A Column-Free and Aqueous Waste-Free Process for Thioamide Preparation with Lawesson’s reagent

After completing thio-substitution with the Lawesson’s reagent, ethanol was found to be able to efficiently decompose the inherent stoichiometric six-membered-ring byproduct from the Lawesson’s reagent to a highly polarized diethyl thiophosphate. This treatment could significantly simplify the following column purification of the desired thioamide in a small scale preparation. As scaling up the preparation of two pincertype thioamides, we have successfully developed a convenient process with ethylene glycol to replace ethanol during the workup, including traditional phase-cut, extraction, and re-crystallization. The newly developed column-free procedure did not generate P-contained aqueous waste, and only organic effluents were discharged. It was believed that the optimized procedure can greatly provide opportunity of the application of the Lawesson’s reagent for various thio-substituted reacions in scaling up preparation.


Introduction
The transformation of carbonyl into thiocarbonyl group is one of the most important reactions in organic synthetic chemistry [1]. The Lawesson's reagent (LR) is widely applied in this transformation, as well as for the syntheses of various sulfur-contained heterocyclic compounds [2][3][4]. Although LR is a powerful, mild and versatile thionation reagent, the workup procedure has been received quite a few negative comments [5][6][7][8][9]. The reason is that an inherent six-member ring structure A (Figure 1) was formed as LR completing thio-substitution [10][11][12]. It was observed that the polarity of the compound A is generally similar to the desire products, and any purification effort of the desired products by extraction operations makes less efficiency because of its good solubility. Thus, the purification was rather difficult and usually a careful column separation was necessary because of both the polarit and the stoichiometric amount of the compound A. With regard to this, LR is always limited to a small-scale preparation [5,7].

Figure 1. Generation of the six-membered by-product A
Other than the exploration of the potential surogates of LR for the thionations, considerable efforts have been devoted to the improvements of the workup of the LR reactions. For example, Soós and coworkers attached perfluorinated alkyl chains bonding to LR, which could simplify the product isolation via a fluorous reversed-phase solid extraction technique [8,9]. This method with long perfluorinated alkyl chains is attractive in parallel synthesis and also in high-throughput biological screening.
However, both modified LRs and fluoro sources are rather high-cost and not practical for scaling up. Besides, basic aqueous solutions were utilized as well in the work-up process. It was believed that the compound A was converted to an aqueous soluble thio-phosphate ( Figure 2) [13][14][15]. This operation indeed simplified the work-up procedure and the scaling up column-free purification, while generated quite a lot of Pcontained aqueous waste. The P-contained aqueous waste was unfavorable during the scaling up because of the difficult treatment in the downstream and also one of the sources of eutrophication. Therefore, optimizing the work-up process of applying LR in thionation reaction is greatly appealing for the potential large-scale preparations. Thioamide compounds are one of the most attractive molecules in pharmaceuticals, agrochemicals, electronic chemicals and material sciences [16][17][18][19][20][21][22]. In coordination chemistry, pincer-type ligands containing thio-amide motif have already exhibited their 4 incomparable chelating ability to the selected transition-metals, and their corresponding complexes have been applied in various areas such as chemical-sensor materials, tunable redox-potential complexes, polymer hybrid luminescence materials, building blocks for multinuclear com-plexes, and catalysts for cross-coupling reactions [23][24][25][26][27][28][29][30]. The thio-substitution of amides with LR is an efficient and straightforward method, either the availability of amide substrates, LR, or the reaction condition [7,8,[31][32][33][34][35]. With thio-substitution of amides as a model, we herein reported an efficient work-up procedure of applying LR by utilizing ethylene glycol to decompose the compound A (Figure 2). With a combination of some usual operations, such as, phasecut, extraction and crystallization, the desired thioamide products were efficiently obtained in excellent yields.

