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. 2018 Aug 23;3(8):9805–9813. doi: 10.1021/acsomega.8b01352

Efficient Gold(I) Acyclic Diaminocarbenes for the Synthesis of Propargylamines and Indolizines

Mélanie Aliaga-Lavrijsen †, Raquel P Herrera ‡,*, M Dolores Villacampa †, M Concepción Gimeno †,*
PMCID: PMC6645035  PMID: 31459109

Abstract

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Mononuclear gold(I) acyclic diaminocarbenes (ADCs) were prepared by the reaction of 1,2-cyclohexanediamine with the corresponding isocyanide complexes [AuCl(CNR)] (R = Cy, tBu). The three-component coupling of aldehydes, amines, and alkynes was investigated by using these gold(I) ADC complexes. The new gold(I) metal complexes are highly efficient catalysts for the synthesis of propargylamines and indolizines in the absence of solvent and in mild conditions. This method affords the corresponding final products with excellent yields in short reaction times. Additionally, chiral gold(I) complexes with ADCs have been prepared and tried in the enantioselective synthesis of propargylamines.

Introduction

The chemistry of gold has attracted the interest of many research groups because of the properties presented by its complexes covering different areas of investigation, such as in medicine as anticancer agents,1−10 in materials chemistry for their optical properties,11−13 or in catalysis because gold is able to promote several organic transformations.14−23

In this field, N-heterocyclic carbenes (NHCs)24,25 are a kind of privileged scaffolds efficiently employed as ligands in gold compounds with applications in catalysis,26,27 medicine,28,29 and optical materials.30 However, some of these NHCs still present some drawbacks. Nowadays, acyclic diaminocarbenes (ADCs) have become a promising alternative to NHCs for transition-metal-catalyzed organic transformations.31 ADCs are free of some disadvantages that are present in the NHCs, such as the difficulty in their preparation when NHCs are unsymmetrically substituted or chiral, or when NHCs are used as ligands with steric hindrance. Remarkably, among them, gold(I) ADC complexes have received less attention in comparison with their cyclic analogues. Therefore, the search for new interesting examples is still an open challenging area of research.32,33

Multicomponent (MC) processes are of great interest because of their atom efficiency, affording structural diversity and complexity in a single reaction step. Their development has attracted the attention and efforts of many research groups over the years for obtaining numerous compound libraries with combinatorial chemistry. Moreover, MC reactions (MCRs) have played an important role in the progress for drug discovery.34,35 Among these processes, the formation of propargylamines via a three-component coupling procedure, commonly called A3-coupling reaction, is an interesting approach center of continuous investigations.36−40 Propargylamines are versatile building blocks for the synthesis of nitrogen-containing molecules. The structural core of the resulting amine derivatives is present in many natural products and drug candidates (Figure 1).41−45 Some examples such as pargyline,46 rasagyline,47 and selegiline48 have found applications in the treatment of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases.49,50

Figure 1.

Figure 1

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Biologically active propargylamines and indolizines. NNRTI: non-nucleoside reverse transcriptase inhibitor; VEGT: vascular endothelial growth factor.

Therefore, the development of a new synthetic procedure to obtain propargylamines is a very attractive aim because they are useful intermediates. Interestingly, the use of gold-based catalysts in these A3-coupling procedures has been shortly explored.51−61

The synthesis of indolizines in a tandem reaction involving an MC approach is also an interesting active goal.62,63 Indolizines, one of the most important N-fused heterocyclic skeletons, are found in a variety of biological active compounds (Figure 1). Indolizines display a broad spectrum of potential pharmacological activities and are used in a variety of applications for drug discovery.64

Gold-based catalysts have been scarcely used for the preparation of indolizines.65−70 It is worth mentioning that only one example where the authors carry out a tandem multicomponent strategy has been described.67 Because of the scarce background found in the literature for this process using gold catalysts along with the interesting biological properties exhibited by indolizines, the search for novel efficient and eco-friendly protocols using benign catalysts still remains a challenging task.

With all these ideas in mind, we planned the preparation of new and challenging gold(I) ADC complexes. Moreover, the resulting carbenes could be promising catalysts in different organic processes. Here, we report on the synthesis of such ADC gold derivatives and the study of their applications in the synthesis of propargylamines and indolizines through MCRs.

