N-Heterocyclic carbene: thiazolylidene–Cu(I) complexes: microwave-assisted synthesis and use as catalyst in A3 reaction

Abstract A simple method involving microwave-assisted reaction of 3-benzylthiazolium/benzothiazolium bromides with cuprous oxide has been developed for the synthesis of four new N-heterocyclic carbene (NHC): thiazolylidene/benzothiazolylidene–Cu(I) complexes. Structures of the complexes could be established on the basis of the IR, 1H, and 13C NMR studies and elemental analysis. A representative NHC:benzothiazolylidene–Cu(I) complex was used as catalyst for the microwave-assisted A3 reaction of phenylacetylene with a secondary amine and aldehyde to obtain new substituted propargylamines in excellent yields. A theoretical investigation of the model A3 reaction at the DFT level reveals initial coordination of the alkyne with the NHC–Cu(I) complex followed by its attack on the iminium ion generated from the reaction of secondary amine with aldehyde. In the presence of the catalyst, the activation free energy barrier (ΔG#) is lowered by ca. 3 kcal mol−1. Graphical Abstract

In 1995, Herrmann et al. used an NHC-Pd o complex as catalyst in the Heck coupling reaction of aryl halides, [9] which was followed by intense activity in the field of the preparation and application of NHC-transition metal complexes as catalysts. [21,22] NHC-Cu(I) complexes were used as catalyst for azide-alkyne cycloaddition. [23,24] Various methods have been employed for the preparation of NHC-metal complexes. [25] These include heating of enetetramines [26] or NHC adduct in the form of N-heterocyclic ring containing alkoxy-, trichloromethyl, or trialkylboryl group at the a-position [27] with metal precursor, using a preformed free NHC [28] and in situ generation of NHC from deprotonation of the azolium salts. [29] In this context, NHC-Cu complexes find prominence for various reasons, such as ease of preparation, possibility of structural diversity, low cost, and versatile applications. [30,31] Liu et al. [32] in their paper summarized different routes followed for the synthesis of NHC-Cu(I) complexes and their limitations. For example, in situ generation of NHC from azolium salt with a strong base in presence of cuprous halide is often accompanied by side reactions and formation of inorganic waste by-products. An elegant synthesis of NHC-Cu(I) complexes was developed by reacting cuprous oxide with imidazolium salt in dichloromethane [33] or THF. [34] Subsequently, water was used as the solvent in place of organic solvent. [35] Landers and Navarro [36] accomplished synthesis of NHC-MCl (M ¼ Ag, Cu, and Au) complexes under microwave conditions.
In recent years, the three components reaction of an aldehyde, a secondary amine and a terminal alkyne, known as A3 reaction to afford chiral propargylamines has received much attention as the latter have been found versatile synthons for the medicinally important and naturally occurring nitrogen-containing compounds (Scheme 1). [37] The classical method for the synthesis of propargylamines required the use of metal acetylides generated in situ from the reaction of terminal alkyne with a base such as butyllithium. However, due to many complications involved therein, it was soon replaced by a more elegant method using transition-metal complex catalyzed addition of a terminal alkyne to the secondary amine or imine. [37c] Recently, NHC-Cu(I) complexes immobilized on silica or directly [38] have been used as catalyst. We recently investigated theoretically electronic structures of some NHCs and their complexes with cuprous halides and calculated their reactivity descriptors. [39] Only scanty reports are available about the preparation of NHC:thiazolylidene-Cu(I) complexes. [40] In recent years, microwave-assisted synthesis has emerged as an attractive tool in Green Chemistry as it not only saves time and energy, but also makes it possible to dispense with hazardous solvents. [41] We report herein a facile microwave-assisted synthesis of NHC:thiazolylidene-Cu(I) complexes and its benzothiazolylidene analog and its use as catalyst in the A3 reaction for the first time.

Synthesis of the complexes
We used a slightly modified version of the method reported by Tulloch et al. [33] for the preparation of NHC: imidazolylidene-CuBr complexes in dichloromethane or THF. A slurry of 3-benzylthiazolium/benzothiazolium bromide and Cu 2 O in 3-4 drops of glacial acetic acid and acetonitrile was microwave irradiated when the desired complexes were obtained in good yields (Scheme 2).

