From Flask to Mill: Reductive Functionalization of Fluoroacetamides as a Case Study for Transferring Solvent-Based Reactions to the Solid State

: The development of sustainable methods is a central focus of modern organic synthesis and has applications in various areas of the chemical industry. Mechanochemistry is a highly desirable green synthetic method as it departs from traditional solution-based reactions and their concurrent generation of waste solvent. Here, we report results of the adaptation of a solution-based method for the reductive functionalization of fluoroacetamides to a mechanochemical protocol as a case study. This greener solid-state, one-pot strategy is based on the partial reduction of amides by an in situ mechanochemically generated zirconocene chloride hydride (Schwartz’s reagent) and tandem nucleophilic addition of indole to afford high-value functionalized fluorinated amines in moderate to good yields. In addition to it being the first time this reductant has been mechanochemically generated, the sustainable approach was complemented by operationally simple purification by an acidic resin. Significant improvements in green metrics (E factor and EcoScale) were observed by this adaptation of the methodology.


■ INTRODUCTION
Mechanochemical synthesis involves the milling of reagents to drive a reaction. This process not only complements conventional methods of energy input but can also often lead to different products through alteration of the reaction environment, providing some control of the reaction pathway. Due to this, it presents an opportunity to explore a potentially novel space of chemical reactivity. 1 Reactions conducted under grinding conditions are also often considered to be a greener alternative to traditional solution-based methods of synthesis. Therefore, an important objective in this field of chemistry is to "translate" processes known from wet synthesis to more sustainable solid-state reactions. In this paper, we present a case study of the step-by-step transfer of reductive functionalization of fluoroacetamides from a reaction in a solvent solution to a mechanochemical process in a mill.
Amides are relatively unreactive, which is usually explained by the donation of the nitrogen lone pair into the anti-bonding (π*) orbital of the carbonyl providing resonance stabilization, which in turn reduces its electrophilicity. 2,3 For this reason, the chemoselective reductive functionalization of amides remains challenging and is still one of the frontier challenges in organic chemistry, which drives an active area of research. 4 The possibility of partial selective reduction of highly stable amides, even in the presence of sensitive functional groups, to imines with subsequent nucleophilic addition to form new C−C or C−Het bonds (dependent on nucleophile structure) has great value for academic and industrial chemists, 5−7 with particular emphasis on medicinal chemistry (e.g., synthesis of antineurodegenerative agents diphenidine, methoxphenidine, fluorolintane, and late-stage functionalization of numerous drugs including anti-dementia donepezil or anesthetic fentanyl). 8 Very recently, we found that the reduction of simple fluorinated acetamides to the corresponding imines can be achieved using Cp 2 Zr(H)Cl 9 with traditional solution-based chemistry. 10 The experiences we have acquired through this research have clearly shown that among the known literature methods of amide reduction, only Schwartz's reagent allows for the combined reduction 11 and addition 12 steps in the reductive functionalization of fluoroacetamides by indoles, which yields highly valuable products from a medicinal chemistry point of view. 13 Herein, we describe a case study employing mechanochemical tools for the reductive functionalization of fluoroacetamides through the step-by-step adaptation of solvent-based conditions to a solid-state process (Scheme 1).

