KA² Coupling, Catalyzed by Well-Defined NHC-Coordinated Copper(I): Straightforward and Efficient Construction of α-Tertiary Propargylamines**

Graphical Abstract

This works describes a new, straightforward, highly efficient, and mild catalytic protocol for the synthesis of α-tertiary propargylamines, via the multicomponent KA² reaction (Ketone-Amine-Alkyne), employing well-defined, sustainable copper(I) complexes bearing N-heterocyclic carbene ligands.

Abstract

A new, straightforward, highly efficient, and mild catalytic protocol for the synthesis of α-tertiary propargylamines, via the multicomponent KA² reaction (Ketone-Amine-Alkyne), employing well-defined, sustainable copper(I) complexes bearing N-heterocyclic carbene ligands, is reported herein. The methodology uses very low catalyst loading under moderate heating to achieve the construction of a wide range of propargylamines in good to excellent yields in very short reaction times. Challenging substrates, including acyclic linear ketones, aromatic ketones, and electron-poor aromatic alkynes, as well as substrates bearing synthetically valuable functionalities, are well tolerated.

Introduction

Propargylamines comprise a wide class of organic compounds, studied by a plethora οf research groups, among others in the field of Pharmaceutical Chemistry, due to their biological activity, as well as due to their value as building blocks for the preparation of various organic scaffolds. Propargylamines exhibit notable therapeutic action against neurodegenerative disorders, like Parkinson's and Alzheimer's disease,^{1, 2} antioxidant activity,³ as well as antidepressant and anxiolytic properties, having been characterized as multi-functional drugs.^{4, 5} Furthermore, their synthetic value has been extensively exploited in the construction of multiple nitrogen containing heterocycles and natural products.^6-11

Access to propargylamines can be achieved by numerous synthetic approaches,⁶ of which the most common and widely used is the catalytic, multicomponent, one-pot, A³ (Aldehyde-Amine-Alkyne) coupling reaction, leading to propargylamines bearing α-primary and α-secondary carbon centers. Since its discovery, the A³ reaction has been exhaustively studied, due to its operational simplicity, wide substrate scope, and compatibility with a broad collection of catalysts.^{12, 13} A diverse assortment of protocols has been developed, based on transition metal catalysts,^14-18 organocatalysts,^{19, 20} or heterogeneous promoters.^21-25 Numerous enantioselective catalytic systems enabling the preparation of highly enantioenriched propargylamines have been also reported.^26-33 Strategies aiming towards the synthesis of multifunctional polymeric scaffolds and dendrimers via the A³ reaction have been developed as well.^34-39

The continuous advancements in the field of the A³ reaction led to the next decisive step, the incorporation of ketones as the carbonyl-containing substrate. However, the poor reactivity of ketones, relative to aldehydes, rendered their utilization a challenging goal.⁴⁰ In 2010, Van der Eycken and co-workers reported the first efficient catalytic protocol for the synthesis of propargylamines bearing quaternary carbon centers, starting from various cyclohexanone derivatives, primary amines, and terminal alkynes, by utilizing CuI under microwave irradiation.⁴¹ This new transformation adopted the name “KA² coupling reaction” (Ketone-Amine-Alkyne), providing easy access to α-tertiary propargylamine substrates (quaternary carbon-bearing propargylamines or tetrasubstituted propargylamines).⁴² The resulting α-tertiary amine motif is an important structure in the field of Medicinal Chemistry, frequently appearing in natural products and compounds of medicinal interest.^{43, 44}

