2-Methyltetrahydrofuran as a Solvent of Choice for Spontaneous

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Article Cite This: ACS Omega 2019, 4, 1831−1837

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2‑Methyltetrahydrofuran as a Solvent of Choice for Spontaneous Metathesis/Isomerization Sequence Adam A. Rajkiewicz,† Krzysztof Skowerski,‡ Bartosz Trzaskowski,$ Anna Kajetanowicz,*,† and Karol Grela*,† Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Ż wirki i Wigury Street 101, 02-089 Warszawa, Poland ‡ Apeiron Synthesis SA, Duńska 9, 54-427 Wrocław, Poland $ Centre of New Technologies, University of Warsaw, 02-097 Warszawa, Poland †

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S Supporting Information *

ABSTRACT: A new protocol for ring-closing metathesis/ isomerization sequence was developed. The reactions of selected dienes were performed in overheated 2-methyltetrahydrofuran at 120 °C and provided a wide range of cyclic vinyl ethers and amides with good yields and selectivities. Computational analysis suggests that the relative yield of products depends on a thermodynamically driven process on the basis of relative stabilities of isomers.

1. INTRODUCTION For many years, the olefin metathesis (OM) reaction has been appearing as an elegant and convenient methodology for carbon−carbon double bond formation commonly used in chemical laboratories all over the world1,2 and more and more frequently in industry.3 With the introduction of well-defined complexes, especially the second generation ones (Figure 1),

this process, the ruthenium catalyst utilized in the metathetical step upon treatment with so-called trigger is transformed into a complex catalyzing a subsequent non-metathetical reaction. One example of such process is the metathesis/isomerization sequence. Double bond isomerization, for many years treated as an undesired side reaction, has traditionally been attributed to the formation of ruthenium hydrides,22 although recent studies indicate that also other ruthenium species such as nanoparticles23 or dimers24 may also be responsible for this byprocess. Because the ruthenium species responsible for the double bond isomerization differ in structure and origin,25 it was of key importance to find the conditions under which C− C bond migration will be induced at a certain moment in the sequence after full completion of the metathesis reaction and will not be competing with the latter process. Pioneering research on this methodology was performed by Snapper et al.26 Upon treatment with molecular hydrogen, cyclic allyl ethers obtained in ring-closing metathesis (RCM) were transformed into their corresponding vinyl isomers. To avoid a competing hydrogenation reaction, hydrogen was utilized as a mixture with nitrogen (95:5 N2/H2). At the same time, Schmidt and co-workers conducted research on the application of different additives converting the metathesis catalyst into the corresponding ruthenium hydrides. Depending on the reaction, they utilized NaOH/i-PrOH,27−29 NaBH 4 or NaH,29−31 ethyl vinyl ether,32 and triethylsilane/toluene33 systems at elevated temperatures. The used methodology enabled preparation of cyclic vinyl ethers, in which direct synthesis in metathesis reactions is problematic because of the readiness of the alkylidene species formed in the catalytic cycle

Figure 1. Selected commercially available second-generation catalysts.

its popularity has further increased. This transformation is easy to maintain, the majority of metathesis reactions are run under mild conditions, often at room temperature, and the catalysts used exhibit high tolerance to a wide range of functional groups. Both these factors enable the use of OM in the final stages in numerous total syntheses.4−7 Moreover, considering the high atom economy, as usually the only by-product is ethylene or other short alkenes, and the increasing tendency to utilize green solvents (e.g., dimethyl carbonate,8−10 cyclopentyl methyl ether,11 ethyl acetate,11,12 2-methyltatrahydrofuran,13,14 or water15,16), which replace the traditionally applied toluene or chlorinated solvents (some of which are or will soon be abolished),17 OM is recognized as a green technology, which suits perfectly the principles of circular economy.18 In addition, OM is often one of the key steps in tandem catalytic reactions,19−21 including assisted tandem catalysis. In © 2019 American Chemical Society

Received: October 31, 2018 Accepted: January 8, 2019 Published: January 23, 2019 1831

DOI: 10.1021/acsomega.8b03027 ACS Omega 2019, 4, 1831−1837

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In the first attempt, a number of substrates were reacted with the nitro analogue of Hoveyda−Grubbs second-generation catalyst (Gre II, loading 0.25−2.5 mol %) under the conditions previously reported in the literature,11 namely, 2methyltetrahydrofuran, which is a green solvent utilized in a number of organic reactions, including the pharmaceutical industry,46 at 80 °C for 4 h (Table 1).

for decomposition to the long-lived hydride complexes.34,35 The metathesis/isomerization sequence was exploited, for example, in the synthesis of centrolobine derivatives.36,37 Reactions leading to cyclic vinyl ethers,38,39 amines,39,40 and lactams,39,41,42 whereby double bond migration was induced by simple heating of the reaction mixture without any chemical triggers, are also possible. However, in most cases, utilization of specially prepared substrates was crucial to achieve satisfactory yields.38,39 When allylic alcohol is used as one of the substrates in sequence metathesis/isomerization, the resulted enol is rapidly tautomerized to its saturated carbonyl compound.43−45 In these cases, the isomerization step was induced thermally. Herein, we examine the influence of different solvents, traditional and “green”, and the reaction conditions on the yield and selectivity of metathesis/isomerization sequences using both experimental and computational methods.

