Hot water-promoted catalyst-free reductive cycloamination of (bio-)keto acids with HCOONH4 toward cyclic amides

J. of Supercritical Fluids 157 (2020) 104698

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Hot water-promoted catalyst-free reductive cycloamination of (bio-)keto acids with HCOONH4 toward cyclic amides Hongguo Wu, Zhaozhuo Yu, Yan Li, Yufei Xu, Hu Li ∗ , Song Yang ∗ State Key Laboratory Breeding Base of Green Pesticide & Agricultural Bioengineering, Key Laboratory of Green Pesticide & Agricultural Bioengineering, Ministry of Education, State-Local Joint Engineering Lab for Comprehensive Utilization of Biomass, Center for R&D of Fine Chemicals, Guizhou University, Guiyang, Guizhou 550025, China

h i g h l i g h t s

g r a p h i c a l

a b s t r a c t

• A combo hot-water/HCOONH4 sys• • • •

tem enables cycloamination of biobased levulinic acid. HCOONH4 is capable of acting as both H and N source without any catalyst or additive. H2 O greatly improves reactivity/rate by promoting H and N source release from HCOONH4 . This catalyst-free/sustainable protocol is applicable to giving various cyclic amides. The reaction pathways are elucidated by deuterium-labeling and kinetic studies.

a r t i c l e

i n f o

Article history: Received 24 September 2019 Received in revised form 18 November 2019 Accepted 19 November 2019 Available online 22 November 2019 Keywords: Hydrothermal conversion Biomass upgrading Reductive amination Pressurized hot water N-heterocycles

a b s t r a c t Controllable functionalization of targeted oxygen-containing species of biomass feedstocks is one of the prevalent approaches to biofuels and important chemicals, and well-designed functional catalytic materials are typically required to promote the smooth proceeding of the desired conversion processes. In this work, HCOONH4 was demonstrated to be capable of acting as both hydrogen and nitrogen source in the absence of any catalyst and additive for the reductive cycloamination of bio-based levulinic acid (LA) to 5-methyl-2-pyrrolidone (MPL) with more than 90 % in just 60 min at 180 ◦ C. Pressurized hot water remarkably enabled the reaction efficiency and rate by promoting the hydrolysis of HCOONH4 to liberate ammonia and formic acid for the cascade reactions, and this catalyst-free protocol is also applicable to the efficient synthesis of various cyclic amides from relevant keto acids. Moreover, the reaction pathways were investigated by conducting deuterium-labeling experiments and kinetic studies of selected reactions. © 2019 Elsevier B.V. All rights reserved.

1. Introduction

∗ Corresponding authors. E-mail addresses: [email protected] (H. Li), [email protected] (S. Yang). https://doi.org/10.1016/j.supflu.2019.104698 0896-8446/© 2019 Elsevier B.V. All rights reserved.

As a unique and abundant source of non-edible while renewable organic carbon, lignocellulosic biomass has been deemed as a promising substitute for the dwindling fossil fuel reserves [1–4]. In view of the oxygen-rich feature of biomass-derived feedstocks (e.g., over 50 % oxygen by weight for pentose and hexose sugars,

