.^[@ref42]^ Another recent approach to accessing tetrasubstituted propargylamines was described by Trost and co-workers, who reported the use of a chiral, dinuclear Zn-based catalyst (Zn-ProPhenol) to facilitate the asymmetric addition of α,β- and β,γ-butenolides to polyfluorinated alkynyl ketimines.^[@ref43]^ A number of catalytic systems based on zinc have also been reported for the A^3^ coupling. Zn(OAc)~2~·2H~2~O in toluene was used to construct a remarkably large library of trisubstituted propargylamines,^[@ref44]^ while the efficiency of Zn(OTf)~2~ under neat conditions was only recently surpassed by the use of zinc prolinate in only 1.0 mol % loading.^[@ref45],[@ref46]^ Notably, zinc catalysis has enabled the multicomponent assembly of chiral propargylamines derived from chiral amines and also their conversion to chiral, disubstituted allenes.^[@ref47],[@ref48]^ ZnS nanoparticles have been used for the synthesis of trisubstituted propargylamines, while a heterogeneous catalytic system based on supported Zn(OAc)~2~ has also been developed for the A^3^ coupling.^[@ref49],[@ref50]^

To the best of our knowledge, homogeneous zinc catalysis has not yet been extended to the KA^2^ coupling. Attempts have been made utilizing Zn(OTf)~2~^[@ref24]^ and ZnI~2~;^[@ref51]^ however, these early efforts were not successful because of the choice of the reaction conditions. Prompted by our continuous interest in the applications of sustainable metal catalysis in green organic transformations,^[@ref11],[@ref52]^ we became interested in studying the potential of homogeneous zinc catalysis in the KA^2^ coupling. Our goal was to develop a highly efficient system based on a simple, widely available, inexpensive, and environmentally benign zinc source, ideally functional under neat conditions and able to facilitate the coupling of challenging and synthetically interesting substrates. Being aware of the central role of zinc in the synthesis of allenes,^[@ref53]^ the possible implications of our findings regarding the synthesis of ketone-derived, trisubstituted allenes are also briefly addressed.

Results and Discussion {#sec2}
======================

In order to obtain proof of concept and identify an optimal, zinc-based catalytic system, cyclohexanone (**1a**), piperidine (**2a**), and phenylacetylene (**3a**) were chosen as model substrates ([Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}). A slight excess of cyclohexanone was used throughout this study, in order to avoid the substrate loss due to self-condensation;^[@ref54],[@ref55]^ however, this proved not to be an issue later on (vide infra). When ZnCl~2~ was employed in 20 mol % loading and the reaction was carried out under neat conditions at 98 °C for 20 h, propargylamine **4a** was obtained in 38% isolated yield after column chromatography (entry 1, [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}). Even though this was a promising result, a considerable number of byproducts were detected by gas chromatography/mass spectrometry (GC/MS) analysis of the reaction mixture. More specifically, enamines, deriving from hydroamination of the alkyne, were frequently observed during our studies (detected by GC/MS analysis and also identified by their characteristic peaks in the ^1^H NMR spectra of column chromatography fractions).^[@ref20]^ It is important to note that propargylamines originating from the alkynylation of ketiminium intermediates deriving from these enamines were never observed.^[@cit20d]^ Repeating the reaction in toluene (1 M) at 120 °C, simultaneously increased product yield and significantly reduced the amounts of side products (entry 2, [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}). An attempt was made to perform the reaction under ultrasonic irradiation, a successful strategy in the A^3^ coupling,^[@ref55]^ nevertheless leading to a negative result in this case (entry 3, [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}). An insignificant increase in yield was observed when the reaction was carried out under neat conditions at 120 °C for a prolonged time (entry 4, [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}), suggesting that different Lewis acids had to be considered. When Zn(OAc)~2~ was used in toluene, propargylamine **4a** was obtained in 75% isolated yield, while the formation of undesirable byproducts was also reduced (entry 5, [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}). Using ZnCO~3~ and ZnSO~4~ led to only traces of the desired product, same as FeCl~3~, which has been reported to be catalytically active in the A^3^ coupling (entries 6----8, [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}).^[@ref56]^ Traces of the desired product could be detected when no metal source was employed (entries 9 and 10, [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}). This is probably because of the high temperature, in combination with traces of metal salts present in the reaction vessel. A significant improvement in the reaction yield was achieved by employing Zn(OTf)~2~ in toluene (entry 11, [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}). However, the 90% yield threshold was crossed only when Zn(OAc)~2~ was used and the reaction was carried out under neat conditions (entry 12, [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}). To our surprise, even though zinc acetate dihydrate has been reported to be catalytically active in toluene in the case of the A^3^ coupling between benzaldehyde, piperidine, and phenylacetylene, the same reaction did not work under neat conditions at 120 °C.^[@ref44]^ ZnBr~2~ and ZnI~2~ also showed high catalytic activities in the absence of solvent, with the latter leading to a similar outcome with Zn(OAc)~2~ (entries 13 and 14, [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}). We did not investigate ZnI~2~ further, at this stage, because this salt is known for its ability to mediate the formation of trisubstituted allenes from pyrrolidine-derived tetrasubstituted propargylamines and, therefore, could lead to complications during the investigation of the reaction scope.^[@cit53b]^ The activity of zinc halides correlates with their Lewis acidity;^[@ref57]^ however, no conclusions can be drawn based on this fact alone, as the relationship between the nature of the corresponding zinc acetylides and other intermediates involved in the cycle might be rather complex, especially in the absence of solvent. Of note, Zn(OTf)~2~ is active under neat conditions as well; however, it also leads to unwanted side reactions, which inhibit efficient conversion to propargylamine **4a** (result not shown). The identification of a mild Lewis acid displaying higher catalytic activity in the KA^2^ coupling under neat conditions than in solution coincides with the earlier findings of Larsen and co-workers,^[@ref27],[@ref28]^ reaffirming the importance of developing synthetic methodologies from a "green" standpoint. Importantly, Zn(OAc)~2~ is less hydroscopic and easier to handle than all zinc halides, while also being much less expensive and more readily available than Zn(OTf)~2~. We chose to proceed with the reaction conditions outlined in entry 12, as we were planning on functionalizing demanding substrates, such as hindered prochiral ketones and primary amines, even though milder conditions can lead to the desired product, depending on the specific substrate triad (vide infra).

###### Metal Source Screening and Optimization of the Reaction Conditions[a](#t1fn1){ref-type="table-fn"}

![](ao-2019-01387d_0010){#GRAPHIC-d7e689-autogenerated}

  entry    metal source   mol %   temp. (°C)         solvent         time (h)   % GC yield[b](#t1fn2){ref-type="table-fn"} (isolated yield)[c](#t1fn3){ref-type="table-fn"}
  -------- -------------- ------- ------------------ --------------- ---------- ---------------------------------------------------------------------------------------------
  1        ZnCl~2~        20      98                 neat            20         43 (38)
  2        ZnCl~2~        20      120                toluene (1 M)   20         64 (61)
  3        ZnCl~2~        20      r.t./ultrasounds   neat            2          0
  4        ZnCl~2~        20      120                neat            70         45
  5        Zn(OAc)~2~     20      120                toluene (1 M)   20         79 (75)
  6        ZnCO~3~        20      120                toluene (1 M)   20         trace
  7        ZnSO~4~        20      120                toluene (1 M)   20         trace
  8        FeCl~3~        20      120                toluene (1 M)   20         trace
  9                       20      120                neat            20         trace
  10                      20      120                toluene (1 M)   20         trace
  11       Zn(OTf)~2~     20      120                toluene (1 M)   20         87 (84)
  **12**   Zn(OAc)~2~     20      120                neat            20         93 (91)
  13       ZnBr~2~        20      120                neat            20         85
  14       ZnI~2~         20      120                neat            20         92

All reactions were performed on a 2.0 mmol scale.

