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Nov 20, 2018 - By employing this task-specific ionic liquid as sustainable catalyst, ... been employed in the synthesis of carboxylic acids [6–8], ...... Yu, B.; Diao, Z.-F.; Guo, C.X.; He, L.N. Carboxylation of olefins/alkynes with CO2 to ..... CO2-cocatalysed efficient hydration of propargylic alcohols to α-hydroxy ketones. Chem.
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Ionic Liquid-Promoted Three-Component Domino Reaction of Propargyl Alcohols, Carbon Dioxide and 2-Aminoethanols: A Thermodynamically Favorable Synthesis of 2-Oxazolidinones Shumei Xia 1 , Yu Song 1 , Xuedong Li 1 , Hongru Li 1,2, * and Liang-Nian He 1, * 1

2

*

State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China; [email protected] (S.M.); [email protected] (Y.S.); [email protected] (X.L.) College of Pharmacy, Nankai University, Tianjin 300353, China Correspondence: [email protected] (H.L.); [email protected] (L.-N.H.); Tel.: +86-22-23506290 (H.L.); +86-22-23503878 (L.-N.H.)

Received: 15 October 2018; Accepted: 20 November 2018; Published: 20 November 2018

 

Abstract: To circumvent the thermodynamic limitation of the synthesis of oxazolidinones starting from 2-aminoethanols and CO2 and realize incorporation CO2 under atmospheric pressure, a protic ionic liquid-facilitated three-component reaction of propargyl alcohols, CO2 and 2-aminoethanols was developed to produce 2-oxazolidinones along with equal amount of α-hydroxyl ketones. The ionic liquid structure, reaction temperature and reaction time were in detail investigated. And 15 mol% 1,5,7-triazabicylo[4.4.0]dec-5-ene ([TBDH][TFE]) trifluoroethanol was found to be able to synergistically activate the substrate and CO2 , thus catalyzing this cascade reaction under atmospheric CO2 pressure. By employing this task-specific ionic liquid as sustainable catalyst, 2-aminoethanols with different substituents were successfully transformed to 2-oxazolidinones with moderate to excellent yield after 12 h at 80 ◦ C. Keywords: ionic liquid; synergistic activation; aminoethanol; 2-oxazolidinone; atmospheric CO2 ; sustainable catalysis

1. Introduction The accumulation of CO2 in atmosphere has aroused considerable concern due to its link to the climate change; hence effective strategies are urgently needed to mitigate the increasing CO2 buildup [1–3]. Among the various strategies, transforming CO2 to valuable chemicals has received much attention by utilizing CO2 as economic and nontoxic C1 source [4,5]. Nowadays, CO2 has been employed in the synthesis of carboxylic acids [6–8], carbonates [9–12], carbamates [13–18], formate [19–21], methanol [21–24], ureas [25–27] and polymers [28–30] as well. Oxazolidinones, which are in the family of carbamates, are important chiral auxiliaries in organic synthesis [31,32] and are also common structural units in drugs [33,34] and agrochemicals [35]. However, the conventional synthetic methods of 2-oxazolidinones rely on hazardous or expensive reagents such as isocyanides [36] and phosgene [37]. Recently, B. Gabriele et al. reported an alternative unconventional synthetic method to produce oxazolidinones starting from 2-amino alcohols with CO in ionic liquids [38]. As the surrogate of CO, CO2 is a more desirable material. Therefore, synthesis of 2-oxazolidinones using CO2 and appropriate substrates has attracted much attention [14,39,40], among which the direct synthesis of oxazolidinones starting from 2-aminoethanols and CO2 is considered as an ideal route because the aqueous amino alcohols have been widely utilized to capture Molecules 2018, 23, 3033; doi:10.3390/molecules23113033

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beeninwidely utilized to capture CO2 in industry Unfortunately, thealcohols direct reaction CO industry [41,42]. Unfortunately, the direct[41,42]. reaction between amino and CObetween 2 2 occurs amino alcohols and CO 2 occurs difficultly due to the thermodynamic limitation [43]. To shift the difficultly due to the thermodynamic limitation [43]. To shift the equilibrium to 2-oxazolidinones, equilibrium toconditions 2-oxazolidinones, reactionagents conditions [44–48], dehydrating agents or auxiliaries harsh reaction [44–48],harsh dehydrating or auxiliaries are often needed [13,49–52]; thus, are generation often needed [13,49–52]; thus, the generation of wasteful is unavoidable. As has an the of wasteful by-products is unavoidable. As an by-products alternative strategy, our group alternative propargyl strategy, our groupinto has the introduced alcohols into the reaction of amino introduced alcohols reaction propargyl system of amino alcohols and CO2 tosystem circumvent this alcohols and COlimitation 2 to circumvent this limitation [53three-component –55]. As descripted in Scheme 1, thermodynamic [53–55]. Asthermodynamic descripted in Scheme 1, this cascade reaction three-component cascadecyclization reaction isand composed of carboxylative cyclization and the following isthis composed of carboxylative the following intermolecular nucleophilic ring-opening intermolecular nucleophilic ring-opening and further intramolecular nucleophilic and further intramolecular nucleophilic cyclization. Although Ag- and Cu-based catalystscyclization. have been Although Agandthree-component Cu-based catalysts havetobeen developed for this three-component reaction to developed for this reaction coproduce 2-oxazolidinones and α-hydroxyl ketones, coproduce 2-oxazolidinones and In α-hydroxyl ketones, high CO2 ispressure is still needed. In this high CO2 pressure is still needed. this context, efficient catalyst still highly desirable to run this context, at efficient catalystpressure. is still highly desirable to run this reaction at atmospheric pressure. reaction atmospheric R1 R2

R1

R1 R2 O

R

H N

R1

O

Step 1: carboxylative cyclization

O

R2

CO2

OH

O

O O

O

O

O

O

Sites need to be activated

O O

R1 R2 O OH

R2

OH N R

R N

R1 R2 OH

O O

Step 2: intermolecular nucleophilic ring-opening and further intramolecular nucleophilic cyclization Scheme be activated. activated. Scheme 1. 1. Stepwise reaction in the three-component domino reaction and sites need to be

ItIt isis speculated may facilitate facilitate this this tandem tandem speculated the the synergistic synergistic activation activation of of the the substrate substrate and and CO CO22 may reaction at atmospheric atmospheric pressure. pressure.Promisingly, Promisingly,the theionic ionic liquids (ILs) show potential reaction running running at liquids (ILs) show thethe potential of of multi-site activation in many organic syntheses by choice or functionalization of cations or multi-site activation in many organic syntheses by choice or functionalization of cations or anions anions Especially, the ILs-promoted carboxylative cyclization of propargyl alcohols [56–59].[56–59]. Especially, the ILs-promoted carboxylative cyclization of propargyl alcohols and CO2 and has CO has been reported [60]. Considering this carboxylative cyclization reaction is the crucial step in 2 been reported [60]. Considering this carboxylative cyclization reaction is the crucial step in this threethis three-component cascadeof reaction of propargyl amino and alcohols 2 , we envisioned component cascade reaction propargyl alcohols, alcohols, amino alcohols CO 2,and we CO envisioned that the that the ILs-catalyzed three-component is feasible. ILs-catalyzed three-component reactionreaction is feasible. Herein, reaction of of propargyl alcohols, CO CO22 and and Herein, aa task-specific task-specific ILs-catalyzed ILs-catalyzed three-component three-component reaction propargyl alcohols, 2-aminoethanols was reported. By subtly selecting the cation and anion of the ionic liquid, 2-aminoethanols was reported. By subtly selecting the cation and anion of the ionic liquid, 1,5,71,5,7-triazabicylo[4.4.0]dec-5-ene trifluoroethanol ([TBDH][TFE]) found themost most suitable suitable triazabicylo[4.4.0]dec-5-ene trifluoroethanol ([TBDH][TFE]) waswas found to to bebethe catalyst and excellent yield of 2-oxazolidinones and α-hydroxyl ketones could be obtained at catalyst and excellent yield of 2-oxazolidinones and α-hydroxyl ketones could be obtained at atmospheric atmospheric CO CO22 pressure. pressure. 2. Results and Discussion 2. Results and Discussion 2.1. Optimization of the Reaction Conditions 2.1. Optimization of the Reaction Conditions The initial attempt to perform the three-component domino reaction of 2-(benzylamino)ethanol The initial attempt to perform the three-component domino reaction of 2-(benzylamino)ethanol (1a), 2-methylbut-3-yn-2-ol (2a) and CO2 using ILs as catalyst was carried out under 1 atm CO2 (1a), 2-methylbut-3-yn-2-ol (2a) and CO2 using ILs as catalyst was carried out under 1 atm CO2 at 80 at 80 ◦ C for 12 h, as summarized in Table 1. Considering the anion may play an important °C for 12 h, as summarized in Table 1. Considering the anion may play an important role in activation role in activation of the substrate 2a, 1a and CO2 , the anions of ILs were firstly screened. Thus, of the substrate 2a, 1a and CO2, the anions of ILs were firstly screened. Thus, five 1,8five 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1,5,7-triazabicylo[4.4.0]dec-5-ene)-based ILs with diazabicyclo[5.4.0]undec-7-ene (DBU) (1,5,7-triazabicylo[4.4.0]dec-5-ene)-based ILs with different different anions were investigated for this purpose (entries 1–5). As a result, the IL with anion [TFE]− anions were investigated for this purpose (entries 1–5). As a result, the IL with anion [TFE]− presented presented the highest activity with 23% yield of the target product 3a (3-benzyl oxazoline-2-ketone) the highest activity with 23% yield of the target product 3a (3-benzyl oxazoline-2-ketone) and 27% and 27% yield of 4a (3-hydroxyl-3-methyl butanone) (entry 3,), which is attributed to the activation yield of 4a (3-hydroxyl-3-methyl butanone) (entry 3,), which is attributed to the activation capacity capacity of [TFE]− to CO2 [61] and to 1a as well, being consistent with the reaction mechanism as of [TFE]− to CO2 [61] and to 1a as well, being consistent with the reaction mechanism as depicted in depicted in Scheme 1. On the other hand, the cation of IL is supposed to activate the triple bond of Scheme 1. On the other hand, the cation of IL is supposed to activate the triple bond of 2a and also 2a and also carbonyl group of the intermediate i.e., α-alkylidene cyclic carbonate, thus facilitates the carbonyl group of the intermediate i.e., α-alkylidene cyclic carbonate, thus facilitates the