Throughout the past decade, the KA² reaction was optimized to tolerate demanding substrates, by Larsen's group, achieving the functionalization of linear acyclic ketones,⁴⁵ which lack the increased reactivity of their cyclic analogues, due to the nonexistent ring strain release occurring during the nucleophilic attack of the metal acetylide. Larsen and co-workers used CuCl₂ in the presence of 1 equivalent of the Lewis acid Ti(OEt)₄, for the activation of the carbonyl group, while Ma's group in 2015 managed to functionalize the previously non-reactive aromatic ketones, utilizing Cu(I) catalysts.⁴⁶ Several protocols employing heterogeneous catalysis have also been reported.^47-54 Although the KA² reaction is closely related to the A³ reaction, it still remains relatively underdeveloped. Our research group has contributed to the field of KA² by developing catalytic methodologies based on inexpensive and environmentally benign metals like zinc^{55, 56} and manganese,⁵⁷ as well as by reporting the one-pot cascade synthesis of trisubstituted allenes from propargylamines, using ZnI₂ as a bifunctional catalyst.^{58, 59} However, despite these developments, in the vast majority of cases, KA² still requires reaction temperatures over 100 °C, prolonged reaction times, and excess of substrates to proceed efficiently.

Aiming to develop a new, more efficient, and mild protocol, we decided to employ well-defined copper(I) complexes bearing N-heterocyclic carbene ligands (NHCs). Over the years, NHCs and their corresponding metal complexes have successfully been used in various organic transformations, such as olefin metathesis,⁶⁰ cross coupling reactions,⁶¹ C−H activation reactions,⁶² as well as organocatalytic protocols.⁶³ Since their discovery, [(NHC)CuX]-type complexes have been extensively used in catalysis, due to the intrinsically compelling nature of copper catalysis, in combination with its natural abundance and low toxicity, their improved performance, in comparison to common copper salts, their stability, and their convenient and straightforward preparation^64-67, which can be achieved efficiently on a large scale by sustainable synthetic routes in water or under solventless conditions by the use of mechanochemistry.⁶⁸ Transformations such as ketone alkynylation,⁶⁹ arylation of allylic bromides,⁷⁰ semihydrogenation of terminal alkynes,⁷¹ and C−H activation reactions^72-74 have been significantly improved in terms of catalytic activity, selectivity, as well as air and water tolerance, by the employment of [Cu(X)NHC] complexes. Likewise, the efficiency of N-heterocyclic carbene complexes of Cu(I),^{75, 76} Ag(I),^77-79 and Au(I)^{80, 81} has been showcased in the A³ reaction, under both homogeneous and heterogeneous conditions.⁸² Nevertheless, the utility of N-heterocyclic carbene metal complexes in the KA² reaction has thus far been overlooked. Herein, we report a highly efficient [Cu(X)NHC]-catalyzed KA² protocol, with short reaction times, under low reaction temperatures, and using a very low loading of easily-accessible low-cost catalysts, for the derivatization of a broad range of substrates.

Results and Discussion

The copper complexes used in this work (Figure 1) were prepared following the method published by Nolan and coworkers.⁶⁷ For the exploratory optimization experiments we used cyclohexanone, pyrrolidine or piperidine, and phenylacetylene in toluene and 4 mol% of catalyst under mild heating at 40 °C. Initially, 4 Å molecular sieves (MS) were added for the removal of the in situ generated water from the reaction mixture.

Figure 1

Copper complexes tested in this study.

