Insight into the Mechanism of Reversible Ring-Opening of 1,3

In DMSO and DMF the COLBERT reaction does not proceed, but it reaches ... ring-opening addition reaction and hence 1,3-benzoxazine recovery when perfo...
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Insight into the Mechanism of Reversible Ring-Opening of 1,3‑Benzoxazine with Thiols Tobias Urbaniak,†,‡ Marc Soto,† Manuel Liebeke,§ and Katharina Koschek*,† †

Fraunhofer Institute for Manufacturing Technology and Advanced Materials (IFAM), Wiener Strasse 12, D-28359 Bremen, Germany ‡ Institute for Organic and Analytical Chemistry, University of Bremen, Leobener Strasse NW2C, D-28359 Bremen, Germany § Max Planck Institute for Marine Microbiology, Celsiusstrasse 1, D-28359 Bremen, Germany S Supporting Information *

ABSTRACT: The reversible ring-opening addition and fragmentation reaction of p-cresol-based N-phenylbenzoxazine with aliphatic and aromatic thiols was investigated in solventmediated and solvent-free reactions. Independently of the used thiol, N-phenylbenzoxazine and the thiols reacted to equilibrium with comparable amounts of reactants and products in aprotic solvent, whereas in protic solvent almost full conversions were reached. In contrast, thiol reactivity was a crucial factor in solvent-free reactions yielding fast and complete conversions for a more acidic thiol and balanced equilibrium concentrations in case of thiols with high pKa values. The strong influence of thiols with low pKa values emphasizes the relevance of the protonation step in the ringopening reactions of 1,3-benzoxazines with thiols in absence of solvents where acidity predominates nucleophilicity. The reverse reactions, namely adduct dissociation and benzoxazine recovery, were successfully conducted at elevated temperatures and reduced pressure facilitated by the removal of the formed thiols yielding up to 95% recovered 1,3-benzoxazine. These results provide deeper understanding of the reversible ring-opening reaction mechanism of 1,3-benzoxazine with thiols.

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INTRODUCTION

The ring-opening reaction of benzoxazines in the presence of thiols was described as catalytic opening of the lateral benzoxazine rings by thiols (COLBERT).18,21 This proposed mechanism contains several proton transfer steps that could be strongly affected by the acidic nature of thiols and solvents used (i.e., protic vs aprotic). The initial thiol-mediated protonation step probably takes place predominantly at nitrogen (A) as it was described for the ring-opening polymerization of 1,3-benzoxazines in the presence of various catalysts.22,23 The protonated benzoxazine can be considered as a system under Curtin−Hammett conditions with rapidly interconverting intermediates (A) and (B). A SN2 type reaction on intermediate (A) would lead to C−N cleavage and formation of −O−CH2−SR, while intermediate (B) undergoes a unimolecular opening to form acyclic iminium intermediate (C) followed by a SN1 type reaction, or alternatively a SN2 type reaction with an appropriate thiolate (Figure 1). In solution, the equilibria strongly depend on the used solvents. In DMSO and DMF the COLBERT reaction does not proceed, but it reaches equilibrium when performed in chloroform.17,19,24 In protic solvents, such as methanol, the

In the past decade, reversible reactions are receiving increasing interest for the preparation of smart materials with self-healing properties.1−3 Examples of reversible reactions applied in materials include transesterification,4,5 Diels−Alder/retro Diels−Alder,6−9 [2+2] photocycloaddition,10 radical reactions,11−14 and olefin metathesis.15 Polybenzoxazines as thermosetting polymers offer a number of outstanding properties such as thermal stability and excellent mechanical performance.16 Recently, the ring-opening reaction of benzoxazines in the presence of thiols was described to be a reversible reaction, which could give access to smart materials. Endo et al. have described this reversible reaction to proceed at room temperature without catalysts and side-product formation. Moreover, this reaction was transferred to bifunctional benzoxazines and dithiols to generate polymers, which could be depolymerized and polymerized by protic/aprotic solvent change.17 Gorodisher et al. developed adhesives based on thiol-benzoxazine chemistry18 and Yagci et al. described mainchain-type polybezoxazines partially reacted with thiols as low temperature curing precursors for high performance thermoset polybenzoxazines.19 Furthermore, thiol-benzoxazine chemistry was used as efficient linking reaction in block copolymer preparation.20 © 2017 American Chemical Society