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carboxylative cyclization of 2a and the following intermolecular nucleophilic ring-opening and +, carboxylative cyclizationnucleophilic of 2a and thecyclization. following intermolecular nucleophilic ring-opening further further intramolecular Therefore, a variety of cations, includingand [DBUH] + , [TBDH]+ , + + + − intramolecular nucleophilic cyclization. Therefore, a variety of cations, including [DBUH] [TBDH] , [TMGH] and [P4444] , were further evaluated with [Im] as the anion (entries 1,6–8), and [TMGH] andfound [P4444to ]+ ,be were evaluated with [Im]−may as the anion (entries and [TBDH]+ [TBDH]++was the further most effective cation, which be related with its1,6–8), stronger interaction was to be the2a most cation, which be related with its stronger interaction withand the withfound the substrate andeffective the intermediate. Themay above findings showed that both the anions substrate 2a and the intermediate. The above findings showed that both the anions and cations can cations can affect the the catalytic ability of the ILs in this reaction. We speculated that the IL with the + and affect the the catalytic ability of the ILs− in this reaction. We speculated IL domino with the reaction. combination combination of [TBDH] [TFE] would be an efficient catalystthat forthe this As + and [TFE]− would be an efficient catalyst for this domino reaction. As expected, the yield of [TBDH] expected, the yield of the products was improved, and 33% yield of 3a and 39% of 4a were obtained of the [TBDH][TFE] products was improved, yield(entry of 3a and when was used asand the33% catalyst 9). 39% of 4a were obtained when [TBDH][TFE] was used as the catalyst (entry 9). Table 1. Screening ILs for the three-component domino reaction [a]. Table 1. Screening ILs for the three-component domino reaction [a] .

Entry 1 2 3 4 5 6 7 8 9

Entry IL (mol%) IL (mol%) 1 2 3 4 5 6 7 8 9

[DBUH][Im] [DBUH][Im] [DBUH][OAc] [DBUH][OAc] [DBUH][TFE] [DBUH][TFE] [DBUH][TFA] [DBUH][TFA] [DBUH][Cl] [DBUH][Cl] [TBDH][Im] [TBDH][Im] [TMGH][Im] [TMGH][Im] [P4444 ][Im] [P4444][Im] [TBDH][TFE] [TBDH][TFE]

[b] [b] Yield/% Yield/% 3a 3a 4a 4a 14 13 14 13 19 19 21 21 23 23 27 27 21 21 21 21 9 13 13 9 27 30 27 30 22 21 22 21 trace trace trace33 trace 39 33 39

[a]

Unless otherwise otherwise specified, specified, the the reaction reaction conditions conditions were: were: 1a1a(302.4 (302.4mg, mg, mmol), 2a (168.2 [a] Unless 2.02.0 mmol), 2a (168.2 mg, mg, 2.0 1 H-NMR with 1,1,2,2-tetrachloroethane 2.0 mmol), IL (5 mol%), CO2 (1 atm), 80 ◦ C, 12 [b] h. [b] Determined by 1 mmol), IL (5 mol%), CO 2 (1 atm), 80 °C, 12 h. Determined by H-NMR with 1,1,2,2-tetrachloroethane as the internal standard. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, [DBUH][Im] = DBU imidazolide, as the internal=standard. DBU[DBUH][TFE] = 1,8-diazabicyclo[5.4.0]undec-7-ene, [DBUH][Im] == DBU [DBUH][OAc] DBU acetate, = DBU trifluoroethanol, [DBUH][TFA] DBU imidazolide, trifluoracetic acid, [DBUH]Cl = DBU chloride, [TBDH][Im] = 1,5,7-Triazabicylo[4.4.0]dec-5-ene imidazolide, [TMGH][Im] = [DBUH][OAc] = DBU acetate, [DBUH][TFE] = DBU trifluoroethanol, [DBUH][TFA] = DBU 1,1,3,3-tetramethylguanidinium imidazolide, [P4444 ][Im] = hexyltributylphosphonium imidazolide, [TBDH][TFE] = trifluoracetic acid, [DBUH]Cl = DBU chloride, [TBDH][Im] = 1,5,7-Triazabicylo[4.4.0]dec-5-ene 1,5,7-Triazabicylo[4.4.0]dec-5-ene trifluoroethanol.

imidazolide, [TMGH][Im] = 1,1,3,3-tetramethylguanidinium imidazolide, [P 4444][Im] = hexyltributylphosphonium imidazolide, [TBDH][TFE] = 1,5,7-Triazabicylo[4.4.0]dec-5-ene Considering the IL amount may also affect the catalytic capability, the amount of the IL was trifluoroethanol.

increased to further improve the reaction (Table 2). Surprisingly, the reduction of yields was observed for most of the ionic liquids when the amount of the tested IL was increased from 5 mol% Considering the IL amount may also affect the catalytic capability, the amount of the IL was to 10 mol% (entries 1–6). It is inferred that the interaction between the cations of ILs and the increased to further improve the reaction (Table 2). Surprisingly, the reduction of yields was observed nucleophilic sites of the substrate became dominant with the increase of the amount of the IL, for most of the ionic liquids when the amount of the tested IL was increased from 5 mol% to 10 mol% which can deactivate these nucleophilic sites and thus impedes the domino reaction. Conversely, (entries 1–6). It is inferred that the interaction between the cations of ILs and the nucleophilic sites of increasing the amount of [TMGH][Im], [P4444 ][Im] and [TBDH][TFE] would promote the reaction the substrate became dominant with the increase of the amount of the IL, which can deactivate these (entries 7–9), wherein [TBDH][TFE] showed higher activity than other ionic liquids used in this nucleophilic sites and thus impedes the domino reaction. Conversely, increasing the amount of study. With [TBDH][TFE] as catalyst, the reaction time and reaction temperature were further studied. [TMGH][Im], [P4444][Im] and [TBDH][TFE] would promote the reaction (entries 7–9), wherein The results showed that extending the reaction time (entry 10) or raising the reaction temperature [TBDH][TFE] showed higher activity than other ionic liquids used in this study. With [TBDH][TFE] (entries 11,12) had no obvious impact on the reaction results. But if the loading of [TBDH][TFE] was as catalyst, the reaction time and reaction temperature were further studied. The results showed that increased to 15 mol%, the 3a yield of up to 94% was obtained (entry 13). Further improving the loading extending the reaction time (entry 10) or raising the reaction temperature (entries 11,12) had no of [TBDH][TFE] to 20 mol% reduced the yield greatly (entry 14), which may be attributed to the solvent obvious impact on the reaction results. But if the loading of [TBDH][TFE] was increased to 15 mol%, effect of the IL and also the deactivation of the nucleophilic sites by [TBDH]+ . No target product was the 3a yield of up to 94% was obtained (entry 13). Further improving the loading of [TBDH][TFE] to obtained without any catalyst or with only TBD or TFE as catalyst (entries 15–17), which indicates the 20 mol% reduced the yield greatly (entry 14), which may be attributed to the solvent effect of the IL importance of free anion and cation in activating substrate and CO2 . Therefore, 15 mol% [TBDH][TFE] and also the deactivation of the nucleophilic sites by [TBDH] +. No target product was obtained was used as catalyst and the reactions were performed at 80 ◦ C for 12 h in subsequent studies. without any catalyst or with only TBD or TFE as catalyst (entries 15–17), which indicates the importance of free anion and cation in activating substrate and CO2. Therefore, 15 mol% [TBDH][TFE] was used as catalyst and the reactions were performed at 80 °C for 12 h in subsequent studies.