Yield determined by GC/MS analysis, using *n*-octane as the internal standard.

After column chromatography.

In order to investigate the scope of ketones, phenylacetylene was used in combination with piperidine, pyrrolidine, or benzylamine ([Scheme [2](#sch2){ref-type="scheme"}](#sch2){ref-type="scheme"}). It was quickly established that ketones other than cyclohexanones could be successfully subjected to this protocol, with cyclopentanone-derived propargylamine **4b** obtained in 63% yield. A dramatic drop in yield was observed when cycloheptanone was screened, possibly because of the increased steric hindrance caused by the conformations of the intermediate ketiminium ion (**4c**, [Scheme [2](#sch2){ref-type="scheme"}](#sch2){ref-type="scheme"}). Linear ketones were also found to be amenable substrates, with prochiral butanone leading to tetrasubstituted propargylamine **4d** in 82% yield. Increasing the size of the alkyl chains led to a slight decrease in yield in the cases of compounds **4e** and **4j**. Propargylamine **4m** was obtained in low yield; however, this was in part due to evident decomposition during purification by column chromatography, a phenomenon which has also been observed for other compounds of this family.^[@cit33i]^ Substituted cyclohexanones were efficiently converted to the corresponding propargylamines (**4f**, **4i**). Interestingly, 3-methylcyclohexanone led to a higher diastereomeric ratio than 2-methylcyclohexanone, which is in contrast with the results reported using a primary amine under microwave irradiation and CuI catalysis.^[@ref22]^ These results might harbor mechanistic information regarding the interplay between torsional strain and steric hindrance in the transition state formed during the acetylide attack on the in situ-formed ketiminium ion or ketimine. When a secondary amine is involved, the torsional strain factor possibly becomes more significant in the case of 2-methylcyclohexanone and the acetylide attack is not primarily controlled by steric hindrance induced by the methyl group. In the case of 3-methylcyclohexanone, it is possible that the angle of the acetylide attack changes when switching from secondary to primary amines because of coordination of the imine to the metal center of the acetylide species.^[@ref28]^ As a result, the degree in which steric control regarding face selection during addition is imparted by the methyl group may change accordingly, which translates to a difference in the diasteromeric ratios (d.r.). Even though the abovementioned differences bare intrinsic informational value, the exact identity of the diastereoisomers was not uncovered in neither case and, therefore, unambiguous conclusions regarding stereocontrol cannot be drawn. It is important to note that the exact nature of the metal acetylide, as well as other factors contributing to π-face selection render the reasons for these differences far from obvious.^[@ref58],[@ref59]^ High yields and remarkably high diastereoselectivities were obtained when norbornanone was used in combination with pyrrolidine and piperidine, leading to single diastereoisomers of tetrasubstituted propargylamines **4g** and **4h**, respectively. Benzylamine was also successfully coupled with norbornanone and phenylacetylene, albeit leading to a substantially lower yield of propargylamine **4k**, a fact which is attributed to the increased stability of the intermediate imine. This intermediate was clearly observed by GC/MS analysis, even after increasing the reaction time to 50 h, which did not lead to an increase in product yield. The level of diastereoselectivity, however, was still maintained, despite the relatively lower yield.^[@ref29]^ Unfortunately, when α-tetralone was used, no conversion to the desired product was observed under these conditions (**4l**). Of note, only one catalytic system capable of functionalizing aromatic ketones via the KA^2^ coupling has been reported to date.^[@ref31]^

![The KA^2^ Coupling Reaction under Zinc Catalysis: Scope of Ketones\
All reactions were performed on a 2.0 mmol scale and isolated yields after column chromatography are shown in parentheses.\
The diastereomeric ratio was determined by ^1^H-NMR analysis (see [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01387/suppl_file/ao9b01387_si_001.pdf)).\
As determined by GC/MS analysis.\
Decomposition during column chromatography was observed, as suggested by the respective color changes.](ao-2019-01387d_0003){#sch2}

Prompted by the exceptionally high diastereoselectivities observed for the norbornanone derivatives, we attempted to elucidate the structure of **4h**. As shown in [Figure [1](#fig1){ref-type="fig"}](#fig1){ref-type="fig"}, the obtained compound could be either *endo*-**4h** or *exo*-**4h**. Based on the related literature, nucleophiles tend to add to norbornanone from the exo side, giving very high diastereoselectivities.^[@cit18a],[@ref60]^ The same also applies to alkynyl-metal reagents.^[@ref61],[@ref62]^ A combination of ^1^H NMR, ^13^C NMR, ^1^H, ^1^H-COSY, ^1^H, ^13^C-HSQC, and ^1^H, ^1^H-NOESY spectroscopies (see [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01387/suppl_file/ao9b01387_si_001.pdf)) leads to the conclusion that the piperidine unit resides on the endo side of the molecule. Because of the complexity of the acquired spectra, our conclusion is not definitive, but in conjunction with the known propensity of nucleophiles to add to norbornanone from the exo side, the data suggest exo alkynylation. Of note, the same should apply in the cases of products **4g** and **4k**.

![Diastereoisomers of **4h** with labeled atoms.](ao-2019-01387d_0001){#fig1}

Continuing with the scope of alkynes ([Scheme [3](#sch3){ref-type="scheme"}](#sch3){ref-type="scheme"}), mostly piperidine and cyclohexanone were coupled with various terminal alkynes to give new propargylamines. Electron-donating groups on the aromatic alkynes had little effect on the reaction outcome, leading to products **4n**, **4q**, and **4r** in good yields. A detrimental effect on the reaction outcome was observed when aromatic alkynes bearing electron-withdrawing groups were used. Product **4o** was observed by GC/MS analysis; however, its isolation proved difficult, while product **4p** was not detected. These results are in agreement with the fact that electron-deficient alkynes are rarely used in similar studies,^[@ref31]^ leading to poor results, attributed to the decreased nucleophilicity of the corresponding metal acetylides. In our case, the competing pathway of alkyne hydroamination was identified as the main issue. Surprisingly, product **4s** was efficiently obtained in 70% yield after column chromatography. ^1^H NMR analysis of related fractions showcased the existence of the corresponding hydroamination product. This new propargylamine bears a particularly useful handle for further synthetic elaboration. In order to probe whether useful aliphatic alkynes could participate in the KA^2^ coupling under zinc catalysis, 2-methyl-3-butynol was used in combination with cyclohexanone and *p*-fluorobenzylamine.^[@ref63]^ The highly functionalized, tetrasubstituted propargylamine **4t** was successfully obtained in moderate yield.