■ RESULTS AND DISCUSSION
Our initial investigations began from promising results obtained in a planetary ball mill. For our first trials, boric acid was selected as a moderate-strength, known effective carbonyl and imine activator, 14 and eco-friendly solid replacement for the liquid acid (TFA) used in the solutionbased methodology. 10 The usage of readily available Schwartz's reagent directly delivered unpromising results, so the strategy turned to the in situ generation of the zirconium-based reductant from inexpensive zirconocene dichloride and lithium tri-tert-butoxyaluminum hydride (LTBA), previously reported in solution by Snieckus. 15 An initial one-pot attempt to functionalize model 2,2,2-trifluoro-N-(2-phenylethyl)acetamide (1a) by Cp 2 ZrCl 2 and LTBA (2.0 and 3.0 equiv, respectively, the excess of aluminum hydride is for efficient in situ formation of Schwartz's reagent), with boric acid (4.0 equiv) as the activator, indole (3.0 equiv) as the nucleophile, and sodium sulfate as grinding auxiliary, gave conversion of the starting amide 1a into the desired amine 2a in only 21% yield. Separation of the reduction and addition steps, as in solution, turned out to be a key factor, and allowed substrate conversion to reach 90%. However, multiple byproducts were detected beside the desired functionalized amine and further investigations were necessary to control the product distribution.
In solid-state reactions, the grinding auxiliary is extremely important to provide appropriate rheology 16 and can play a key role in efficient mass and energy transfer. 1 In this regard, various types of grinding auxiliaries were tested due to ineffective mixing of neat reagents. The best and comparable results were obtained with soda-lime glass beads and sodium sulfate ( Table 1, entries 5 and 6). The former was selected as the optimal agent due to the beneficial effect of a small amount of water at the nucleophile addition step, which may help in the efficient unleashing of imine from its zirconium complex (based on density functional theory studies 17 and by analogy with the solution-based protocol 10 ). In this context, the application of a common drying agent was not desirable and completely neutral glass beads were consciously chosen. Moreover, the volume of the auxiliary is significant (optimally reagents and auxiliary should fill half to two-thirds of grinding jar space), as well as preventing the reagents from clumping in a cohesive state. 16 For this purpose, intervals with direction reversal were applied which have a significant impact on the post-reaction mixture appearance obtained in planetary ball mills (Table 1).
A key part of the study was the selection of an acid activator, promoting efficient destruction of the zirconacycle and releasing the free imine with its subsequent additional activation. 18 Its role is crucial and reactions carried out under ball-milling conditions without an acid additive provide a complex reaction mixture with little contribution of desired product 2a ( Table 2, entry 1). Boric acid used in the preliminary results unfortunately delivers a significant amount of byproducts (Table 2, entry 5). Searching for a solid acid, which could minimize the formation of undesired compounds, included various acids�from soft proton donor triethylamine hydrochloride to the strong silica-supported perchloric acid. The best suppression of fluorinated byproducts with the simultaneous absence of indole dimer (forming under acidic conditions) 19 gave 4-nitrophenol (Table 2, entry 6).  3 (3.0 equiv), Cp 2 ZrCl 2 (2.0 equiv) and grinding auxiliary (∼4 mass equiv), 1 h; (2) indole (3.0 equiv), H 3 BO 3 (4.0 equiv) and grinding auxiliary (∼4 mass equiv), 4 h; both steps were performed in the same 12 mL stainless steel jar with 15 × 0.25 and 3 × 4 g stainless steel balls, 500 rpm with reverse intervals (10 min), planetary mill. b Determined by 19

Scheme 1. Course of Action for the Adaptation Process
Although the application of 4-nitrophenol allowed for the control of the selectivity of the reaction, the next step focused on the improvement of the processes efficiency. A prolonged reaction time did not raise the yield appreciably; however, shortening it allowed only for a slight increase (Table 3, entries 1−3). For this reason, a common extension of the standard mechanochemical technique in the form of liquid-assisted grinding (LAG) 20 was implemented and it was found that the addition of toluene is beneficial (Table 3, entry 7), and this result turned out to be optimal. Testing of other solvents with borderline polarity did not give a better outcome (Table 3, entries 4−6). All the reactions were set up in a glovebox under an inert atmosphere; however, the control experiment showed that the yield of the final product does not decrease drastically without these precautions (78% vs 50%, Table 3, entries 7 and 8) in contrast to solution-based protocol which strongly required the use of Schlenk techniques. 10 As mentioned, the reaction with a previously prepared Schwartz's reagent gave a dramatic suppression of yield (Table 3, entry 9), probably due to the disruption of its subtle dimeric bridged structure. 21 As expected, the reaction does not occur when only LTBA is applied due to the mild reducing ability of this hydride (Table  3, entry 10).
The sustainability of the presented approach was complemented by an operationally simple purification by an acidic resin. The chromatographic separation of the desired amine from an excess of 4-nitrophenol, indole, and traces of amide, as well as zirconium-containing impurities appeared to be complex and inefficient. Of course, nitrophenol can be washed out under basic conditions but this only partially solves the problem. In order to address the separation and purification problems and to make the process more sustainable,  3 (3.0 equiv), Cp 2 ZrCl 2 (2.0 equiv) and glass beads (∼4 mass equiv), 1 h; (2) indole (3.0 equiv), acid (4.0 equiv) and glass beads (∼4 mass equiv), 4 h; both steps were performed in the same 12 mL stainless steel jar with 15 × 0.25 and 3 × 4 g stainless steel balls, 500 rpm with reverse intervals (10 min), planetary mill. b Determined by 1 H NMR. c Determined by 19 F NMR. d Starting amide residue due to conversion level >94% in all cases as well as values on bars <5% were omitted for clarity (for details, see Table S1 in the Supporting Information).   3 (3.0 equiv), Cp 2 ZrCl 2 (2.0 equiv) and glass beads (∼4 mass equiv), 1 h; (2) indole (3.0 equiv), 4-nitrophenol (4.0 equiv), glass beads (∼4 mass equiv) and optionally liquid (1 μL mg −1 ), various times; both steps were performed in the same 12 mL stainless steel jar with 15 × 0.25 and 3 × 4 g stainless steel balls, 500 rpm, reverse intervals (10 min) and breaks (5 min) after each interval at second step, planetary mill. b Determined by 1 H NMR.