Results and Discussion
Our initial exploration began with the thio-substitution of N-phenyl benzamide (1a) with LR in the reflux of toluene (Eqn 1). After completing the reaction, the splitting solutions were treated with different active additives under different temperature in order to find a reagent which can efficiently decompose the compound A [36]. MeOH or EtOH was initially tested. The experimental results showed that MeOH can't fully decompose the compound A between 40 o C to reflux, either stripping toluene or not. To our delight, EtOH worked well under refluxing temperature, a new spot with much higher polarity on TLC plate was observed. With a mixed solvent of ethyl acetate/petroleum ether (1:3) as the eluent, Rf of the compound A was around 0.5, while Rf of the new generated compound was around 0.05 either from MeOH or EtOH treatment. Later, the new generated compound by EtOH treatment was assigned as diethyl pmethoxyphenylthiophosphate (C1) via GC-MS and confirmed by GC-TOF [37]. The polarity variation after MeOH or EtOH treatment indicated that the column separation can be greatly simplified in small-scale preparation. With this improvement, various thioamides were conveniently synthesized with the simplified column separation in good to excellent yields (Table 1). Although the small synthesis of thioamides was addressed, the column purification was extremely unfavorable during scaling-up preparations. After considerable efforts for the 6 reaction mixture with EtOH treatment, either solvent extraction/phase-cut with different polarity or even with aqueous workup, it was disappointedly found that the compound C1 can be well distributed in most solvents and acted as a polar solvent component.
Although less polar solvent, such as heptane, is able to reject part of the compound C1, it can't extract the desired thioamide. Water can partially extract the compound C1 into aqueous phase, but the aqueous mixture pulled some products too. Moreover, aqueous workup after EtOH treatment is also problematic because of P-contained aqueous waste, and this two-step treatment procedure was not as good as the direct saturated aqueous NaHCO3 procedure [14]. With the above observation, we reckoned that converting the compound A to a more polarized by-product can probably make a breakthrough. As a common knowledge, the more polarized alcohols over EtOH are those diols or polyols, while the simplest MeOH was previously ruled out. Ethylene glycol, a basic chemical and the simplest diol, can be slightly soluble in toluene and attracted our interests. Both its strong polarity and layering ability showed that ethylene glycol seemed to be an ideal choice.
After the completion of the thioamide reaction with 1e (0.20 mol) and LR (0.102 mol) (Eqn 2) ( Figure 3, d3&d4), excess ethylene glycol was added to decompose the compound A, following the previous EtOH treatment procedure. To our astonishment, the decomposition was much slower as expected by TLC monitoring (Figure 3, d5). It was assumed that the ring-opening could be interfered by water or accelerated by the in-situ generated thiophosphoric acid. Thus, 1.0 mL water was added into the mixture.
We were pleased to find that the compound A can be smoothly decomposed by ethylene glycol at 95 o C in 3.5 h. With the decline of compound A in toluene layer, a new compound C2 was observed (Figure 3, d7). It was also noticed that the pH of ethyl glycol layer came up to about 2-3. Thus, we reckoned that the assumed by-product C2 was further decomposed to the thio-phosphoric acid which was well soluble in ethylene extracted with toluene (Figure 3, b). The cooled toluene layers were treated with activated carbon and filtered off. Toluene and the potential volatiles were stripped off, the residual was re-crystallized with mixed solvents of toluene and heptane to afford 36.0 g of the desired thioamide (2e) as a yellow crystalline (Figure 3, c).

Scheme 1. Modified process for synthesis of pincer ligand 6
As can be seen from Scheme 1, it is clear that the modified process only discharged organic wastes (toluene, and toluene/heptane mixture), C2/ethylene glycol mixture, along with some waste carbons [40].

Conclusion
In conclusion, we have developed a highly efficient process for workup of thiosubstitution with the Lawesson's reagent. In the newly developed procedure, ethylene glycol played a crucial role in the column-free and P-contained aqueous-free workup.
With The combined toluene layers were treated with 3.

Supporting Information
Supporting Information File 1: The NMR data for compounds 2-6 and thio-phosphoric acid.