![The KA^2^ Coupling Reaction under Zinc Catalysis: Scope of Alkynes\
All reactions were performed on a 2.0 mmol scale and isolated yields after column chromatography are shown in parentheses.\
The compound was detected by GC/MS analysis; however, it is decomposed during column chromatography.\
As determined by GC/MS analysis.](ao-2019-01387d_0004){#sch3}

The *N*-phenylpiperazine scaffold is frequently observed as a key component in biologically active compounds and, therefore, has proven useful in combinatorial synthesis.^[@ref64]^ In light of that, we thought the KA^2^ coupling of *N*-phenylpiperazine with 2-methyl-3-butynol and cyclohexanone would lead to interesting results. Indeed, propargylamine **4u** ([Scheme [3](#sch3){ref-type="scheme"}](#sch3){ref-type="scheme"}) was obtained under the standard conditions; however, an unprecedented occurrence was also observed in this case. Copious amounts of a white solid precipitated from the reaction mixture, which was filtered off using ethyl acetate, prior to the purification of the desired compound. Under our presumption that this solid was *N*-phenylpiperazinium acetate,^[@ref65]^ the latter was synthesized by directly mixing *N*-phenylpiperazine and acetic acid and the ^1^H- and ^13^C NMR spectra of the two solids were compared (see [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01387/suppl_file/ao9b01387_si_001.pdf)). Both *N*-phenylpiperazine and acetate groups could be identified in the unknown compound in a 1:1 ratio, with peaks in ^13^C NMR being slightly displaced (1----3 ppm), when compared with those of *N*-phenylpiperazinium acetate. Comparison of the ^1^H NMR and Fourier-transform infrared spectroscopy (FTIR) spectra clearly shows that the unknown compound is not *N*-phenylpiperazinium acetate, but possibly an *N*-phenylpiperazine-coordinated zinc complex, which is in agreement with recent reports on amine coordination to zinc in related processes.^[@ref66]^ Unfortunately, attempts to identify the compound by high resolution mass spectrometry (HRMS) analysis only confirmed the existence of *N*-phenylpiperazine.^[@ref57]^ The fact that *N*-phenylpiperazine and the acetate anions are present in a 1:1 ratio, as suggested by ^1^H NMR analysis, prompted us to embark upon further investigations, in order to gain more insight regarding the components of this complex. IR analysis suggested that hydroxide species could also be present in this compound,^[@ref67]^ which can be explained considering that water is a byproduct of the KA^2^ coupling (see [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01387/suppl_file/ao9b01387_si_001.pdf)). Direct mixing of *N*-phenylpiperazine (1.0 equiv) with anhydrous zinc acetate (0.2 equiv), followed by heating at 120 °C and then washing the resulting precipitate with diethyl ether afforded the same complex, as judged by NMR and FTIR spectroscopies (see [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01387/suppl_file/ao9b01387_si_001.pdf)). Furthermore, ^1^H NMR spectra of (a) *N*-phenylpiperazinium acetate, (b) the solid that precipitated from the reaction, and (c) the solid that precipitated as a result of directly mixing *N*-phenylpiperazine (1.0 equiv) and anhydrous zinc acetate (0.2 equiv) were obtained in a sequential manner and addition of D~2~O to the samples showcased that the complex decomposes in the presence of water (see [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01387/suppl_file/ao9b01387_si_001.pdf)). Based on these results, we believe that this compound is an off-cycle zinc complex (general structure **5**, [Scheme [4](#sch4){ref-type="scheme"}](#sch4){ref-type="scheme"}). Despite our repeated attempts, it was not possible to obtain single crystals of good quality that would enable the X-ray structure elucidation of this compound. Although the exact structure of the obtained solid was not determined beyond any doubt, the above results suggest the formation of amine-coordinated zinc species during the catalytic cycle and also suggest that using bidentate amines might cause complications under the conditions reported herein.

![Isolation of a Complex Originating from Zinc Acetate and *N*-Phenylpiperazine](ao-2019-01387d_0005){#sch4}

For the first installment in the scope of amines, pyrrolidine was used in combination with cyclohexanone and phenylacetylene to furnish propargylamine **4v** in 96% isolated yield ([Scheme [5](#sch5){ref-type="scheme"}](#sch5){ref-type="scheme"}). It is interesting to note that, for this compound, when the catalyst loading and temperature were lowered to 5.0 mol % Zn(OAc)~2~ and 110 °C, respectively, an 83% isolated yield was reached. Also, under the standard conditions, an 83% isolated yield was obtained after 4 h, while a 96% yield was reached after 8 h. Propargylamine **4w**, bearing a versatile ester handle for further synthetic elaboration was obtained in 67% isolated yield under the standard conditions. Benzylamine led to product **4x** in 71% isolated yield, while the same compound was obtained in 17% yield when Zn(OTf)~2~ in 20% loading was used in toluene (1.0 M) in preliminary studies.^[@ref38]^ Product **4y** was obtained in slightly lower yield, possibly because of steric hindrance, while products **4z** and **4e** were obtained in moderate yields. When morpholine was used, the corresponding propargylamine (**4za**) was obtained in a lower yield than expected, possibly owing to the bidentate nature of this cyclic amine. *N*-octylamine led to the desired product (**4zc**) in good yield, while a hindered secondary amine was also amenable to this catalytic system (**4zb**). Increasing the steric bulk of the amine proved detrimental to the reaction outcome in the case of propargylamine **4ze**, while a primary amine bearing a hindered, secondary amine site led to product **4zg** in moderate yield.

![The KA^2^ Coupling Reaction under Zinc Catalysis: Scope of Amines\
All reactions were performed on a 2.0 mmol scale and isolated yields after column chromatographic purification are shown in parentheses.\
5.0 mol % Zn(OAc)~2~, 110 °C, equimolar amounts of starting materials.\
As determined by GC/MS analysis.\
The diastereomeric ratio was determined by ^1^H-NMR analysis (see [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01387/suppl_file/ao9b01387_si_001.pdf)).](ao-2019-01387d_0006){#sch5}

The derivatization of nicotine has been a topic of continuous interest and, therefore, we became interested in the potential outcome of using the biologically relevant nornicotine (**2c**, [Scheme [6](#sch6){ref-type="scheme"}](#sch6){ref-type="scheme"}) as the amine component in the KA^2^ coupling.^[@ref68]^ The corresponding propargylamine was obtained as a single diastereoisomer in 70% isolated yield (**4zf**, [Scheme [5](#sch5){ref-type="scheme"}](#sch5){ref-type="scheme"}). However, the case of propargylamine **4zf** was particularly interesting, as this compound precipitated in crystalline form after ethyl acetate was used to filter off inorganic compounds from the reaction mixture ([Scheme [6](#sch6){ref-type="scheme"}](#sch6){ref-type="scheme"}). As a result, this compound was obtained in the pure form without the need for column chromatography. Of note, propargylic amines are usually obtained as viscous oils after chromatographic purification using petroleum ether and ethyl acetate, a fact which inarguably compromises the sustainable aspects of their multicomponent synthesis and is rarely addressed. Although it is obvious that sustainable methods of purification depend on the exact nature of a specific compound, we found that the use of nornicotine in such a manner might prove useful in studies of propargylic amines. Interestingly, nornicotine is naturally occurring, biologically relevant, and possesses a bulky pyridine group able to dictate face selection during the acetylide attack. Also, the pyrrolidine framework is particularly useful for synthetic applications of propargylic amines.^[@ref51],[@cit53b],[@cit53c]^

![Synthesis and Purification of a Nornicotine-Derived, Crystalline Propargylamine: Column Chromatography Can Be Circumvented](ao-2019-01387d_0007){#sch6}