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Table 2. Optimization of the reaction conditions.[a].

Yield/% [b] 3a conditions 4a [a] . Table 2. Optimization of the reaction 1 [DBUH][Im] (10) 13 11 [b] 2 [DBUH][OAc] (10) 7 Yield/% 6 Entry IL (mol%) 3 [DBUH][TFE] (10) 3 3a 5 4a 4 [DBUH][TFA] (10) 9 9 1 [DBUH][Im] (10) 13 11 5 [DBUH][OAc] [DBUH]Cl (10) 13 7 16 2 (10) 6 3 5 6 [DBUH][TFE] [TBDH][Im](10) (10) 5 3 9 4 9 7 [DBUH][TFA] [TMGH][Im](10) (10) 33 9 37 5 [DBUH]Cl (10) 13 16 8 [P4444][Im] (10) 25 26 6 [TBDH][Im] (10) 5 9 9 [TMGH][Im] [TBDH][TFE] (10) 59 33 55 7 (10) 37 10[c] [TBDH][TFE] 8 [P4444 ][Im] (10)(10) 57 25 58 26 9 55 11[d] [TBDH][TFE] [TBDH][TFE](10) (10) 47 59 47 58 10 [c] 12[e] [TBDH][TFE] [TBDH][TFE](10) (10) 56 57 53 [TBDH][TFE] (10) 47 47 11 [d] 13 [TBDH][TFE] (15) 94 97 [TBDH][TFE] (10) 56 53 12 [e] 14 [TBDH][TFE] [TBDH][TFE](15) (20) 44 94 46 13 97 15 [TBDH][TFE] TBD (15)(20) trace44 trace 14 46 15 TBD tracetrace trace 16 TFE(15) (15) trace 16 TFE — (15) tracetrace trace 17 trace 17 — trace trace [a] Reactions were carried out at 80 °C for 12 h with 1a (302.4 mg, 2.0 mmol), 2a (168.2 mg, 2.0 mmol) [a] Reactions were carried out at 80 ◦ C for 12 h with 1a (302.4 mg, 2.0 mmol), 2a (168.2 mg, 2.0 mmol) and CO 2 and CO2 (1 atm). [b] Determined by 1H-NMR with 1,1,2,2-tetrachloroethane as the internal standard. [c] (1 atm). [b][d]Determined by 1 H-NMR with 1,1,2,2-tetrachloroethane as the internal standard. [c] 18 h. [d] 60 ◦ C. [e] 100 °C. 18 h. 60 °C. [e] 100 ◦ C. Entry

IL (mol%)

2.2. Investigation of Substrate Applicability

2.2. Investigation of Substrate Applicability

Having selected suitable IL as catalyst, we proceeded to investigate the substrate applicability

Having as catalyst, we proceeded to investigate theglycols substrate as as listedselected in Tablesuitable 3. The IL propargyl alcohols, 2-aminoalcohols and even withapplicability different listedsubstituents in Table 3. were The propargyl alcohols, 2-aminoalcohols and even glycols with different substituents employed in this cascade reaction. A wide range of propargyl alcohols with methyl, wereethyl, employed in this A widesubstitute range ofatpropargyl alcohols with cyclohexyl, arylcascade and evenreaction. other complicated the propargylic position (2amethyl, –e), couldethyl, be transformed effectively to afford the corresponding and α-hydroxyl ketones in be cyclohexyl, aryl and even other complicated substitute2-oxazolidinones at the propargylic position (2a–e), could moderateeffectively to high yields (entriesthe 1–5). Notably, this protocol showed itsand potential application in transformed to afford corresponding 2-oxazolidinones α-hydroxyl ketones in pharmaceutical industry by realizing the transformation of ethisterone (2e) to αmoderate to high yields (entries 1–5). Notably, this protocol showed its potential application in hydroxyprogesterone (4e)realizing with 63%the of yield and the chiralofstructure retained 5). Subsequently, pharmaceutical industry by transformation ethisterone (2e)(entry to α-hydroxyprogesterone the suitability 2-aminoalcohols withstructure different substitutes was further examined (entries 6–suitability 11). Both (4e) with 63% of of yield and the chiral retained (entry 5). Subsequently, the of aryl-substituted and alkyl-substituted 2-aminoalcohols proceeded smoothly and generated the 2-aminoalcohols with different substitutes was further examined (entries 6–11). Both aryl-substituted corresponding products in excellent yields with the exception of aromatic 2-aminoalcohols bearing and alkyl-substituted 2-aminoalcohols proceeded smoothly and generated the corresponding products nitro group at para-position (entry 10). The results may be interpreted by the weakened in excellent yields with the exception of aromatic 2-aminoalcohols bearing nitro group at para-position nucleophilicity of amino caused by the strong electron-withdrawing nitro group at benzene ring (entry[62,63]. 10). The results may be interpreted by the weakened nucleophilicity of amino caused by the Besides 2-aminoalcohols, glycols (1h–j) were also converted to the corresponding cyclic strong electron-withdrawing benzene ring [62,63]. Besides 2-aminoalcohols, glycols (1h–j) carbonates in moderate tonitro goodgroup yields at (entries 12–14). were also converted to the corresponding cyclic carbonates in moderate to good yields (entries 12–14). Table 3. Scope of the substrates for the reaction under optimized conditions.[a].

Table 3. Scope of the substrates for the reaction under optimized conditions [a] .

Molecules 2018, Molecules 2018, 23,23, Molecules 2018, 23, xx x Entry Molecules 2018, 23, Molecules 2018, 23, x xx Molecules 2018, 23, Entry

[b] [b] Yield/% Yield/%

Substrate Substrate 11

22

3 3

4

4

11 1

1 1 11

2 22 2

2 22

33 3 3 33

1a1a 1a 1a1a

1a 1a

1a

2a2a 2a 2a2a2a

2a

1a1a 1a 1a1a1a

2b

1a1a 1a 1a1a1a

2c2c2c 2c2c2c

2b 2b 2b 2b 2b 2b

(94, 3a3a (94, 90c90 3a (94, 90 )c)c) 3a (94, 90cc cc) c (94, 3a3a3a (94, 909090 ))) (94,

3a (80)

(97, 4a4a (97, 93c93 4a (97, 93 )c)cc) 4a (97, 93 ) cc93 (97, 4a4a4a (97, 9393 )c)c) (97,

4b (79)

(80) 3a3a (80) 3a (80) (80) 3a3a3a (80) (80)

4b (79) 4b (79) 4b (79) 4b (79) 4b (79) 4b (79)

(73) 3a3a (73) 3a (73) (73) 3a3a3a (73) (73)

(76) (76) 4c4c4c (76) (76) 4c4c4c (76) (76)

of1313 5 5of5of13 of1313 5 5of5of13

111 1 11 1 22 12221 12 21221 12 121221 Molecules 2018, 23, 3033 222 2 232 32 3 233332 23 32332 23 232332 333 3 Entry 343 43 44 34443 34 43443 34 33 43443 444 4 55 454 4 5 45554 45 45 4554 45 5 4 4554 555 5 565 65 6 556 6665 56 65665 56 6 5 5665 666 6 6 67 6 76 77 67776 67 76776 67 766776 7 777 7 787 87 88 78887 78 87887 78 8 8 88 77 7 888 8 898 98 8999998 89 99 8998 89 898998 999 9 9 910 910 10 1010 9 9 9 1010 10 10 910 Molecules 2018, 23, x9 Molecules 2018, x910 Molecules 2018, 23,23, x10 10 Molecules 2018, 23, x9 Molecules 2018, 23, x910 Molecules 2018, 23, x910 10 Molecules 2018, 23, x Molecules 2018, 23, x10 Molecules 2018, 23, x10 10 10 1111 1110 10 10 11 11 1111 11 11 10 1010 1111 11 11 101010 12 12 12 11 1111 1010 10 12 11 12 1112 11 11 1212 11 1112 1112 111111 111111 111111 131313 1313 1313 131313 Molecules 2018, 23, Molecules 2018, 23, Molecules 2018, 23, x x2x2