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and 30−40 wt% oxygen content for lignin monomers), a variety of catalytic strategies such as pyrolysis and hydrodeoxygenation have been developed to selectively accomplish C O bond scission through removal of water, which can be further integrated with either C C coupling or C C bond cleavage for the production of liquid fuels and chemicals [5–10]. It is worth noting that bio-based platform molecules functionalized with different types of oxygen species (e.g., carboxyl, carbonyl, and hydroxy groups) formed by partial oxidation or hydrogenation open new avenues to access to further downstream chemical commodities (e.g., plastic polymers and pharmaceuticals) [11–17]. Nitrogen-containing compounds are versatile chemical feedstocks extensively applied in the pharmaceutical industry, and also successfully employed as catalytic materials, dyes, surfactants, solvents, and so on [18–20]. Among these nitrogenous molecules, N-substituted pyrrolidones have been disclosed to be efficiently synthesized by catalytic tandem reductive amination and cyclization of various primary amines with levulinic acid (LA, Fig. 1) [21–25], which is facilely accessible from pentose and hexose carbohydrates in the presence of an acidic catalyst [26–28]. To implement the two-step reaction process (Fig. 1), metal catalysts (e.g., Au, Ru, Ir, Pt, Ni, Cu, and Fe) in combination with HCOOH or H2 as H-donor are developed to be efficient for the synthesis of N-substituted pyrrolidones in good yields (84–99 %) at moderate reaction temperatures of 80−150 ◦ C for appropriate control of product selectivity but requiring relatively long reaction time (6−24 h) [29–39]. Accompanying with the great achievements obtained by metal-mediated catalytic approaches, a metal-free reaction system consisting of triethylamine (Et3 N) and HCOOH developed by Wei et al. [40] was able to mimic the LeuckartWallach reaction to afford N-substituted pyrrolidones (72–93 % yields) from LA and primary amines in DMSO (dimethyl sulfoxide) at 100 ◦ C after 12−15 h. However, the prerequisite of a basic additive Et3 N and non-volatile organic solvent DMSO makes the overall reaction process produce unwanted waste, posing difficulty in product separation. Using sub- or supercritical water as conversion medium that is widely available, non-toxic, eco-friendly and inexpensive, hydrothermal processes have being developed as green chemistry approaches for upgrading of biomass to biofuels and bio-based chemicals, especially applicable to the direct conversion of wet biomass (70−90 wt% natural water content) without drying [41,42]. Hydrothermal gasification is an important tool for a one-step biorefinery to produce hydrogen, and methane in some cases [43], while typically suffering from high-energy consumption, corrosion caused by water above its critical point, and largely unexplored reaction kinetics and routes [44,45]. Unlike industrial biomass gasification processes, scale-up of hydrothermal carbonization and liquefaction is quite limited because of high organic loadings in the aqueous phase [44], and heating up and cooling down a large amount of water are the dominant challenge toward all hydrothermal processes [46]. At relatively low processing temperatures (≤180 ◦ C), employing pressurized hot water without any additive is likely able to eliminate the complex processes of desalination and neutralization and avoid the recovery of organic solvents, thus possibly showing great potential in minimizing the waste generation [47]. In the present study, ammonium formate (HCOONH4 ) assisted by pressurized hot water is capable of in situ releasing HCOOH and NH3 ·H2 O to be respectively used as hydrogen and nitrogen source, which remarkably enables the reductive cycloamination of LA to yield 5-methyl-2-pyrrolidone (MPL), an unsubstituted cyclic amide rather than N-substituted pyrrolidones that have been reported everywhere. This catalyst-free, single-step protocol is also illustrated to be suitable for synthesizing a wide range of cyclic amides from various keto acids. Moreover, the reaction kinetics and