Received: November 11, 2016 Published: March 27, 2017 4050

DOI: 10.1021/acs.joc.6b02727 J. Org. Chem. 2017, 82, 4050−4055

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The Journal of Organic Chemistry

Figure 1. Proposed mechanism for the reversible ring-opening of 1,3-benzoxazines with thiols.

model reaction of N-phenylbenzoxazine 1 and 1-dodecanethiol 2a in stoichiometric ratio in deuterated chloroform. Thereby, the reversible reaction progress was investigated in dependence of the initial reactant concentration ranging from 0.01 to 0.24 M with respect to both starting points, namely, the addition reaction of N-phenylbenzoxazine 1 and 2a as well as the dissociation reaction from the adduct 3a back to N‑phenylbenzoxazine 1 (Figure 3).

ring-opening addition reaction achieves high conversions probably due to zwitterion formation (D). Alcohols are known to stabilize ions, for that the benzoxazine/thiol adduct is partially found in its zwitterionic form (D).17,21,24 Endo’s group described the effect of protic and aprotic solvents on the addition and fragmentation equilibrium of benzoxazine in the presence of 1-octadecanethiol,17 but studies on further factors influencing the equilibrium reaction are missing so far. Therefore, this contribution aims to gain deeper insight studying the reaction of N-phenylbenzoxazine 1 as model compound with various aromatic and aliphatic thiols under solvent-mediated vs solvent-free conditions. In addition to Endo’s work, variations in reactant concentrations as well as thiol acidity are studied and related to the proposed mechanism. Moreover, this contribution elucidates in particular the access to a reversible ring-opening addition reaction and hence 1,3-benzoxazine recovery when performed under solvent-free conditions.

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RESULTS AND DISCUSSION Reversible ring-opening addition and fragmentation reactions were performed with the p-cresol-based N-phenylbenzoxazine 1 as a benzoxazine representative and aliphatic and aromatic thiols 2a−g (Figure 2). With the aim to study the impact on

Figure 3. Equilibrium concentration of 1 vs initial concentration of 1 or 3a determined in ring-opening reaction of 1 and 2a, and in a dissociation reaction of 3a in CDCl3, respectively, monitored by 1H NMR (mean values with a confidence interval of 90%).

At an initial concentration of 0.01 M N-phenylbenzoxazine 1 in chloroform, chemical equilibrium was reached after 25 h with approximately 40% conversion of 1 to the addition product 3a. With an increasing initial concentration of 1 the equilibrium was shifted even further to 3a. However, the conversion of N‑phenylbenzoxazine 1 even at the highest initial concentration of 0.24 M did not exceed 58% yielding equilibrium concentrations with a slight excess of 3a. Studying the reaction starting from the addition product 3a, the reaction proceeded equivalently showing a higher conversion with increasing initial concentration of 3a. At its highest initial concentration 42% of 3a were converted. Thus, the conversions starting from 1 and 3a increased with increasing initial concentrations yielding chemical equilibrium after 25 h. At the highest initial concentration of 1 and 3a, respectively, the equilibrium concentration position was shifted to an excess of 3a (Figure 3).

Figure 2. Reversible ring-opening addition−fragmentation reaction of 1 in the presence of the thiols 2a−g.

the addition−fragmentation equilibrium of 1 and 3a−g, the reaction setup was varied with respect to the solvent composition, reactant concentration and bulk conditions. Solvent-Mediated Reversible Ring-Opening and Fragmentation Reaction. In the first step, the influence of concentration on the reaction equilibrium was studied as a 4051

DOI: 10.1021/acs.joc.6b02727 J. Org. Chem. 2017, 82, 4050−4055

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The Journal of Organic Chemistry