Spectral characterization of the complexes
Our repeated attempts to grow a single crystal of the NHC:thiazolylidene/benzothiazolylidene-Cu(I) complexes were not successful. Nevertheless, it has been possible to establish the structures of the complexes unambiguously on the basis of extensive spectral studies and elemental analysis. In IR, absorption bands at 1650 and $540 cm À1 result due to C ¼ N and C-Cu stretching vibrations, respectively. Although initially the NHCs were regarded as the pure r-donor ligands, later experimental, [42] and theoretical [43] studies established the presence of significant back donation from the d-orbital of the metal to the p Ã orbital of NHC. Energy decomposition analysis (EDA) calculations also revealed the presence of this phenomenon. [44] Recently, on the basis of natural bond orbital (NBO) analysis, we established the existence of dp-pp interactions in the NHC-CuX complexes. [39] Interestingly, in the present case also, the 1 H NMR spectrum reveals conspicuous upfield shiftin of the NMR signals as compared to the corresponding signals of the 3-alkylthiazolium/benzothiazolium bromides confirming dp-pp back donation from the metal to the NHC. For example, in the case of the complex 2a, the NMR signal for the proton C4H is observed at d 8.04, C5H at d 7.11, C6H at d 7.28, CH 2 at d 4.87 as compared to d 8.28, 7.77, 7.73, and 6.42 ppm, respectively, for the corresponding protons in its precursor 1a. A similar pattern is observed in all other NHC-Cu(I) complexes also. In the 13 C NMR spectra, the most downfield weak signal in the range of d 182-193 results due to carbon atom bonded to Cu.

A3 reaction of phenylacetylene, secondary amine, and aldehyde
An equimolar mixture of phenylacetylene, a secondary amine and an aldehyde with the complex 2d (0.1 mol %) as catalyst on being microwave irradiated affords propargylamines 6a-f in quantitative yields (Scheme 3).

Spectral characterization of the propargylamines 6a-f
All the products are new and could be well characterized on the basis of spectral studies. A weak IR absorption band in the range of 2100-2400 cm À1 results due to CC stretching vibration. In the 1 H NMR spectra, a singlet at d $4.95-4.99 is observed due to C3H. In the case of the products obtained from the reaction with 4-substituted benzaldehydes, such as 4-chlorobenzaldehyde and 4-nitrobenzaldehyde, an AB spin system could be detected; for example in the 1 H NMR spectrum of 3-(4-chlorophenyl)-3-diethylamino-1-phenylpropyne (6a), two doublets at d 7.82 ( 3 J HH ¼ 11.2) and d 7.51 ( 3 J HH ¼ 11.2) could be assigned to the protons C3ˊˊ,3ˊˊH and C2ˊˊ,2ˊˊH respectively. In the 1 H NMR spectra of 3-(2-thienyl)propyne derivatives (6d and 6e), characteristic double doublets (dd) are observed for the protons of the thiophene ring due to long range ( 4 J HH ) coupling. For example in the 1 H NMR spectrum of 1-phenyl-3-(1-piperidinyl)-3-(2-thienyl)propyne (6d), three dds at d 7.52 ( 3 J HH ¼ 9.2 Hz, 4 J HH ¼ 4.4 Hz), 7.32 ( 3 J HH ¼ 7.2 Hz, 4 J HH ¼ 4.4 Hz), and 7.25 ( 3 J HH ¼ 9.2 Hz, 3 J HH ¼ 7.2 Hz) could be assigned to the protons C5H, C3H and C4H, respectively, of the thiophene ring. 13 C NMR results were equally helpful in the characterization of the products. For example, two signals in the range of d 84-89 ppm result from the acetylenic carbon atoms C1 and C2. In the case of 6a, however, these signals are not observed possibly due to their overlapping with the signal of DMSO.

