Cu-Catalyzed Cross-Coupling Reactions of Enamines and Terminal Alkynes: Access of Propargylamines as Neurodegenerative Disorder Agents

Abstract

Reactions between enamine analogues and terminal alkynes were explored. Copper(I) complex of 1,10-phenanthroline catalyzed these reactions to generate a diastereoselective propargylamines via C–C bond formation. In the presence of Zn²⁺, the chiral propargylamines converted into the β-allenoates with an excellent yield and enantioselectivity achieved up to 99 %. Models of synthesized propargylamines were used for molecular docking and dynamic simulations, which indicate that this class of molecules shows promise for anti-neurodegenerative activity.

Introduction

Neurodegeneration has emerged as a prominent feature of a wide range of disorders included under the generalized term “neurodegenerative disease.” Memory loss, cognitive impairment, and dementia are among the hallmarks of Alzheimer’s disease (AD).^[1] The use of extracellular amyloid β-peptide (Aβ) aggregates (senile plaques) and collates of the hyperphosphorylated tau protein (neurofibrillary tangles)^[2] and also with tau hyperphosphorylation have become the most envisaged pathogenetic pathways,^[3] and the mitochondrial sequential speculation might have attracted intensive far more attention.^[4] The inflammatory hypothesis, vascular hypothesis, cholesterol hypothesis, tau hypothesis, metal hypothesis, cell cycle hypothesis, and oxidative stress hypothesis are all widely discussed AD speculations.^[5] Currently, the only acetylcholinesterase enzyme (AChE) inhibitors licensed for AD therapy are donepezil, galantamine, and rivastigmine, which varies in chemical structures as well as pharmacokinetic and pharmacologic properties. Developing and testing new drug targets that might show activity as AChE inhibitors is challenging.

The propargylamine functional group is present in a breadth of natural antioxidants, including some that were shown to be powerful antidrugs, which prevent neurons from apoptosis in cell culture and animal assays of neurodegenerative diseases (Scheme 1).^[6] Selegiline (Anipril^®) and rasagiline (Azilect^®) are two prominent propargylamine-containing drugs prescribed to persons with Parkinson’s disease at initial and moderate to ad-vanced illness.^[7] Pargyline (Eutonyl^®) is an irreversible antihypertensive monoamine oxidase (MAO) inhibitor.^[8] Other propargylamines have shown promise as therapeutics toward breast and pancreatic cancer cells,^[9] and as anti-coagulation agents in cardiovascular systems.^[10]

Scheme 1.

Representative bioactive molecules.

Propargylamines are powerful building blocks often seen in bioactive molecules and natural products, as well as valuable synthons for neurodegenerative diseases.^[11] Several methods have been reported for the preparation of various propargylamine analogues using A³ (Amine-Aldehyde-Alkyne) and KA² (Ketone-Aldehyde-Alkyne) coupling reactions (Scheme 2a).^[12] However, only a few methods have described for the preparation of propargylamines using transition metal-based catalysts.^[13] Furthermore, propargylamines have been widely used as precursors for biologically active compounds such as pyrroles, phenanthrolines, quinolones, indolizines, pyrrolidines, and oxazolidinones, to highlight a very few.^[14] They have furthermore been used as starting materials for C—C and C—H activation mediated by transition metals,^[15] as well as intermediates in the total synthesis of various natural and medicinal compounds.^[16]

Scheme 2.

Comparison of previous studies and our development on C—N and C—C bond construction.

In contrast, a protocol for the synthesis of diastereoselective propargylamines via the asymmetric nucleophilic addition (prochiral nucleophiles) to imines was reported (Scheme 2b).^[17] Notably, these limited reports exclusively generate anti-configured propargylamine compounds, and selective catalytic asymmetric nucleophilic addition reaction to enamines is still unattainable, despite the significant synthetic usefulness. As a result, we became interested in developing catalytic methods for asymmetric, carbon nucleophile additions to enamines to target specific diastereoselective, chiral propargylamines and their resulting conversion to β-allenoates (Scheme 2c). Theoretical models of these products have been applied to molecular docking and simulation studies, which show promise as AChE inhibitors.