mechanism are also investigated to understand the predominant pathways. 2. Materials and methods 2.1. Materials Levulinic acid (LA, 99 %), 3-benzoylpropionic acid (99 %), 5-methyl-2-pyrrolidone (MPL, 98 %), ethyl levulinate (≥98 %), 4acetylbutyric acid (97 %), 3-(4-fluorobenzoyl)propionic acid (97 %), 7-oxooctanoic acid (98 %), 4-oxo-4-(2-thienyl)butyric acid (97 %), deuterium oxide (D2 O, 99.994 atom % D), and DMSO-d6 (99.9 atom % D) were bought from Sigma-Aldrich (Shanghai). Ammonium formate (HCOONH4 , 99 %), 4-(4-fluorobenzoyl)butyric acid (98 %), 6-oxoheptanoic acid (98 %), 4-benzoylbutyric acid (97 %), 3-(4-chlorobenzoyl)propionic acid (>98 %), methanol (99.9 %), and CH2 Cl2 (99.9 %) were purchased from Innochem Inc. (Beijing). 2.2. Methods 2.2.1. Reaction procedures All the experiments were implemented in a Teflon-lined stainless steel autoclave (inner volume 15 mL). Prior to starting this experiment, the oil-bath was preheated to a specified reaction temperature (120–180 ◦ ). In a typical procedure, certain amounts of LA (2 mmol), HCOONH4 (12 mmol), and deionized water (60 mmol) were added into the autoclave, which was then placed in the oil-bath preheated to the desired temperature with autogenous pressures of no more than 1.4 MPa, and the record of the reaction time was started. After a certain reaction time, the autoclave was removed out of the oil bath, followed by promptly cooling down to room temperature with flow tap-water. Finally, the autoclave was opened up and deionized water or methanol was added into the reaction mixture, which was determined by HPLC (volumetric dilution with water) or GC (using naphthalene as internal standard) after undergoing filter membrane. Each independent experiment was performed and reiterated for 2–3 times under the same conditions. The gained conversions and yields are average of 2–3 independent experiments, with standard deviation (␴) in the range of 0.5–4.3 %. CH2 Cl2 was optimized as a valid extractant to separate the product from the reaction mixture. Upon completion of the reaction (pH = ∼8.4), 3−5 mL deionized water was added into the mixture. The product cyclic amides (e.g., MPL) can be separated by extraction with CH2 Cl2 for 3 times (5 mL × 3), and the purified product was attained by evaporating the combined extractant under reduced pressure. 2.2.2. Continuous-flow reactions A Labtrix® Start microreactor system (Chemtrix BV, NL) with a glass microreactor (type 3227, volume: 19.5 ␮L) was utilized for the continuous-flow reactions. Initially, LA, deionized water, and HCOONH4 in a molar ratio of 1:30:6 was evenly mixed and added into a flask. The resulting solution was pumped into the microreactor (rate: 25 ␮L/min) under cooling until the reactor is full. Upon the reactor temperature was raised to 180 ◦ C, the solution flow rate was set at 1.5 ␮L/min. After running for 60 min, sampling at timed intervals was executed for GC analysis. 2.2.3. Sample analysis Liquid products were identified by GC–MS (Agilent 6890 N GC/5973 MS, Santa Clara, CA). HPLC (Agilent 1260 Infinity) equipped with a refractive index (RI) detector and an Agilent HiPlex column was utilized to determine the concentrations of keto acids (e.g., LA). GC (Agilent 7890B) fitted with a flame ionization detector and an HP-5 column (30 m ×0.320 mm ×0.25 ␮m) was

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Fig. 1. General pathways for the production of N-substituted pyrrolidones from primary amines and biomass-derived levulinic acid (LA).

used to quantitatively analyze the reaction mixtures with naphthalene as the internal standard (Fig. S1). 1 H and 13 C NMR spectra of samples were recorded in DMSO-d6 on Bruker NMR spectrometers at 400 MHz and 101 MHz, respectively, using tetramethylsilane (TMS) as the internal standard. 2.2.4. Isotopic labeling experiments 1 H and 13 C DEPT 90 spectra of the reaction mixtures were applied in the experiments under the given deuterium water reaction conditions. Analyses were performed on a JEOL-ECX 500 NMR spectrometer with the deuterated solvent DMSO-d6 . GC–MS Analyses of the reaction mixtures conducted using either normal or deuterium water were performed after dilution with methanol to determine the incorporated D in the products. 3. Results and discussion 3.1. Effect of water content and HCOONH4 dosage on reductive cycloamination of LA Typically, it is necessary to include both hydrogen (H2 or HCOOH) and nitrogen sources (primary amines) for implementing the reductive amination process, followed by cyclization capable of leading to the formation of N-heterocycles [48–50]. In this study, HCOONH4 was proposed to simultaneously act as H- and N-donor in the reductive cycloamination of LA toward MPL. Preliminary experiments were conducted using 2 mmol LA and 6 equiv. HCOONH4 in the absence of any catalyst or additive at 160 ◦ C for 120 min, and around 46 % yield of MPL was obtained (Fig. 2A). It was interesting to find that the addition of water could remarkably improve the reaction efficiency, and ca. 90 % MPL yield could be achieved as 30 equiv. water was added. These results indicate that water-mediated hydrolysis of HCOONH4 to in situ liberate HCOOH (H-donor) and NH4 OH (N-donor) contribute to the pronounced reactivity in the synthesis of MPL from LA. Moreover, the slight increase in the MPL yield from 90 % (30 equiv. water) to 92 % with the further rise of water content to 40 equiv. (Fig. 2A) shows the existence of reaction equilibrium, proving that the water-enhanced hydrolysis step most likely plays a dominant role in the overall reaction process. Apart from the promotional effect of water in a certain amount (30 equiv.), the dosage of HCOONH4 was also demonstrated to linearly correlate with the MPL yield (Fig. 2B). With the HCOONH4 dosage of no more than 4 equiv. relative to LA, a maximum MPL yield of only 76 % was acquired at 160 ◦ C after 120 min. The use of 6 equiv. HCOONH4 makes the MPL yield (90 %) reach the plateau and no apparent enhancement in MPL formation was observed as the HCOONH4 dosage kept increasing to 8 equiv. (Fig. 2B). This ten-