interconversion (Figure 1, A and B). Furthermore, a protic environment would promote a proton transfer from phenol to amino group yielding zwitterion (D), and shifting equilibrium to the addition product (Figure 1). From these results, it is clear that solvent effects dominate over thiol effects. Therefore, to determine the influence of thiol acidity on this reaction; the next step was to investigate the reactions under solvent-free conditions. Solvent-free Ring-Opening Addition Reaction. Gorodisher et al. described that the ring-opening reaction of benzoxazines and thiols can be performed in bulk.21 In order to study the impact of thiol reactivity on the equilibrium, all reactions were performed at room temperature by dissolving N‑phenylbenzoxazine 1 in the corresponding thiols 2a−g, respectively, and followed by 1H NMR in DMSO-d6. In case of 4-nitrothiophenol (2d), which is a solid, both reagents were homogenized by grinding (Figure S1). The reaction rate k was calculated considering the final conversions and reaction times. Almost full conversion of 1 was observed in case of the aromatic thiols 2c and 2d after 4 and 1 h reaction times, respectively. The reaction mixture of the highly acidic 2g changed from a liquid state to solid state in less than 5 min, pointing to an extremely fast reaction. However, 1H NMR gave no clear results as in this case the equilibrium reaction did not stop in DMSO-d6, acetonitrile-d3, or acetone-d6, which was not observed up to now for other thiols. In contrast, the aliphatic thiols 2a, 2b, 2e, and 2f reacted much slower reaching the final equilibrium after 48 h. The relationship between the logarithm of the reaction rate constant log(k) and the logarithm of the acid ionization constant Ka is known as Brønsted catalysis law or Brønsted relation and describes the relation of acidic strength and catalytic activity or reactivity of involved acids. Plotting log(k) as a function of the pKa values showed a linear relationship (Figure 5) implying that the different thiols act through the

The reactions proceeded typically for chemical equilibrium reactions, namely with a favored dissociated state at low reactant concentrations and an increase in the relative amount of the addition product with increasing reactant concentration. Based on the model reactions of N-phenylbenzoxazine 1 with 1-dodecanethiol (2a) the reversible nature of the addition dissociation reaction and the impact of reactant concentration was proven. Next, the reversible ring-opening addition and dissociation reaction of N-phenylbenzoxazine 1 was extended to further thiols varying in their reactivity with respect to nucleophilicity and acidity. Therefore, the impact of thiols with different pKa values was investigated by studying the reaction of N‑phenylbenzoxazine 1 with 1-dodecanethiol (2a), benzylthiol (2b), thiophenol (2c), and 4-nitrothiophenol (2d), respectively. The reactions were performed with an initial reactant concentration of 0.2 M in CDCl3 as an aprotic solvent and a mixture of CDCl3/MeOD as a protic solvent, respectively, and followed by 1H NMR (Figure 4).

Figure 4. Equimolar reactions of N-phenylbenzoxazine 1 (0.2 M in CDCl3 and CDCl3/MeOD, respectively) with thiols 2a−d. Yields of adducts 3a−d were determined after 25 h reaction time at room temperature.

In neat CDCl3 all reactions of N-phenylbenzoxazine 1 and the thiols 2a−d yielded between 51 and 70% of the appropriate adduct 3a−d within 25 h. The aromatic thiols 4-nitrothiophenol (2d) and thiophenol (2c) yielded almost an equimolar mixture of 1 in relation to 3d and c. The aliphatic ones 2a and b caused a slight shift in equilibrium to the addition products 3a (58%) and b (70%). However, in case of a solvent mixture of CDCl3 and MeOD (1:1) the equilibria were shifted strongly to the appropriate addition products yielding up to 95% 3a−d after 25 h (Figure 4). That process was also shown for reactions with cyclohexanethiol (2e), 1-butanethiol (2f), and pentafluorothiophenol (2g) that formed the corresponding adducts 3e−g in excellent yields (>91%). These observations solvents having a high impact on the equilibrium are consistent with the ones reported by Gorodisher et al. and the studies described by Kawaguchi et al.17,21 In polar aprotic solvents (DMSO, DMF)17 reactions do not take place, whereas less polar aprotic solvents, such as chloroform, give equilibria and a polar protic environment (MeOD:CDCl3) provides almost full conversions. A protic solvent, such as methanol, promotes the first protonation step of the benzoxazine by stabilizing the resulting ionic pairs, which provide a Curtin−Hammett-like situation due to rapid

Figure 5. Logarithmic plot of the Brønsted relation of the benzoxazine/thiol reaction rate vs thiols acid ionization constant Ka (reaction scheme in Figure 2).

same reaction mechanism. Thus, the protonation step takes place at the same reaction site, either the oxygen or the nitrogen, for all of the thiols (Figure 1, A and B). Additionally, the prelogarithmic factor α exhibits a low value (α = 0.16) pointing to a reactant-like transition state and to the protonation as rate-determining step. Comparing the thiol reactivities with respect to their nucleophilicity, one would expect the opposite situation, namely, the best result for the highly nucleophilic aliphatic thiols 2a, 2e, and 2f. The dependence of the rate constant on the acidity of the thiols and its insensitivity to their nucleophilic 4052