141414 14

1a1a1a 2a2a2a 1a1a 1a 1a 2a2a 2a 2a 1a 1a 1a1a 1a 2a 2a2b 2a 2b 1a 1a 1a1a 1a 2b 1a 2b 2a2a 2a 2b 2b 2b 2b 1a1a 1a 1a 2a 2a 2a 2b2b 2b 2b 1a 1a1a 1a 1a 1a 2a 2a 2a 2b 2b 2b 1a1a 1a 1a 2b 2b 2b 2b 1a1a 1a 2c2c 2b 2b 2b 1a 1a 2c 2c Table 3. Cont. 1a 1a 1a 1a 1a 2c 2c 2c 2c 2b 2b 2b 1a1a 1a 1a 2c 2c2b 2c 2c 2b Substrate 2b 1a1a1a 2c2c2c 2b 2b 2b 11a 22c 1a1a 1a 2c2c 2c 1a 1a 1a1a1a 2d 2c 2c2d 2c 1a 1a 2d 2d 1a1a 1a 1a 2c 2c 2c 2d 2d 2d 2d 1a1a 1a 1a 2c 2c2d 2c 2d 2d 2d 1a 2c 1a1a1a 1a 1a 2d 2c 2c2d 2c2d 1a1a 1a 1a 2d 2d 2d 2d 1a1a 2e 2e2d 1a1a 1a 2d 2d 1a 1a 2e 2e 1a 1a 1a 1a1a1a 2e 2e 2e 2e 2d 2d 2d 1a 1a 1a 1a 2d 1a 2e 1a 1a1a 2e 2e 2e 2d 2d 2d 1a1a 1a1a 2e 2e 2e 1a 1a 2d 2d 2d 1a1a 1a 1a 2e2e 2e 2e 1b 1b 2a 2a 1a1a1a 2e2e 2e 1b 1b 2a 2a 1a 2e 1b 1b 1b 1b 2a 1a 2a 1a 2a 1a 2a 2e2e 2e 1b 1b 1b 2a 2a 2a 1a 2a 1a1b 1a 2e2e2e 1b 2a 2a2e 2a 1a 1a1b 1a1b 2e 2e 1b 1b 1b 1b 2a2a 2a 2a 1b1c1b 2a 2a 1b1c 1b 2a 2a2a 2a 1c 2a 1c 2a 1b 1b 1c1b 2a2a 1c 1c 2a 1c 2a 1c 2a 1b 1b 1c1b 2a2a 1c 2a 1c 2a 1c 2a 1c 2a 1c 2a 1b 1b 1b 2a2a2a 2a 1c 1c1c 2a2a 1c 2a 1c 2a 1d 2a 1c 1c1d 2a2a 1c 2a 1d 1d 2a 2a 1d 1d 1c1d 1d 1c 2a 2a2a 1c 2a 1d 1d 1d 1c 1c1d 2a2a 2a 1c 2a 1d 2a 1d 2a2a2a 1c1d 1c 1c1d 1d 1d 1d 1d 2a2a 2a 2a 1d 1d 1e 1e1d 2a2a 2a 1e 2a 1e 2a 1d 1d 1d 2a2a 2a 1e 1e 2a 1e 2a 1e 2a 2a 1e 1d 1d 1d 2a 2a 1e 1e 1e 1e 2a2a 2a 1d 1d 1d 1e 1e 1e 2a2a2a 1e1e 1e 1e 2a2a 2a 2a 1e1e 2a 1f 1f1e 2a2a 1f 2a 1f 2a 2a 1f 1e 2a 1e 2a2a 1f1e 2a 1f 2a 1f 2a 1f 2a 1e 1e 2a 1e 2a 1f1f 2a2a 1f 2a 1f 2a 1e 2a2a2a 1f 1f1e 1f1e 1f 1f 2a2a 1f 2a 1f 2a 1g 2a2a 1g1g 2a 1f1f 2a2a 1f 2a 1g 1g 2a 2a 1g1g 1g 1g 2a2a 2a 2a 2a2a 1f1f1f 2a 1g1g 1g 1g 2a2a 2a 2a 1f1f1f 2a2a2a 1g 1g1h 1g 2a2a 1h 2a 1h 1f 1f1g 2a2a 1f 2a 1g 1g 1g 2a2a 2a 1h 1h 2a 1h 2a 1h 1g 1g 1g 2a2a2a 1h 1h 1h 1g1g 1g 2a2a2a 1g 1g 1g 2a2a2a 1g1g 1g 2a2a2a 2a2a2a 2a 1i1i1i 2a2a 2a 1i 1i1i1i 2a2a2a 1i1i1i