Copper complex [(SIPr)CuCl] showed limited catalytic activity (Table 1, entry 1), leading to 19 % of product 4 a, while [(SIPr)CuBr] led to only traces of propargylamine (Table 1, entry 2). This observation agrees with studies conducted by Navarro and Zou, who noted that large counterions inhibit the catalytic activity of the NHC complexes in the A³ reaction.^{78, 79} When [(SIMes)CuCl] was used as the catalyst, the yield substantially increased to 79 % (Table 1, entry 3). Next, we employed 1 equivalent of Ti(OEt)₄ as additive, instead of molecular sieves. Besides reacting with the water generated, to give TiO₂, Ti(OEt)₄ also acts as a Lewis acid, rendering the carbonyl groups more electrophilic. The addition of Ti(OEt)₄ proved beneficial for the formation of the desired propargylamine 4 a, which was isolated in 86 % yield (Table 1, entry 4). The complex bearing the unsaturated ligand IMes exhibited slightly lower catalytic activity, leading to 85 % yield (Table 1, entry 5). On the other hand, when we employed [(IPr)CuCl] we obtained 4 a in 22 % yield (Table 1, entry 6). These results indicate that a key factor for catalyst performance in our protocol is the steric bulk around the metal center, with less bulky ligands leading to increased reaction yields, most likely due to easier alkyne complexation to the copper atom and to easier acetylide nucleophilic attack to the ketiminium cation. As expected, in the absence of copper complex, no propargylamine was detected by GC-MS (Table 1, entry 7). By increasing the concentration of the reaction mixture to 1 M, the desired product was formed in excellent yield (97 % after 4 h of stirring, Table 1, entry 8). By decreasing the catalytic loading, less product formation was detected (Table 1, entries 9 and 10). Furthermore, we evaluated simple copper(I) salts CuCl and CuBr, under identical reaction conditions, but the reaction yields were considerably lower (Table 1, entries 11 and 12). Next, we probed the influence of a series of solvents. The “green” solvent p-cymene proved unsuitable, as it led to 21 % product yield (Table 1, entry 13). Unreacted phenylacetylene was observed by GC-MS analysis, in addition to the formation of the enamine byproduct. The use of ethyl acetate resulted in 83 % yield (Table 1, entry 14), while water was shown to be not suitable for this reaction, leading to 8 % yield (Table 1, entry 15). In the case of 2-MeTHF we observed formation of propargylamine 4 a in 74 % yield, while in the case of ^tAmylOH in 81 % yield (Table 1, entries 16 and 17). When a bulkier and less nucleophilic amine, piperidine, was employed, the yield of product 4 b was decreased to 43 % (Table 1, entry 18), but an increase in temperature to 70 °C led to an excellent yield of 94 % (Table 1, entry 19).

Table 1. Probing and optimizing the reaction conditions.^[a]

Entry	Catalyst	n	Solvent (additive)	Time [h]	Yield [%]^[b]
1	[(SIPr)CuCl] (4 mol%)	1	toluene (0.5 M) (4 Å MS)	6	19
2	[(SIPr)CuBr] (4 mol%)	1	toluene (0.5 M) (4 Å MS)	6	traces
3	[(SIMes)CuCl] (4 mol%)	1	toluene (0.5 M) (4 Å MS)	6	79 (74)
4	[(SIMes)CuCl] (4 mol%)	1	toluene (0.5 M) (Ti(OEt)4)	6	90 (86)
5	[(IMes)CuCl] (4 mol%)	1	toluene (0.5 M) (Ti(OEt)4)	6	85
6	[(IPr)CuCl] (4 mol%)	1	toluene (0.5 M) (Ti(OEt)4)	6	22
7	–	1	toluene (1 M) (Ti(OEt)4)	6	0
8	[(SIMes)CuCl] (4 mol%)	1	toluene (1 M) (Ti(OEt)4)	4	97 (93)
9	[(SIMes)CuCl] (2 mol%)	1	toluene (1 M) (Ti(OEt)4)	4	82
10	[(SIMes)CuCl] (1 mol%)	1	toluene (1 M) (Ti(OEt)4)	4	71
11	CuCl	1	toluene (1 M) (Ti(OEt)4)	4	46
12	CuBr	1	toluene (1 M) (Ti(OEt)4)	6	57
13	[(SIMes)CuCl] (4 mol%)	1	p-cymene (1 M) (Ti(OEt)4)	4	21
14	[(SIMes)CuCl] (4 mol%)	1	EtOAc (1 M) (Ti(OEt)4)	4	83
15	[(SIMes)CuCl] (4 mol%)	1	H2O (1 M)	4	8
16	[(SIMes)CuCl] (4 mol%)	1	2-MeTHF (1 M) (Ti(OEt)4)	4	74
17	[(SIMes)CuCl] (4 mol%)	1	^tAmylOH (1 M) (Ti(OEt)4)	4	81
18	[(SIMes)CuCl] (4 mol%)	2	toluene (1 M) (Ti(OEt)4)	4	43
19^[c]	[(SIMes)CuCl] (4 mol%)	2	toluene (1 M) (Ti(OEt)4)	4	94 (90)

• [a] Unless otherwise stated, reactions were carried out in 0.5 mmol scale at 40 °C. [b] Yields calculated by GC-MS analysis. Isolated yields after column chromatography in parentheses. [c] Reaction was carried out at 70 °C.