Table 4. Impact of Solvent System on the Purification of Model Amine by an Ion-Exchange Resin a a
After work-up, a mixture was dissolved in the solvent system and Dowex 50W X8 (12 mass equiv) was added; then, the suspension was shaking in an orbital shaker (600 rpm) for 24 h or to full conversion of amine (controlled by TLC); after this time, the mixture was filtered and washed (solvent system, DCM and MeOH); the resulted resin was flooded with ammonia solution in MeOH (8 M, 15 mL) and again shaking in an orbital shaker (600 rpm) for 16 h; and after this time, the suspension was filtered, the resin was washed (MeOH), and then the filtrate was evaporated and dried under vacuum to give the final pure product or its mixture with indole dimer (as indicated). purification of the amine products using commercial acidic resin Dowex 50W was developed and applied. In theory, the adsorption and the pure amine cleavage step should not cause any problems; however, the experimental reality turned out to be more complicated. The immobilization in methanol, as the most common solvent for this type of operation, heightens the acid-driven formation of the indole dimer (Table 4, entry 1). 22 Decreasing the methanol concentration by mixing it with THF gave only suppression (Table 4, entries 2 and 3), not the elimination of the dimer (in pure THF, as well as in EtOH or iPrOH, the dimer appears after several minutes of contact with resin). The simple replacement of MeOH by H 2 O in the THF mixture gets rid of undesired contamination (Table 4, entry 4). This was crucial, even at the expense of the final yield of the product because the formed dimer, as a secondary cyclic amine (see Table 2), was also captured by the resin and made effective purification of desired product impossible. In this way, the final amine was purified with excellent purity (see NMR spectra in Table 4 and caption of Scheme 2).
As the final stage of studies, the direct comparison of two types of mills applying different forces was made. To our delight, the mixer mill delivered an improvement of product 2a yield (78% vs 88%, respectively). It is highly possible that this result is also influenced by process conditions that are straightforward convertible and switching the dominant shear force in a planetary mill to impact force by the grinding frequency, which in a mixer mill can be achieved with a much higher rate than in a planetary mill. 23 Moreover, the clumping of the reaction mixture was dramatically decreased under horizontal milling conditions.
The performed studies opened the way into exploring the scope of amides useable with indole as the model nucleophile (Scheme 2). Due to the significant impact of the amine structure on the immobilization, the yield was also determined by NMR of the crude reaction mixtures. We started with aliphatic amides, which allowed for the demonstration of the chemoselectivity of the process. The amines with dimethoxy-2b, fluoro-2c, nitrophenethyl 2d substituents in the aryl ring, as well as imidazole moiety (histamine functionalization) 2e Scheme 2. Scope of Amides a a Conditions: (1) amide (0.15 mmol), LiAlH(tBuO) 3 (3.0 equiv), Cp 2 ZrCl 2 (2.0 equiv) and glass beads (∼4 mass equiv), 1 h; (2) indole (3.0 equiv), 4-nitrophenol (4.0 equiv), glass beads (∼4 mass equiv), and toluene (1 μL mg −1 ), 2 h; both steps were performed in the same 5 mL stainless steel jar with 4 g stainless steel ball, 30 Hz, mixer mill. The purity of all isolated products ≥96% (based on 19 F NMR).

