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ARTICLES PUBLISHED ONLINE: 22 JULY 2011 | DOI: 10.1038/NCHEM.1089 Efficient hydrogenation of organic carbonates, carbamates and formates indicates alternative routes to methanol based on CO2 and CO Ekambaram Balaraman1, Chidambaram Gunanathan1, Jing Zhang1, Linda J. W. Shimon2 and David Milstein1 * Catalytic hydrogenation of organic carbonates, carbamates and formates is of significant interest both conceptually and practically, because these compounds can be produced from CO2 and CO, and their mild hydrogenation can provide alternative, mild approaches to the indirect hydrogenation of CO2 and CO to methanol, an important fuel and synthetic building block. Here, we report for the first time catalytic hydrogenation of organic carbonates to alcohols, and carbamates to alcohols and amines. Unprecedented homogeneously catalysed hydrogenation of organic formates to methanol has also been accomplished. The reactions are efficiently catalysed by dearomatized PNN Ru(II) pincer complexes derived from pyridine- and bipyridine-based tridentate ligands. These atom-economical reactions proceed under neutral, homogeneous conditions, at mild temperatures and under mild hydrogen pressures, and can operate in the absence of solvent with no generation of waste, representing the ultimate ‘green’ reactions. A possible mechanism involves metal–ligand cooperation by aromatization–dearomatization of the heteroaromatic pincer core. T he hydrogenation of polar bonds, in particular organic carbonyl groups, has captured much attention during the past four decades1–3, mainly due to its synthetic significance as an environmentally benign approach to fundamental synthetic building blocks such as alcohols and amines. Much progress has been made in the hydrogenation of ketones and aldehydes and, more recently, rare examples of the significantly more difficult hydrogenation of esters4,5 and amides6,7 have also been reported. However, the hydrogenation of organic carbonates and carbamates remains a major challenge. Indeed, as far as we know, catalytic hydrogenation of these important families of compounds has never been reported, be it under heterogeneous or homogeneous catalysis. In fact, organic carbonates have been used as solvents in catalytic hydrogenation reactions8. Moreover, the popular amine protecting groups, benzyl carbamates, undergo deprotection by heterogeneous hydrogenation, which involves cleavage of the benzyl–O bond, but with the carbonyl group not being reduced 9. In addition, hydrogenation of cyclic N-acylcarbamates leads to cleavage of the C–N bond without affecting the carbamate group10. Hydrogenation of carbonates and carbamates is of considerable interest conceptually and practically, because these compounds can be readily formed from CO2 or from CO, and their mild hydrogenation would effectively mean indirect hydrogenation of the latter compounds to methanol. In addition, mild hydrogenation of methyl formate, which can be produced from CO2 or CO, is of great interest as an alternative route to the conversion of these gases to methanol. Heterogeneously catalysed hydrogenation of methyl formate under high pressure and temperature has been reported11,12, but we are unaware of reports of homogeneously catalysed hydrogenations. Attempts at homogeneous hydrogenations of formate esters resulted in decomposition to CO and alcohol, with no methanol formation13. Methanol is industrially produced from syngas at high temperatures (250–300 8C) and high pressures (50–100 atm) using a copper-zinc-based oxide catalyst14,15. In contrast, the carbonylation of methanol to methyl formate16,17 or oxidative carbonylation to dimethyl carbonate18,19 occurs under relatively mild conditions, and their mild hydrogenation could provide a desirable route to methanol (Fig. 1). Production of methanol from CO2 by direct hydrogenation under mild conditions is an attractive goal, but a practical catalytic process has not