In order to assess the scalability of our protocol,^[@ref30]^ the synthesis of 1-(1-(phenylethynyl)cyclohexyl)pyrrolidine (**4v**) was carried out on a gram scale, using equimolar amounts of starting materials and 10 mol % Zn(OAc)~2~ ([Scheme [7](#sch7){ref-type="scheme"}](#sch7){ref-type="scheme"}). The product was efficiently obtained in 91% isolated yield and adequate purity after a simple filtration through a pad of silica using ethyl acetate and evaporation of the (recyclable) solvent. This is indicative of the mild Lewis acidity of Zn(OAc)~2~, given that byproduct formation is minimized and, therefore, the product can be obtained in high yield in a straightforward, user-friendly, and cost-efficient fashion. As the chemistry of ZnI~2~ and propargylamines is of high interest^[@cit53a],[@cit53b]^ and we found that ZnI~2~ is able to mediate the formation of tetrasubstituted propargylamines under neat conditions, we deemed it necessary to explore whether allenes could be produced in a one-pot fashion using only ZnI~2~. Indeed, trisubstituted allene **6** was obtained in 20% isolated yield, without prior isolation of its propargylamine precursor, following a one-pot procedure ([Scheme [7](#sch7){ref-type="scheme"}](#sch7){ref-type="scheme"}, also see [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01387/suppl_file/ao9b01387_si_001.pdf)). Propargylamine **4v** was still present in the reaction mixture, possibly because of the deactivation of the catalyst by 1 equivalent of water generated by the KA^2^ reaction. Repeating the reaction under neat conditions with 0.8 equiv of ZnI~2~ resulted in consumption of propargylamine **4v** to give a series of unidentified products, possibly arising from cycloaddition reactions of the produced allene.^[@ref69]^ These results are highly important, proving that generation of trisubstituted allenes is feasible under our conditions and may provide a novel possible gateway to developing synthetic protocols for their preparation.^[@cit53c]^

![(a) Synthesis of 1-(1-(Phenylethynyl)cyclohexyl)pyrrolidine (**4v**) on a Gram Scale; (b) Preliminary Result Regarding the Zinc Iodide-Mediated, One Pot Synthesis of Trisubstituted Allenes from Pyrrolidine, Ketones and Terminal Alkynes\
Isolated yields are shown.](ao-2019-01387d_0008){#sch7}

Based on our observations, as well as on previous studies on the KA^2^ coupling,^[@ref28]^ we propose a plausible, zinc-based catalytic cycle ([Scheme [8](#sch8){ref-type="scheme"}](#sch8){ref-type="scheme"}). The cycle commences with the formation of a π-complex between alkyne **3** and Zn(OAc)~2~, which is transformed into a zinc acetylide (**3′**) by the action of amine substrate **2**. Therefore, the intermediates involved in the next steps are generated in step **I**. Step **II** is the reversible formation of ketiminum ion or imine intermediates **7** and **7′**, respectively, depending on whether a secondary or primary amine is involved. In the case of secondary amines, the zinc acetylide attack on the ketiminium ion in step **III** should lead directly to the formation of product **4** and regeneration of the catalyst, while, if a primary amine is involved, a proto-demetallation step (**IV**) should facilitate product release. The addition of the metal acetylide to the ketiminium ion or imine intermediate is considered to be rate-determining. Step **V** represents a possible catalyst deactivation pathway, with the interaction of amine substrates and in situ produced water with zinc, giving coordination complexes that might be either off-cycle species, or able to participate in the next cycle, depending on their exact nature. It is important to mention that although the addition of zinc acetylides to electrophiles is usually considered to involve mononuclear zinc species, recent advancements regarding the elucidation of a dinuclear mode of action of zinc catalysts should also be taken into consideration.^[@ref66],[@ref70]^

![The KA^2^ Coupling Reaction under Zinc Catalysis: Proposed Mechanism](ao-2019-01387d_0009){#sch8}

Conclusions {#sec3}
===========

The identification of zinc acetate as a mild Lewis acid catalyst for the KA^2^ coupling has led to the development of a reliable, highly efficient, user-friendly, cost-efficient, green catalytic system for the expedient assembly of propargylic amines bearing tetrasubstituted carbon centers. This advancement highlights the potential of efforts toward the design of green synthetic methodology, as it clearly demonstrates the improvement or even the emergence of catalytic activity in the absence of solvent. The combination of sustainable zinc catalysis, neat conditions, and the multicomponent synthesis of propargylamines renders this system an arguably ideal example in terms of atom and step economy. In light of that, integrating homogeneous zinc catalysis into the KA^2^ coupling reaction raises some interesting points. Zinc alone, is up to the task, when it comes to the construction of propargylamines deriving from nearly all substrate types. In this regard, even though cyclohexanone leads to the best results, the efficient functionalization of sterically demanding cyclohexanones, as well as bicyclic ketones, such as norbornanone is also feasible. Notably, linear and also prochiral ketones are amenable substrates when zinc acetylides are the active nucleophiles, thus potentially setting the stage for an enantioselective version of this reaction. Under the same conditions, primary amines led to the corresponding propargylamines in isolated yields ranging from 33 to 71%, depending on the remaining two reaction components. Slight modification of the reaction conditions for each triad of substrates could improve the yield and, therefore, each independent reaction should be approached accordingly for synthetic purposes. Another promising discovery disclosed herein, is the highly sustainable synthesis and purification of a nornicotine-derived propargylic amine, which could prove to be especially useful either as a synthon or as a template for further studies on this reaction and its products. Also, the unprecedented ability of zinc iodide to mediate the direct formation of trisubstituted allenes, from ketones, pyrrolidine, and terminal alkynes, holds great promise, as new protocols for accessing such valuable molecules might be developed through appropriate optimization. As a final note, despite all the major advancements, the KA^2^ coupling is arguably still in its infancy and, as is the case with the majority of newly found, metal-catalyzed reactions, rationally designed systems are expected to emerge as a result of a gradual increase in the understanding of its underlying mechanistic parameters. A prerequisite of such design is the discovery of new metals that can catalyze this process, with zinc being the latest addition, providing a unique range of options for new advancements. Studies on improvements and extensions of the green system reported herein, as well as the development of new ones are already underway in our laboratory.

Experimental Section {#sec4}
====================

General Reagent Information {#sec4.1}
---------------------------

All chemicals were obtained from commercial sources and were used without any further purification, with the exception of cyclohexanone, which was distilled before use. All metal sources were anhydrous and at least 98% pure. Zinc acetate anhydrous (99.99%) and zinc acetate anhydrous (98%) gave indistinguishable results. Toluene was purified according to published procedures, distilled and stored under argon over 3 Å molecular sieves. All reactions were set up under air and carried out in flame-dried, Teflon seal screw-cap pressure tubes under an atmosphere of argon. The course of the reactions was followed with either GC/MS or thin-layer chromatography, using aluminum sheets (0.2 mm) coated with silica gel 60 with fluorescence material that absorbs at 254 nm (silica gel 60 F254). The purification of the products was carried out by flash column chromatography, using silica gel 60 (230--400 mesh). FTIR spectra were recorded with a Shimandzu IRAffinity-1 spectrometer, using KBr pellets.