Given that we were planning to among others use challenging substrates, we decided to carry out the rest of the reactions at 70 °C, although some of the reactions can proceed very efficiently at lower temperatures.

With the optimized reaction conditions in hand, we continued our investigation by examining a series of ketone substrates (Scheme 1). The cyclic ketones cyclopentanone and cyclododecanone led to propargylamines 4 c and 4 d in 94 % and 78 % yield, respectively. Linear ketones proved to be good substrates for our catalytic protocol as well, given that they reacted efficiently with pyrrolidine and phenylacetylene. Starting from 2-pentanone, propargylamine 4 e was isolated in 92 % yield, while a decrease in yield was observed when 3-pentanone was employed, probably due to the greater steric hinderance around the electrophilic center of the intermediate ketiminium cation. The same trend was noticed when 4-decanone was used, leading to propargylamine 4 g in 74 % yield. Using 2-cyclohexenone, we detected a complex mixture of byproducts. More importantly, our catalytic system allows the functionalization of challenging aromatic ketones. In specific, acetophenone led to propargylamine 4 i in 42 % yield and 4-chloro-acetophenone to propargylamine 4 j in 47 %. Note that the number of catalytic systems that allow the incorporation of aromatic ketones remains fairly limited, especially in temperatures under 100 °C.^{46, 54, 57, 84, 85}

Scheme 1

Substrate scope of ketones. All reactions were performed on a 0.5 mmol scale. Isolated yields after column chromatography are shown in parentheses.

For the examination of terminal alkynes scope, both electron rich and electron poor aromatic alkynes were investigated, as well as aliphatic alkynes (Scheme 2). Electron rich aromatic alkynes resulted in excellent yields, with p-methyl-phenylacetylene leading to propargylamine 4 k in 86 % isolated yield and p-methoxy-phenylacetylene to 4 l in 95 % isolated yield. Importantly, the use of alkynes bearing electron withdrawing groups did not substantially lower the reaction yield. More specifically, propargylamine 4 m derived from p-chloro-phenylacetylene was isolated in 83 % yield. Our methodology proved to be tolerable to even more electron-poor moieties. Propargylamine 4 n was synthesized starting from p-trifluoromethyl-phenylacetylene in very good yield (72 % isolated). Aromatic alkynes that are substituted with strongly deactivating groups are usually challenging substrates for the KA² coupling, as they render the in situ generated metal-acetylide less nucleophilic, resulting in low yields or complete quenching of the reaction.^{53, 55, 57} In our case, we hypothesize that an activating effect of the NHC-coordinated catalyst enables the deactivated acetylide to efficiently react with the ketiminium cation towards the desired propargylamine. When p-nitro-phenylacetylene was employed, no propargylamine was detected in the reaction mixture, a fact that is attributed to some kind of incompatibility of our system with nitro groups, in addition to the electron poor nature of the alkyne. We continued our studies by employing a series of aliphatic alkynes, leading to products 4 p-4 s in very good to excellent isolated yields (Scheme 2).

Scheme 2

Substrate scope of alkynes. All reactions were performed on a 0.5 mmol scale. Isolated yields after column chromatography are shown in parentheses.