Results and Discussion

The common synthesis of metal acyclic carbenes is based on the nucleophilic attack of an amine over a metal isocyanide complex. This procedure does not proceed easily for all the amines, and in some cases with aryl or less activated amines, the reaction does not work.71 (±)-1,2-Cyclohexanediamine (2a), as a racemic mixture of trans isomers, has been employed by the first time for the preparation of gold ADCs 3a and 3b using isocyanides 1a and 1b following the reaction depicted in Scheme 1.

Scheme 1. Synthesis of ADC Gold Carbene Complexes.

Scheme 1

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Acyclic carbenes 3a and 3b were easily prepared via the reaction of the isocyanide chloride gold(I) compound and the racemic mixture of 1,2-cyclohexanediamine (2a) at room temperature, giving rise to very good yields in both cases. It is remarkable that the mononuclear complexes are also obtained even in the case where a 2:1 molar ratio is used. Probably, the high insolubility of compounds 3a and 3b in dichloromethane is a driving force to solely produce the mononuclear species. Complexes 3a and 3b are sparingly soluble in common organic solvents. The 1H NMR spectrum of complex 3b carried out in methanol-d4 shows the expected resonances for the cyclohexyl skeleton, with two multiplets for the −CH– protons, four multiplets for the −CH2– protons, and a singlet for the tert-butyl protons. The amine protons are not observed as they interchange with the deuterium of the solvent. In the 13C-attached proton test (APT) NMR spectrum, all the signals can be easily assigned (Figure S4) and corroborate the inequivalence of all the carbons in the cyclohexyl moiety, thus indicating that only one gold center has formed the ADC unit. The resonance due to the carbene carbon atom appears at 192.0 ppm.

In contrast, in complex 3a because of the higher steric hindrance of the substituents and also because the carbene C–N bond shows a considerable multiple character in this type of complexes, an important restriction to rotation is produced, giving rise to stereoisomers or rotamers (see Figure 2).

Figure 2.

Figure 2

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Different structural conformations for ADCs.

For this reason, complex 3a shows a very complicated 1H NMR spectrum, and the resonances of the −CH2– protons at the cyclohexyl ring appear as multiplets. It is possible to observe the resonances of the cyclohexyl −CH– protons in the less congested area in three different rotamers, with two of them in higher proportion. In the 13C-APT NMR spectrum, two resonances with different intensities are observed for the carbene carbon atoms, which are probably due to the two major rotamers. The matrix-assisted laser desorption ionization mass spectra show the cationic peak arising at the loss of the chlorine ligand for complex 3a at m/z = 420.1759 [M – Cl]+ and both the molecular peak [M + H]+ at m/z = 430.1327 and the cationic [M – Cl]+ at m/z = 394.1524 for complex 3b. Additionally, the analytical data for these complexes also agree with the proposed formulation. In the infrared (IR) spectra, the most significant absorptions are the ν(Au–Cl), which appears at around 320 cm–1, and the ν(N–H) in the range 2600–3000 cm–1.

With both gold complexes in hand and in the context of our research program focused on the development of new catalytic processes, we first centered our attention in the preparation of propargylamines 7 via the A3-coupling reaction following an easy and straightforward procedure. To test the efficiency of our precatalytic structures 3a,b, the viability of the reaction model illustrated in Table 1 was initially explored.

Table 1. Screening of the A3-Coupling Reactiona.

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entry cat. solvent t (h) T (°C) conv. (%)b
1 3a–AgNTf2 MeOH-d4 5 60 85
2 3a–AgNTf2 CD3CN 5 60 46
3 3a–AgNTf2 CD3CN 5 70 85
4 3a–AgNTf2 toluene-d8 5 60 56
5 3a–AgNTf2 toluene-d8 5 70 70
6 3a–AgNTf2   5 60 >99
7 3ac   5 60 n.r.
8 AgNTf2   5 60 20
9 3b–AgNTf2   5 60 90
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a

Reaction conditions: benzaldehyde 4a (0.25 mmol), piperidine 6a (0.275 mmol), phenylacetylene 5a (0.3 mmol), 3a,b (0.0025 mmol), AgNTf2 (0.0025 mmol), and solvent 0.7 mL.

b

The conversions of the reactions are given by 1H NMR using mesitylene as the internal standard.

c

Without addition of AgNTf2.