Results and Discussion

Using a sequence of homoleptic phenanthroline-containing copper(I) complexes (10 mol %),^[18] we initiated the reaction between the enamine and acetylene. At first, subjecting 1 a and phenylacetylene 2 a with copper catalyst I in toluene at 110 °C for 2 h led to producing the propargylamine 3 a in 52 % yield and the corresponding β-allenoate was obtained in 2 % yield (Table 1, entry 1). Other substituted-1,10-phenanthroline copper(I) complexes were investigated (Table 1.) The copper complex II led to reasonable enhancement in the yield of propargylamine 3 a (70 %) with 5 % yield of β-allenoate (Table 1, entry 2), emphasizing the existence of electronic and steric factors in the catalyst. Similarly, the use of copper complex III afforded the diastereoselective propargylamine 3 a in 65 % yield (Table 1, entry 3) and copper complex IV gave the diastereoselective propargylamine 3 a in reasonable yield (Table 1, entry 4). In addition, the screening of other catalysts such as V and VI furnished the diastereoselective propargylamine 3 a in 46–50 % yield (Table 1, entries 5 and 6). To our delight, the propargylamine 3 a yields were improved when the phenanthroline copper catalyst II loading was increased under the same conditions (Table 1, entry 7). Fortunately, the propargylamine yield was enhanced by increasing the reaction time (Table 1, entry 8). We furthermore altered the solvent to dioxane to obtain propargylamine 3 a in 82 % yield with 5 % yield of β-allenoate (Table 1, entry 9). Likewise, we performed the reaction in other solvents such as acetonitrile (CH₃CN), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) under reflux conditions that did not afford the propargylamine 3 a (Table 1, entries 10–12). Moreover, the copper salts could afford the propargylamine in 53–65 % yield (Table 1, entries 13 and 14). As a result, the Cu(I) catalyst of 1,10-phenanthroline (II) was chosen for further substrate scope of the reaction.

Table 1.

Optimization of the reaction conditions.^[a]

Entry	Solvent	Cu+ (mol%)	Time (h)	3 %[f]	4 %[f]
1	Toluene	I (10)	2	52	2
2	Toluene	II (10)	2	70	5
3	Toluene	III (10)	2	65	3
4	Toluene	IV (10)	3	67	5
5	Toluene	V (10)	3	46	2
6	Toluene	VI (10)	3	50	2
7	Toluene	II (15)	2	72	7
8	Toluene	II (20)	4	85	8
9[b]	Dioxane	II (10)	5	82	5
10[c]	CH3CN	II (10)	12	20	-
11[d]	DMF	II (10)	24	5	-
12[e]	DMSO	II (10)	24	10	-
13	Toluene	CuBr (20)	10	65	10
14	Toluene	CuCl (20)	10	53	5

^[a]All reactions were performed with 1 a (1.0 mmol), 2 a (1.0 mmol), and Cu⁺-catalyst in 3.0 mL of solvents at 110 °C,

^[b]100 °C,

^[c]80 °C,

^[d]150 °C,

^[e]170 °C.

^[f]Reaction yields were determined for the crude product through 400 MHz ¹H-NMR spectroscopy with mesitylene as an internal standard. ^#Configuration assumed based on previous reports.^[12]

The substrate scope and limitations of the copper(I)-catalyzed reaction of the enamine analogues and acetylenes were explored, and the results are shown in Scheme 3. The addition of terminal alkynes to the enamine analogue was efficient and afforded the propargylamine derivative in 3 aa in 85 % yield. Electron-rich group (Me and OMe) substitution on the para and meta position of the phenylacetylenes effectively performed nucleophilic addition to the enamine analogue to produce the desired propargylamines in 72–82 % yields (3 ab, 3 ac, 3 ad and 3 ae). Similarly, the n-propyl and n-pentyl substitution on the para position of phenylacetylenes provided the respective propargylamine products (3 af and 3 ag) in 75– 80 % yields. Moreover, para-fluoro (F), para-chloro (Cl), and para-phenyl (Ph) substitution of phenylacetylene afforded the propargylamine in 70–72 % yields (3 ai, 3 aj, and 3 ak). Propargylamine reaction was readily observed in terminal alkynes featuring diverse electron-substituents on the para-phenyl ring. Remarkably, electron-deficient groups resulted in the corresponding propargylamine products (3 al–3 ao), although their yields were slightly diminished (46–59 %). The optimized conditions proved highly compatible with functional groups like cyano (CN), nitro (NO₂), aldehyde (CHO), and ester (CO₂Me). Even the aliphatic 1-alkynes survived under catalytic conditions to generate the respective propargylamine product in 65–68 % yields (3 ap and 3 aq). In addition, the different enamine esters (1 b and 1 c) were reacted with phenylacetylene to produce an effective propargylamine product (3 ba and 3 ca) in 60–62 % yields. Finally, two substrates containing 2-naphthyl acetylenes were treated under standard conditions with the enamine 1 a to produce their corresponding propargylamines in 70 %−85 % yields (3 a and 3 dn). The (R)-isomer 1 d, based on (R)-α,α-diphenyl-D-prolinol, was used to gain some mechanistic insights regarding the chirality established by compound 1 in the reaction. Since we failed to prepare good quality, X-ray diffracting crystals of the propargylamines after exhaustive attempts, we turned to other means to understand the stereo-selectivity in the reaction. The propargylamines configuration was determined to be S based on previous reports.^[12]

