Synthesis of Cyclic Imides by Acceptorless Dehydrogenative Coupling

The first example of base-metal-catalyzed dehydrogenative coupling of diols and amines to form cyclic imides is reported. The reaction is catalyzed by...
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Synthesis of Cyclic Imides by Acceptorless Dehydrogenative Coupling of Diols and Amines Catalyzed by a Manganese Pincer Complex Noel Angel Espinosa-Jalapa,† Amit Kumar,† Gregory Leitus,§ Yael Diskin-Posner,§ and David Milstein*,† †

Department of Organic Chemistry and §Chemical Research Support, The Weizmann Institute of Science, Rehovot 76100, Israel S Supporting Information *

Scheme 1. Dehydrogenative Coupling of Alcohols and Amines to Form Cyclic Imides and the Pyridine-Based Pincer Complexes Used in This Study

ABSTRACT: The first example of base-metal-catalyzed dehydrogenative coupling of diols and amines to form cyclic imides is reported. The reaction is catalyzed by a pincer complex of the earth abundant manganese and forms hydrogen gas as the sole byproduct, making the overall process atom economical and environmentally benign.

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yclic imides are an important class of organic compounds, valuable for synthetic, biological and polymer chemistry.1 They are also used for a variety of pharmacological purposes such as sedatives, hypnotics, anticonvulscants, hypotensive agents, antitubercular agents and carcinostatics.1a,2 Several drugs containing the cyclic imide group, such as thalidomide,3 phensuximide,4 buspirone5 and luracidone,6 are on the market and many derivatives are potential drug candidates.7 Because of such high industrial value, an atom economic, sustainable and environmentally benign synthetic route to cyclic imides from cheap starting materials is highly desirable. However, the conventional method for the synthesis of cyclic imides involves harsh thermal conditions and generates stoichiometric amounts of waste.1a,8 Recent developments toward efficient transition metal catalyzed synthesis of cyclic imides include iridium catalyzed three component reaction of nitriles, olefins and water to produce glutarimides;9 palladium catalyzed carbonylative cyclization of o-halobenzoates and primary amines to form isoindole-1,3-diones;10 ruthenium catalyzed carbonylation of aromatic amides to form phthalimides,11 and rhodium catalyzed conjugate addition of phenyl boronic acids to unprotected maleimides.12 Asymmetric cyclic imides have also been synthesized using rhodium catalysts.13 Drawbacks of these methods include expensive and toxic noble-metal based systems, limited availability of appropriate starting materials and, in some cases, waste generation. Fe3(CO)12 catalyzed carbonylation of alkynes using excess ammonia and CO pressure to form succinimides has also been reported.14 Hong reported the synthesis of cyclic imides from diols and amines using a ruthenium catalyst,15 and recently the coupling of nitriles and diols to form cyclic imides catalyzed by RuH2(PPh3)4.16 Both these synthetic methods use ruthenium (5 mol %) and base (20 mol %). Herein we report the first base-metal (manganese) catalyst for the dehydrogenative coupling of diols with amines (Scheme 1). Both the substrate diols and amines are inexpensive and readily available, and the reaction generates valuable dihydrogen as the only byproduct. © 2017 American Chemical Society