Table 1. Results of RCM/Isomerization in 2Methyltetrahydrofuran at 80 °Ca

2. RESULTS AND DISCUSSION To investigate how different reaction conditions (solvent, concentration, temperature) affect the tandem metathesis/ isomerization (Scheme 1), a series of substrates belonging to Scheme 1. Tandem RCM/Isomerization

different classes of compounds like allylic ethers, N,Ndiallyltosylamides, N,N-diallylamides, and C,C-diallyl hydrocarbons, have been studied (Figure 2).

entry

substrate

[Ru] loading (mol %)

conversion (%)

Xb:Xc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

1a

0.25 0.5 1 0.25 2.5 0.25 0.25 0.5 2.5 0.25 0.5 0.25 2.5 0.25 0.25b 0.25c 2.5b 0.25 0.25

100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 18 100

98:2 98:2 98:2 79:21 1:99 5:95 79:21 75:25 64:36 64:36 60:40 75:25 19:81 87:13 81:19 75:25 63:37 70:30 98:2

2a 4a 6a

7a 8a 9a

10a 11a

a

Reaction conditions: 0.25−2.5 mol % Gre II, 2-methyltetrahydrofuran, c = 0.1 M, 80 °C, 4 h. bc = 0.05 M. cc = 0.025 M.

With the exception of anthrone derivative 10a, the conversion of all substrates was complete, but at the same time, significant differences in the effectiveness of the subsequent isomerization reaction were observed. Thus, when 1-(allyloxy)-1-vinylcyclohexane (1a) was used, almost exclusively product of RCM, 1b was observed regardless of catalyst loading (Table 1, entries 1−3). When 3-(allyloxy)oct1-ene (2a) was used, the compound with a structure similar to 1a but without a spirocyclic motif, the corresponding vinyl ether 2c was obtained quantitatively in the presence of an enlarged amount of catalyst. Such a dramatic difference in the reactivities of these two allylic ethers may be related to steric hindrance elicited by the strained spiro system. Similar differences in subsequent isomerization were observed for derivatives of allylic tosylamides and amides. For example, in the case of N,N-diallyltosylamide (4a) (Table 1, entry 6), almost quantitative conversions to a product with a shifted double bond were observed, whereas for N,N-bisallylamide derivatives, this subsequent process was noticeably less effective (Table 1, entries 7, 10, 12, and 14). Moreover, in the reaction of N,N-diallyl-2-(1H-indol-3-yl)-2-oxoacetamide (9a), because of its low solubility even in boiling 2methyltetrahydrofuran, higher dilutions were necessary to obtain improved isomerization yield (Table 1, entries 14−16).

Figure 2. Model substrates used in this study: (a) allylic ethers, (b) N,N-diallyltosylamides, N,N-diallylamides, and (c) C,C-diallyl hydrocarbons. 1832


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Of note, in all cases, an increased catalyst amount resulted in improved isomerization efficiency. This fact suggests a rather low stability of isomerization active species. Furthermore, when the substrates without heteroatoms in close proximity to the double bonds were subjected to the metathesis/isomerization sequence (Table 1, entries 18 and 19), mostly the products of the RCM reaction were observed, with as little as 30 or 2% (for 10a and 11a, respectively) of the product with a shifted double bond. A possible explanation for limited isomerization in the case of carbocyclic compounds based on quantum-mechanical calculations is provided below. Next, the influence of different solvents on the effectiveness of the isomerization step was studied. For this purpose, toluene, typically used in a number of OM reactions, and ethyl acetate, one of the so-called green solvent, were compared with previously used 2-methyltetrahydrofuran (Table 2).

Table 3. Results of RCM/Isomerization in 2Methyltetrahydrofuran at 120 °Ca

Table 2. Results of RCM/Isomerization in Different Solvents at 80 °Ca substrate

solvent

conversion (%)

Xb:Xc

1 2 3 4 5 6 7 8 9

2a

2-MeTHF EtOAc toluene 2-MeTHF EtOAc toluene 2-MeTHF EtOAc toluene

100 100 100 100 100 100 100 100 100

79:21 94:6 94:6 79:21 82:18 95:5 81:19 88:12 94:6

9ab

substrate

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

1a 3a 4a 5a

6a 7a 8a 9a 10a 11a

[Ru] loading (mol %)

conversion (%)

Xb:Xc

2.5 2.5 1b 0.25 2.5 10 0.5 1 0.5 0.5 0.5c 2.5c 2.5 2.5

100 100 100 100 100 100 100 100 100 100 100 100 100 100

0:100 3:97 4:96 82:18 49:51 4:96 45:55 6:94 4:96 5:95 44:56 9:91 66:34 96:4

isolated yield of Xc (%) 85 84 80

86 91 81 94 80

a

entry

6a

entry

Reaction conditions: Gre II, 2-methyltetrahydrofuran, c = 0.1 M, 80 °C, 4 h. bc = 0.075 M. cc = 0.05 M.