Fig. 2. Effect of water content (A) and HCOONH4 dosage (B) on the synthesis of MPL from LA. Reaction conditions: 2 mmol LA, 0–40 equiv. H2 O, 0–8 equiv. HCOONH4 , 160 ◦ C, 120 min.

dency is in good agreement with the influence of water content for reductive cycloamination of LA to MPL, manifesting that the hydrolysis ability of HCOONH4 with water is responsible for the smooth proceeding of the whole processes. In view of the intrinsic reversibility of the salt hydrolysis reaction, it is quite reasonable to explain the need of excess HCOONH4 (6 equiv.) and water (30 equiv.) to achieve relatively improved MPL yields. To uncover the trail of water in the cascade reactions, a kinetic study of the LA-to-MPL conversion using H2 O and D2 O, assumed as a pseudo-first-order process, was carried out (Fig. 3).

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Fig. 3. Kinetic profiles for reductive cycloamination of LA with HCOONH4 and H2 O or D2 O. Reaction conditions: 2 mmol LA, 30 equiv. H2 O or D2 O, 6 equiv. HCOONH4 , 160 ◦ C, 10−60 min.

The good linear correlation between -ln(1 - X) and t clearly indicates the pseudo-first-order reaction, where X and t denote LA conversion and reaction time, respectively. It is not difficult to notice the rate constant for the reductive cycloamination of LA occurred in either H2 O (kH =0.0492 min−1 ) or D2 O (kD =0.0537 min−1 ), suggesting a secondary hydrogen isotope effect (kH /kD = 0.92). To a large extent, this result can illustrate the water-participated reversible processes in the overall LA-to-MPL reaction [51]. 3.2. Effect of reaction temperature and time on reductive cycloamination of LA As discussed above, the required key feedstock (HCOOH and NH4 OH) for LA cycloamination can be adequately supplied by the in situ hydrolysis of HCOONH4 enabled by hot water. Several reaction steps including amination (C N bond formation), transfer hydrogenation, and cyclization are probably involved for the catalyst-free synthesis of MPL from LA and HCOONH4 in hot water. Alongside with the increase of H- and N-donor concentration, reaction temperature and time would also be parameters exerting the influence on the reaction efficiency. As shown in Fig. 4, LA conversion was closely correlated with both reaction temperature and time, where 60, 90, and around 180 min were needed for complete consumption of LA at 180, 160, and 140 ◦ C, respectively. In particular, the MPL selectivity obtained at a high temperature of 180 ◦ C was obviously superior to those at 160 and 140 ◦ C, and more intermediates were observed, elaborating that relatively higher reaction barriers have to overcome prior to yielding MPL. It is interesting to mention that a satisfactory MPL yield of 91 % and 96 % could be attained at 180 ◦ C after just 60 and 120 min, respectively (Fig. 4B). In sharp contrast, only 69 % yield of MPL was detected at 140 ◦ C even after 180 min and the co-produced intermediates account for about 30 %. This temperature-dependent characteristic of the LA cycloamination process is consistent with that of the conventional Leuckart-Wallach reaction [52]. Moreover, the extra addition of either 10 mol% aqueous ammonia or 10 mol% HCOOH was found to afford slightly low MPL yield of 78 % and 76 %, respectively, as compared with the reaction system (82 % yield) without adding aqueous ammonia and HCOOH under identical conditions (180 ◦ C for 30 min), manifesting the significance of HCOONH4 hydrolysis to efficiently supply both hydrogen (HCOOH) and nitrogen (NH4 OH) sources for the reductive cycloamination of LA. In order to investigate the real-time reaction of LA to MPL, ex-situ 1 H NMR spectra of reaction mixtures were recorded after

