Effect of the ortho-hydroxy group of salicylaldehyde in the A3 coupling reaction: A metal-catalyst-free synthesis of propargylamine

The synthesis of propargylamines via A3 coupling mostly under metal-catalyzed procedures is well known. This work invented an unprecedented effect of salicylaldehyde, one of the A3 coupling partners, which could lead to the formation of propargylamine, an important pharmaceutical building block, in the absence of any metal catalyst and under mild conditions. The role of the hydroxy group in ortho position of salicylaldehyde has been explored, which presumably activates the Csp–H bond of the terminal alkyne leading to the formation of propargylamines in good to excellent yields, thus negating the function of the metal catalyst. This observation is hitherto unknown, tested for a variety of salicylaldehyde, amine and acetylene, established as a general protocol, and is believed to be of interest for synthetic chemists from green chemistry.

Because of diverse applications of propargylamine, several methods are developed among which the three-component reaction of aldehyde, amine and terminal alkyne, commonly known as A 3 coupling reaction, remains the most common and straightforward method for the synthesis of propargylamine. The A 3 coupling reaction is reported under transition-metal-catalyzed conditions using copper [12,[17][18][19], gold [17,20,21], silver [17,22], zinc [17,23], nickel [24], iron [25], mercury [26], cobalt [27], iridium [28], ruthenium [29], indium [30] etc. Other methods towards the synthesis of propargylamine include: alkynylation of imine [31][32][33], enamine [34], and C sp³ -H bonds adjacent to N-atoms [35,36]. In the A 3 coupling, the role of the metal catalyst is believed to activate the terminal acetylene primarily, which then undergoes a nucleophilic addition to the iminium electrophile generated from the aldehyde and the amine. Among different transition metals, copper metal has been mostly explored as the catalyst to activate the terminal acetylene, though there is a possibility for the Glaser coupling of the terminal alkyne as the byproduct [37]. Interestingly, hitherto there is no report for the A 3 coupling reaction in the absence of a metal catalyst except of one example in a threecomponent reaction using an alkynylcarboxylic acid instead of a terminal alkyne [38]. In this case, activation of the C sp -COOH occurs via decarboxylation followed by the coupling with an iminium electrophile to produce the propargylamine. Although the strategy is interesting, functionalized acetylene carboxylic acids are difficultly accessible and the reaction is less 'atom economic'. Therefore, the development of a metal-free and straightforward greener protocol for the preparation of propargylamine is highly desirable. A schematic presentation of various metal-catalyzed protocols including the present work is outlined in Scheme 2.

Results and Discussion
In connection with our interest in developing new organic reaction methodologies as well as to synthesize propargylamine, we performed one reaction of salicylaldehyde, morpholine and phenylacetylene at 80 °C in the presence of a Cu(I) dithianebased complex as the catalyst that gave rise to the formation of 3a in good yield (89%, Table 1, entry 1). To check the role of our Cu(I) catalyst, we performed the same reaction under similar conditions in the absence of the copper catalyst (Table 1, entry 2). To our surprise, the same product spot was noticed on TLC plate and further work-up and purification afforded the product in comparable isolated yield. We became interested about our findings and wanted to explore the reaction further in the absence of a metal catalyst. We did the same experiment with o-anisaldehyde and 2-chlorobenzaldehyde without using any copper catalyst, and interestingly, there was no desired product formed in these two reactions (  [12,[19][20][21][22][23][24] reported their experiments with salicylaldehyde only in the presence of metal catalysts (e.g., Cu, Au, Ag, Zn and Ni). We therefore explored further to optimize the reaction conditions in the absence of Cu catalysts at varying temperatures and solvents. In the optimization process (Table 1), we found that the reaction was very slow at room temperature even after 24 h (<10%; Table 1, entry 7), and raising the reaction temperature to 60 °C afforded an improved Scheme 2: Various metal-catalyzed methods for the synthesis of propargylamine.   yield of the product (64%; . Although high yields were achieved in the first two solvents (85-88%), the use of ethanol resulted in a low yield (47%). Thus the A 3 coupling of salicylaldehyde, phenylacetylene and morpholine can be achieved under solvent-free conditions as well as in solvents like toluene or acetonitrile with the formation of the coupled product in 85-90% isolated yields. We also conducted similar reactions with cyclohexylamine and benzylamine instead of morpholine. In both cases, we ended up with the formation of corresponding imines ( Table 1, entries 12 and 13).
After the successful optimization, further extension of the reaction protocol was made by varying the other two components viz. the secondary cyclic amine and the terminal alkyne. The results are not only encouraging but constitute a hitherto unknown general protocol for the preparation of propargylamines under metal-catalyst-free A 3 coupling of salicylaldehyde as the aldehyde component (Figure 1). Changing the phenylacetylene to other substituted arylacetylenes like p-tolylacetylene, o-bromophenylacetylene, p-bromophenylacetylene or switching from morpholine to other amines like piperidine, 4-benzylpiperidine and pyrrolidine also react smoothly to afford the corresponding propargylamine (the A 3 coupled product) in Scheme 3: Plausible mechanism for the metal-free A 3 coupling from salicylaldehyde. (Figure 1, 3a-j). Substituted salicylaldehyde like 3,5-dibromosalicylaldehyde or o-vanillin also reacted easily when treated with morpholine and phenylacetylene, p-tolylacetylene or oand p-bromophenylacetylene as the other coupling components at 80-90 °C (Figure 1, 3k-p).