What is important, under the new chemical additive free conditions, it was also possible to obtain products containing 6- (5c) and 7-membered (3c) rings, which was a major challenge in earlier studies by Schmidt.32 Unfortunately, despite the use of these improved reaction conditions, satisfactory yields were not obtained for the carbocyclic systems (substrates 10a and 11a, Table 3, entries 13 and 14). This is probably related to the absence of a heteroatom in the resulting ring, thereby the lack of coupling resulting from double bond isomerization, as is the case for other heteroatomcontaining substrates. 2.1. Ab Initio Studies. To gain better insight into the experimental selectivity patterns, we performed theoretical calculations using the DFT and DLPNO-CCSD(T) approach for the RCM/isomerization in 2-methyltetrahydrofuran at 120 °C and high catalyst loadings. Because the reactions were run for a relatively long time and in high temperatures, we assumed that the selectivity is a thermodynamically driven process and assessed the relative stabilities of isomers b and c. The results of the differences in Gibbs free energies for substrates 1−11 translated into relative concentrations using Boltzmann distributions are presented in Table 4 and show very good agreement with experimental data from Table 3. In most cases, the isomerized product is energetically more favorable than the metathesis product by 2−4 kcal/mol, yielding more than 90% of this product in the final solution. There are, however, instances where the computational results are not in good agreement with the experimental data. This is true for 3 and 7, for which the computational estimates of Xb:Xc are 36:64 and 26:74, respectively, but in the experiment, the product of isomerization was obtained in more than 90% yield. There is also one instance (11) where the experimental yield of Xb:Xc of 96:4 is way off the computational estimate of 60:40. At this point, we do not have a good explanation to this discrepancy, though it is worth noting that the accuracy of our calculations is not better than 1 kcal/mol and a small error in Gibbs free energies can translate into a relatively large one (up to ±25%) in estimates’ relative yields. Another feasible explanation is the possibility of the second step of the reaction (isomerization) being at least partially kinetically driven, which would be in agreement with experimental results presented in Table 3,

Reaction conditions: 0.25 mol % Gre II, c = 0.1 M, 80 °C, 4 h. bc = 0.05 M.

a

As shown in Table 2, in all examined solvents, the OM reaction proceeded with the same effectiveness, as quantitative conversions of all substrates were observed. On the contrary, differences in promoting the subsequent isomerization reaction were clearly visible. In toluene, only the minor double bond migration in the range of 5−6% was observed (Table 2, entries 3, 6, and 9). When ethyl acetate was utilized, a slight improvement in isomerization process was noted. The highest level of isomerization, but still unsatisfactory, was achieved in 2-methyltetrahydrofuran, which was used for further studies. Because the reaction conditions studied so far have not sufficiently favored the metathesis/isomerization sequence, the temperature of the process was increased and the reaction time was extended to shift the reaction equilibrium in favor of the desired products Xc (Table 3). As the selected process temperature was higher than the boiling point of 2-MeTHF (120 and 80.2 °C, respectively), the reactions were carried out in pressure ampoules. As expected, the significant increase of the reaction temperature and the extension of its time shifted the equilibrium almost exclusively toward the isomerized products Xc. For practical usefulness, the quantitative yield in a metathesis/isomerization sequence is crucial. This is due to the very similar polarity of the metathesis Xb and the subsequent isomerization Xc products, which would make the application of standard purification techniques troublesome. To achieve that goal, high catalyst loadings, up to 10 mol %, were required in some cases, as in the transformation of 5a (Table 3, entries 4−6). 1833