Fig. 4. Effect of reaction time and temperature on LA conversion (A) and MPL yield (B) in the reductive cycloamination of LA with HCOONH4 and H2 O. Reaction conditions: 2 mmol LA, 30 equiv. H2 O, 6 equiv. HCOONH4 .

Fig. 5. Ex situ 1 H NMR spectra of reaction mixtures after reductive cycloamination of LA with HCOONH4 and D2 O for different time intervals (diluted with DMSO-d6 ). Reaction conditions: 2 mmol LA, 30 equiv. D2 O, 6 equiv. HCOONH4 , 180 ◦ C, 10−60 min.

reductive cycloamination of LA with HCOONH4 and D2 O at 180 ◦ C for different time intervals (10−60 min, Fig. 5), and the 1 H NMR spectra of pure HCOONH4 , LA, and MPL were provided in Fig. S2 for reference. HCOOH (in situ released from HCOONH4 hydrolysis) was detected at ca. 8 ppm in a short time of 10 min, the content of which rapidly increased to the plateau in 20 min and then no signif-

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Fig. 7. Ex situ 13 C NMR (DEPT 90) spectra of reaction mixtures after reductive cycloamination of LA with HCOONH4 and D2 O for different time intervals (diluted with DMSO-d6 ). Reaction conditions: 2 mmol LA, 30 equiv. D2 O, 6 equiv. HCOONH4 , 180 ◦ C, 10−60 min.

Fig. 6. Product distribution in the reductive cycloamination of LA with HCOONH4 and H2 O to MPL at 120 ◦ C for 60−300 min. Reaction conditions: 2 mmol LA, 30 equiv. H2 O, 6 equiv. HCOONH4 , 120 ◦ C

icant change in peak intensity was observed after 30 or even 60 min. This result clearly authenticates the existence of a hydrolytic equilibrium between aqueous HCOONH4 and HCOOH/NH4 OH, which is in line with the isotope labeling experimental results (Fig. 4). It is surprising to see that LA was almost completely converted within 30 min, and MPL was exclusively generated without detecting any other coproduct at 180 ◦ C (Fig. 5). These results indicate that a relatively high temperature (e.g., 180 ◦ C) facilitates both hydrolysis of HCOONH4 to liberate HCOOH/NH4 OH, and conversion of key intermediates such as imine and linear amine to yield MPL via cascade reactions like transfer hydrogenation and cyclization. In this regard, the study of product distribution for the amination reactions conducted at low temperatures (e.g., 120 ◦ C) would be preferable due to relatively inferior reactivity of the cascade elemental conversion reactions. 3.3. Study of product distribution To elaborate on the dominant products formed in the LA reductive cycloamination process, a low reaction temperature of 120 ◦ C in a varying time course was adopted accordingly. Fig. 6 shows the possible reaction pathways based on the yields of intermediates (denoted as Int-1, Int-2, and Int-3), which could not be detected in a high quantity at high temperatures (≥140 ◦ C). The structures of these intermediates were identified by GC–MS, as illustrated in Fig. S3. It was found that Int-1 and Int-2 were initially formed with maximum MPL yields of 5 % and 9 %, respectively, in the early stage of 60 min. Then, both Int-1 and Int-2 intermediates were slightly consumed even by further prolonging the reaction time to 300 min, with the MPL yield decreasing to 2 % and 6 %, respectively (Fig. 6). The imine and amine derived from LA and in situ formed NH3 (Fig. 6), which were reported as the dominant species toward MPL [53,54], were not detectable in the present work. Instead of directly obtaining from LA, the detected Int-1 and Int-2 intermediates could be originated from the amine by reaction with HCOOH (Fig. 6). It