In the first screening of solvent at 60 °C, encouraging results were found with MeOH-d4 for 1 mol % of the catalyst (Table 1, entry 1) after short reactions times (5 h). In contrast, with CD3CN and toluene-d8, better conversions were only achieved when the temperature of the reaction was increased until 70 °C for the same reaction time (entries 3 and 5). Interestingly, a complete conversion was observed when the reaction was performed in the absence of solvent at 60 °C after 5 h of the reaction (entry 6). It is worth noting that the gold precatalyst3a does not promote the reaction in the absence of the Ag species (entry 7). The same is observed when the reaction was performed only with the cocatalyst AgNTf2 (entry 8). A good result was obtained using catalyst 3b (entry 9), although a slight lower conversion was observed in comparison with catalyst 3a. With the best reaction conditions found, different aldehydes 4a–c, acetylenes 5a,b, and amines 6a–f were explored to extend the scope of the reaction. The results are shown in Table 2.

Table 2. Catalytic Synthesis of Propargylamines 7 via the Three-Component Addition Reaction.

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Very good results were obtained for the complete scope of the reaction using different cyclic secondary amines such as piperidine (6a), morpholine (6b), or pyrrolidines (6c and 6e) and even noncyclic secondary amines such as Et2NH (6d) and Bu2NH (6f). Good results were also achieved for the use of different aldehydes (4a–c) and acetylenes (5a and 5b). For aldehydes 4b,c, which are solids, the addition of a small amount of 100 μL CH3CN was needed prior to the reaction. Otherwise, the crude mixture becomes very dense, and the stirring is really difficult. It is remarkable that our work is one of the scarce examples in which a gold catalyst is used to promote this process, in addition of using very low catalyst loading (1 mol %) and short reaction times (5 h). Our reaction represents an improvement in the synthesis of propargylamines in comparison with other reported examples where several metal complexes or metal salts such as Ag(I),72 Cu(I),73 Zn(II),74,75 or Ir(II)76 have been employed, among others, because in our case lower catalyst loading, shorter reaction times, and lower temperature were able to promote the process. Moreover, this is one of the scarce examples where Au(I) has been used against the examples reported with Au(III) and even in the absence of solvent and without inert atmosphere. Additionally, in many cases, the authors only used their catalysts to obtain propargylamines. In contrast and encouraged by these results, following this simple and effective method, our next step was to apply this catalytic system in the synthesis of indolizines 8 (Table 3).

Table 3. Scope for the Gold(I)-Catalyzed Multicomponent Synthesis of Aminoindolizines 8.

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a

Results obtained with catalyst 3b.

Under the same optimized reaction conditions, the corresponding 1-aminoindolizine products 8 were obtained with very good yields in short reaction times. The generality of the protocol was evaluated by the synthesis of differently substituted 1-aminoindolizines 8. Thus, the reaction between pyridine-2-carboxaldehyde (4d) and 2-quinolinecarboxaldehyde (4e) with various secondary amines and terminal alkynes 5a,b affords the desired product in all cases using 1 mol % of catalysts 3a. Interestingly, less studied alkynes 5c and 5d also provided the corresponding final products with moderate yields, although the starting material remained unreacted. Maybe longer reaction times would afford better yields. When the process was performed with aldehyde 4d, the reactions worked with cyclic secondary amines 6a–c and even noncyclic secondary amines 6d,f, more scarcely employed until now in this process. Interestingly, 2-quinolinecarboxaldehyde (4e) was also efficiently employed in the reaction with piperidine 6a and different noncyclic secondary amines 6d,f,g, giving rise to the corresponding aminoindolizine products 8 with very good results. On the other hand, when aldehyde 4e was used, the final products were obtained with yield values that were a bit lower compared with those achieved with 4d. In order to check the effectiveness of catalyst 3b, we tested some model reactions, and in all of them, very good results were obtained (Table 3).

The formation of the propargylamines 7 and the corresponding indolizines 8 can be explained by a plausible mechanism depicted in Scheme 2 and based on the chemistry of gold14−23 (routes a and b). In both cases, the aldehyde initially reacts with the secondary amine to generate the iminium ion A. Because the bases present in the reaction are not able to deprotonate the terminal alkyne by themselves, the formation of an intermediate π-metal–alkyne complex is envisioned, involving a C–H activation of the alkyne by the gold catalyst. Complex B should make the alkyne proton more acidic for further abstraction. The in situ generated metal acetylide C reacts with the iminium ion A, giving rise to the formation of the propargylamines 7, releasing the gold catalyst for the subsequent catalytic cycle (Scheme 2, route a). Otherwise, if we have a pyridine aldehyde derivative (Scheme 2, route b) once the corresponding propargylamine D is generated, it undergoes a cyclization (5 endo-dig) affording intermediate E. In this step, a plausible activation of the alkyne by the metal to allow the cyclization is assumed. A subsequent isomerization of E and final protodeauration of F would release the gold catalyst to start with the catalytic cycle.