DOI: 10.1021/acs.joc.6b02727 J. Org. Chem. 2017, 82, 4050−4055

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The Journal of Organic Chemistry strength suggests the protonation step to be the ratedetermining step with a favored protonation on benzoxazines nitrogen being in rapid equilibrium with the protonated oxygen intermediate. The protonated benzoxazine and the generated thiolate, which is a stronger nucleophile than the corresponding thiol, overcome the low nucleophilicty of the more acidic thiols. This agrees with the studies of Gorodisher et al. changing the residues at benzoxazines nitrogen atom. Benzoxazine derivatives with more basic amines reacted faster in the presence of thiols.21 Hence, acidic thiols and increased basicity of benzoxazine enhance benzoxazine/thiol reactions in bulk. Reversibility of Solvent-free Ring-Opening Addition Reactions. Solvent mediated reactions of benzoxazine and thiols proved to be reversible upon adjusting the environment with appropriate solvent compositions. However, systematic studies on the reversibility of the solvent free reaction are missing. Benzoxazine/thiol adducts 3a−g were placed in a Schlenk tube and exposed to vacuum, respectively, with the aim to shift the equilibrium by removing recovered thiol. The amount of recovered N-phenylbenzoxazine 1 was determined by 1H NMR measurements and correlated with the boiling points of the appropriate thiols 2a−g (Figure 6). Adducts 3a,

Figure 7. 1H NMR-spectrum (200 MHz, DMSO-d6) of pure Nphenylbenzoxazine 1, pure benzoxazine/thiol adduct 3c and recovered N-phenylbenzoxazine 1 after 6 h in vacuum at 90 °C.

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CONCLUSIONS Reversible ring-opening addition and fragmentation reactions of p-cresol-based N-phenyl-1,3-benzoxazine with various aliphatic and aromatic thiols with a wide range of acidities were shown to proceed in solvents and in bulk. When the reaction of benzoxazine 1 and thiols 2a−g was performed in solution, the effect of the solvent dominated over the acidity of the thiol. The polar protic solvent mixture CDCl3/MeOD 1:1 favored the ring-opening addition reaction of the benzoxazine and yielded excellent conversions, whereas the slightly polar aprotic solvent CDCl3 gave equilibrium concentrations for all studied thiols. In solvent-free reactions, the reaction rate was strongly related to the thiol acidity. The acidic thiols thiophenol, 4-nitrothiophenol, and pentafluorothiophenol with low pKa values reacted faster than the aliphatic 1‑butanethiol, 1-dodecanethiol, and cyclohexanethiol with higher pKa values. This indicated that the initial protonation is the rate-determining step giving a Curtin−Hammett-like situation. Studies of the backward reaction showed that benzoxazine could be recovered by ring-closing of the benzoxazine/thiol adducts 3 using vacuum to remove the simultaneously formed thiols. Applying thiols with boiling points lower than 170 °C, the reaction yielded the recovered benzoxazines in high yields and purities.

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Figure 6. Dissociation reaction of adducts 3a−g upon removal of the thiol 2a−g at 4 Pa, 90 °C. Conversion of adducts 3a−g to N‑phenylbenzoxazine 1 in dependency of the corresponding boiling point of thiols 2a−g.

EXPERIMENTAL SECTION

Materials. Aniline (≥99.5%), p-cresol (99%), 1-dodecanethiol (≥98%), benzylthiol (99%), thiophenol (97%), n-hexane (99.9%), 4nitrothiophenol (≥90%), cyclohexanethiol (97%), 1-butanethiol (99%), 2,3,4,5,6-pentafluorothiophenol (97%), toluene (≥99.3%), paraformaldehyde (pure), methanol-d4 (99.8%), chloroform-d (99.8%), dimethyl sulfoxide-d6 (99.8%), acetonde-d6 (99.8%), and acetonitrile-d3 (99.8%) were used as received. Methods. 1H NMR and 13C NMR spectra were recorded at 200 and 50 MHz, respectively. In case of CDCl3 tetramethylsilane, in case of DMSO-d6 residual protons, and in case of MeOD/CDCl3 residual protons of MeOD were used as internal standard. Infrared spectroscopy was performed with a Golden Gate ATR unit. Highresolution mass spectra were recorded on a MALDI-TOF or a MALDI-Orbitrap. The MALDI-TOF samples were prepared with 2,5dihydroxybenzoic acid as matrix in acetonitrile. Measurements were conducted in reflection mode with an acceleration voltage of 2000 V and an extraction delay time of 70 ns. The MALDI- Orbitrap samples were prepared by dissolving the products in the matrix solution (2,5dihydroxybenzoic acid at 10 mg mL−1 in methanol) and depositing them using the dry droplet method on a multigrid glass slide. Exact