yet been developed20–22. On the other hand, efficient transformation of CO2 to formic acid and its derivatives (for example, methyl formate) is known and well investigated23–29. Heterogeneous hydrogenation of methyl formate to methanol in the gas phase30–33 as well as the liquid phase using a semi batch a CO + MeOH MeOH CO2 + H2 b CO 2H2 O H 1/2 O2 + 2 MeOH MeO CO2 + 2 MeOH OMe O –H2O c 2 MeOH 3H2 3 MeOH OMe O 3H2 MeOH CO2 R NH2 R N H OMe – R 2 MeOH NH2 Figure 1 | Alternative routes to methanol based on methyl formate, dimethyl carbonate and organo-carbamates. a, Synthesis of methyl formate either from CO or CO2 followed by hydrogenation. b, Synthesis of dimethyl carbonate either from CO or CO2 followed by unprecedented hydrogenation. c, Synthesis of organo-carbamates from CO2 followed by unprecedented hydrogenation. 1 Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, 76100, Israel, 2 Department of Chemical Research Support, The Weizmann Institute of Science, Rehovot, 76100, Israel. *e-mail: [email protected] NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry © 2011 Macmillan Publishers Limited. All rights reserved. 609 ARTICLES NATURE CHEMISTRY reactor34 has been reported at elevated temperatures, with low selectivity. However, this method suffers from side reactions such as the formation of CO by-product from the decomposition of methyl formate, making it less attractive. The synthesis of dimethyl carbonate from CO2 is well documented35,36, but to the best of our knowledge the hydrogenation of organic carbonates (such as dimethyl carbonate) to methanol remains unknown25,37. Methods for the synthesis of methyl carbamates from CO2 , methanol and amines have also been reported36,38,39. Thus, catalytic hydrogenation of the organic carbonates, carbamates and formates to methanol under mild conditions could provide an indirect method to obtain methanol from CO2 and from CO (Fig. 1). We have developed several reactions catalysed by pincer complexes based on pyridine4,40–46 and acridine backbones47,48, including the hydrogenation of esters4 catalysed by 1 and, very recently, selective hydrogenation of amides7 to the corresponding alcohols and amines by cleavage of the C–N bond under homogeneous conditions, catalysed by bipyridine-based pincer complex 2. These reactions are thought to involve a new mode of metal–ligand cooperation based on ligand aromatization–dearomatization, which has also led to consecutive water splitting promoted by complex 1 (ref. 49). tBu tBu H N tBu Ru N N P 1 tBu CO 2 H H tBu tBu N P tBu Ru N P Ru N CO N H CO 3 H P tBu Ru N Cl CO 4 Here we report the first examples of catalytic hydrogenation of organic carbonates to alcohols and organic carbamates to alcohols and amines, and homogeneously catalysed hydrogenation of alkyl formates to methanol and the corresponding alcohols. The reactions are selective, proceed efficiently under mild, neutral conditions, have high turnover numbers, and generate no waste. In addition, they also proceed very efficiently under solvent-free conditions. These new reactions provide interesting alternatives for the mild hydrogenation of CO2 and CO to methanol, which is a timely topic in the context of the ‘methanol economy’50. Some key mechanistic insight is also provided. Results and discussion 610 Table 1 | Hydrogenation of dimethyl carbonate to methanol. O MeO OMe 1 or 2 + 3H2 Entry Cat. Solvent pH2 1† 2† 3‡ 4§ 5} 6} 1 1 2 2 2 2 1,4-dioxane 1,4-dioxane THF THF Neat Neat 40 60 10 50 10 10 3 MeOH Δ Time (h) 3.5 1 48 14 2 8 Conv. (%)* .99 .99 96 89 89 .99 Yield (%)* .99 .99 96 88 89 .99 TON 2,500 2,500 960 4,400 890 .990 *Yields of methanol and conversion of dimethyl carbonate were determined by gas chromatography (GC) using m-xylene as an internal standard. †Complex 1 (0.01 mmol), dimethyl carbonate (25 mmol) and 1,4-dioxane (20 ml) were heated in a Parr apparatus at 145 8C. ‡Complex 2 (0.01 mol) and dimethyl carbonate (10 mmol) were heated in a Fischer-Porter tube at 110 