is entirely different to notice that the yield of Int-3 increased first and then decreased in a relatively small range (10–13 %), implying that Int-3 was relatively stable during the overall reaction. These results, on the other hand, verify the requirement of a relatively high reaction barrier to undergo the elemental step of transfer hydrogenation (Int-3 to MPL), which may also find clues from the relatively inferior yields of Int-1 and Int-2. Considering the important role of hydrogen transfer step in the overall reaction, several deuterium-labeled experiments for reductive cycloamination of LA with HCOONH4 assisted by D2 O were thus conducted to elaborate the feasibility of in situ HCOOH-mediated hydrogen transfer process. As demonstrated by ex-situ 13 C NMR (DEPT 90, exclusively recording the methenyl signal), HCOOH(D) derived from hot D2 O-enabled hydrolysis of HCOONH4 exhibited a distinct peak at 164 ppm (Fig. 7), indicating that the hydrogen source was mainly originated from the formyl species −CHO of HCOONH4 without the influence of D2 O. In addition, the methenyl species (located at 50 ppm) in the 5-position of MPL could also be observed from the DEPT 90 spectra, the peak intensity of which slightly increased with the time extension (Fig. 7). However, two weak peaks at 28 and 30 ppm respectively belonging to 4- and 3position of MPL (Fig. 7) showed the incorporation of D during the transfer hydrogen process, and also suggested the existence of Int3 tautomeric structures where ion-exchange and hydrogen transfer between D (of D2 O) and H (of the shiftable double bonds) may take place. This speculation can be well supported by the results of GC MS, in which the molecular ion peak of MPL obtained from LA and HCOONH4 in D2 O had additional 2–5 amu (Fig. S4). 3.4. Control experiments with kinetics study A series of reaction routes, especially reductive amination (toward Int-1) and amidation (toward Int-2), were involved in the overall LA-to-MPL conversion, while it would be highly desirable to comprehend which pathway is more preferentially applicable to the formation of MPL. Two control experiments respectively using 2-pentanone and pentanoic acid as starting material subjecting to hydrothermal treatment with HCOONH4 were conducted at 180 ◦ C to evaluate the relative reactivity between amination and amidation (Fig. 8). It was found that 2-pentanone was instantly consumed in 30 min, while ca. 85 % conversion of pentanoic acid demanded a much longer period of duration (300 min) to fulfill (Fig. 8A). The corresponding kinetic profiles listed in Fig. 8B explicitly clarify that

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Fig. 9. Results of EL-to-MPL conversion with HCOONH4 and H2 O (A), and kinetic profiles for reductive cycloamination of EL or LA with HCOONH4 and H2 O to MPL (B). Reaction conditions: 2 mmol EL or LA, 30 equiv. H2 O, 6 equiv. HCOONH4 , 180 ◦ C, 10−90 min.