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were recorded on a Thermo Scientific Nicolet iS 50 FT-IR spectrometer; wavenumbers (ṽ) are given in cm−1. HRMS spectra were collected on a LCT Micromass TOF HiRes apparatus at the Faculty of Chemistry, University of Warsaw. GC measurements were performed on a PerkinElmer Clarus 580 instrument with an InertCap 5MS-Sil column. Elemental analyses were performed by the Institute of Organic Chemistry, PAS, Warsaw. All other commercially available compounds were used as received unless stated otherwise. Synthesis of substrates is described in the Supporting Information. 4.2. General RCM-Isomerization Tandem Procedures: Protocol 1RCM (80 °C). Substrate (1 mmol), durene (1 mmol), and 2-MeTHF (10 mL) were placed under argon in a dry Schlenk tube. The Schlenk tube was placed in an oil bath heated to 100 °C to obtain intensive reflux of solvent. Then, an adequate amount of Gre-II precatalyst in DCM (100−500 μL, depends on the amount of used catalyst) solution was added. Reaction was stirred for 4 h under an argon atmosphere before being quenched with ethyl vinyl ether (1 mL, 0.2 M solution in DCM) and then analyzed via GC. 4.3. General RCM-Isomerization Tandem Procedures: Protocol 2RCM-Isomerization Tandem (120 °C). Substrate, durene (1 equiv) and 2-MeTHF were placed under argon in an oven-dried pressure ampoule. Then, an adequate amount of Gre-II precatalyst was added (100−500 μL, depends on the amount of used catalyst). The ampoule was closed under positive argon pressure and transferred to the oil bath heated to 120 °C (blast-shield was used for safety features). The resulting reaction mixture was stirred at this temperature for 24 h. After cooling to ambient temperature, the reaction was quenched with ethyl vinyl ether (1 mL, 0.2 M solution in DCM). 100 μL of solution was taken for GC analysis, and the rest was evaporated and purified by column chromatography. 4.3.1. 1-Oxaspiro[4.5]dec-2-ene (1c). 1-Oxaspiro[4.5]dec2-ene (1c) was prepared according to the general procedure (protocol 2) from 1-(allyloxy)-1-vinylcyclohexane (1a) (1 mmol, 166 mg) and 2.5 mol % Gre II (25 μmol, 16.8 mg) in 10 mL 2-MeTHF (c = 0.1 M). After purification by column chromatography (silica gel, AcOEt/cyclohexane: 1:19), the product was isolated as a colorless oil (117 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 6.20 (dd, J = 5.0, 2.4 Hz, 1H), 4.74 (dd, J = 5.2, 2.6 Hz, 1H), 2.33 (t, J = 2.4 Hz, 2H), 1.75− 1.60 (m, 4H), 1.58−1.35 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 147.4, 98.4, 78.1, 46.1, 40.7, 26.3, 22.3. Spectral data are in agreement with those reported in the literature.32 4.3.2. 2-(4-Methoxyphenyl)-2,3,4,5-tetrahydrooxepine (3c). 2-(4-Methoxyphenyl)-2,3,4,5-tetrahydrooxepine (3c) was prepared according to the general procedure (protocol 2) from 1-(1-(allyloxy)pent-4-en-1-yl)-4-methoxybenzene (3a) (1 mmol, 232 mg) and 2.5 mol % Gre II (25 μmol, 16.8 mg) in 10 mL 2-MeTHF (c = 0.1 M). After purification by column chromatography (silica gel, AcOEt/cyclohexane: 1:19), the product was isolated as a colorless oil (171 mg, 84% yield). 1H NMR (400 MHz, CDCl3) δ 7.33−7.28 (m, 2H), 6.91−6.87 (m, 2H), 6.40 (dd, J = 6.8, 1.3 Hz, 1H), 4.87 (ddd, J = 6.8, 5.9, 5.1 Hz, 1H), 4.74 (dd, J = 10.4, 2.9 Hz, 1H), 3.81 (s, 3H), 2.20−1.95 (m, 4H), 1.68−1.56 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 157.8, 147.8, 131.4, 128.0, 114.1 107.7, 85.2, 55.8, 38.1, 31.6, 24.0. Spectral data are in agreement with those reported in the literature.32

Table 4. Computational Estimates of the Difference in Gibbs Free Energies between Isomers and Their Corresponding Relative Ratios Calculated by the DFT and DLPNO-CCSD(T) Levels of Theory for RCM/ Isomerization in 2-Methyltetrahydrofuran at 120 °C substrate

DFT ΔG (b and c)

DFT Xb:Xc

DLPNO-CCSD(T) ΔG (b and c)

DLPNO-CCSD(T) Xb:Xc

1a 2a 3a 4a 5a 6a 7a 8a 9a 10a 11a

2.91 3.03 0.08 3.81 4.07 1.67 0.61 1.44 4.23 0.01 −0.03

2:98 2:98 47:53 1:99 0:100 10:90 31:69 14:86 0:100 50:50 51:49

2.40 2.57 0.44 2.83 3.56 1.57 0.80 0.49 4.07 0.47 0.30

4:96 4:96 36:64 3:97 1:99 12:88 26:74 35:65 0:100 35:65 40:60

showing different isomerization rates corresponding to different catalyst loadings.