General Analytical Information {#sec4.2}
------------------------------

^1^H, ^13^C, and ^19^F NMR spectra were measured on a Varian Mercury 200 MHz or a Bruker Advance 500 MHz spectrometer, using CDCl~3~ as the solvent and its residual solvent peak as a reference. NMR spectroscopic data are given in the order: chemical shift, multiplicity (s, singlet, br s, broad singlet, d, doublet, t, triplet, q, quartet, m, multiplet), coupling constant in hertz (Hz), and number of protons. HRMS spectra were recorded in a QTOF maXis impact (Bruker) spectrometer with electron spray ionization (ESI). The GC/MS spectra were recorded with a Shimandzu R GCMS-QP2010 Plus Chromatograph Mass Spectrometer using a MEGAR (MEGA-5, F.T: 0.25 μm, I.D.: 0.25 mm, *L*: 30 m, *T*~max~: 350 °C, column ID\# 11475) column, using *n*-octane as the internal standard. 2D NMR spectra (COSY, HSQC, and NOESY) were measured on a Bruker ADVANCE 500 MHz spectrometer using CDCl~3~ as the solvent.

General Procedure {#sec4.3}
-----------------

Unless otherwise noted, the following procedure was used for the synthesis of all products: a flame-dried, Teflon seal screw-cap pressure tube equipped with a stirring bar and a rubber septum was charged with 20 mol % Zn(OAc)~2~ (73.4 mg, 0.4 mmol). Under a flow of argon, 2.0 mmol of the amine was added and the mixture was stirred until the solid was partially dissolved. 2.0 mmol of the alkyne was added and the mixture was stirred at room temperature and under argon until the solid was either completely or partially dissolved. Finally, 2.2 mmol of the ketone was added and the rubber septum was quickly replaced by a Teflon seal screw-cap under argon pressure. The reaction was allowed to stir in an oil bath, preheated at 120 °C, for 20 h. After cooling to room temperature, ethyl acetate was added (2 × 5 mL) and the mixture was stirred for 5 min in order to completely remove the usually viscous product from the reaction vessel. The mixture was filtered through a short silica gel plug in order to remove inorganic impurities, concentrated under vacuum and loaded atop a silica gel column. Gradient column chromatography with ethyl acetate/petroleum ether furnished the desired products. All products were characterized by ^1^H NMR, ^13^C{^1^H} NMR, ^19^F NMR, and HRMS, which were all in agreement with the assigned structures.

Modified Procedure for the Synthesis of 3-(1-(1-(Phenylethynyl)cyclohexyl)pyrrolidin-2-yl)pyridine (**4zf**, Single Diastereoisomer) {#sec4.4}
------------------------------------------------------------------------------------------------------------------------------------

The general procedure was followed. Upon cooling to room temperature, the mixture almost solidified. Ethyl acetate (2 × 5 mL) was added, the mixture was stirred rapidly until all viscous materials were removed from the reaction vessel and it was filtered through a short silica gel plug. The yellow solution was placed in the refrigerator overnight, after which time, colorless crystals had precipitated. The solid product was filtered, washed with ethyl acetate, and dried under vacuum (462 mg, 1.40 mmol, 70% yield). ^1^H NMR (200 MHz, CDCl~3~): δ 8.65 (s, 1H), 8.43 (d, *J* = 4.6 Hz, 1H), 7.76 (d, *J* = 7.8 Hz, 1H), 7.47 (dd, *J* = 6.5, 2.8 Hz, 2H), 7.37--7.27 (m, 3H), 7.21 (dd, *J* = 7.8, 4.8 Hz, 1H), 4.38 (d, *J* = 9.2 Hz, 1H), 3.33--3.16 (m, 1H), 2.97 (dd, *J* = 16.6, 8.4 Hz, 1H), 2.33--2.09 (m, 1H), 2.08--1.96 (m, 1H), 1.90--1.33 (m, 10H), 1.08 (m, 2H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 148.7, 147.4, 144.8, 134.3, 131.8, 128.3, 127.7, 123.6, 123.0, 91.6, 84.9, 60.6, 60.3, 49.8, 39.3, 38.2, 36.2, 25.5, 23.8, 23.1, 22.9. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~23~H~27~N~2~, 331.2169; found, 331.2167.

Modified Procedure for the Synthesis of 1-(1-(Phenylethynyl)cyclohexyl)pyrrolidine (**4v**) on a Gram Scale {#sec4.5}
-----------------------------------------------------------------------------------------------------------

A flame-dried, Teflon seal screw-cap pressure tube equipped with a stirring bar and a rubber septum was charged with 10 mol % Zn(OAc)~2~ (179.6 mg, 0.98 mmol). Under a flow of argon, 9.79 mmol of pyrrolidine (0.696 g, 0.817 mL) was added and the mixture was stirred until the solid was partially dissolved. 9.79 mmol of phenylacetylene (1.00 g, 1.08 mL) was added and the mixture was stirred at room temperature and under argon until the solid was completely dissolved. Finally, 9.79 mmol of cyclohexanone (0.961 g, 1.01 mL) was added and the rubber septum was quickly replaced by a Teflon seal screw cap under argon pressure. The reaction was allowed to stir in an oil bath, preheated at 120 °C, for 20 h. After cooling to room temperature, ethyl acetate was added and the mixture was stirred for 5 min in order to completely remove the viscous product from the reaction vessel. The crude product was pushed through a short silica gel pad using 200 mL of ethyl acetate. The solvent was evaporated under reduced pressure, affording the sufficiently pure product as a yellow oil in 91% yield (2.27 g, 8.94 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.44 (dd, *J* = 6.7, 3.1 Hz, 2H), 7.30 (m, 3H), 2.82 (t, *J* = 5.9 Hz, 4H), 2.13--1.94 (m, 2H), 1.91--1.41 (m, 12H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 131.7, 128.1, 127.6, 123.6, 90.3, 86.1, 59.3, 47.0, 37.8, 25.7, 23.5, 23.0.^[@cit33i]^

Procedure for the Synthesis of (2-Cyclohexylidenevinyl)benzene (**6**) in One Pot {#sec4.6}
---------------------------------------------------------------------------------

A flame-dried, Teflon seal screw-cap pressure tube equipped with a stirring bar and a rubber septum was charged with 20 mol % ZnI~2~ (127.7 mg, 0.4 mmol). Under a flow of argon, 2.0 mmol of pyrrolidine (0.142 g, 0.164 mL) were added and the mixture was stirred until the solid was partially dissolved. 2.0 mmol of phenylacetylene (0.205 g, 0.220 mL) were added and the mixture was stirred at room temperature and under argon until the solid was completely dissolved. Finally, 2.2 mmol of cyclohexanone (0.216 g, 0.228 mL) were added and the rubber septum was quickly replaced by a Teflon seal screw cap under argon pressure. The reaction was allowed to stir in an oil bath, preheated at 120 °C, for 16 h. After cooling to room temperature, the Teflon seal screw cap was replaced by a rubber septum under argon pressure. The mixture was charged with 60 mol % ZnI~2~ (383.0 mg, 1.2 mmol) and toluene (3.0 mL). The pressure tube was resealed and the reaction was allowed to stir in an oil bath which was preheated at 120 °C for 1 h. The reaction mixture was allowed to cool to room temperature and ethyl acetate (2 × 5 mL) was used in order to filter through a short silica gel plug. The solvents were evaporated under reduced pressure and the crude mixture and loaded atop a silica gel column. Eluting with hexane afforded the desired compound as clear, colorless oil in 20% yield (73.7 mg, 0.4 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.31--7.22 (m, 4H), 7.22--7.10 (m, 1H), 6.02--5.96 (m, 1H), 2.36--2.10 (m, 4H), 1.77--1.49 (m, 6H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 199.8, 136.3, 128.6, 126.6, 126.4, 106.6, 92.5, 31.5, 27.9, 26.3.^[@cit53b]^