Fig. 8. Reaction results (A) and kinetic profiles (B) for reductive amination of 2pentanone or pentanoic acid with HCOONH4 and H2 O. Reaction conditions: 2 mmol 2-pentanone or pentanoic acid, 30 equiv. H2 O, 6 equiv. HCOONH4 , 180 ◦ C, 5−90 min.

the amination of 2-pentanone (k =0.1136 min−1 ) proceeds much faster than the pentanoic acid amidation process (k =0.0111 min−1 ). These results are in good accordance with the relatively lower yield of Int-1 as compared with that of Int-2 in the reductive cycloamination of LA with HCOONH4 in water, also implying that Int-1 along with Int-3 could be the key intermediates mainly leading to MPL through cascade amination-reduction-cyclization or amination-cyclization-reduction, respectively (Fig. 7). In order to examine the potential role of the carboxyl group (COOH) of LA in the overall reductive cycloamination process, ethyl levulinate instead of LA was thus employed as feedstock for the synthesis of MPL at 180 ◦ C for 10−90 min. It could be easily aware that a good MPL yield of 91 % was rapidly obtained from LA in 60 min, while the reaction starting from EL afforded only 47 % MPL under identical reaction conditions, despite comparable MPL yield attained after 120 min (Figs. 4 & 9 A). In the case of LA, the reaction process was significantly enhanced possibly due to the hydrolysis of HCOONH4 as well as the cyclization of Int-1, Int-2

and imine being assisted by the acidic species (COOH). The reaction rate (k =0.1243 min−1 ) of LA-participated process superior to that (k =0.0270 min−1 ) of using ethyl levulinate as starting feedstock further indicated the promotional effect of –COOH of LA. 3.5. Reductive cycloamination of LA using continuous flow microreactor In the practical production process, aqueous LA solution is directly available from sugar via an acid-catalyzed liquid-phase process [55,56]. As such, our developed protocol shows great potential in the rapid production of MPL from sugar-derived LA by hydrothermal treatment with HCOONH4 using a continuous-flow apparatus (Fig. 10). In the present preliminary investigations, a Labtrix® Start microreactor system (Chemtrix BV) was employed for reductive cycloamination of LA with HCOONH4 and hot water under the above-optimized reaction conditions (with the molar ratio of LA/H2 O/HCOONH4 = 1:30:6, reactor temperature: 180 ◦ C). The flow rate of the reaction solution was set at 1.5 ␮L/min, and sampling at timed intervals was executed for GC analysis. It is interesting to find that a good yield of MPL (ca. 83 %) could be obtained with a residence time of ca. 16 min. The reaction

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Fig. 10. Schematic diagram of producing MPL from aqueous LA and HCOONH4 solutions.

duration is remarkably shortened from a couple of hours approximately to a quarter, and further studies on the reactor design and the optimization of reaction parameters are being carried out. Especially, the final product MPL can be facilely separated from the resulting aqueous mixtures by extraction with a non-polar solvent (e.g., CH2 Cl2 ), which may further facilitate the efficient production and purification of MPL directly from biomass feedstock.

3.6. Substrate scope expansion In the previous reports, much attention was mainly placed on the synthesis of N-substituted pyrrolidones from LA and primary amines in the presence of a metal catalyst with hydrogen or HCOOH as H-donor, as listed in Table 1 [18,21,23,29–32,34–40]. It can be seen that relatively high pressures (3−30 bar) of molecular hydrogen gas with a longish reaction time of 6−24 h at 80−175 ◦ C were necessary to realize satisfactory yields (88–100 %) of N-substituted pyrrolidones (entries 1–8). When liquid HCOOH instead of H2 was used, a little higher reaction temperatures (100−180 ◦ C) with 6−15 h reaction time were required to achieve comparable pyrrolidones yields of 86–97 % (entries 9–14). In the absence of any catalyst, N-substituted pyrrolidones with moderate yields were also reported to be capable of producing from LA (entry 14) [40], while basic additive Et3 N and non-volatile solvent DMSO must be utilized, which may cause the unwanted waste formation and the difficulty in product separation. As an improved approach, our catalyst-free reaction system consisting of only HCOONH4 and H2 O was able to greatly enable the reductive cycloamination of LA to MPL with good yields of 91 and 96 % in 1 and 2 h, respectively (entry 15), and the target product could be separated by simple extraction. The enhanced reactivity of our developed green and sustainable protocol could be ascribed to the facile release of H- and N-donor from HCOONH4 with pressurized hot water, which shows great potential in the production of N-unsubstituted cyclic amides from various keto acids. To disclose the feasibility in the reductive cycloamination of different types of substrates, the combo HCOONH4, and hot-water reaction system was also applied for the hydrothermal conversion of various keto acids to N-unsubstituted cyclic amides (Fig. S5), and the obtained results are shown in Table 2. In addition to LA, other substituted 1,4-keto acids including ethyl levulinate could also be converted to N-unsubstituted pyrrolidones in 85–92 % yields by reacting with HCOONH4 in water at 180 ◦ C after 120 min (entries 1–6). It is interesting to note that six-membered cyclic amides in almost quantitative yields (92–98 %) without an N-substitute were able to be achieved from 1,5-keto acids (entries 7–9). The use of a 1,6-keto acid as starting material could also furnish the formation of corresponding seven-membered cyclic amide, and the resulting low yield (33 %, entry 10) was possibly due to the relatively low solubility of the substrate in water. Therefore, this simple and green protocol is highly applicable to synthesizing a