c90 c93 (94, (97, 3a3a3a (94, 9090 )c)c) 4a4a4a (97, 9393 )c)c) (94, (97, c c c c c (94, (97, 3a3a (94, 9090 4a4a (97, 9393 3a (94, 90 4a (97, 93 3a (94, 90 ))) ) 4a (97, 93 )cc))c) c 3a (80) 3a (80) c c c c c 4b (79) 4b (79) (94, (97, (94, (97, 9393 3a3a3a (94, 909090 ) ) ) 4a4a4a (97, 93 )c)c) 3a (80) (80) c c 3a 4b (79) 4b (79) c 3a (80) 3a (80) 3a (80) (94, 9090 (97, 9393 3a3a (94, 90 ) )c) 4a4a (97, 93 )c)c) 3a (80) (94, 4a (97, 4b (79) 4b (79) 4b (79) 4b (79) c c 3a (80) 3a (80) 3a (80) 3a (80) 3a3a (94, 90 )c)c) 4a4a (97, 93 )c)c) (94, 9090 (97, 9393 4b (79) (94, 4a (97, 4b (79) 4b (79) 4b (79) 3a (80) 3a (80) c90 c93 3a (80) 4b (79) 4b (79) 4b (79) 3a (94, 4a (97, (94, 90 (97, 93 3a3a (94, 90 )c)c) 4a4a (97, 93 )c)c) (80) 3a3a (80) 3a (80) 3a (80) 4b (79) 4b (79) 4b (79) 4b (79) 3a (73) 3a (73) (80) (80) 3a (80) (79) 4c (76) 4c4b (76) 4b (79) 4b (79) 3a (73) (73) 3a 4c (76) 4c (76) (80) 3a (80) (80) 3a3a (73) 4b (79) (73) 4b (79) 3a (73) 4b (79) 3a (73) 4c4c (76) (76) 4c (76) 4c (76) (80) (80) (80) (73)Yield/% [b] 3a3a (73) 3a (73) 4b (79) 3a (73) 4b (79) (79) 4c (76) 4c4b (76) 4c (76) 4c (76) (73) (80) (73) (80) (73) 3a3a3a (80) 4b 4b (79) 4c (76) 4b (79) 4c (76) 4c (76) 3 4(79) (73) 3a3a (73) 3a (73) 3a (73) (76) 4c4c (76) 4c (76) 4c (76) 4d(99) (99) 4d (99) 3a (99) 3a (73) 3a3a (73) 3a (73) 4c (76) 4c (76) 4c (76) 4d (99) (99) 4d 3a (99) (99) 3a 4d (99) (99) 4d (99) 3a3a (99) (73) (99) 4d (99) 3a (73) 3a (99) (73) (99) OHO OHO 4c4d (76) 4c (76) 4c (76) O OHO HOH H(99) 4d (99) 4d (99) (99) 4d (99) 3a3a (99) 3a (99) (73) 3a (99) (73) (73) 4c (76) 4c4d (76) 4c (76) O O OOH OH O OH H HOH H 3a3a (73) HH H 4c (76) 4d (99) (99) (99) (99) 3a3a (99) O4d O4d (99) 3a (73) (73) 3a (73) H OOO HH H 4c (76) (76) 4c4c (76) HH OHOHO OH HH OH O 4d H H H(99) O 4d (99) HH HH 4d 4d (99) (99) (99) 3a3a (99) 3a (99) 3a (99) HHH H O OH OO O4e OO OHOH O 4e (63) (63) (61) 3a3a (61) H H H H(99) H(99) H HH 4d 4d 3a (99) 4d (99) 3a (99) 3a (99) H H H OOOH 4e (63) O O (63) 4e O O O O OH OH OH 3a (61) 3a (61) 4e 4e 4e (63) 4e H(63) H(63) HH H(63) 3a (61) 3a (61) 3a (61) (61) 4d 4d (99) 3a (99) 4d H 3a3a (99) HH(99) H(99) (99) O OO OHO O OO OH OH OH 4d 3a3a (99) 4e (63) 4e4d 4e (63) H(99) 4e (63) HH H HH(63) H (61) 3a (61) 3a (61) 3a (61) 4d (99) 4d 3a (99) H 3a3a (99) (99) H(99) H H(99) OOO O O OH OO O OHOH OH 4e (63) 4e (63) 4e (63) H (61) H HH H HH H 3a3a (61) 3a3a (61) 4d4d (99) 3a (99) (99) H(99) H(99) 3a (99) HOHO O O O O O O4d H O OHOHOH (63) 4e4e (63) 4e (63) 4e (61) 3a3a (61) 3a (61) 3a (61) H H(63) HH H HHH H H H H OO O OOO O 3b (89) 3b (89) O OH OHOH OH 4a (89) 4a (89) 4e (63) 4e (63) 4e (63) 3a (61) 3a(61) (61) 3a H HH H HHH 3b (89) H H(63) 3b (89) H O H 4a (89) O 4e O O4a (89) 3a (61) 3b (89) 3b (89) 4e (63) 3b (89) 4e (63) 4e (63) 3b (89) 4aH4a 4a (89) (61) 4a H(89) 3a3a3a (61) H(89) H H (61) H(89) H OO O O (89) 3b (89) 3b (89) 4e (63) 3b (89) 4e4e (63) (63) 4a (89) 4a (89) 4a (89) 4a (89) 3a (61) 3a3b (61) 3a (61) (89) 3b (89) (89) (89) 4a4e (89) 4e (63) 4a4a (89) (63) 4e (63) 3a (61) 3a3b (61) 3a3b (61) 3b (89) 3b (89) 3b (89) 3b (89) (89) 4a4a (89) 4a (89) 4a (89) 3b (89) 4a(82) (89) 3c (85) (82) 3c3b (85) 4a (89) 3b (89) 3b (89) 4a (89) 4a4a (89) 4a (89) 3c (85) (85) 4a (82) (82) 3c 4a 3b (89) 3b (89) 3c3b (85) 4a4a (82) 3c (85) (82) (89) 3c (85) 4a (82) (89) 3c (85) (82) 4a (89) (89) 3c (85) 4a (82) 3b (89) 3b (89) 3c3b (85) 4a4a (82) 3c (85) 4a (82) (89) 3c (85) 4a (82) (89) (89) (89) 3c (85) (82) 3c (85) 4a (82) 3c (85) 4a4a (82) 3b (89) 3b (89) 3b (89) 4a (89) 4a (89) 4a (89) 4a (82) 3c (85) (85) (82) 3c3c (85) 4a4a (82) 3c (85) 4a (82) 3c (85) 4a (82) (99) 4a (99) 3c (85) (82) (99) 3d (99) 3c3d (85) 4a4a (82) 3c (85) 4a (82) 4a (99) (99) 4a 3d (99) 3d (99) 3c (85) (82) 3c (85) 4a (82) 4a (99) (99) 3c (85) 4a (82) 4a (99) (99) 3d (99) 3d (99) 3d (99) 3d (99) (99) 3c (85) (82) 3c3d (85) (82) 4a4a (99) 4a (99) 3c (85) (82) 4a (99) (99) 3d (99) 3d (99) 3d (99) 4a (99) 3d (99) (99) (99) (99) 3c (85) (82) (99) 3c3d (85) (82) 3d (99) 3c3d (85) 4a4a4a (82) (99) (99) 4a4a (99) 4a (99) 4a (99) 3d (99) 3d (99) 3d (99) 3d (99) 4a (80) 4a (80) (99) (99) 4a (99) (99) 3e (82) 3e3d (82) 3d (99) 3d (99) 4a (80) (80) 4a 3e (82) 3e (82) (99) 4a (99) (99) 4a4a (80) 3d (99) (80) 3d (99) 4a (80) 3d (99) 4a (80) 3e (82) 3e (82) 3e (82) 3e (82) 4a (80) 3e (82) (99) (99) 4a (99) (80) 4a (80) 4a (80) 3d (99) 4a (80) 3d (99) 3d (99) 3e (82) 3e (82) 3e (82) 3e (82) (80) (80) (99) (80) (99) 4a4a4a (99) 3d (99) 3d (99) 3e (82) 3d (99) 3e (82) 3e (82) (80) 4a4a (80) 4a (80) 4a (80) (82) 3e3e (82) 3e (82) 3e (82) (80) (80) 4a (80) 4a (23) 4a (23) 3e (82) (82) 3e3e (82) (24) 3f3f(24) 4a (23) 4a (23) 4a (23) 3f (24) 4a (80) 4a (80) 3f (24) 4a (80) 3f3e (24) 3e (82) 3e (82) (82) 4a4a (23) (23) 4a (23) 4a (23) 3f3f (24) (24) 3f (24) 3f (24) 4a (80) 4a (80) 4a (80) 3e (82) 3e (82) 3e (82) 4a (23) 4a (23) 4a (23) 3g (93) (92) (23) 3g (93) 4a (92) 3g (93) 4a (92) 3f (24) 3f (24) 3f (24) 3f (24) (80) 4a (80) 4a (80) 4a (23) 3e (82) 3e (82) (23) 3e (82) (23) (93) (92) (93) 4a(92) (92) 3g (93) 4a 3f (24) 3f3g (24) 3f3g (24) (23) 4a4a (23) 4a (23) 4a (23) 3g (93) 4a (92) 3g (93) (92) 3f (24) 3g (93) 4a (92) 3f (24) 3f (24) 3f (24) 3g (93) 4a (92) 4a (23) 4a (23) 4a (23) (24) (24) 3f3f3f (24) 4a (23) 4a (23) 4a (23) (24) 3f3f3f (24) (24) 4a4a4a (23) (23) (23) 3f3f3f (24) (24) (24) (97) (97) 4a4a4a (97) 3h (95) 3h (95) 3h (95) 4a (23) (23) 4a4a(23) (24) (24) 3f3f3f (24) (97) 4a4a (97) 4a (97) 3h (95) 3h (95) 4a (97) 3h (95) (97) (97) 3h (95) 4a4a4a (97) 3h (95) 3h (95) 3h (95)

3i(58) (58) 3i3i(58) 3i (58) (58) (58) 3i3i3i (58) (58) (58) 3i3i3i (58)

of1313 5 5of5of13

5 of 12

of1313 6 6of6of13 of1313 6 6of6of13 of1313 6 6of6of13

(57) (57) 4a4a4a (57) 4a (57) (57) 4a4a (57) 4a (57) (57) (57) 4a4a4a (57)

1j

2a 1j1j1j 2a2a2a 4a (98) 3j (94) (98) (98) 3j(94) (94) 4a4a4a (98) 3j3j(94) 1j1j1j 2a 2a 2a [a] Reactions were performed using 1 (2.0 mmol), 2 (, 2.0 mmol), [TBDH][TFE] (71.8 mg, 154a mol%) with CO2 pressure 4a (98) 4a (98) (98) 3j (94) 3j (94) 3j (94) 1j 1j1j [b] Determined 1 mmol), [a] Reactions [a] [a][a] 2a2a were using 1by (2.0 mmol), 2(,2.0 (,2.0 2.0 mmol), [TBDH][TFE] (71.8 mg, 15mol%) mol%) with Reactions were performed using (2.0 2(,with mmol), [TBDH][TFE] (71.8 mg, with Reactions using 1 1(2.0 mmol), 22a mmol), [TBDH][TFE] (71.8 mg, 1515 mol%) with of 1 atm at 80 ◦ C were for 12performed h.performed H-NMR 1,1,2,2-tetrachloroethane as the internal standard. 4a (98) 4a (98) 3j (94) 3j (94) 4a (98) 3j (94) [c] [b] 11 1 1 [b][b][b] [a][a][a]