Characterization Data for New Compounds {#sec4.7}
---------------------------------------

### 1-(2-Methyl-1-(phenylethynyl)cyclohexyl)pyrrolidine (**4f**, Obtained as a Mixture of Diastereoisomers) {#sec4.7.1}

Prepared according to the general procedure and obtained as a yellow oil in 72% yield (385 mg, 1.44 mmol) and 56:44 d.r. according to ^1^H NMR. ^1^H NMR (200 MHz, CDCl~3~): δ 7.47--7.38 (m, 4H), 7.33--7.22 (m, 6H), 2.74 (m, 8H), 2.19--1.29 (m, 26H), 1.15 (d, *J* = 6.8 Hz, 3H, CH~3~, major diastereoisomer), 1.03 (d, *J* = 7.2 Hz, 3H, CH~3~, minor diastereoisomer). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 131.8, 131.7, 128.2, 128.2, 127.6, 124.0, 91.8, 91.7, 86.1, 85.3, 62.2, 61.5, 46.8, 46.1, 37.4, 36.7, 31.6, 30.0, 29.5, 29.2, 24.0, 23.6, 22.8, 22.3, 19.7, 16.8, 13.0. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~19~H~26~N, 268.2060; found, 268.2070.

### 1-(2-(Phenylethynyl)bicyclo\[2.2.1\]heptan-2-yl)pyrrolidine (**4g**) {#sec4.7.2}

Prepared according to the general procedure and obtained as a yellow oil in 90% yield and \>99:1 d.r. (478 mg, 1.80 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.45--7.38 (m, 2H), 7.33--7.24 (m, 3H), 2.69 (s, 4H), 2.35 (d, *J* = 3.5 Hz, 1H), 2.24 (s, 1H), 2.06--1.87 (m, 3H), 1.82--1.69 (m, 4H), 1.56--1.20 (m, 5H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 131.7, 128.2, 127.5, 124.1, 93.2, 84.2, 64.8, 49.1, 48.1, 45.2, 38.3, 36.7, 29.9, 23.8, 21.6. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~19~H~24~N, 266.1903; found, 266.1928.

### 1-(2-(Phenylethynyl)bicyclo\[2.2.1\]heptan-2-yl)piperidine (**4h**) {#sec4.7.3}

Prepared according to the general procedure and obtained as a yellow oil in 78% yield and \>99:1 d.r. (436 mg, 1.56 mmol). ^1^H NMR (500 MHz, CDCl~3~): δ 7.42 (dd, *J* = 7.9, 1.6 Hz, 2H), 7.31--7.25 (m, 2H), 2.50 (s, 4H), 2.43 (d, *J* = 3.3 Hz, 1H), 2.22 (s, 1H), 1.96 (d, *J* = 9.5 Hz, 1H), 1.94--1.86 (m, 2H), 1.58 (m, 4H), 1.48 (ddd, *J* = 11.2, 7.0, 3.0 Hz, 1H), 1.44 (s, 2H) (overlapping peaks), 1.36 (s, 1H), 1.34 (s, 1H), 1.32--1.21 (m, 2H). ^13^C{^1^H} NMR (126 MHz, CDCl~3~): δ 131.8, 128.3, 127.5, 124.3, 93.3, 84.3, 66.3, 50.2, 46.9, 45.5, 38.4, 36.5, 30.1, 26.5, 25.0, 21.1. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~20~H~26~N, 280.2060; found, 280.2076.

### 1-(3-Methyl-1-(phenylethynyl)cyclohexyl)pyrrolidine (**4i**, Obtained as a Mixture of Diastereoisomers) {#sec4.7.4}

Prepared according to the general procedure and obtained as a yellow oil in 82% yield (439 mg, 1.64 mmol) and 87:13 d.r. according to ^1^H NMR. ^1^H NMR (200 MHz, CDCl~3~): δ 7.40 (dd, *J* = 6.6, 3.1 Hz, 2H), 7.32--7.22 (m, 3H), 2.70 (s, 4H), 2.12--1.97 (m, 2H), 1.87--1.07 (m), 1.02 (d, *J* = 6.1 Hz, CH~3~, minor diastereoisomer), 0.87 (d, *J* = 6.6 Hz, CH~3~, major diastereoisomer). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 131.8, 131.7, 128.2, 128.2, 127.6, 124.0, 91.8, 91.7, 86.1, 85.3, 62.2, 61.5, 46.8, 46.1, 37.4, 36.7, 31.6, 30.0, 29.5, 29.2, 24.0, 23.6, 22.8, 22.3, 19.7, 16.8, 13.0. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~19~H~26~N, 268.2060; found, 268.2080.

### 1-(4-(Phenylethynyl)decan-4-yl)pyrrolidine (**4j**) {#sec4.7.5}

Prepared according to the general procedure and obtained as a yellow oil in 64% yield (399 mg, 1.28 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.41 (dd, *J* = 6.6, 3.1 Hz, 2H), 7.32--7.24 (m, 3H), 2.76 (s, 4H), 1.88--1.58 (m, 8H), 1.51--1.18 (m, 10H), 1.00--0.77 (m, 6H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 131.7, 128.2, 127.6, 123.7, 91.6, 84.7, 61.3, 47.5, 39.4, 37.1, 31.9, 29.8, 23.6, 22.8, 17.2, 14.6, 14.2. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~22~H~34~N, 312.2686; found, 312.2686.

### *N*-Benzyl-2-(phenylethynyl)bicyclo\[2.2.1\]heptan-2-amine (**4k**) {#sec4.7.6}

Prepared according to the general procedure and obtained as a yellow oil in 33% yield and \>99:1 d.r. (199 mg, 0.66 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.51--7.21 (m, 10H), 4.01 (d, *J* = 12.3 Hz, 1H), 3.71 (d, *J* = 12.3 Hz, 1H), 2.51 (d, *J* = 3.1 Hz, 1H), 2.28 (s, 1H), 2.23--2.11 (m, 1H), 2.02 (m, 2H), 1.61--1.21 (m, 6H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 141.0, 131.7, 128.5, 128.5, 128.3, 127.7, 127.0, 123.9, 96.1, 82.8, 60.4, 50.2, 47.7, 46.9, 38.8, 36.7, 29.3, 21.7. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~22~H~24~N, 302.1903; found, 302.1911.

### 1-(3-Ethyl-1-phenylpent-1-yn-3-yl)pyrrolidine (**4m**) {#sec4.7.7}

Prepared according to the general procedure and obtained as a yellow oil in 30% yield (145 mg, 0.60 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.41 (dd, *J* = 6.7, 3.1 Hz, 2H), 7.32--7.23 (m, 3H), 2.78 (s, 4H), 1.88--1.66 (m, 8H), 0.96 (t, *J* = 7.4 Hz, 6H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 131.9, 128.3, 127.7, 123.8, 91.5, 85.0, 62.2, 47.6, 29.0, 23.7, 8.3. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~17~H~24~N, 242.1903; found, 242.1908.

### 1-(1-(*m*-Tolylethynyl)cyclohexyl)piperidine (**4n**) {#sec4.7.8}

Prepared according to the general procedure and obtained as a yellow oil in 68% yield (383 mg, 1.36 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.30--7.05 (m, 5H), 2.69 (s, 4H), 2.33 (s, 3H), 2.10 (d, *J* = 12.3 Hz, 2H), 1.84--1.34 (m, 14H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 137.9, 132.3, 128.8, 128.6, 128.1, 123.6, 90.3, 86.4, 59.5, 47.2, 35.8, 26.6, 25.8, 24.8, 23.2, 21.3. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~20~H~28~N, 282.2216; found, 282.2227.