3b, and 3d with boiling points of 2 above 195 °C featured N‑phenylbenzoxazine 1 recovery around 65% with a higher amount of side product formation. 3c, 3e, 3f, and 3g with boiling points of 2 below 170 °C featured a recovery of 1 with yields higher than 92% and with high purity. As illustrative example of benzoxazine recovery, 1H NMR spectra of 3c before and after treatment are shown in Figure 7. Even though 1 was converted to 3 in bulk, those reactions were still chemical equilibrium reactions, as was proven by benzoxazine recovery upon vacuum exposure. The reversible nature of the ring-opening reaction in bulk and the impact of the used thiols were proven and shown successfully. 4053

DOI: 10.1021/acs.joc.6b02727 J. Org. Chem. 2017, 82, 4050−4055

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The Journal of Organic Chemistry

1497, 1245, 945, 817, 770, 743, 695. HRMS (MALDI/Orbitrap): m/z [M+H]+ calcd26 for [C27H42NOS]+ 428.2982; found 428.2983. 4-Methyl-2-((phenyl((benzylthio)methyl)amino)methyl)phenol 3b. Light yellow solid. 1H NMR (200 MHz, DMSO-d6): δ 9.38 (s, 1 H), 7.36−7.07 (m, 7 H), 6.89−6.00 (m, 6 H), 4.72 (s, 2 H), 4.42 (s, 2 H), 3.82 (s, 2 H), 2.09 (s, 3 H).13C NMR (50 MHz, DMSO-d6): δ 152.6, 147.0, 138.8, 128.9, 128.7, 128.4, 128.0, 127.7, 127.2, 126.8, 123.6, 117.2, 114.9, 113.4, 55.0, 49.2, 35.0, 20.4. IR (ATR): ṽ (cm−1) 3350, 3032, 2960, 2859, 1601, 1495, 1247, 952, 820, 764, 695. mp (DSC onset 10 K min−1): 49 °C. HRMS (MALDI/TOF): m/z [M +H]+ calcd26 for [C22H24NOS]+ 350.1573; found 350.1562. 4-Methyl-2-((phenyl((phenylthio)methyl)amino)methyl)phenol 3c. White solid. 1H NMR (200 MHz, DMSO-d6): δ 9.33 (s, 1 H), 7.49−7.40 (m, 2 H), 7.35−7.07 (m, 5 H), 6.87−6.63 (m, 6 H), 5.13 (s, 2 H), 4.34 (s, 2 H), 2.04 (s, 3 H).13C NMR (50 MHz, DMSO-d6): δ 152.5, 146.7, 135.6, 131.8, 129.1, 128.9, 128.0, 127.1, 126.9, 123.4, 117.7, 114.9, 113.7, 59.3, 49.3, 20.3. IR (ATR): ṽ (cm−1) 3164, 3023, 2919, 2859, 1601, 1495, 1247, 825, 769, 738, 688. mp (DSC onset 10 K min−1): 87 °C; HRMS (MALDI/Orbitrap): m/z [M+H]+ calcd26 for [C21H22NOS]+ 336.1417; found 336.1417. 4-Methyl-2-((phenyl((4-nitrophenylthio)methyl)amino)methyl)phenol 3d. Yellow solid. 1H NMR (200 MHz, DMSO-d6): δ 9.38 (s, 1 H), 8.16−8.04 (m, 2 H), 7.65−7.56 (m, 2 H), 7.25−7.12 (m, 2 H, 6.91−6.66 (m, 6 H), 5.40 (s, 2 H), 4.44 (s, 2 H), 2.05 (s, 3 H). 13C NMR (50 MHz, DMSO-d6): δ 152.5, 147.2, 146.4, 144.9, 129.3, 129.0, 128.2, 128.1, 127.1, 123.7, 123.2, 118.2, 114.9, 114.0, 58.1, 49.4, 20.3. IR (ATR): ṽ (cm−1) 3211, 3082, 3019, 2922, 2859, 1594, 1524, 1495, 1339, 1218, 954, 849, 824, 767, 740, 691. mp (DSC onset 10 K min−1): 86 °C; HRMS (MALDI-TOF): m/z [M+H]+ calcd26 for [C21H21N2O3S]+ 381.1267; found 381.1237. 