Subsequently, various cyclic and acyclic amines were probed. As mentioned above, piperidine reacted with cyclohexanone and phenylacetylene to give propargylamine 4 b in 90 % isolated yield. The same amine also led to product 4 t, in combination with 2-pentanone and phenylacetylene, in 78 % yield (Scheme 3). In the case of morpholine, a drop in the reaction yield of the desired propargylamine 4 u was observed. This result is attributed to the lower nucleophilicity of the amine, due to the presence of the electron withdrawing oxygen atom. Benzylamine and n-octylamine (primary amines) were also employed. The desired product 4 v could not be detected, while the yield of propargylamine 4 w was less than 5 %; therefore, we did not proceed with product purification. In this case, GC-MS analysis showed that the reaction stopped at the imine intermediate. Propargylamine 4 x, derived from di-n-propylamine, was isolated in moderate yield (47 %). Furthermore, we used N-methyl-cyclohexylamine combined with 2-pentanone and phenylacetylene, leading to the isolation of propargylamine 4 y in 70 % yield. GC-MS analyses of the crude mixtures of propargylamines 4 w and 4 x showed unreacted starting materials, but no side-reactions. Finally, functionalized cyclic amines ethyl isonipecotate and 1-Boc-piperazine were successfully utilized, leading to products 4 z and 4 za in 73 % and 65 % isolated yields, respectively. In these cases, we did not observe any side-reactions involving the ester or the carbamate functional groups, showcasing the mild nature of our protocol and its ability to be utilized in late-stage functionalizations.

Scheme 3

Scope of amines. All reactions were performed on a 0.5 mmol scale. Isolated yields after column chromatography are shown in parentheses. [a] Determined by GC-MS analysis.

Based on the literature,^{42, 55, 57, 84} a proposed catalytic cycle is shown in Scheme 4. In step I, the [(NHC)CuCl] complex forms a π-complex with the triple bond of the alkyne, from which the metal acetylide is generated during Step II, by the assistance of the amine. Concomitantly, the amine condenses with the Lewis acid-activated ketone to generate a ketiminium cation and a molecule of H₂O, which then reacts with Ti(OEt)₄ to form TiO₂. In the rate determining step III, the metal acetylide attacks the ketiminium cation, forming the propargylamine and regenerating the catalyst.

Scheme 4

Proposed catalytic cycle for the [(NHC)CuCl] catalyzed KA² reaction.

Conclusions

In conclusion, we have herein established a new, highly efficient catalytic protocol for the KA² coupling reaction, employing easily-accessible, sustainable, well-defined Cu(I)-NHC complexes as catalysts. Our methodology introduces a very useful approach for the synthesis of α-tertiary propargylamines, achieving high performance with low catalyst loading, operating under low temperatures, in short reaction times. A wide range of substrates have been successfully utilized, employing stoichiometric amounts of starting materials. Demanding substrates, such as acyclic linear ketones, aromatic ketones, and electron-poor aromatic alkynes are well tolerated. Synthetically valuable propargylamines bearing functionalities such as ester, amide, aryl halide, or methoxy can be efficiently prepared. The low temperatures of our protocol, along with the well-defined nature of the herein reported Cu(I)-NHC catalysts, comprise a first step towards the development of the elusive asymmetric KA² reaction.

General Experimental Section

In a flame dried Schlenk tube equipped with a magnetic stirring bar, [(SIMes)CuCl] (0.0083 g, 0.02 mmol, 0.04 equiv.), Ti(OEt)₄ (0.114 g, 0.5 mmol, 1 equiv.), the ketone (0.5 mmol, 1 equiv.), the alkyne (0.5 mmol, 1 equiv.) and the amine (0.5 mmol, 1 equiv.) were added under an argon atmosphere. Toluene (0.5 mL) was added, and the reaction was stirred at 70 °C for 4 h. Then, the reaction mixture was cooled to room temperature, diluted with CH₂Cl₂ and filtered through a short Celite plug (3×5 mL CH₂Cl₂). The crude mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (PE/EtOAc) to afford the desired propargylamine.

Supporting Information

Additional references cited within the Supporting Information.^86-88

Acknowledgments

The research project was financially supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “1st Call for H.F.R.I. Research Projects to support Faculty Members & Researchers and the procurement of high-cost research equipment grant” (Project Number: 16).

Conflict of interest

The authors declare no conflict of interest.

Open Research

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.