### 1-(1-((4-Methoxy-2-methylphenyl)ethynyl)cyclohexyl)piperidine (**4r**) {#sec4.7.9}

Prepared according to the general procedure and obtained as a yellow solid in 70% yield (436 mg, 1.40 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.34 (d, *J* = 8.4 Hz, 1H), 6.73 (s, 1H), 6.66 (d, *J* = 8.5 Hz, 1H), 3.77 (s, 3H), 2.73--2.63 (m, 4H), 2.42 (s, 3H), 2.11 (d, *J* = 11.5 Hz, 2H), 1.75--1.52 (m, 10H), 1.55--1.37 (m, 4H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 159.1, 141.5, 133.3, 116.0, 115.0, 111.1, 92.9, 84.8, 59.7, 55.3, 47.2, 36.0, 26.6, 25.8, 24.8, 23.3, 21.5 HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~21~H~30~NO, 312.2322; found, 312.2327.

### 1-(1-((2-Bromophenyl)ethynyl)cyclohexyl)piperidine (**4s**) {#sec4.7.10}

Prepared according to the general procedure and obtained as an orange oil in 70% yield (485 mg, 1.40 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.57 (dd, *J* = 7.8, 1.3 Hz, 1H), 7.48 (dd, *J* = 7.6, 1.7 Hz, 1H), 7.24 (td, *J* = 7.5, 1.3 Hz, 1H), 7.17--7.08 (m, 1H), 2.75 (s, 4H), 2.17 (d, *J* = 11.1 Hz, 2H), 1.79--1.42 (m, 14H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 133.5, 132.3, 128.8, 126.9, 125.8, 125.5, 95.8, 84.8, 59.7, 47.1, 35.7, 26.6, 25.7, 24.8, 23.2. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~19~H~25~BrN, 346.1165; found, 346.1176.

### 4-(1-((4-Fluorobenzyl)amino)cyclohexyl)-2-methylbut-3-yn-2-ol (**4t**) {#sec4.7.11}

Prepared according to the general procedure and obtained as an orange oil in 51% yield (295 mg, 1.02 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.36--7.27 (m, 2H), 7.05--6.94 (m, 2H), 3.83 (s, 2H), 2.97--2.88 (m, 1H), 1.89--1.77 (m, 3H), 1.69--1.58 (m, 4H), 1.56 (s, 6H), 1.48--1.32 (m, 4H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 161.9 (d, *J* = 244.6 Hz), 136.5 (d, *J* = 2.9 Hz), 130.1 (d, *J* = 8.0 Hz), 115.2 (d, *J* = 21.2 Hz), 89.9 (s), 85.4 (s), 65.3 (s), 54.8 (s), 47.2 (s), 38.0 (s), 32.0 (s), 25.9 (s), 23.0 (s). ^19^F NMR (188 MHz, CDCl~3~): δ −116.4 to −116.7 (m). HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~18~H~25~FNO, 290.1915; found, 290.1924.

### 2-Methyl-4-(1-(4-phenylpiperazin-1-yl)cyclohexyl)but-3-yn-2-ol (**4u**) {#sec4.7.12}

Prepared according to the general procedure and obtained as an orange solid in 32% yield (209 mg, 0.64 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.26 (m, 2H), 6.93 (d, *J* = 8.6 Hz, 2H), 6.89--6.80 (m, 1H), 3.31--3.15 (m, 4H), 2.88--2.73 (m, 4H), 2.04--1.38 (m, 16H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 151.3, 129.1, 119.7, 115.9, 91.6, 81.8, 65.2, 58.1, 49.6, 46.0, 35.6, 32.1, 25.7, 22.8. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~21~H~31~N~2~O, 327.2431; found, 327.2433.

### 1-(1-(Phenylethynyl)cyclohexyl)piperidine-4-carboxylate (**4w**) {#sec4.7.13}

Prepared according to the general procedure and obtained as a yellow oil in 67% yield (455 mg, 1.34 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.42 (dd, *J* = 6.7, 3.0 Hz, 2H), 7.35--7.23 (m, 3H), 4.13 (q, *J* = 7.1 Hz, 2H), 3.15 (d, *J* = 11.6 Hz, 2H), 2.42--2.18 (t, *J* = 11.0 Hz, 3H), 2.13--1.43 (m, 14H), 1.24 (t, *J* = 7.1 Hz, 3H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 175.5, 131.9, 128.4, 127.9, 123.8, 90.5, 86.3, 60.4, 59.1, 46.0, 41.7, 36.1, 29.1, 25.9, 23.1, 14.5. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~22~H~30~NO~2~, 340.2271; found, 340.2299.

### *N*-(1-Phenylethyl)-1-(phenylethynyl)cyclohexanamine (**4y**) {#sec4.7.14}

Prepared according to the general procedure and obtained as a yellow oil in 63% yield (382 mg, 1.26 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.53--7.41 (m, 4H), 7.38--7.18 (m, 6H), 4.39 (q, *J* = 6.7 Hz, 1H), 2.16--1.89 (m, 2H), 1.82--1.49 (m, 7H), 1.45 (d, *J* = 6.7 Hz, 3H), 1.31--1.08 (m, 1H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 148.7, 131.9, 128.5, 128.0, 127.0, 126.7, 124.1, 123.9, 94.3, 84.9, 56.3, 54.0, 40.1, 38.9, 27.2, 26.0. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~22~H~26~N, 304.2060; found, 304.2059.

### *N*-(4-Fluorobenzyl)-1-(phenylethynyl)cyclohexanamine (**4z**) {#sec4.7.15}

Prepared according to the general procedure and obtained as a yellow oil in 52% yield (319 mg, 1.04 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.47 (dd, *J* = 6.5, 3.1 Hz, 2H), 7.41--7.28 (m, 5H), 7.01 (t, *J* = 8.7 Hz, 2H), 3.95 (s, 2H), 2.41--2.26 (m, 1H), 2.07--1.40 (m, 10H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 162.0 (d, *J* = 244.5 Hz), 136.8 (d, *J* = 3.3 Hz), 131.8 (s), 130.1 (d, *J* = 8.0 Hz), 128.4 (s), 128.0 (s), 115.3 (d, *J* = 21.2 Hz), 93.4 (s), 84.9 (s), 55.5 (s), 47.4 (s), 38.3 (s), 26.0 (s), 23.1 (s). ^19^F NMR (188 MHz, CDCl~3~): δ −116.56 (s). HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~21~H~23~FN, 308.1809; found, 308.1807.

### *N*-Cyclohexyl-*N*-methyl-1-(phenylethynyl)cyclohexanamine (**4zb**) {#sec4.7.16}

Prepared according to the general procedure and obtained as a yellow oil in 52% yield (307 mg, 1.04 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.44--7.36 (m, 2H), 7.33--7.25 (m, 3H), 3.03 (td, *J* = 10.9, 3.3 Hz, 1H), 2.40 (s, 3H), 2.12--1.91 (m, 4H), 1.69 (m, 11H), 1.32 (m, 5H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 131.53, 128.33, 127.71, 124.04, 93.37, 85.77, 58.87, 57.01, 37.06, 30.91, 29.89, 26.67, 26.43, 25.81, 23.20. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~21~H~30~N, 296.2373; found, 296.2374.