This makes the overall process atom economical and environmentally benign. Hydrogenation and dehydrogenation reactions catalyzed by Mn pincer complexes became a hot area of research, after our initial report on Mn catalyzed dehydrogenative coupling of alcohols and amines to form imines.17 We have recently reported the synthesis and reactivity of the Mn(I) complex 1 bearing a pyridine-based PNNH pincer ligand.17d In the presence of a base, complex 1 showed high catalytic activity for a broad-scope hydrogenation of nonactivated esters under mild conditions. The active catalyst was characterized as the amido complex 2, which was prepared by the deprotonation of 1 and also generated in situ (Scheme 1). H2 activation takes place by metal−ligand cooperation (MLC),18 in which the manganese metal center and the PNNH-pincer ligand participate synergistically. We now report that the manganese complex 1, in the presence of a catalytic amount of KH, catalyzes the atom-economical and environmentally benign synthesis of cyclic imides from diols and amines (Scheme 1). Several years ago, we reported the dehydrogenative coupling of alcohols and amines to form amides, involving metal−ligand cooperation, catalyzed by a Ru-PNN* (the asterisk denotes the dearomatized ligand) complex 4,19 which can be obtained by treatment of the hydrido chloride complex 3 by a base. We have now synthesized the analogous Mn−PNN complexes 5 and 6. Complex 5 was prepared by the reaction of Mn(CO)5Br with the PNN ligand in THF. It was isolated in 88% yield and characterized by NMR and IR spectroscopy and single crystal X-ray diffraction. Upon addition of 1.2 equiv of KOtBu to a suspension of 5 in pentane, the solution became dark green, yielding the dearomatized Mn−PNN* complex 6 that was Received: August 7, 2017 Published: August 10, 2017 11722

DOI: 10.1021/jacs.7b08341 J. Am. Chem. Soc. 2017, 139, 11722−11725

Communication

Journal of the American Chemical Society

open system 7a was obtained quantitatively). Thus, 3.7 equiv of hydrogen gas was collected per one equivalent of cyclic imide. The catalytic activity of the PNNH complex 1 was also compared with that of the ruthenium PNN complex 3. Reaction of 1,4-butanediol with benzylamine in the presence of 3 (5 mol %) and KH (10 mol %) resulted in the formation of 7b in 59% yield after 24 h. Under the same conditions, when complex 1 (5 mol %) and KH (10 mol %) were used, 48% of the cyclic imide was obtained after 24 h exhibiting comparable catalytic activity relative to ruthenium. On the other hand, the Mn−PNN complex 5, analogous to the Ru complex 3, is not catalytically active. Following the facile synthesis of succinimide derivatives from 1,4-butanediol, we explored the possibility of the synthesis of N-substituted glutarimides from 1,5-pentanediol and various amines (see SI, Table S5). Preliminary studies of the reaction of 1,5-pentenediol under conditions established for the synthesis of N-benzyl succinimides afforded the desired N-benzyl glutarimide in only 12% yield, along with other unidentified products. Using a higher catalyst loading (10 mol %) and lower substrate concentration (0.125 M) glutarimide derivatives were isolated in good to moderate yields (49−72%). Reaction of the more challenging 1,3-propanediol and 4-methylbenzylamine under conditions described in Table 1 (same as that of 7a) did not result in any consumption of amine after 40 h and no formation of lactone or amide was observed by 1H NMR spectroscopy and GC−MS. Investigating the mechanism of cyclic imide formation, we first studied the catalytic dehydrogenation of diols. When a toluene solution containing 1 mmol of 1,2-benzene-dimethanol, complex 1 (1 mol %) and KH (2 mol %) was refluxed under argon atmosphere for 18 h, quantitative conversion of the diol was observed to give phthalide in 99% yield. The aliphatic 1,4butanediol and 1,5-pentanediol were also successfully dehydrogenated, yielding γ-butyrolactone and δ-valerolactone respectively (see SI, Table S6). The dehydrogenative cyclization of diols to lactones was mainly reported with noble metals such as ruthenium, iridium and palladium.20 Beller recently reported the synthesis of lactones from diols catalyzed by an iron(II) pincer complex with a wide substrate scope.21 The catalytic activity of the Mn complex 1 reported here is similar to that of the iron complex. Very recently, dehydrogenative coupling of alcohols to form esters catalyzed by a Mn pincer complex was reported by Gauvin.17e The facile dehydrogenation of diols to form lactones suggests that a lactone might be an intermediate in the formation of imides from diols. In fact, the reaction of γ-butyrolactone with 4-methylbenzylamine catalyzed by 1 (5 mol %) and KH (10 mol %) resulted in 68% conversion of the amine with 65% yield of the corresponding cyclic imide, along with unreacted γbutyrolactone (20%) after 28 h (Scheme 2, n = 1). The reaction of δ-valerolactone with 4-methylbenzylamine rendered quantitative conversion of the amine after 28 h with 78% isolated yield of the corresponding cyclic imide (Scheme 2, n = 2). When the reaction of γ-butyrolactone with 4-methylbenzylamine was conducted in the absence of catalyst, 50% consumption of 4-methylbenzylamine was observed by NMR spectroscopy after 40 h. Hydroxyamide was isolated in 48% yield along with the unreacted γ-butyrolactone (50%) and no cyclic imide was observed after the reaction. This suggests that the manganese catalyst is essential for the formation of cyclic imides as also previously reported by Hong in case of a ruthenium catalyst.15