1414 14 141414

Isolated CO 2 pressure 1atm atm at8080 °C for h.mmol), Determined by H-NMR with 1,1,2,2-tetrachloroethane CO 2yield. pressure of1ofperformed 1atm °C for h.mmol), Determined by H-NMR with 1,1,2,2-tetrachloroethane asas Reactions performed using 112 mmol), (,2.0 2.0 mmol), [TBDH][TFE] (71.8 mg, mol%) with were performed using (2.0 mmol), [TBDH][TFE] (71.8 mg, mol%) with CO 2Reactions ofwere atat80 °C for 12 h.(2.0 Determined by H-NMR with 1,1,2,2-tetrachloroethane as 2 pressure Reactions were using 1 112 (2.0 2 2(,2(,2.0 mmol), [TBDH][TFE] (71.8 mg, 151515 mol%) with [c] Isolated yield. [b] 1H-NMR [b]Determined 1H-NMR [c] [c] [b] 1H-NMR [a] [a] [a]CO the the internal standard. Isolated yield. CO 2internal pressure 1atm atm at °C for h. Determined by with 1,1,2,2-tetrachloroethane 2pressure pressure of1ofperformed 1atm 8080 °C for h. Determined by with 1,1,2,2-tetrachloroethane asas the internal standard. Isolated yield. CO 2Reactions ofstandard. at[c]at 80 °C for h. by with 1,1,2,2-tetrachloroethane as Reactions were performed using 112 (2.0 mmol), (,2.0 2.0 mmol), [TBDH][TFE] (71.8 mg, mol%) with were performed using 1(2.0 (2.0 mmol), mmol), [TBDH][TFE] (71.8 mg, mol%) with Reactions were using 11212 mmol), 2 2(,2(,2.0 mmol), [TBDH][TFE] (71.8 mg, 151515 mol%) with

[c] [c][c]Isolated [b] 1H-NMR 1 1H-NMR the Isolated yield. the standard. Isolated yield. the standard. yield. CO 2internal pressure 1atm atm at80 80 °C for h.[b]Determined Determined by with 1,1,2,2-tetrachloroethane CO 2internal pressure of1of1atm °C for 1212 Determined by with 1,1,2,2-tetrachloroethane CO 2internal pressure ofstandard. atat 80 °C for 12 h.h.[b] by H-NMR with 1,1,2,2-tetrachloroethane asasas [c] [c] [c] 2.3. Recycle Tests 2.3. Recycle Tests 2.3. Recycle Tests the internal standard.Isolated Isolated yield. the internal standard. Isolated yield. the internal standard. yield.

2.3. Recycle Tests 2.3. Recycle Tests 2.3. Recycle Tests As ILs are non-volatile and thermal stable, they can easily recovered by evaporating the low As ILs are non-volatile and thermal stable, they can easily recovered evaporating the low As ILs are non-volatile and thermal stable, they can bebebe easily recovered byby evaporating the low 2.3. Recycle Tests 2.3. Recycle Tests 2.3. Recycle Tests As ILs are non-volatile and thermal stable, they can be easily recovered by evaporating the low As ILs are non-volatile and thermal stable, they can be easily recovered by evaporating the low boiling point components. So, we subsequently explored the recycle performance of[TBDH][TFE] [TBDH][TFE] for As ILs are non-volatile and thermal stable, they can be easily recovered by evaporating the low boiling point components. So, we subsequently explored the recycle performance of for boiling point components. So, we subsequently explored the recycle performance of [TBDH][TFE] for As ILs are non-volatile and thermal stable, they can be easily recovered by evaporating the low As ILs are non-volatile and thermal stable, they can be easily recovered by evaporating the low boiling point components. So, we subsequently explored the recycle performance of [TBDH][TFE] for boiling point components. So, we subsequently explored the recycle performance of [TBDH][TFE] for this tandem reaction using 1a and as model substrates under the optimum conditions. After boiling point components. So, we subsequently explored the recycle performance of [TBDH][TFE] for As ILs are non-volatile and thermal they can be easily recovered by evaporating the low this tandem reaction using 1a and as model substrates under the optimum conditions. After this tandem reaction using 1a and 2a2a2a asstable, model substrates under the optimum conditions. After

2a

1i

4a (57)

3i (58)

14 1j

Molecules 2018, 23, 3033

2a

6 of 12

4a (98)

3j (94)

Reactions were performed using 1 (2.0 mmol), 2 (, 2.0 mmol), [TBDH][TFE] (71.8 mg, 15 mol%) with CO2 pressure of 1 atm at 80 °C for 12 h. [b] Determined by 1H-NMR with 1,1,2,2-tetrachloroethane as the internal standard. [c] Isolated yield. [a]

2.3. Recycle Tests

Recycle Tests and thermal stable, they can be easily recovered by evaporating the low As ILs are 2.3. non-volatile As ILs are non-volatile and thermal stable, they can bethe easily recovered by evaporating the boiling point components. So, we subsequently explored recycle performance oflow [TBDH][TFE] for boiling point components. So, we subsequently explored the recycle performance of [TBDH][TFE] for this tandem reaction usingreaction 1a and 2a 1a asand model under conditions. this tandem using 2a as substrates model substrates underthe theoptimum optimum conditions. After After reaction, reaction,and the gas was released and the reaction was subjected to vacuum distillation forfor at at least 1 h at the gas was released the reaction system wassystem subjected to vacuum distillation least 1 h at 180 °C. After removing the reactant and product, the catalyst was directly used in the next 180 ◦ C. After removing the reactant and product, the catalyst was directly used in the next round of round of the reaction. As depicted in Figure 1, the IL can be reused without considerable activity loss the reaction. Asfor depicted intimes. Figure 1, theproduct IL can bestill reused without considerable activity at least four The target could be obtained at a 75% yield after the catalyst was loss for at least for 5 times, suggesting that the system has a good recyclability (as shown in Figure 1). four times. Thereused target product could still be obtained at a 75% yield after the catalyst was reused for 5 times, suggesting that the system has a good recyclability (as shown in Figure 1).

Yield (%)

3a

4a

100 80 60 40

4a

20

3a

0 1

2

3

4

5

Recycling number Figure. 1 Reusability of the [TBDH][TFE] system. Reaction conditions: 1a (302.4 mg,1a 2.0 (302.4 mmol), 2a Figure 1. Reusability of the [TBDH][TFE] system. Reaction conditions: mg, 2.0 mmol), (168.2 mg, 2.0 mmol), [TBDH][TFE] (71.8 mg, 15 mol%), CO2 (1 atm), 80 °C, 12 h. ◦ 2a (168.2 mg, 2.0 mmol), [TBDH][TFE] (71.8 mg, 15 mol%), CO2 (1 atm), 80 C, 12 h.

2.4. Mechanism Study

2.4. Mechanism Study

According to our early reports [54,55], this cascade reaction is composed of carboxylative cyclization and the following intermolecular nucleophilic ring-opening and further intramolecular

According to our early reports [54,55], this cascade reaction is composed of carboxylative cyclization and the following intermolecular nucleophilic ring-opening and further intramolecular nucleophilic cyclization. To gain deeper insight on the role of [TBDH][TFE] in the catalysis, the stepwise reactions were conducted (Table 4). To begin with, we performed the carboxylative cyclization of 2-methylbut-3-yn-2-ol (2a) with CO2 using 10 mol% of IL as catalyst. A variety of DBU-based ILs such as [DBUH][Im]), [DBUH][OAc], [DBUH][Cl], and Im-based ILs including [TBDH][Im], [TMGH][Im] showed high efficiency to produce 4,4-dimethyl-5-methylene-1,3-dioxolan-2-one (m) with excellent yield under mild conditions (entries 1–2,5–7). In contrast, [TBDH][TFE] and [DBUH][TFE] showed lower activity in the carboxylative cyclization reaction, probably due to the weaker hydrogen bond receptors of anions (entries 3,4,9, vs. 1–2,5–7) [64–66]. The same reason may be used to explain the low activity of [DBUH][TFA]. For [P4444 ][Im] (tetra butylphosphonium imidazolide), the large steric hindrance may impede the interaction of cation and carbon-carbon triple bond and thus the substrate can’t be activated efficiently (entry 8). The activity of different ILs on the subsequent reaction of vinyl cyclic carbonate (m) and aminoethanol (1a) was further examined under the otherwise identical conditions (Table 3). Noticeably, [DBUH][Im], [DBUH][OAc] and [TBDH][TFE] exhibited similar catalytic behavior to afford quantitative yield of 3a and 4a (entries 1,2,9, Table 3), while other ILs showed moderate activities (entries 3–8, Table 3). The interesting results can be obtained by comparing the results of stepwise reaction with three-component cascade reaction. Most ionic liquids, which can promote the stepwise reaction, display reduced performance in the three-component reaction (Tables 2 and 4). Depressingly, the reason for the decreased catalytic activity of ILs in the three-component reaction is not clear at this stage. Fortunately, the catalytic activity of [TBDH][TFE] is retained in the three-component reaction and its catalytic performance can be improved by increasing the loading amount from 10 mol% to 15 mol% (Table 2). It is inferred that α-alkylidene cyclic carbonate is the key intermediate in this multistep cascade reaction [53–55]. Although [TBDH][TFE] was not so efficient in the carboxylative cyclization, we speculated that the added ethanolamine can act as a base to facilitate the activation of hydroxyl in propargyl alcohol, thus efficiently promoting carboxylative cyclization of 2-methylbut-3-yn-2-ol