ACS Sustainable Chemistry & Engineering pubs.acs.org/journal/ascecg
Research Article were synthesized with moderate to good yield. The application of benzylic amides as substrates also works quite well and corresponding secondary amines 2f, ready for deprotection to functionalized primary amines, were obtained with good yield. On the other hand, the use of a secondary aryl amide unfortunately gave inconvenient product 2g for the purification on acidic resin due to the susceptibility of 4-methoxyaniline to elimination. This effect has been noticed in the case of electron-withdrawing groups on the aryl ring; 10 however, in this case, even an electron-rich group did not prevent undesired hydrolysis. Not only trifluoro-but also difluoro-2h, heptafluoro-2i, and extremely interestingly, in context of further functionalization, bromodifluoroamine 2j could be obtained by the developed methodology. Besides secondary amides, also simple tertiary amides were examined and the corresponding trifluoro-2k and difluoroamine 2l were obtained with moderate yield. Although the overall yields may seem unsatisfactory at first glance, the fact that the process consists of three independent steps connected with chromatography-free purification should be kept in mind, and in this context, the methodology becomes preparatively useful.
To estimate the sustainability of the developed methodology, the E factors 24 and EcoScale 25 were calculated for the model reaction purified by an ion-exchange resin (Table 5, for details, see Tables S2−S4 in the Supporting Information). The first of these is based on the ratio between the mass of waste and mass of product, 26 and the second concentrates on yield, cost, safety, conditions, and ease of workup/purification of the reaction. 25 The obtained results were compared with parameters for the analogous solution process, including the synthesis of Schwartz's reagent 27 and the reductive functionalization of amide steps. 10 The developed mechanochemical process is enabled by organozirconium hydride and acid activator, both used in a molar ratio, and needs a grinding auxiliary which increases the waste mass. Due to this, its green metrics are higher than can be expected, but the approach nevertheless allows for a decrease in the simple E factor (sEF) by more than 25 fold. The difference mainly results from classical chromatography and mass of wasted silica gel using the solvent-based methodology. In the case of the complete E factor (cEF), taking into account the solvents, the mechanochemical metric is better by more than 30%. For this reduction in cEF, it is essential to limit the solvent to the minimum necessary (in the developed methodology, solvents are mostly required to perform solid-phase purification of products). On the other hand, EcoScale focuses on the efficiency and simplicity of the process (no chromatography necessary, among others). The purification of the desired amines by the ion-exchange resin turned out not to be quantitative and the final isolated yield of model product was 58% (for reference, 88% confirmed by NMR). However, the consumption of solvents by chromatography is so high that even an excellent reaction yield in solvent is insufficient to reach this level. Due to this, the mechanochemical approach is on the verge of satisfaction from a green chemistry point of view (Table 5), while the solvent-based methodology is remarkably insufficient (>75 excellent; >50 acceptable; <50 inadequate). 25 The calculated green factors clearly illustrate benefits of applying ball-milling techniques 28 for the title process despite the lower efficiency than in the solvent.

■ CONCLUSIONS
The mechanochemical synthesis of medicinally relevant, highvalue secondary and tertiary fluorinated amines from corresponding fluoroacetamides has been developed. This has several benefits over solution-based methods including better green metrics, due to lower solvent consumption, and shorter reaction times in addition to avoiding chromatographic purification steps. The methodology adaptation required the performed for the first time under ball-milling conditions in situ generation of a zirconium-based reductant instead of using Schwartz's reagent directly, selection of grinding auxiliary, application of a liquid assistant, determination of a solid acid replacement for liquid TFA to control the product distribution, and transition from planetary to mixer mill. The generation of an active organometallic reagent and its further in situ application is still rarely achieved under mechanochemical conditions 29,30 and opens the door for other similar catalytic or stoichiometric reagents to be utilized for greener synthetic procedures.