82-90% isolated yields
Varying the secondary amine component with 4-benzylpiperidine, piperidine also worked efficiently to produce the corresponding propargylamine derivatives (3q-t). All products were characterized by FTIR, 1 H and 13 C NMR spectral data. Scaling up the reaction to gram-scale operation using phenylacetylene, morpholine and salicylaldehyde (5 mmol each) also afforded the desired propargylamine cleanly in 86% yield.
A mixture of salicylaldehyde or its derivative (1 mmol), amine (1 mmol) and alkyne (1 mmol) was stirred at 80 °C (90 °C for dibromo derivative of salicylaldehyde) in a sealed tube for 4-8 h (4 h for 3a-l and 8 h for 3m-t). Isolated yields after purification by column chromatography are given.

Mechanism
As regard to the mechanism of the reaction, it is generally believed that the metal catalyst activates the terminal alkyne so as to generate metal acetylide species, which then undergoes nucleophilic addition at the electrophilic iminium ion 4, eventually providing the A 3  Again, in the case of o-hydroxyacetophenone, the corresponding iminium salt might form with difficulty as well as the iminium carbon would be less elctrophilic. Furthermore, the reaction does not proceed well in a protic solvent like ethanol. This suggests that the hydroxy group of salicylaldehyde can also make the hydrogen bonding with protic ethanol solvent and thereby reducing the possibility of activating the sp carbon (C-H) of the alkyne. Furthermore, reactions with primary amines like cyclohexylamine and benzylamine produce only the imine and no A 3 -coupled product, signifying that imines are less efficient than iminium species to initiate further reaction with terminal alkyne.

Conclusion
In conclusion, the present study demonstrates an unusual but added role of the hydroxy group of salicylaldehyde, which paves the way to develop metal-free as well as solvent-free A 3 coupling reactions leading to the formation of propargylaminethe useful synthetic intermediate and an important unit of many bio-active compounds. The reaction conditions are straightforward and products are obtained in good to excellent yields. The metal-free approach also offers the advantages of avoiding any possible byproduct arising out from the Glaser coupling of terminal alkynes as well as contamination with metal species. The present protocol supersedes the only metal-catalyst-free approach from acetylene carboxylic acids that are difficultly accessible and with low atom economy. Thus the present reaction from easily available A 3 components leading to the formation of propargylamine under metal-catalyst-free and solventfree conditions could attract the interest of synthetic and medicinal chemists.

Supporting Information
Supporting Information File 1 Experimental procedure, characterization data and scan copies of 1 H and 13 C NMR spectra (3a-t).