Scheme 2. Plausible Mechanistic Reaction.

Scheme 2

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At this stage, we planned to synthesize chiral-related catalysts following the same synthetic procedure (Scheme 3). For such a purpose, chiral amines 2b and 2c were selected. Chiral symmetric carbene 3c and nonsymmetric carbene 3d were easily prepared via the reaction of isocyanide 1a and the chiral amines 2b and 2c, affording the chiral ADCs in very good yields.

Scheme 3. Synthesis of Chiral Gold ADCs.

Scheme 3

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Surprisingly, the chiral complex 3c, which is analogous to the racemic mixture 3a, was obtained as the dinuclear species. As this compound has a greater solubility in dichloromethane, it does not precipitate from the reaction media, and then the reaction proceeds to the complete nucleophilic attack of both amine units. To shed more light on this matter, we have measured the optical rotation of compound 3a in methanol, which interestingly has a slightly different value from zero ([α]D20 −1.12), whereas the optical rotation of complex 3c is [α]D −26.07. Therefore, we propose that there was a slight enrichment in one of the enantiomers (1S,2S) because of the high insolubility of this mononuclear species compared to that of the dinuclear 3c, which is the 1R,2R enantiomer.

The analytical data and the mass spectrum corroborate the proposed formulation. Complex 3c shows NMR spectra with a different integral ratio for the cyclohexyl protons, similar to that of the racemic mixture 3a, with the presence of rotamers. In this case, three resonances for the carbene carbon atom are clearly observed at 190.9, 185.9, and 185.8 ppm, indicating the presence of three different rotamers. For complex 3d, three rotamers are also clearly observed in the 1H NMR spectrum for the resonances of the tolyl group. The ν(Au–Cl) and ν(N–H) absorptions are also observed in the IR spectra of these compounds. The analytical data for both complexes agree with the proposed formulation.

Interestingly, with these two chiral structures, we have demonstrated the possibility to easily obtain chiral or unsymmetrically substituted ADCs, also using substituents with steric properties, which is still a challenging task in the preparation of NHCs. Furthermore, we set out on the exploration of the reactivity of these promising structures to generate propargylamines 7aaa and 7aab. Although at this point only <10% of enantiomeric excess has been reached in a model reaction between benzaldehyde 4a, phenylacetylene 5a, and morpholine 6b, more efforts are necessary to improve these values and they are currently ongoing in our lab.

Conclusions

In summary, new gold(I) ADCs have been synthesized following a straightforward protocol. This synthetic method of the ADC metal complexes offers a great versatility for the synthesis of gold(I) species with different scaffolds, including chiral derivatives. These precatalysts have resulted to be efficient for the preparation of propargylamines and indolizines. These interesting scaffolds have been achieved following an easy and green protocol by a three-component coupling of carboxaldehydes, secondary amines and terminal alkynes. The potential of our procedure is reflected by the substrate scope, the operational simplicity, short reaction times, and good to excellent isolated yields. We believe that these MCRs demonstrate the strong capacity of our complex to act as an efficient catalyst. In addition, the reactions were performed under solvent-free conditions, an important feature from a sustainable point of view, without inert atmosphere and in the presence of light, in contrast to previous reported examples. The chiral version of these catalysts has also been synthesized, and the asymmetric catalysis in the reaction of propargylamines has been tried. The results were not good probably because the chiral center is far from the catalytic site of the complex. We cannot discard that the free single bond rotations in the chiral catalysts, leading to multiple transition states, would also be responsible for the low ee. Further studies to improve the design of the catalysts are ongoing in our laboratory.