4-Methyl-2-((phenyl((cyclohexylthio)methyl)amino)methyl)phenol 3e. Transparent-yellow oil. 1H NMR (200 MHz, MeOD/ CDCl3): δ 7.22−7.14 (m, 2 H), 6.91−6.67 (m, 6 H), 4.64 (s,1 H), 4.62 (s, 2 H), 4.51 (s, 2 H), 2.61−2.51 (m, 1 H), 2.16 (s, 3 H), 1.92− 1.86 (m, 2 H), 1.71−1.59 (m, 2 H), 1.30−1.16 (m, 6 H). 13C NMR (50 MHz, MeOD/CDCl3): δ 153.4, 148.6, 129.5, 129.2, 129.0, 129.0, 123.9, 119.4, 115.8, 115.5, 54.7, 50.5, 44.3, 34.8, 26.6, 26.2, 20.8. IR (ATR): ṽ (cm−1) 3361, 3027, 2925, 2850, 1598, 1495, 1247, 1227, 948, 884, 816, 748, 691. HRMS (MALDI/Orbitrap): m/z [M+H]+ calcd26 for [C21H28NOS]+ 342.1886; found 342.1889. 4-Methyl-2-((phenyl((butylthio)methyl)amino)methyl)phenol 3f. Transparent-yellow oil. 1H NMR (200 MHz, MeOD/CDCl3): δ 7.22−7.14 (m, 2 H), 6.91−6.65 (m, 6 H), 4.65(s,1 H), 4.61 (s, 2 H), 4.53 (s, 2 H), 2.47 (t, 2 H), 2.15 (s, 3 H), 1.56−1.22 (m, 4 H), 0.83 (t, 3 H). 13C NMR (50 MHz, MeOD/CDCl3): δ 153.1, 148.2, 129.3, 129.0, 128.7, 128.7, 123.6, 119.1, 115.4, 115.2, 56.2, 50.3, 32.6, 31.9, 22.2, 20.5, 13.6. IR (ATR): ṽ (cm−1) 3349, 3027, 2956, 2926, 2860, 1598, 1495, 1455, 1377, 1246, 1197, 1144, 1033, 949, 873, 747, 691. HRMS (MALDI/Orbitrap): m/z [M+H]+ calcd26 for [C19H26NOS]+ 316.1730; found 316.1731. 4-Methyl-2-((phenyl((2,3,4,5,6 pentafluorophenythio)methyl)amino)methyl)phenol 3g. White solid. 1H NMR (200 MHz, MeOD/CDCl3): δ 7.17−7.09 (m, 2 H), 6.91−6.63 (m, 6 H), 5.00 (s,2 H), 4.65 (s, 1 H), 4.47 (s, 2 H), 2.15 (s, 3 H). 13C NMR (50 MHz, MeOD/CDCl3): δ 153.4, 147.5, 129.6, 129.4, 129.3, 129.2, 123.2, 120.4, 116.2, 115.5, 60.9, 49.6, 20.6. IR (ATR): ṽ (cm−1) 3343, 2913, 1643, 1513, 1455, 1289, 1113, 978, 899, 859, 764, 697. mp (DSC onset 10 K min−1): 97 °C. HRMS (MALDI/Orbitrap): m/z [M +H]+ calcd26 for [C21H17NOSF5]+ 426.0946; found 426.0943. Benzoxazine/Thiol Reactions in Bulk. Ring-Opening Reaction. The yield of 3 was estimated by integrating 1H NMR signals (recorded in DMSO-d6) belonging to the methylene groups of the starting material and of the addition reaction product 3a−g, respectively, and calculating the relative amount of methylene groups, respectively (eq 2). 4-Methyl-2-((phenyl((dodecylthio)methyl)amino)methyl)phenol 3a. N-phenylbenzoxazine 1 (0.45 g, 2.0 mmol) and 1-dodecanethiol (2a) (0.41 g, 2.0 mmol) were mixed and the suspension was heated for 5 min at 50 °C. The resulting solution was stirred for 48 h at ambient