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nucleophilic cyclization. To gain deeper insight on the role of [TBDH][TFE] in the catalysis, the stepwise reactions were conducted (Table 4). To begin with, we performed the carboxylative cyclization of 2-methylbut-3-yn-2-ol (2a) with CO2 using 10 mol% of IL as catalyst. A variety of DBUMolecules 2018, 23, 3033 7 of 12 based ILs such as [DBUH][Im]), [DBUH][OAc], [DBUH][Cl], and Im-based ILs including [TBDH][Im], [TMGH][Im] showed high efficiency to produce 4,4-dimethyl-5-methylene-1,3dioxolan-2-one (m) with excellent yield under mild conditions (entries 1–2,5–7). In contrast, (2a) with CO2 . To verify our conjecture, 1 H NMR (400 MHz, DMSO-d6) measurement was performed [TBDH][TFE] and [DBUH][TFE] showed lower activity in the carboxylative cyclization reaction, to characterize thedue interaction between propargyl alcohol and(entries 2-aminoalcohol. results probably to the weaker hydrogen bond receptors of anions 3,4,9, vs. 1–2,5The –7) [64 –66]. showed that the peak shape for hydroxylic in low 2-methylbut-3-yn-2-ol (2a) after addition of The same reason may be used hydrogen to explain the activity of [DBUH][TFA]. Foraltered [P4444][Im] (tetra butylphosphonium imidazolide), steric hindrance may impede interaction of cation and 2-(benzylamino)ethanol (1a), proving the thelarge formation of hydrogen bondthebetween propargyl alcohol and carbon-carbon triple bond and thus the substrate can’t be activated efficiently (entry 8).

2-aminoalcohol (see Figure S1 in Supplementary Materials).

Table 4. Catalytic effect of ionic liquids to stepwise reactions in the domino reaction. [a].

Table 4. Catalytic effect of ionic liquids to stepwise reactions in the domino reaction [a] . O

O ionic liquid OH + CO2

ionic liquid

O

O

(1 atm)

Ph m

2a

1 2 3 4 5 6 7 8 9

Entry 1 2 3 4 5 6 7 8 9

H N 1a

O OH

+

N

Ph OH

3a

4a

Step 2

Step 1

Entry

O

Yield/% [b]

IL

IL

[DBUH][Im] [DBUH][Im] [DBUH][OAc] [DBUH][OAc] [DBUH][TFE] [DBUH][TFE] [DBUH][TFA] [DBUH][TFA] [DBUH]Cl [DBUH]Cl [TBDH][Im] [TBDH][Im] [TMGH][Im] [TMGH][Im] [P4444][Im] [P 4444 ][Im] [TBDH][TFE]

[TBDH][TFE]

m

3a

87 88 46 54 75 75 76 34 43

97 90 63 55 50 57 49 44 99

m 87 88 46 54 75 75 76 34 43

Yield/% [b] 3a

4a

97 90 63 55 50 57 49 44 99

99 93 62 54 50 54 46 43 99

4a

99 93 62 54 50 54 46 43 99

Reaction conditions: 1a (302.4 mg, 2.0 mmol), 2a (168.2 mg, 2.0 mmol), IL (47.8 mg, 10%), CO2 (1 atm), 80 °C, 12 h. [b] Determined by 1H-NMR with 1,1,2,2-tetrachloroethane as the internal standard. [a]

Reaction conditions: 1a (302.4 mg, 2.0 mmol), 2a (168.2 mg, 2.0 mmol), IL (47.8 mg, 10%), CO2 (1 atm), 80 ◦ C, 12 h. Determined by 1 H-NMR with 1,1,2,2-tetrachloroethane as the internal standard. The activity of different ILs on the subsequent reaction of vinyl cyclic carbonate (m) and aminoethanol (1a) was further examined under the otherwise identical conditions (Table 3). Noticeably, [DBUH][OAc] and [TBDH][TFE] exhibited similar catalytic behavior mechanism to On the basis of[DBUH][Im], the experimental studies and previous reports [54], the possible afford quantitative yield of 3a and 4a (entries 1,2,9, Table 3), while other ILs showed moderate for the [TBDH][TFE]-catalyzed three-component reaction was proposed as depicted in Scheme 2. 2018, 8 of 13 activities Molecules (entries 3–23, 8,xTable 3). This cascade reaction includes the initial carboxylative cyclization of 2-methylbut-3-yn-2-ol (2a) with The interesting results can be obtained by comparing the results of stepwise reaction with three(benzylamino)ethanol (1a), proving the formation of hydrogen bond between propargyl alcohol and CO2 and the subsequent nucleophilic addition of α-alkylidene cyclic carbonate with 2-aminoalcohol. component cascade reaction. Most ionic liquids, which can promote the stepwise reaction, display 2-aminoalcohol (see Figure S1 in Supplementary Materials). On the basis thethree-component experimental studiesreaction and previous reports [54], the possible mechanism fortheCreason In step I, propargyl alcohol simultaneously activated by2 the coordination of the ≡C bond with reduced performance inisof the (Table and Table 4). Depressingly, the [TBDH][TFE]-catalyzed three-component was proposed as depictedisinnot Scheme 2. This for the+ decreased catalyticbonding activity ofwith ILs in2-aminoethanol thereaction three-component reaction clear at this stage. cation [TBDH] and hydrogen to form the intermediate A, while CO2 cascade reaction includes the initial carboxylative cyclization of 2-methylbut-3-yn-2-ol (2a) with CO2 Fortunately, the catalytic activity of [TBDH][TFE] is retained − in the three-component reaction and its and the subsequent nucleophilic addition of α-alkylidene cyclic carbonate with 2-aminoalcohol. In is activated through the formation of the anion [TFECOO] . Then the α-alkylidene cyclic carbonate catalytic performance be improved by increasing loading amount from 10with mol% to 15 mol% step I, propargylcan alcohol is simultaneously activated bythe the coordination of the C≡C bond cation intermediate is 2). generated bythat theα-alkylidene nucleophilic of O atom in the A, intermediate A to CO2 and + and hydrogen (Table It is inferred cyclicattack carbonate is the intermediate in CO this [TBDH] bonding with 2-aminoethanol to form thekey intermediate while 2 ismultistep −. Then the α-alkylidene cyclic carbonate activated[53–55]. through the formation of the anion cascade reaction Although [TBDH][TFE] was so efficient inN theatom carboxylative cyclization, subsequent intramolecular cyclization. In step II,[TFECOO] the not nucleophilic of 2-aminoethanol attacks intermediate is generated by the nucleophilic attack of O atom in the intermediate A to CO2 and we speculated that the added ethanolamine can act as a base to facilitate the activation of hydroxyl α-alkylidene cyclicsubsequent carbonate to form the corresponding β-oxopropylcarbamate species C [54]. Finally, intramolecular cyclization. In step II, the nucleophilic N atom of 2-aminoethanol attacks in propargyl alcohol,cyclic thuscarbonate efficiently promoting carboxylative cyclization of 2-methylbut-3-yn-2-ol to α-hydroxyl form the corresponding β-oxopropylcarbamate species C [54]. 2-oxazolidinones α-alkylidene and equal amount of ketones are formed through the intramolecular 1H NMR (400 MHz, DMSO-d6) measurement was performed (2a) with CO 2. To2-oxazolidinones verify our conjecture, Finally, and equal amount of α-hydroxyl ketones are formed through the + + cyclizationtoofcharacterize intermediate C facilitated bypropargyl [TBDH] . by [TBDH] intramolecular cyclization of intermediate C facilitated . the interaction between alcohol and 2-aminoalcohol. The results showed that the peak shape for hydroxylic hydrogen in 2-methylbut-3-yn-2-ol (2a) altered after addition of 2[a]

[b]

Scheme 2. Plausible mechanism. Scheme 2. Plausible mechanism.