### *N*-Octyl-1-(phenylethynyl)cyclohexanamine (**4zc**) {#sec4.7.17}

Prepared according to the general procedure and obtained as a yellow oil in 70% yield (436 mg, 1.40 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.42 (dd, *J* = 6.7, 3.1 Hz, 2H), 7.33--7.23 (m, 3H), 2.79 (t, *J* = 7.1 Hz, 2H), 1.94 (d, *J* = 11.6 Hz, 2H), 1.74--1.07 (m, 20H), 0.88 (dd, *J* = 9.7, 6.6 Hz, 3H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 131.6, 128.1, 127.7, 123.6, 93.3, 84.6, 55.2, 43.2, 38.1, 31.8, 30.5, 29.5, 29.3, 27.5, 25.9, 23.1, 22.7, 14.1. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~22~H~34~N, 312.2686; found, 312.2686.

### 2,2,6,6-Tetramethyl-*N*-(1-(phenylethynyl)cyclohexyl)piperidin-4-amine (**4zg**) {#sec4.7.18}

Prepared according to the general procedure and obtained as a yellow oil in 45% yield (305 mg, 0.90 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.48--7.27 (m, 2H), 7.31--7.06 (m, 3H), 3.36 (ddd, *J* = 11.9, 9.7, 3.4 Hz, 1H), 2.06--0.80 (m, 27H). ^13^C{^1^H} NMR (50 MHz, CDCl~3~): δ 131.6, 128.5, 127.9, 123.9, 94.3, 84.3, 55.5, 52.1, 49.0, 45.6, 39.6, 34.9, 28.6, 23.3. HRMS (ESI-TOF) *m*/*z*: \[M + H\]^+^ calcd for C~23~H~35~N~2~, 339.2795; found, 339.2800.

Characterization Data for Known Compounds {#sec4.8}
-----------------------------------------

### 1-(1-(Phenylethynyl)cyclohexyl)piperidine (**4a**) {#sec4.8.1}

Prepared according to the general procedure and obtained as a yellow oil in 91% yield (487 mg, 1.82 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.47--7.36 (m, 2H), 7.28--7.23 (m, 3H), 2.66 (s, 4H), 2.11--2.05 (m, 2H), 1.83--1.34 (m, 14H).^[@ref27],[@cit33b],[@cit33i]^

### 1-(1-(Phenylethynyl)cyclopentyl)piperidine (**4b**) {#sec4.8.2}

Prepared according to the general procedure and obtained as a yellow oil in 63% yield (319 mg, 1.26 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.41 (dd, *J* = 6.5, 3.2 Hz, 2H), 7.31--7.25 (m, 3H), 2.65--2.62 (m, 4H), 2.13--2.10 (m, 2H), 1.87--1.44 (m, 12H).^[@cit33b]^

### 1-(1-(Phenylethynyl)cycloheptyl)pyrrolidine (**4c**) {#sec4.8.3}

Prepared according to the general procedure and obtained as a yellow oil in 35% yield (187 mg, 0.70 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.42 (dd, *J* = 6.6, 3.1 Hz, 2H), 7.28 (dd, *J* = 6.6, 2.7 Hz, 3H), 2.79 (t, *J* = 6.0 Hz, 4H), 2.10--1.83 (m, 4H), 1.78 (p, *J* = 3.2 Hz, 4H), 1.71--1.46 (m, 8H).^[@cit33b]^

### 1-(3-Methyl-1-phenylpent-1-yn-3-yl)pyrrolidine (**4d**) {#sec4.8.4}

Prepared according to the general procedure and obtained as an orange/brown oil in 82% yield (373 mg, 1.64 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.45--7.38 (m, 2H), 7.32--7.26 (m, 3H), 2.80 (t, *J* = 5.8 Hz, 4H), 1.84--1.79 (m, 4H), 1.74--1.65 (m, 2H), 1.42 (s, 3H), 1.05 (t, *J* = 7.5 Hz, 3H).^[@ref30],[@cit33i]^

### 1-(3-Methyl-1-phenylhex-1-yn-3-yl)pyrrolidine (**4e**) {#sec4.8.5}

Prepared according to the general procedure and obtained as an orange/brown oil in 69% yield (333 mg, 1.38 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.45--7.36 (m, 2H), 7.28--7.25 (m, 3H), 2.79 (t, *J* = 5.4 Hz, 4H), 1.85--1.74 (m, 4H), 1.73--1.47 (m, 4H), 1.43 (s, 3H), 0.95 (t, *J* = 7.1 Hz, 3H).^[@cit33i]^

### 1-(1-(*p*-Tolylethynyl)cyclohexyl)piperidine (**4q**) {#sec4.8.6}

Prepared according to the general procedure and obtained as a yellow oil in 72% yield (405 mg, 1.44 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.33 (d, *J* = 6.5 Hz, 2H), 7.09 (d, *J* = 6.5 Hz, 2H), 2.69 (s, 4H), 2.33 (s, 3H), 2.14--2.07 (m, 2H), 1.73--1.44 (m, 14H).^[@cit33b]^

### *N*-Benzyl-1-(phenylethynyl)cyclohexanamine (**4x**) {#sec4.8.7}

Prepared according to the general procedure and obtained as a yellow oil in 71% yield (411 mg, 1.42 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.56--7.16 (m, 10H), 3.97 (s, 2H), 2.01--1.95 (m, 2H), 1.77--1.41 (m, 8H).^[@ref22]^

### 4-(1-(Phenylethynyl)cyclohexyl)morpholine (**4za**) {#sec4.8.8}

Prepared according to the general procedure and obtained as an orange oil in 62% yield (334 mg, 1.24 mmol).^1^H NMR (200 MHz, CDCl~3~): δ 7.53--7.38 (m, 2H), 7.37--7.22 (m, 3H), 3.76 (s, 4H), 2.71 (s, 4H), 2.11--1.92 (m, 1H), 1.82--1.43 (m, 6H), 1.36--1.20 (m, 2H).^[@ref24]^

### *N*-(4-Methoxybenzyl)-1-(phenylethynyl)cyclohexanamine (**4zd**) {#sec4.8.9}

Prepared according to the general procedure and obtained as an orange oil in 49% yield (313 mg, 1.24 mmol). ^1^H NMR (200 MHz, CDCl~3~): δ 7.53--7.40 (m, 2H), 7.36--7.27 (m, 5H), 6.86 (d, *J* = 8.7 Hz, 2H), 3.91 (s, 2H), 3.79 (s, 4H), 2.00--1.94 (m, 2H), 1.75--1.39 (m, 5H), 1.25 (m, 2H).^[@ref22]^

The Supporting Information is available free of charge on the [ACS Publications website](http://pubs.acs.org) at DOI: [10.1021/acsomega.9b01387](http://pubs.acs.org/doi/abs/10.1021/acsomega.9b01387).Copies of the ^1^H, ^13^C, and ^19^F NMR spectra, 2D NMR spectra (COSY, HSQC, and NOESY), and FTIR spectra ([PDF](http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01387/suppl_file/ao9b01387_si_001.pdf))

Supplementary Material
======================

###### 

ao9b01387_si_001.pdf

The authors declare no competing financial interest.

The authors acknowledge the contribution of COST Action CA15106 (C--H Activation in Organic Synthesis---CHAOS). The Special Account for Research Grants of the National and Kapodistrian University of Athens is also gratefully acknowledged for funding (research program 70/3/14872).