Theoretical investigation of the mechanism of A3 reaction
Although A3 reaction has been extensively reported, [37] we could not find any report about the investigation of its mechanism theoretically. In view of this, we investigated the mechanism of a model reaction at the DFT level. In order to understand the role of the catalyst, we investigated two model reactions: Model 1: Reaction of phenylacetylene with iminium ion (initially generated from the reaction of aldehyde with secondary amine) directly (Scheme 4). The optimized geometries of different species and thermodynamic data are given in Figure 1 and Table 1, respectively.
In the presence of NHC:thiazolylidene-Cu(I) iodide catalyst, alkyne is first coordinated to the Cu atom and then it attacks the iminium ion involving TS3. It may be noted that the activation free energy barrier (DG # ) for the attack of the complexed alkyne on the iminium ion is smaller than that for the attack of the uncomplexed alkyne by ca. 3 kcal mol À1 . The most characteristic feature of the reaction catalyzed by the NHC-CuI complex is that in contrast to the uncatalyzed reaction, which is highly endergonic (DG 0 ¼ 254.40 kcal mol À1 ), it is exergonic (DG 0 ¼ À53.93 kcal mol À1 ) for the first step, namely formation of the NHC-CuI-alkyne complex (Int.1) and negligibly endergonic (DG 0 ¼ 0.03 kcal mol À1 ) for the second step, i.e., formation of the NHC-CuI-alkyne-imine adduct (Int. 2) before the final product (Pr) is liberated.

Frontier molecular orbitals
The HOMOs of the alkyne, and the NHC-CuI-alkyne complex and the LUMO of the iminium ion are shown in Figure 2.
It is noteworthy that the HOMO in the free alkyne is diffused over the whole molecule, whereas in the NHC-CuIalkyne complex, it is centered on the C-H carbon atom which attacks the iminium ion. The NBO calculations show that the Mulliken charge at the C-H atom in the complexed alkyne (À0.294) is almost double as compared to the free alkyne (À0.129). Furthermore, the energy level of the HOMO in the NHC-CuI-alkyne complex is raised in comparison to the uncomplexed alkyne thereby narrowing down the HOMO-LUMO gap in the former (Figure 3).

Molecular electrostatic potential (MEP) maps
MEP surface diagram is a useful tool to predict qualitatively electrophilic and nucleophilic sites in a molecule. [45,46] It depicts distribution of electron density with varying colors, the region of highest and least electron densities being shown in red and blue colors respectively. The electron density decreases in the order: red > orange. MEP maps of the phenylacetylene and its adduct with the NHC-CuI complex are shown in Figure 4.
It may be noted that in the uncomplexed alkyne, negative charge (red color) is spread over a large surface area whereas in the NHC-CuI-alkyne adduct, it is concentrated over a small area thereby enhancing its nucleophilicity.

Experimental details
Melting points were determined on paramount apparatus and are uncorrected. The IR spectra were scanned on Bruker Alpha-II spectrometer using KBr pellet. The 1 H and 13 C NMR spectra were recorded on a JEOL RESONANCE 400 NMR spectrometer at the frequencies 399.8 and 100.5 MHz, respectively, in CDCl 3 or DMSO-d 6 using TMS as an internal reference. Elemental analyses were done on a CHNS Analyzer Perkin Elmer Ser. Second 2400. Microwave reactions were carried out using microwave reactor, CEM Discover. The Supplemental Materials contain sample 1 H and 13 C NMR and IR spectra of the products 1, 2, and 6 ( Figures S1-S39).
The solvents were dried according to the standard procedures and all the reactions were carried out under anhydrous conditions. Cuprous oxide, benzothiazole, 4,5dimethylthiazole, benzyl bromide, p-nitrobenzyl bromide, p-chlorobenzaldehyde, diethylamine, piperidine, morpholine, and phenylacetylene were purchased from Sigma- Aldrich (St. Louis, MO) and used as such without further purification.

Computational methods
All calculations were done using Gaussian 16 suite of programs.. [47] The geometries were optimized by using a hybrid of Becke3 and LYP correlation functional [48,49] with Karlsruhe basis sets def2-SVP. [50] Frequency calculations were done at the same level to determine zero-point corrections and to characterize energy minimum with no imaginary frequency. The total enthalpies of different species were obtained by adding thermal correction to the sum of electronic and thermal enthalpies calculated at the same level.

Conclusions
The NHC:3-alkylthiazolylidene/benzothiazolylidene-Cu(I) bromide complexes can be conveniently prepared in good yields from microwave-assisted reaction of the corresponding 3-alkylthiazolylidene/benzothiazolylidene salts with cuprous oxide in the presence of acetic acid and acetonitrile. The 1 H NMR spectra reveal the existence of the dp-pp bonding between metal and the NHC. The synthesized complexes can be used as catalyst in the A3 reaction of phenylacetylene, secondary amine, and aldehyde under microwave irradiation. A theoretical investigation at the DFT level indicates that the NHC-CuI catalyst orients HOMO of the alkyne in the optimum direction thereby making occurrence of the reaction faster.