isolated in 79% yield (see SI for the synthesis and characterization of complexes 5 and 6). The new complex 6 was first tested for the synthesis of cyclic imides. However, no reaction was observed upon refluxing a toluene solution (2 mL) of 1,4butanediol (1 mmol) and 4-methyl-benzylamine (1 mmol) for 40 h in the presence of 6 (5 mol %) or in the presence of 5 (5 mol %) and KH (10 mol %, see SI, Table S4). On the other hand, using catalyst 1 (5 mol %) and KH (5 mol %) under the same reaction conditions, 87% conversion of the amine was observed after 40 h to give the correspondig succinimide in 72% isolated yield (Table S4, Entry 5). Increasing the amount of base to 10 mol % resulted in the quantitative conversion of the amine and the product succinimide was isolated in 92% yield (Table 1, 7a). Under these catalytic conditions, aromatic Table 1. Synthesis of N-Substituted Succinimide Derivativesa,b

a

Conversions based on consumption of the amine, determined by 1H NMR and GC−MS with mesitylene as internal standard. All reactions were performed in open Schlenk tube under argon bYields of isolated product in brackets. cReaction conditions: [Mn] = 1 (5 mol %), KH (10 mol %), toluene (2 mL), 1,4-butanediol (1.0 mmol), amine (1.0 mmol), internal standard (mesitylene, 1 mmol), reflux, 40 h. d1,4Butanediol (0.5 mmol), amine (0.5 mmol), internal standard (mesitylene, 0.5 mmol). e1,4-Butanediol (0.5 mmol), amine (0.25 mmol), and internal standard (mesitylene, 0.5 mmol).

amines were converted to succinimide derivatives in good to excellent isolated yields (7a−j). In the case of hexylamine, quantitative conversion of the amine was observed under analogous catalytic conditions, but the respective succinimide was isolated in only 29% yield, along with unidentified products. However, performing the reactions at lower concentration (0.25 M of diols and amines) improved the yield of the N-alkyl substituted imides. The low isolated yields (42−67%) in the case of aliphatic amines are a result of formation of some uncharacterized byproducts (7k−p). In the case of tert-butylamine and 4-methylaniline, formation of cyclic imides was not observed and 1H NMR spectroscopy showed only formation of lactone along with the unreacted amines. For the detection of hydrogen gas, a reaction for the synthesis of 7a was performed in a closed Schlenk tube under the conditions of Table 1 for the synthesis of 7a. Analysis of the gas phase after 40 h by GC showed formation of H2. Using a gas-buret, 56 mL of gas were collected (see SI for details), and 1H NMR spectroscopy showed the formation of 63% yield of 7a (in an 11723

DOI: 10.1021/jacs.7b08341 J. Am. Chem. Soc. 2017, 139, 11722−11725

Communication

Journal of the American Chemical Society Scheme 2. Reaction of Lactones with Aminesa

Scheme 4. Proposed Mechanism for the Dehydrogneative Coupling of Diols and Amines to Form Cyclic Imides

a Conditions for (I): [Mn] 1 (5 mol %), KH (10 mol %), toluene (2 mL), reflux 28 h, lactone (1 mmol for n = 1 and 0.5 mmol for n = 2), 4-methylbenzylamine (1 mmol for n = 1 and 0.5 mmol for n = 2).