mass determination was performed using an atmospheric pressure scanning microprobe MALDI source with a Q Exactive HF Fourier transform orbital trapping mass spectrometer. A nitrogen laser with a wavelength of 337 nm and 60 Hz repetition rate was used for desorption and ionization purpose. Mass spectral acquisition was done in positive mode (m/z 50−750 Da, mass resolving power 240.000 at 200 Da), with fixed automatic gain control and 500 ms injection time from a minimum of 20 positions per droplet. Mass calibration was performed using matrix cluster peaks. Melting points were determined by differential scanning calorimetry (DSC) as the onset of the endothermic melting signal heating at 10 K min−1. Preparation of 6-Methyl-3-phenyl-3,4-dihydro-2H-1,3-benzoxazine 1. The 6-methyl-3-phenyl-3,4-dihydro-2H-1,3-benzoxazine (1) (N-phenylbenzoxazine 1) was prepared according to the literature.17,21,25 Aniline (8.8 g, 95 mmol) and paraformaldehyde (2.9 g, 97 mmol) were dissolved in 110 mL toluene and heated under reflux in a 250 mL three-necked round-bottomed flask equipped with a Dean−Stark device for 18 h. Cresol (10.3 g, 94.5 mmol) and paraformaldehyde (3.8 g, 130 mmol) were added to the mixture, which was heated under reflux for 60 h. The solution was allowed to cool to ambient temperature and the crude product was washed three times with aqueous 0.5 M NaOH, two times with aqueous saturated NaCl solution and two times with distilled water. The organic phase was dried with anhydrous Na2SO4, the toluene was removed at low pressure and the resulting solid was recrystallized from n-hexane. The product was isolated as white crystalline solid (15.9 g, 75%). White solid. 1H NMR (200 MHz, DMSO-d6): δ 7.28−7.17 (m, 2 H), 7.15−7.07 (m, 2 H), 6.93−6.80 (m, 3 H), 6.64−6.58 (m, 1 H), 5.40 (s, 2 H) 4.60 (s, 2 H), 2.19 (s, 3 H). 13C NMR (50 MHz, DMSOd6,): δ 151.7, 147.9, 129.1, 128.1, 127.3, 120.9, 120.4, 117.3, 116.0, 78.6, 48.9, 20.2; IR (ATR): ṽ (cm−1) 3028, 2908, 1599, 1493, 1367, 1217, 943, 815, 800, 745, 684. mp (DSC onset 10 K min−1): 49 °C. Benzoxazine/Thiol Reactions in Solution. Study of Effect of Reactant Concentration on the Ring-Opening and Dissociation Reaction. N-phenylbenzoxazine 1 and 1-dodecanethiol 2a were dissolved in deuterated chloroform with various concentrations from 0.01 to 0.24 M, respectively. For the dissociation reaction adduct 3a was dissolved in deuterated chloroform with various concentrations from 0.01 to 0.24 M, respectively. The equilibrium concentration of 1 was determined after a reaction time of 25 h, respectively, by integrating 1H NMR methylene groups signals belonging to the starting material 1 and adduct 3a (eq 1).

[1]eq /[1]0 =

∫ CH 2(1) ∫ CH 2(1) + ∫ CH 2(3a)

(1)

Study of Effect of Thiols 2 and Solvents on the Ring-Opening and Dissociation Reaction. N-phenylbenzoxazine 1 (0.2 mmol) and the appropriate thiol 2a−g (0.2 mmol) were dissolved in the studied deuterated solvent (1 mL) under inert gas conditions and stirred at room temperature for 25 h. The conversion was determined with 1H NMR spectroscopy. Assuming that the benzoxazine/thiol adduct 3a−g is formed during ring-opening reaction exclusively, the N-phenylbenzoxazine 1 conversion was estimated by integrating 1H NMR signals belonging to the methylene groups of the starting material and of the addition reaction product 3a−g and calculating the relative amount of methylene groups, respectively (eq 2).

Yield of 3/% = 100·

∫ CH 2(3) ∫ CH 2(1) + ∫ CH 2(3)

(2)

4-Methyl-2-((phenyl((dodecylthio)methyl)amino)methyl)phenol 3a. Transparent-yellow oil. 1H NMR (200 MHz, DMSO-d6): δ 9.36 (s, 1 H), 7.21−7.07 (m, 2 H), 6.91−6.59 (m, 6 H), 4.73 (s, 2 H), 4.46 (s, 2 H), 2.59−2.46 (m, 2 H), 2.09 (s, 3 H), 1.58−1.42 (m, 2 H), 1.32−1.16 (m, 18 H), 0.88−0.82 (m, 3 H). 13C NMR (50 MHz, DMSO-d6): δ 152.6, 147.1, 128.8, 128.0, 127.7, 127.1, 123.7, 117.1, 114.9, 113.3, 55.0, 49.0, 31.3, 30.8, 29.8, 29.1, 29.0, 28.9, 28.8, 28.6, 22.1, 20.4, 14.0. IR (ATR): ṽ (cm−1) 3392, 3026, 2920, 2849, 1597, 4054