Experimental Details

Instrumentation

Purification of reaction products was carried out by column chromatography using silica gel (0.063–0.200 mm). Analytical thin-layer chromatography was performed on 0.25 mm silica gel 60-F plates. 1H and 13C{1H}-APT NMR spectra were recorded at room temperature on a Bruker AVANCE 400 spectrometer (1H, 400 MHz; 13C, 100.6 MHz) or on a Bruker AVANCE II 300 spectrometer (1H, 300 MHz; 13C, 75.5 MHz), with chemical shifts (ppm) reported relative to the solvent peaks of the deuterated solvent. CDCl3, CD2Cl2, CD3COCD3, and CD3OD were used as the deuterated solvents. Chemical shifts were reported in the δ scale relative to residual CHCl3 (7.28 ppm), CH2Cl2 (5.32 ppm), CH3COCH3 (2.05 ppm), and CH3OH (3.31) for 1H NMR and to the central line of CDCl3 (77 ppm), CD2Cl2 (54 ppm), CD3COCD3 (29.84 ppm), and CD3OD (49.0 ppm) for 13C-APT-NMR. Mass spectra were recorded on Bruker ESQUIRE 3000 PLUS, with the electrospray ionization technique. The attenuated total reflection (ATR)–Fourier transform infrared (FTIR) spectra of solid samples were recorded on a PerkinElmer FTIR spectrometer equipped with a universal ATR sampling accessory.

Starting Materials

All reactions were performed under air atmosphere and solvents were used as received without further purification or drying. The starting materials [AuCl(CNR)] were prepared according to published procedures.77−79 Starting materials, yields, and spectroscopic data for compounds 7abf, 8dad, 8dbf, 8ead, 8eag, and 8ebd are described in the Supporting Information. 1H and 13C NMR spectra for compounds 7aaa,807aab,817aac,817aad,817aba,827abb,837abc,847abd,857baa,867cac,878daa,678dab,678dac,678daf,888dba,888dbb,898eaa,67 and 8eaf(90) are consistent with the values previously reported in the literature.

General Procedure for the Synthesis of Complexes 3a–d

A mixture of [AuCl(CNR)] R = Cy (0.0683 g, 0.2 mmol), R = tBu (0.0613 g, 0.2 mmol) and 1,2-cyclohexanediamine (as a racemic mixture of trans isomers, 2a) (0.0228 g, 0.2 mmol) or (1R,2R)-1,2-cyclohexanediamine (2b) (0.0114 g, 0.1 mmol) or (1R,2R)-(−)-N-p-tosyl-1,2-cyclohexanediamine (2c) (0.0537 g, 0.2 mmol) in dichloromethane (20 mL) was stirred at room temperature for 24 h (3a,b,d) or 4 days (3c). Complexes 3a and 3b precipitated as white solids and were filtered off. For compounds 3c and 3d, the volume was reduced to 5 mL, and addition of n-hexane afforded the complexes as white solids.

General Procedure for the Au-Catalyzed Three-Component Synthesis of Propargylamines 7

To a mixture of gold complex 3a (2 mg, 0.0025 mmol) and AgNTf2 (0.97 mg, 0.0025 mmol), aldehyde 4a–c (0.25 mmol), amine 6a–f (0.275 mmol), and acetylene 5a,b (0.30 mmol) were added under solvent-free conditions. The resulting reaction mixture was stirred at 60 °C for 5 h and monitored by thin-layer chromatography. After this reaction time, products 7 were isolated by flash chromatography (SiO2, using Hex/Et2O 95:5). The yields are reported in Table 2.

General Procedure for the Au-Catalyzed Three-Component Synthesis of Indolizines 8

To a mixture of gold complex 3a (3.99 mg, 0.005 mmol) and AgNTf2 (1.94 mg, 0.005 mmol), aldehyde 4d,e (0.50 mmol), amine 6a–d, f, g (0.55 mmol), and acetylene 5a,b (0.60 mmol) were added under solvent-free conditions. The resulting reaction mixture was stirred at 60 °C for 5 h and monitored by thin-layer chromatography. After the reaction time, products 8 were isolated by flash chromatography (SiO2, using Hex/Et2O 95:5). The yields are reported in Table 3.

Acknowledgments

This work is dedicated to Professor Antonio Laguna in recognition of his outstanding contribution to modern organometallic chemistry, on the occasion of his 70th birthday. The authors thank the Ministerio de Economía y Competitividad (MINECO/FEDER CTQ2016-75816-C2-1-P and CTQ2017-88091-P) and Gobierno de Aragón-Fondo Social Europeo (E07_17R) for the financial support of our research. M.A.-L. thanks the MINECO for a predoctoral fellowship.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01352.

  • Characterization of all new compounds and 1H and 13C-APT NMR spectra (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ao8b01352_si_001.pdf (753.3KB, pdf)

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