We further studied the reaction of 1,5-pentanediol with 4methyl benzylamine, under identical condition to those used for the synthesis of glutarimide derivatives (Table S5), and monitored the reaction by NMR spectroscopy. Interestingly, when the reaction was stopped after 1 h, a mixture of hydroxyamide (B) and lactone was obtained in 14% and 22% yields, respectively, whereas formation of glutarimide was not observed at this stage (Scheme 3I). Over time, a white

dehydrogenation of D can lead to the cyclic imide (Scheme 4). Noteworthy, Hong reported a mechanism for the Rucatalyzed reaction which excludes lactone intermediacy.15a Exploring the role of the metal complex, we strongly believe that deprotonation of N−H proton is important for the formation of active catalyst, as the dearomatized -NEt2 manganese complex 6 is catalytically inactive. In a control experiment, when the independently prepared amido complex 2 was used as the catalyst under the condition described in Table 1, 68% of succinimide was obtained starting from 1,4butanediol and 4-methylbenzylamine, confirming that 2 is an active catalyst. Further, we studied the stoichiometric reactivity of the deprotonated manganese complex 2 with diols. Addition of 2 equiv of 1,4-butanediol to the dark blue solution of complex 2 in tol-d8 at room temperature resulted in an immediate color change to dark red and formation of a new complex, characterized as the manganese alkoxy complex 8. The IR spectrum of 8 exhibits two strong absorption bands at 1832 (νasym) and 1915 cm−1 (νsym) in 1:1 ratio, in agreement with an approximately 90° angle between the two CO ligands. A signal at 2937 cm−1 was assigned to ν(N−H). In the 1H NMR spectrum, the OCH2R and NH protons resonate at 3.45 (brs, broad) and 2.97 (brt, 3JHH = 14.6 Hz), respectively. The 31 P NMR spectrum showed a singlet at 116.0 ppm, shifted upfield relative to that of 2 (135.0 ppm).17d Heating a solution of 8 in tol-d8 at 130 °C for 30 min in a sealed NMR tube resulted in appearance of three hydride signals in the 1H NMR spectrum, a doublet centered at −1.41 ppm (JHP = 55.3 Hz), attributed to complex 10,17d and two uncharacterized doublets at −4.62 (JHP = 53.8 Hz) and −7.78 ppm (JHP = 31.6 Hz). γButyrolactone was observed as the main organic product. Attempts to isolate the hydride intermediates were not successful. In line with these observations, we propose a catalytic cycle for the formation of cyclic imides as shown in Scheme 5. The first step is the reaction of the diol with the amido-complex 2 to form the intermediate 8, which can undergo β-hydride elimination of the bound alkoxy group, possibly via amine “arm” opening, to form a hydride intermediate such as 9.22 9 can then react with the amine to form the hydroxyamide B and complex 10. Another possibility is an outer sphere mechanism: the dissociation of alkoxide moiety from 8 followed by hydride and proton extraction to give complex 9 and the free hydroxyaldehyde. Liberation of hydrogen gas from 10 can regenerate the active catalyst 2 as recently reported by us.17d A similar cycle involving B can lead to the amido aldehyde, which can cyclize to the observed imide. In conclusion, we have developed the first base-metal catalyzed synthesis of cyclic imides from the readily available diols and amines. This reaction, catalyzed by a manganese

Scheme 3. Reaction of 1,5-Pentanediol (0.5 mmol) with 4Methylbenzylamine (0.5 mmol) (I) after 1 h, (II) after 40 h and Then Rechargeda

a

Conditions: (i) [Mn] 1 (10 mol %), KH (20 mol %), toluene (4 mL), reflux. (ii) [Mn] 1 (5 mol %), KH (10 mol %), reflux.