DOI: 10.1021/acs.joc.6b02727 J. Org. Chem. 2017, 82, 4050−4055

Article

The Journal of Organic Chemistry Notes

temperature. The product 3a was obtained without further purification as a pale yellow oil (72%). 4-Methyl-2-((phenyl((benzylthio)methyl)amino)methyl)phenol 3b. N-phenylbenzoxazine 1 (0.45 g, 2.0 mmol) and benzylthiol (2b) (0.45 g, 2.0 mmol) were mixed and stirred at ambient temperature and after 24 h the solution turned into an oil. After further 24 h stirring at ambient temperature the product was isolated without further purification as a pale yellow solid (96%). 4-Methyl-2-((phenyl((phenylthio)methyl)amino)methyl)phenol 3c. N-phenylbenzoxazine 1 (0.45 g, 2.0 mmol) and thiophenol (2c) (0.45 g, 2.0 mmol) were mixed and after 2 h stirring at ambient temperature the solution became an oil. Further stirring for 2 h at ambient temperature yielded the product as a white solid (99%). 4-Methyl-2-((phenyl((4-nitrophenylthio)methyl)amino)methyl)phenol 3d. N-phenylbenzoxazine 1 (0.45 g, 2.0 mmol) and 4‑nitrothiophenol (3d) (0.31 g, 2.0 mmol) were mixed in a mortar and grinded for a short time. After 15 min at ambient temperature the homogeneous solid melted and turned in to oil after 30 min. The product was yielded as a yellow solid without further purification after 45 min (97%). 4-Methyl-2-((phenyl((cyclohexylthio)methyl)amino)methyl)phenol 3e. N-phenylbenzoxazine 1 (0.45 g, 2.0 mmol) and cyclohexanethiol (2e) (0.24 g, 2.0 mmol) were mixed and the resulting solution was stirred for 48 h at ambient temperature. The product 3e was obtained without further purification as a pale yellow oil (87%). 4-Methyl-2-((phenyl((butylthio)methyl)amino)methyl)phenol 3f. N-phenylbenzoxazine 1 (0.45 g, 2.0 mmol) and 1-butanethiol (2f) (0.18 g, 2.0 mmol) were mixed and the resulting solution was stirred for 48 h at ambient temperature. The product 3f was obtained without further purification as a pale yellow oil (92%). 4-Methyl-2-((phenyl((2,3,4,5,6 pentafluorophenythio)methyl)amino)methyl)phenol 3g. N-phenylbenzoxazine 1 (0.45 g, 2.0 mmol) and 2,3,4,5,6-pentafluorothiophenol (2g) (0.40 g, 2.0 mmol) were mixed. The resulting solution was stirred for 2 min at ambient temperature. After 5 min the oil turned into a solid. The product 3g was obtained without further purification as white solid. (80% in DMSO-d6; containing errors due to continuing reaction in DMSO) Dissociation Reaction of Benzoxazine/Thiol Adducts 3a−g. Benzoxazine/thiol adducts 3a−g were placed in Schlenk tubes and were heated to 90 °C. Schlenk tubes were evacuated (4 Pa) for 6 h to remove the corresponding thiol. The conversions were calculated by comparing integrals of the appropriate methylene groups with δ = 4.57 ppm (N−CH2−C) from N-phenylbenzoxazine 1 and the hydroxyl groups with a chemical shift of δ = 9.7−8.8 ppm (Ar−OH). Integrals in that range represent the corresponding adduct and possible side products. The conversion of adduct to the N‑phenylbenzoxazine 1 was calculated with (eq 3).

Yield of 1/% = 100·

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the financial support from the Bundesministerium für Bildung und Forschung (BMBF) through the NanoMatFutur award (DuroCycleFVK 03XP0001), Prof. Martens at Carl von Ossietzky Universität Oldenburg for the helpful discussions, and the Universitat Autònoma de Barcelona where the initial idea for the work arose.

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1 2

∫ CH 2(1) ∫ OH + 12 ∫ CH 2(1)

(3)

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b02727. Compound characterization spectra (1H and 13C NMR, IR) (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Marc Soto: 0000-0002-3939-0486 Katharina Koschek: 0000-0001-7398-3528 4055

DOI: 10.1021/acs.joc.6b02727 J. Org. Chem. 2017, 82, 4050−4055