Scheme 3.

Scope table of propargylamine. Reaction conditions: [a] All reactions were performed with substrate 1 (1.0 mmol), 2 (1.0 mmol), and catalyst II (20 mol %) in 3.0 mL of toluene at 110 °C for 4 h. [b] (R)-enamine was used. ^#Configuration assumed based on previous reports.^[12]

In an attempt to gain some understanding of the configuration of propargylamine, we performed circular dichroism (CD) measurements for (S)-α,α-diphenyl-L-prolinol, (R)-α,α-diphenyl-D-prolinol, 3 an, and 3 dn in methanol (Figure 1 & SI, Figure S5). The spectra of the pure propargylamines in methanol show an opposite Cotton effect, which is characteristic for molecules having an opposite handedness when subjected to plane-polarized light. If 3 an is an (S,S)-compound and 3 dn is an (R,R)-compound, one would expect to observe this phenomenon in the CD signals. Compounds 3an and 3dn showed absorption maxima at 245 nm but were in different phases. When compared with references,^[12] it is likely that the acetylene addition to the enamine under copper-catalyzed conditions should produce the same configuration as the existing stereo-center i. e., the (S)-enamine produces the (S,S)-propargylamine and the (R)-enamine produces the (R,R)-propargylamine.

Figure 1.

CD spectra of 3 an (blue), and 3 dn (red) in methanol at 25 °C.

To expand the synthetic versatility of propargylamines, common organic transformations were performed using amines such as piperidine and morpho-line moiety having enamine analogs with phenylacetylene in the presence of copper catalyst II gave the propargyl-amines in 52–58 % yields (Scheme 4).

Scheme 4.

Propargylamine derivatives of piperidine & morpholine. Zinc-catalyzed formation of β-allenoates. Reaction conditions: [a] the reactions were performed with substrates (5, 1.0 mmol), 2 (1.0 mmol), and catalyst II (20 mol %) in 3.0 mL of toluene at 110 °C for 4 h.

These propargylamines were then converted into the (R)-β-allenoates with excellent enantioselectivity and yield in the presence of zinc(II) salt (Scheme 5). A tentative mechanism may be considered as outlined in Scheme 6.^[12] Initially, the enamine analog 1 would form an iminium ion in situ and would react with alkynyl copper complex A to generate the intermediate copper complex B.^[19] Afterwards, the removal of a copper(I) catalyst resulted in the generation of propargylamines D. The propargylamine reaction with ZnBr₂ provides the intermediate E, which is followed by an intramolecular H-shift or the addition of H and ZnBr₂ group across triple bond to form intermediate F, and subsequent removal of ZnBr₂ to produce the (R)-β-allenoate 7 and the resulting by-product G.

Scheme 5.

Zinc-catalyzed formation of β-allenoates and one-pot reaction. Reaction conditions: Propargylamine (3, 1.0 mmol), ZnBr₂ (0.5 mmol) in 3.0 of toluene mixture was stirred under N₂ atmosphere at 120 °C for 1.5 h. One-pot reaction conditions: compound (1 a, 1.0 mmol), phenylacetylene (2 a, 1.0 mmol), catalyst II (20 mol %), ZnBr₂ (0.5 mmol) in 3.0 of toluene mixture was stirred under N₂ atmosphere at 120 °C for 4.0 h.