precipitate was observed, presumably due to formation of the less soluble glutarimide. After 40 h, glutarimide and B were isolated in 57% and 20% yield, respectively (Scheme 3II). Interestingly, when a separate reaction was carried out for 40 h and then recharged with the catalyst (5 mol % 1 and 10 mol % KH), B was completely consumed after 12 h of recharge and the corresponding glutarimide was isolated in 80% yield (Scheme 3II), see Figure S13 in SI for more details), suggesting that cyclic imide formation occurs via the hydroxyamide intermediate (B). On the basis of the above experiments, we propose that the dehydrogenative coupling of diols and amines proceeds first through diol dehydrogenation to form a hydroxyaldehyde intermediate A (Scheme 4). A then reacts with the amine to form the observed hydroxyamide intermediate B (pathway I). Alternatively, A can also cyclize to form a lactone that can further react with the amine to form the hydroxyamide B (pathway II). Observation of the lactone after 1 h of catalysis (Scheme 3I) and the formation of cyclic imides upon reaction of lactones with amines, as discussed above (Scheme 3II), supports pathway II. However, the observation of hydroxyamide after 1 h of the catalytic reaction (Scheme 3I) suggests that pathway I also operates. The remaining hydroxy group of the hydroxyamide B can then dehydrogenate to form the aldehyde C which can undergo intramolecular cyclization to produce the cyclic hemiaminal intermediate D. Finally, 11724