Table 2 Reductive cycloamination of various keto acids with HCOONH4 in hot water to Nunsubstituted cyclic amides.

Entry

Product

Time (min)

Yield (%)

1

60 [120]

91 [96]

2a

120

97

3

120

92

4

120

88

5

120

85

6

120

86

7

120

98

8

150

95

9

180

92

10

150

33

Reaction conditions: 2 mmol keto acid, 30 equiv. water, 6 equiv. HCOONH4 , 180 ◦ C. a Ethyl levulinate (EL) was used as substrate.

wide range of N-unsubstituted cyclic amides from corresponding keto acids. 4. Conclusions Without using any catalyst or additive, the developed reaction system consisting of HCOONH4 and water was illustrated to be highly efficient for the reductive cycloamination of biomassderived LA to MPL with >90 % yields in a reaction time of as short as 60 min under thermal conditions (180 ◦ C), which is comparable and even superior to the previously reported results of metal-mediated catalytic systems. The pressurized hot water played a promotional effect in the in situ release of H and N source from HCOONH4 for the cascade conversion processes. Deuterium-labeling experiments and kinetic study of model control reactions demonstrated that both Int-1 and Int-3 could be the dominant intermediates furnishing the formation of MPL from LA via tandem amination-reduction-cyclization or aminationcyclization-reduction, respectively. This catalyst-free and versatile

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Table 1 Comparison of previous results in the synthesis of pyrrolidones from LA using different catalysts and H-donors.

Entry

Catalyst

R

H-donor

Temp.(◦ C)

Time (h)

LA conv.(%)

Product yield(%)

Ref.

1 2 3 4 5 6 7 8 9 10 11 12 13 14a 15b

Pt-MoOx /TiO2 Pt/TiO2 CNFx @Ni@CNTs Pt-MoOx /TiO2 Ir/SiO2 -SO3 H Ir complex Cu15 Pr3 /Al2 O3 Cp*Ir-L Ru-P complex Ru complex Au/ZrO2 -VS Fe3 (CO)12 Raney Ni – –

n-Octyl Phenyl Benzyl Benzyl Phenyl Phenyl n-Butyl Phenyl Propyl Benzyl Benzyl Ethyl Phenyl Benzyl H

7 bar H2 10 bar H2 30 bar H2 3 bar H2 >17 bar H2 5 bar H2 50 bar H2 25 bar H2 HCOOH HCOOH HCOOH HCOOH HCOOH HCOOH HCOONH4

110 120 130 100 100 110 175 80 140 120 130 180 180 100 180

24 18 6 20 24 16 20 10 12 12 12 15 6 12 1 [2]

– 100 100 – – – 99.6 – 86 – 98 – 100 – 100

92 100 99 94 88 98 94.2 96 86 95 97 90 92 87 91 [96]

[18] [21] [29] [31] [34] [36] [37] [39] [23] [30] [32] [35] [38] [40] This work

a b

1 equiv. triethylamine (Et3 N) as additive with DMSO as solvent was added. 30 equiv. deionized water was added.

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