3. CONCLUSIONS The use of 2-methyltetrahydrofuran and the careful selection of reaction conditions enabled the synthesis of the number of products with shifted double bonds in the metathesis/ isomerization sequence. Under these conditions in the processes involving substrates containing heteroatoms in close proximity to the double bond (like in allylic ethers, N,N-diallyltosylamides, and N,N-diallylamides) almost exclusively one isomer was reached. Due to that fact, the studied reaction can be considered as an effective synthesis method of the vinylic ethers and amides. When the heteroatom-free substrates were applied, the subsequent isomerization was very limited because the isomerized product c has similar energy to the product b, resulting from the RCM reaction. Computational estimates of the relative Gibbs free energies of isomers are in good agreement with experimental data and suggest that there exists a thermodynamic control of reaction products, though a partial kinetic control at lower catalyst loadings cannot be ruled out. 4. EXPERIMENTAL SECTION 4.1. General Information. All reactions were carried out under magnetic stirring. 2-Methyltetrahydrofuran (2-MeTHF) bought from Sigma-Aldrich (ReagentPlus, 150−400 ppm BHT as stabilizer, 155810-2.5L) was distilled from sodium/ benzophenone. Dry solvents were purified on an SPS column. Reactions were monitored by thin layer chromatography with Sigma-Aldrich silica gel plates (56524-25EA). Visualization was accomplished with either UV light or by immersion in solutions of KMnO4 followed by heating using a heat gun for about 15 s. Purification of starting materials and products was carried out by flash chromatography using a Merck silica gel 60 (230−400 mesh). 1H-NMR and 13C-NMR spectra were obtained using an Agilent Mercury 400 MHz (400 MHz for 1 H and 101 MHz for 13C) spectrometer. Chemical shifts are reported relative to chloroform (δ = 7.26) for 1H NMR and chloroform (δ = 77.16) for 13C NMR. Data are reported as br = broad, s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. Coupling constants are given in hertz. IR spectra 1834


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2H), 2.74−2.67 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 165.5, 163.6, 161.6, 138.0(d, JC−F = 7.1 Hz), 130.3 (d, JC−F = 8.2 Hz), 123.5 (d, JC−F = 3.1 Hz), 117.5 (d, JC−F = 21.1 Hz), 115.1 (d, JC−F = 22.8 Hz), 112.5, 45.8, 28.5. 19F NMR (376 MHz, CDCl3) δ −111.8 (td, J = 8.7, 5.6 Hz). HRMS-TOF (m/z) calcd for [C11H11NOF+]: 192.0819; found, 192.0823. 4.3.7. 1-[(2S)-1-(4-Methylbenzenesulfonyl)pyrrolidine-2carbonyl]-2,3-dihydro-1H-pyrrole (8c). The title compound was prepared according to the general procedure (protocol 2) from (2S)-1-(4-methylbenzenesulfonyl)-N,N-bis(prop-2-en-1yl)pyrrolidine-2-carboxamide (8a) (0.5 mmol, 219 mg) and 0.5 mol % Gre II (2.5 μmol, 1.7 mg) in 10 mL 2-MeTHF (c = 0.05 M). After purification by column chromatography (silica gel, AcOEt/cyclohexane: 1:1), the product was isolated as a colorless crystalline (151 mg, 94% yield). 1H NMR (400 MHz, CDCl3) major rotamer:a δ 7.75 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.82 (ddt, J = 43.8, 4.3, 2.1 Hz, 1H), 5.31−5.26 (m, 1H), 4.57 (ddd, J = 23.3, 7.6, 4.6 Hz, 1H), 4.01 (dtd, J = 112.7, 10.4, 7.0 Hz, 1H), 3.81−3.76 (m, 1H), 3.51−3.35 (m, 2H), 2.84−2.76 (m, 1H), 2.64−2.56 (m, 1H), 2.41 (s, 3H), 2.17−1.90 (m, 3H), 1.85−1.71 (m, 1H). 13C NMR (101 MHz, CDCl3) major rotamer:a δ 167.0, 143.6, 135.8, 129.6, 128.4, 127.7, 112.8, 111.7, 59.5, 48.5, 45.7, 30.6, 24.9, 21.7. IR [νmax (diamond tip) cm−1] 3103, 3034, 2974, 2955, 2876, 1654, 1614, 1597, 1471, 1375, 1353, 1338, 1323, 1310, 1295, 1285, 1256, 1236, 1208, 1196, 1153, 1141, 1117, 1095, 1067, 1049, 1022, 1004, 951, 930, 920, 887, 870, 851, 830, 803, 771, 728, 716, 707, 691, 662, 636, 592, 544, 539, 494, 460, 414. Anal. calcd for C16H20N2O3S: C, 59.98; H, 6.29; N, 8.74; O, 14.98; S, 10.01; found: C, 59.80, H, 6.37; N, 8.60; S, 9.85. HRMSTOF (m/z) calcd for [C16H21N2O3S+]: 321.1267; found, 321.1268.48 4.3.8. 1-(2,3-Dihydro-1H-pyrrol-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (9c). The title compound was prepared according to the general procedure (protocol 2) from 2-(1Hindol-3-yl)-2-oxo-N,N-bis(prop-2-en-1-yl)acetamide (9a) (0.5 mmol, 134 mg) and 2.5 mol % Gre II (12.5 μmol, 8.4 mg) in 10 mL 2-MeTHF (c = 0.05 M). After purification by column chromatography (silica gel, AcOEt/cyclohexane: 3:7 to 1:1), the product was isolated as a colorless crystalline (105 mg, 80% yield). 1H NMR (500 MHz, CDCl3) major rotamer: δ 9.74 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 3.3 Hz, 1H), 7.38 (dd, J = 7.9, 0.8 Hz, 1H), 7.33−7.25 (m, 2H), 6.92 (dt, J = 4.4, 2.3 Hz, 1H), 5.33 (dt, J = 4.4, 2.7 Hz, 1H), 4.02−3.97 (m, 2H), 2.71−2.66 (m, 2H). 13C NMR (126 MHz, CDCl3) major rotamer: δ 184.2, 162.6, 136.8, 136.5, 129.4, 128.8, 125.9, 124.4, 123.4, 122.3, 114.1, 112.0, 45.4, 27.9. IR [νmax (diamond tip) cm−1] 3150, 3111, 3049, 2980, 2953, 2921, 2866, 2743, 1630, 1596, 1582, 1517, 1495, 1474, 1457, 1429, 1372, 1352, 1314, 1292, 1284, 1240, 1198, 1185, 1162, 1137, 1110, 1096, 1047, 1021, 1009, 967, 931, 885, 853, 812, 782, 773, 747, 721, 699, 639, 610, 551, 524, 500, 456, 427. HRMS-TOF (m/z) calcd for [C14H13N2O2+]: 241,0972; found, 241,0962. Computational Data. In this work, we used the DFT and DLPNO-CCSD(T) methods using all-atom models for all studied organic compounds.49 In the geometry optimization step, we used the M06 density functional with the 6-31G** for all atoms.50 In all calculations, we have used the standard energy convergence criterion of 5 × 10−5 Hartree. For each structure, frequencies were calculated to verify the nature of each stationary point (zero imaginary frequencies for minima). In the second step, we performed solvation energy calculations using the Poisson−Boltzmann self-consistent polarizable