3. Materials and Methods 3.1. Materials and General Analytic Methods Unless otherwise noted, carbon dioxide (99.999%), commercially available DBU (99%), TBD (98%), TMG (99%), Imidazole (99.5%), TFE (99.5%) and TFA (99.5%) were obtained from Shanghai Aladdin Bio-Chem Technology Co., LTD. (Shanghai, China). All starting materials including propargyl alcohols, monoethanolamine and aromatic aldehydes, were obtained from Aladdin, Alfa

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3. Materials and Methods 3.1. Materials and General Analytic Methods Unless otherwise noted, carbon dioxide (99.999%), commercially available DBU (99%), TBD (98%), TMG (99%), Imidazole (99.5%), TFE (99.5%) and TFA (99.5%) were obtained from Shanghai Aladdin Bio-Chem Technology Co., LTD. (Shanghai, China). All starting materials including propargyl alcohols, monoethanolamine and aromatic aldehydes, were obtained from Aladdin, Alfa Aesar (Haverhill, MA, USA), and Heowns (Tianjin, China) and used as received. All operations were carried out by using standard high vacuum and Schlenk technique unless otherwise noted. 1 H NMR spectra were recorded on Bruker AVANCE III HD 400 spectrometer (Bruker BioSpin, Rheinstetten, Germany) using CDCl3 (99.8%, Wilmad, Beijing, China) or DMSO-d6 (99.9%, Wilmad, Beijing, China) as solvent referenced to Molecules x 9 of 13 CDCl32018, (7.2623,ppm) or DMSO-d6 (2.50 ppm). 13 C NMR was recorded at 100.6 MHz in CDCl3 (77.00 ppm). Multiples were assigned as singlet, doublet, triplet, doublet of doublet, multiplet and broad singlet. Shimadzu, Japan) with a RTX-5MS capillary column (Restek, Shimadzu, Japan)with at an Mass spectra wereequipped recorded on a Shimadzu GCMS-QP2010 (Restek, Shimadzu, Japan) equipped ionization voltage of 70 eV. The data are given asJapan) mass at units per charge (m/z).of 70 eV. The data are a RTX-5MS capillary column (Restek, Shimadzu, an ionization voltage given as mass units per charge (m/z). 3.2. General Procedure for the Synthesis of 2-Aminoethanol Derivatives [33] 3.2. General Procedure for the Synthesis of 2-Aminoethanol Derivatives [33] A mixture of an aromatic aldehyde (10 mmol), 2-aminoethanol (0.61 g, 10 mmol) and Na2SO4 aldehyde mmol), 2-aminoethanol (0.61 g, 10 flask mmol) and Na2 SO (1.42 g,A10mixture mmol) of in an CHaromatic 3OH (20.0 mL) was(10 added into a 100 mL round bottom and stirred for 4 2 (1.42 g, 10 mmol) in CH OH (20.0 mL) was added into a 100 mL round bottom flask and stirred for 2 h 3 h at room temperature. Then, the solution was obtained after removing the drying agent. The solution at treated room temperature. Then, the was obtained after The solution was with the addition of solution NaBH4 (0.19 g, 5 mmol) in removing ice water the anddrying stirredagent. for 1 h. The mixture was treated with the addition of NaBH (0.19 g, 5 mmol) in ice water and stirred for 1 h. The mixture 4 was concentrated under vacuum, and the residue was extracted with CH2Cl2 (3 × 20 mL), washed waswater concentrated under and the was extracted with CH2 Clconcentrated washedvacuum with 2 (3 × 20 mL), under with (20.0 mL), andvacuum, dried with Na2residue SO4. The CH 2Cl2 solution was water mL), andpurified dried with The CH2 Cl2 solution under vacuum and 2 SO4 . chromatography and the (20.0 residue was by Na column on was silicaconcentrated gel using petroleum ether/ethyl the residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate acetate (v/v, 10:1–1:2) as eluent to give the desired products. (v/v, 10:1–1:2) as eluent to give the desired products.

3.3.3.3. General Procedure General Procedurefor forthe theSynthesis Synthesis of of ILs ILs [67]. [67]

All ionic liquids (ILs) were synthesized based on the procedure’s reported [59]. Typically, for All ionic (ILs) were synthesized based on the procedure’s reported [59]. Typically, for thethe the synthesis ofliquids [TBDH][TFE], TBD was added to the methanol solution of CF 3CH 2OH by using synthesis of [TBDH][TFE], TBD was added to the methanol solution of CF CH OH by using the h. 2 anion-exchange resin method. Then the mixture was stirred at room 3temperature for 24 anion-exchange resin method. Then the mixture was stirred at room temperature for 24 h. Subsequently, Subsequently, methanol was distilled off at 70 °C under vacuum for 24 h. The as-synthesized ILs were methanol was off at 70 ◦ C under for are 24 h.listed The as-synthesized ILs were characterized characterized bydistilled NMR spectroscopy. The vacuum NMR data in Supplementary Material. by NMR spectroscopy. The NMR data are listed in Supplementary Material. 3.4. General Procedure for the Synthesis of 2-Oxazolidinones and α-Hydroxyl Ketones. 3.4. General Procedure for the Synthesis of 2-Oxazolidinones and α-Hydroxyl Ketones [TBDH][TFE] mol%), propargylic alcohol 1a1a (2.0 mmol) and 2-aminoethanol (2.0 [TBDH][TFE](69.9 (69.9mg, mg,1515 mol%), propargylic alcohol (2.0 mmol) and 2-aminoethanol mmol) were added successively to a 10 mL Schlenk tube equipped with a magnetic stir bar. Then the (2.0 mmol) were added successively to a 10 mL Schlenk tube equipped with a magnetic stir bar. flask was andcapped attached to attached a CO2 balloon with purity of 99.95%. Subsequently, the reaction Then thecapped flask was and to a CO 2 balloon with purity of 99.95%. Subsequently, ◦ mixture was stirred at 80 °C for 12 h. When the reaction the vessel cooled with an the reaction mixture was stirred at 80 C for 12 h. When thecompleted, reaction completed, thewas vessel was cooled ice-bath, remove balloon. The residue was flushed withwith 2 ×23×mL CH 2ClCl 2 and purified by with anand ice-bath, and the remove the balloon. The residue was flushed 3 mL CH 2 2 and purified column chromatography on silica gel (n-butylamine saturation) using petroleum ether/ethyl acetate by column chromatography on silica gel (n-butylamine saturation) using petroleum ether/ethyl acetate (v/v, 50:1–1:1) (v/v, 50:1–1:1)asaseluent eluenttotogive givethe thedesired desired products. products. 4. Conclusion In summary, we have developed a new strategy to promote the three-component cascade reaction of propargyl alcohols, atmospheric CO2 and 2-aminoethanols efficiently under mild conditions by utilizing ILs as both catalyst and solvent, which successfully addresses the thermodynamic issue in the synthesis of 2-oxazolidinones starting from 2-aminoethanols with CO2 and avoids the generation of wasteful by-products. The protic IL [TBDH][TFE] showed the best performance amongst the tested ILs due to its ability to synergistically activate the substrate by its

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4. Conclusions In summary, we have developed a new strategy to promote the three-component cascade reaction of propargyl alcohols, atmospheric CO2 and 2-aminoethanols efficiently under mild conditions by utilizing ILs as both catalyst and solvent, which successfully addresses the thermodynamic issue in the synthesis of 2-oxazolidinones starting from 2-aminoethanols with CO2 and avoids the generation of wasteful by-products. The protic IL [TBDH][TFE] showed the best performance amongst the tested ILs due to its ability to synergistically activate the substrate by its cation and anion. Besides, it can be easily recovered and reused at least for 5 times without obvious loss of its activity. A wide range of propargyl alcohols and 2-aminoethanols, were successfully transformed to 2-oxazolidinones and α-hydroxyl ketones with moderate to excellent yield after 12 h at 80 ◦ C. We believe that employing easily recyclable ILs as catalyst and CO2 as starting material renders the synthesis of 2-oxazolidinones in sustainable mode. Supplementary Materials: The following are available online, Figure S1: 1 H NMR for propargyl alcohol and mixtures of propargyl alcohol and 2-aminoalcohol. Author Contributions: Conceptualization, L.-N.H. and X.L.; methodology, X.L. and Y.S.; software, S.X.; validation, X.L.; formal analysis, X.L.; investigation, X.L. and Y.S.; resources, L.-N.H.; data curation, X.L.; writing—original draft preparation, H.L. and S.X.; writing—review and editing, S.X. and H.L.; visualization, H.L. and S.X.; supervision, L.-N.H.; project administration, L.-N.H. and H.L.; funding acquisition, L.-N.H. Funding: This research was funded by National Key Research and Development Program (2016YFA0602900), the National Natural Science Foundation of China (21672119), the Natural Science Foundation of Tianjin Municipality (16JCZDJC39900). Acknowledgments: We thank the Ministry of Science and Technology of China (National Key Research and Development Program), the National Natural Science Foundation of China, the Natural Science Foundation of Tianjin Municipality for financial support. Conflicts of Interest: All authors declare no conflict of interest.

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