DOI: 10.1021/jacs.7b08341 J. Am. Chem. Soc. 2017, 139, 11722−11725

Communication

Journal of the American Chemical Society

(3) (a) Shoji, A.; Kuwahara, M.; Ozaki, H.; Sawai, H. J. Am. Chem. Soc. 2007, 129, 1456. (b) Luzzio, F. A.; Duveau, D. Y.; Lepper, E. R.; Figg, W. D. J. Org. Chem. 2005, 70, 10117. (c) Franks, M. E.; Macpherson, G. R.; Figg, W. D. Lancet 2004, 363, 1802. (4) Miller, C. A.; Long, L. M. J. Am. Chem. Soc. 1951, 73, 4895. (5) Wu, Y.-H.; Rayburn, J. W.; Allen, L. E.; Ferguson, H. C.; Kissel, J. W. J. Med. Chem. 1972, 15, 477. (6) Ishiyama, T.; Tokuda, K.; Ishibashi, T.; Ito, A.; Toma, S.; Ohno, Y. Eur. J. Pharmacol. 2007, 572, 160. (7) (a) Verschueren, W. G.; Dierynck, I.; Amssoms, K. I. E.; Hu, L. L.; Boonants, P.; Pille, G. M. E.; Daeyaert, F. F. D.; Hertogs, K.; Surleraux, D.; Wigerinck, P. J. J. Med. Chem. 2005, 48, 1930. (b) Cui, S.- X.; Qu, X.-J.; Gao, Z.-H.; Zhang, Y.-S.; Zhang, X.-F.; Zhao, C.-R; Xu, W.-F.; Li, Q.-B.; Han, J.-X. Cancer Lett. 2010, 292, 153. (c) Li, Q.; Fang, H.; Wang, X.; Xu, W. Eur. J. Med. Chem. 2010, 45, 1618. (d) Machado, K. E.; Oliveira, K. N. D.; Santos-Bubniak, L.; Licínio, M. A.; Nunes, R. J.; Santos-Silva, M. C. Bioorg. Med. Chem. 2011, 19, 6285. (8) (a) Da Settimo, A.; Primofiore, G.; Da Settimo, F.; Simorini, F.; La Motta, C.; Martinelli, A.; Boldrini, E. Eur. J. Med. Chem. 1996, 31, 49. (b) Mehta, N. B.; Phillips, A. P.; Lui, F. F.; Brooks, R. E. J. Org. Chem. 1960, 25, 1012. (9) Takaya, H.; Yoshida, K.; Isozaki, K.; Terai, H.; Murahashi, S.-I. Angew. Chem., Int. Ed. 2003, 42, 3302. (10) Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2008, 73, 7175. (11) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 6898. (12) Iyer, P. S.; O'Malley, M.; Lucas, M. C. Tetrahedron Lett. 2007, 48, 4413. (13) (a) Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T. Angew. Chem., Int. Ed. 2005, 44, 4611. (b) Shintani, R.; Duan, W. L.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 5628. (14) Driller, K. M.; Klein, H.; Jackstell, R.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 6041. (15) (a) Zhang, J.; Senthilkumar, M.; Ghosh, S. C.; Hong, S. H. Angew. Chem., Int. Ed. 2010, 49, 6391. (b) Muthaiah, S.; Hong, S. H. Synlett 2011, 2011, 1481. (16) Kim, J.; Hong, S. H. Org. Lett. 2014, 16, 4404. (17) (a) Mukherjee, A.; Nerush, A.; Leitus, G.; Shimon, L. J. W.; Ben-David, Y.; Espinosa-Jalapa, N. A.; Milstein, D. J. Am. Chem. Soc. 2016, 138, 4298. (b) Elangovan, S.; Topf, C.; Fischer, S.; Jiao, H.; Spannenberg, A.; Baumann, W.; Ludwig, R.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2016, 138, 8809. (c) Elangovan, S.; Neumann, J.; Sortais, J.-B.; Junge, K.; Darcel, C.; Beller, M. Nat. Commun. 2016, 7, 12641. (d) Espinosa-Jalapa, N. A.; Nerush, A.; Shimon, L. J. W.; Leitus, G.; Avram, L.; Ben-David, Y.; Milstein, D. Chem. - Eur. J. 2017, 23, 5934. (e) Nguyen, D. H.; Trivelli, X.; Capet, F.; Paul, J.; Dumeignil, F.; Gauvin, R. M. ACS Catal. 2017, 7, 2022. (f) Mastalir, M.; Glatz, M.; Pittenauer, E.; Allmaier, G.; Kirchner, K. J. Am. Chem. Soc. 2016, 138, 15543. (g) Kallmeier, F.; Irrgang, T.; Dietel, T.; Kempe, R. Angew. Chem., Int. Ed. 2016, 55, 11806. (18) Recent review: Khusnutdinova, J. R.; Milstein, D. Angew. Chem., Int. Ed. 2015, 54, 12236. (19) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790. (20) (a) Fujita, K.-I.; Ito, W.; Yamaguchi, R. ChemCatChem 2014, 6, 109. (b) Zhang, J.; Balaraman, E.; Leitus, G.; Milstein, D. Organometallics 2011, 30, 5716. (c) Musa, S.; Shaposhnikov, I.; Cohen, S.; Gelman, D. Angew. Chem., Int. Ed. 2011, 50, 3533. (d) Ito, M.; Osaku, A.; Shiibashi, A.; Ikariya, T. Org. Lett. 2007, 9, 1821. (e) Zhao, J.; Hartwig, J. F. Organometallics 2005, 24, 2441. (21) Peña-Lopez, M.; Neumann, H.; Beller, M. ChemCatChem 2015, 7, 865. (22) (a) Vuzman, D.; Poverenov, E.; Shimon, L.; Diskin-Posner, Y.; Milstein, D. Organometallics 2008, 27, 2627. (b) Lindner, R.; van den Bosch, B.; Lutz, M.; Reek, J. N. H.; van der Vlugt, J. I. Organometallics 2011, 30, 499.

Scheme 5. Proposed Catalytic Cycle for the Formation of Cyclic Imides

pincer complex, liberates hydrogen as the only byproduct and is environmentally benign.

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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/jacs.7b08341. Experimental and spectroscopic details of the catalytic reactions (PDF) Data for C21H35BrMnN2O2P (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

David Milstein: 0000-0002-2320-0262 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the European Research Council (ERC AdG 692775). D.M. holds the Israel Matz Professorial Chair of Organic Chemistry. N.A.E.-J. thanks Mr. Armando Jinich for a postdoctoral fellowship. A.K. is thankful to the Israel Planning and Budgeting Commission (PBC) for a fellowship.

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REFERENCES

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DOI: 10.1021/jacs.7b08341 J. Am. Chem. Soc. 2017, 139, 11722−11725