4.3.3. 1-(4-Methylbenzenesulfonyl)-2,3-dihydro-1H-pyrrole (4c). 1-(4-Methylbenzenesulfonyl)-2,3-dihydro-1H-pyrrole (4c, gram-scale synthesis) was prepared according to the general procedure (protocol 2) from 4-methyl-N,N-bis(prop-2en-1-yl)benzene-1-sulfonamide (3a) (15 mmol, 3.77 g) and 1.0 mol % Gre II (0.15 mmol, 101 mg) in 20 mL 2-MeTHF (c = 0.75 M). After purification by column chromatography (silica gel, AcOEt/cyclohexane: 3:17), the product was isolated as a colorless solid (2.67 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.67−7.63 (m, 2H), 7.33−7.28 (m, 2H), 6.35 (dt, J = 4.3, 2.2 Hz, 1H), 5.10 (dt, J = 4.2, 2.6 Hz, 1H), 3.49−3.42 (m, 2H), 2.49−2.42 (m, 2H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 143.8, 130.7, 129.7, 129.6, 127.7, 111.3, 47.2, 29.6, 21.5. Spectral data are in agreement with those reported in the literature.11 4.3.4. 1-(4-Methylbenzenesulfonyl)-1,2,3,4-tetrahydropyridine (5c). 1-(4-Methylbenzenesulfonyl)-1,2,3,4-tetrahydropyridine (5c) was prepared according to the general procedure (protocol 2) from N-(but-3-en-1-yl)-4-methyl-N-(prop-2-en-1yl)benzene-1-sulfonamide (5a) (1 mmol, 265 mg) and 10 mol % Gre II (0.1 mmol, 67.2 mg) in 10 mL 2-MeTHF (c = 0.1 M). After purification by column chromatography (silica gel, AcOEt/cyclohexane: 1:9), the product was isolated as a colorless oil (196 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.72−7.61 (m, 2H), 7.34−7.28 (m, 2H), 6.63 (dt, J = 8.3, 1.9 Hz, 1H), 4.96 (dt, J = 8.1, 3.9 Hz, 1H), 3.39−3.34 (m, 2H), 2.42 (s, 3H), 1.90 (tdd, J = 6.1, 3.9, 2.0 Hz, 2H), 1.65 (dt, J = 12.0, 6.1 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 143.6, 135.3, 129.8, 127.2, 125.2, 108.4, 44.0, 21.7, 21.1, 21.0. Spectral data are in agreement with those reported in the literature.47 4.3.5. 4-(2,3-Dihydro-1H-pyrrole-1-carbonyl)-N,N-dimethylaniline (6c). 4-(2,3-Dihydro-1H-pyrrole-1-carbonyl)-N,Ndimethylaniline (6c) was prepared according to the general procedure (protocol 2) from 4-(dimethylamino)-N,N-bis(prop-2-en-1-yl)benzamide (6a) (1 mmol, 244 mg) and 1.0 mol % Gre II (10 μmol, 6.7 mg) in 10 mL 2-MeTHF (c = 0.1 M). After purification by column chromatography (silica gel, AcOEt/cyclohexane: 1:9 to 1:3), the product was isolated as a colorless solid (196 mg, 91% yield). 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 8.8 Hz, 3H), 5.15 (s, 1H), 3.98 (t, J = 8.9 Hz, 2H), 3.00 (s, 6H), 2.73−2.63 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 167.5, 151.8, 131.6, 129.8, 122.8, 111.1, 110.6, 46.0, 40.3, 28.5. IR [νmax (diamond tip), cm−1] 3089, 2953, 2905, 2856, 2805, 1588, 1543, 1532, 1478, 1442, 1428, 1396, 1374, 1365, 1325, 1309, 1293, 1285, 1234, 1205, 1191, 1160, 1138, 1068, 1044, 1010, 996, 972, 949, 935, 920, 820, 757, 715, 693, 637, 613, 604, 565, 517, 482, 455, 426, 408. Anal. calcd for C13H16N2O: C 72.19, H 7.46, N 12.95, O 7.40; found: C 72.06, H 7.67, N 12.85. HRMS-TOF (m/z) calcd for [C13H17N2O+]: 217.1335; found, 217.1342. 4.3.6. 1-(3-Fluorobenzoyl)-2,3-dihydro-1H-pyrrole (7c). 1(3-Fluorobenzoyl)-2,3-dihydro-1H-pyrrole (7c) was prepared according to the general procedure (protocol 2) from 3-fluoroN,N-bis(prop-2-en-1-yl)benzamide (7a) (1 mmol, 219 mg) and 0.5 mol % Gre II (5 μmol, 3.4 mg) in 10 mL 2-MeTHF (c = 0.1 M). After purification by column chromatography (silica gel, AcOEt/n-hexane: 1:4), the product was isolated as a yellowish oil (155 mg, 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.42−7.35 (m, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.24− 7.19 (m, 1H), 7.13 (tdd, J = 8.4, 2.6, 1.1 Hz, 1H), 6.41 (dt, J = 4.4, 2.2 Hz, 1H), 5.22 (dt, J = 4.5, 2.7 Hz, 1H), 4.04−3.98 (m, 1835