Scheme 6.

Possible mechanistic pathway.

Pharmacophore-based molecular docking is a very well- known method used by computer-assisted drug discovery and development to identify the preciseness of binding alignment (poses) of the inhibitors into the protein active site (Figure 2). Four potential scenarios involving molecular dynamics investigation are encountered while undertaking computational approaches (Supporting Information file). A structure for one inhibitor is possible to detect cooperative interactions but obtaining 3D information for several inhibitors is important.

Figure 2.

The novel compounds (3 ba and 3 ca) and their interaction with the AChE protein.

In this study, since both the inhibitors and the receptor protein provided information about the structure, the LigandFit module was utilized to determine the optimal orientation of the molecules in the active site or inactive conformation of the AChE enzyme domain. Molecular docking involves three steps: inhibitor preparation, target protein preparation, and molecular docking (supporting information). Many of the propargylamine analogs were subjected to a docking procedure, which is shown in the supporting information. The crystal structure of AChE (acetylcholinesterase enzyme) complexed with anti-Alzheimer drug molecules of the donepezil or E2020 was retrieved from Protein Data Bank (PDB) with PDB ID code: 1EVE. The X-ray diffraction structure of AChE protein had a resolution of 2.80 Å and R-value of 0.195. The water molecules and inhibitor molecules were deleted and then UCSF chimera added the hydrogen atoms.^[20] The newly synthesized propargylamines were used in molecular docking to evaluate binding affinity. The co-crystallized inhibitor included a substantially higher binding affinity in terms of total energy needed for binding, although their binding energy was determined to be appropriate in relation to their moderate activity in the bioactivity assays, as shown in supporting information Table S1. Among all the propargylamine compounds, the compound 3 ba (docking score is —9.9 kcal/mol) and 3 ca (docking score is —9.4 kcal/mol) performed well compared to standard drugs like Donepezil (docking score is —10.3 kcal/mol) because of H-bonding and hydrophobic interactions with Tyr A:70, Phe A:288, Phe A:331, and Tyr A:334 (Figure 2). This demonstrates that molecule 3 ba effectively accommodated into the active site and remains quite strongly attached to the receptor AChE. Whereas the compound 3 ca demonstrated considerable activity attributed to the following H-bonds and hydrophobic interactions with Tyr A:70, Asp A:72, Trp A:84, Tyr A:121, Trp A:279, Ile A:287, Phe A:330, Phe A:331, and Tyr A:334 as shown in Figure 2.

The new compounds 3 ba and 3 ca, which had the best docking score, were subjected to molecular dynamics (MD) simulations. The root-mean-square deviation (RMSD) of known and novel inhibitors bound to acetyl-cholinesterase enzyme. MD simulation was employed to evaluate the protein-inhibitor stability and investigate the major motions during inhibitor binding/unbinding. During the initial MD simulation period, the convergence of RMSD for the protein complex with known and new inhibitor molecules was detected after 5 ns with an average value of 2.5 Å, while in two complexes, it was observed after 5 ns to 50 ns with an average value of 2.5 to 3 Å. We noticed that compound 3 ca has a better RMSD value compared to compound 3 ba in the MD simulation against the AChE protein (Figure 3), indicating that it is more stable in the protein pocket. Thus, these propargylamines could be considered as potential drugs.

Figure 3.

Molecular dynamics (MD) simulation of protein-inhibitor complex.

Conclusions

In conclusion, we have reported an effective approach utilizing 1,10-phenanthroline copper(I) complexes to catalyze an asymmetric nucleophilic carbon addition to an enamine to construct diastereomerically pure propargyl-amines in good yields. Using zinc(II) bromide, propargyl-amines were also able to be converted into allenes in excellent yield and enantioselectivity. As a consequence, the methods described here could have a strong potential for further synthetic applications. Several molecules isolated here, also exhibited drug-like properties in silico. Molecular docking studies and molecular dynamics studies suggest the most active propargylamines are 3 ba and 3 ca. As a result, we are actively developing new collaborations to screen the synthesized propargylamines as potential Alzheimer’s drugs.

Supplementary Material

Supporting information for this article is available on the WWW under https://doi.org/10.1002/ajoc.202300375

Data Availability Statement

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