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Chemicals Manufacturing. Angew. Chem., Int. Ed. 2016, 55, 3552− 3565. (4) Cheng-Sánchez, I.; Sarabia, F. Recent Advances in Total Synthesis via Metathesis Reactions. Synthesis 2018, 50, 3749−3786. (5) Lecourt, C.; Dhambri, S.; Allievi, L.; Sanogo, Y.; Zeghbib, N.; Ben Othman, R.; Lannou, M.-I.; Sorin, G.; Ardisson, J. Natural products and ring-closing metathesis: synthesis of sterically congested olefins. Nat. Prod. Rep. 2018, 35, 105−124. (6) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Metathesis Reactions in Total Synthesis. Angew. Chem., Int. Ed. 2005, 44, 4490−4527. (7) Metathesis in Natural Product Synthesis: Strategies, Substrates and Catalysts; Cossy, J., Arseniyadis, S., Meyer, C., Eds.; Wiley: Weinheim, Germany, 2010. (8) Miao, X.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Dimethyl Carbonate: An Eco-Friendly Solvent in Ruthenium-Catalyzed Olefin Metathesis Transformations. ChemSusChem 2008, 1, 813−816. (9) Bilel, H.; Hamdi, N.; Zagrouba, F.; Fischmeister, C.; Bruneau, C. Cross-metathesis transformations of terpenoids in dialkyl carbonate solvents. Green Chem. 2011, 13, 1448−1452. (10) Ż ukowska, K.; Pączek, Ł.; Grela, K. Sulfoxide-Chelated Ruthenium Benzylidene Catalyst: a Synthetic Study on the Utility of Olefin Metathesis. ChemCatChem 2016, 8, 2817−2823. (11) Skowerski, K.; Białecki, J.; Tracz, A.; Olszewski, T. K. An Attempt to Provide an Environmentally Friendly Solvent Selection Guide for Olefin Metathesis. Green Chem. 2014, 16, 1125−1130. (12) Sytniczuk, A.; Leszczyńska, A.; Kajetanowicz, A.; Grela, K. Preparation of Musk-Smelling Macrocyclic Lactones from Biomass: Looking for the Optimal Substrate Combination. ChemSusChem 2018, 11, 3157−3166. (13) Smoleń, M.; Kędziorek, M.; Grela, K. 2-Methyltetrahydrofuran: Sustainable solvent for ruthenium-catalyzed olefin metathesis. Catal. Commun. 2014, 44, 80−84. (14) Smoleń, M.; Kośnik, W.; Gajda, R.; Woźniak, K.; Skoczeń, A.; Kajetanowicz, A.; Grela, K. Ruthenium Complexes Bearing Thiophene-Based Unsymmetrical N-Heterocyclic Carbene Ligands as Selective Catalysts for Olefin Metathesis in Toluene and Environmentally Friendly 2-Methyltetrahydrofuran. Chem. - Eur. J. 2018, 24, 15372−15379. (15) Grela, K.; Gułajski, Ł.; Skowerski, K. Alkene Metathesis in Water. In Metal-Catalyzed Reactions in Water; Dixneuf, P. H., Cadierno, V., Eds.; Wiley: Weinheim, Germany, 2013; 291−336, DOI: 10.1002/9783527656790.ch8. (16) Tomasek, J.; Schatz, J. Olefin metathesis in aqueous media. Green Chem. 2013, 15, 2317−2338. (17) Sherwood, J. European Restrictions on 1,2-Dichloroethane: C− H Activation Research and Development Should Be Liberated and not Limited. Angew. Chem., Int. Ed. 2018, 57, 14286−14290. (18) EU Action Plan for the Circular Economy; COM/2015/0614 final: eur-lex.europa.eu/legal-content/EN/TXT/?uri= CELEX:52015DC0614. (19) Fogg, D. E.; dos Santos, E. N. Tandem catalysis: a taxonomy and illustrative review. Coord. Chem. Rev. 2004, 248, 2365−2379. (20) Schmidt, B.; Krehl, S. Domino and Other Olefin Metathesis Reaction Sequences. In Olefin Metathesis: Theory and Practice; Grela, K., Ed.; 2014; 187−232, DOI: 10.1002/9781118711613.ch5. (21) Zieliński, G. K.; Grela, K. Tandem Catalysis Utilizing Olefin Metathesis Reactions. Chem. - Eur. J. 2016, 22, 9440−9454. (22) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs, R. H. Decomposition of ruthenium olefin metathesis catalysts. J. Am. Chem. Soc. 2007, 129, 7961−7968. (23) Higman, C. S.; Lanterna, A. E.; Marin, M. L.; Scaiano, J. C.; Fogg, D. E. Catalyst Decomposition during Olefin Metathesis Yields Isomerization-Active Ruthenium Nanoparticles. ChemCatChem 2016, 8, 2446−2449. (24) Higman, C. S.; Plais, L.; Fogg, D. E. Isomerization During Olefin Metathesis: An Assessment of Potential Catalyst Culprits. ChemCatChem 2013, 5, 3548−3551.

continuum method as implemented in Jaguar v.7.9 (Schrödinger, 2013) to represent 2-MeTHF, using the dielectric constant of 6.97 and the effective radius of 2.52 Å. For all stationary points, we have also performed single-point energy calculations using the larger 6-311++G** basis set as well as the DLPNO-CCSD(T) method and the def2-svp basis set. Gibbs free energies discussed in this work were calculated as the sum of electronic energy [either from single-point 6-311+ +G** or DLPNO-CCSD(T) calculations], solvation energy, zero-point energy correction, thermal correction to enthalpy, and the negative product of temperature and entropy (at 120 °C). DFT calculations were performed in the Jaguar v.7.9 software, whereas DLPNO-CCSD(T) was done in the Orca v.4.0.0.1 software.51,52

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b03027. Detailed experimental procedures for the synthesis of substrates and NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (A.K.). *E-mail: [email protected] (K.G.). ORCID

Krzysztof Skowerski: 0000-0003-0552-3989 Karol Grela: 0000-0001-9193-3305 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding

The research was supported by NCN MAESTRO (grant no. DEC-2012/04/A/ST5/00594). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Authors are grateful to the National Science Centre (Poland) for the NCN MAESTRO (grant no. DEC-2012/04/A/ST5/ 00594). The study was carried out at the Biological and Chemical Research Centre, University of Warsaw, established within the project co-financed by European Union from the European Regional Development Fund under the Operational Programme Innovative Economy, 2007−2013.

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ADDITIONAL NOTE Separated signals from rotamers are characteristic of some N2,3-dihydropirolamides.48

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REFERENCES

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2-Methyltetrahydrofuran as a Solvent of Choice for Spontaneous

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