8C. § Complex 2 (0.005 mmol), dimethyl carbonate (25 mmol) and dry THF (5 ml) were heated in an autoclave at 110 8C. }Complex 2 (0.01 mmol) and dimethyl carbonate (10 mmol) were heated at 100 8C. of dimethyl carbonate with H2 (10 atm) at 110 8C in tetrahydrofuran (THF) for 48 h yielded 96% of methanol (Table 1, entry 3). It is quite remarkable that this novel hydrogenation reaction can proceed under such mild pressure (10 atm) and with high TON (960). Even higher TONs (4,400) were obtained using complex 2 as a catalyst with 50 atm of dihydrogen (Table 1, entry 4). Remarkably, the hydrogenation of dimethyl carbonate proceeds smoothly under solvent-free conditions with catalyst 2. Thus, performing the reaction at 100 8C resulted in 89% conversion of dimethyl carbonate to methanol after 2 h, and quantitative conversion was observed after 8 h (Table 1, entries 5 and 6). This represents an ultimate green transformation—no solvent, no waste, complete selectivity, quantitative yield and under very mild conditions. Complex 2 also efficiently catalyses the hydrogenation of other organic carbonates to the corresponding alcohols. For example, diethyl carbonate was selectively hydrogenated to ethanol (91%) and methanol (89%) after 8 h in almost complete conversion (93%) and with a good TON (910, based on ethanol). The Table 2 | Hydrogenation of methyl carbamates to methanol and amines. O N H R Entry OMe 2 + 3H2 Carbamate 2 MeOH Δ – R NH2 Amine Alcohol Yield* O 1 N H O N H 97 MeOH 98 MeOH 94 NH2 OMe MeO MeOH NH2 OMe 2 Catalytic hydrogenation of organic carbonates. Complexes 1 and 2 were investigated as catalysts for the catalytic hydrogenation of organic carbonates to alcohols. Dimethyl carbonate was selected as a benchmark substrate for the hydrogenation reactions. Thus, treatment of dimethyl carbonate (25 mmol) with dihydrogen (40 atm) at 145 8C for 3.5 h with a catalytic amount of 1 (0.01 mmol), using 1,4-dioxane as solvent, resulted in complete conversion with selective formation of methanol, with a turnover number (TON) of 2,500 (Table 1, entry 1). With 60 atm of H2 , quantitative formation of methanol was observed even after 1 h (TOF ¼ 2,500 h21), with corresponding consumption of dihydrogen (Table 1, entry 2). Using catalyst 2 (0.1 mol%), reaction DOI: 10.1038/NCHEM.1089 MeO O 3 Pentyl N H OMe NH2 Complex 2 (0.01 mmol), carbamate (1 mmol), H2 (10 atm) and dry THF (2 ml) were heated in a Fischer-Porter tube at 110 8C (bath temperature). *Yields of product (based on MeOH) were analysed by GC using m-xylene as an internal standard. NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry © 2011 Macmillan Publishers Limited. All rights reserved. NATURE CHEMISTRY ARTICLES DOI: 10.1038/NCHEM.1089 Catalytic hydrogenation of carbamates. In still another unprecedented reaction, complex 2 catalyses the hydrogenation of methyl carbamates to methanol and the corresponding amines. Thus, heating a solution of methyl N-benzyl carbamate (1.0 mmol) and dihydrogen (10 atm) with a catalytic amount of complex 2 (0.01 mmol) at 110 8C in THF for 48 h selectively yielded methanol and benzylamine in quantitative yields. Other examples are listed in Table 2. Remarkably, benzyl carbamates were also selectively hydrogenated to yield methanol, the corresponding amines and benzyl alcohol, without cleavage of the benzyl–O bond. Thus, upon treatment of benzyl morpholine-4-carboxylate with H2 (10 atm) at 110 8C in dry THF for 52 h with a catalytic amount of 2 (1 mol%), 88% of benzyl alcohol, 87% of morpholine and 81% of methanol were obtained (Fig. 2a). It is important to note that in the hydrogenolysis of benzyl carbamates, used for deprotection of carbamate-N functional groups catalysed by Pd/C, the deprotected amine and free CO2 (via a carbamic acid intermediate) are formed 9. The reaction occurs by cleavage of the benzyl–O bond, but the carbonyl group is not reduced, unlike the benzyl carbamate hydrogenation reported here (Fig. 2b). complexes 1–4 as catalysts. Reaction of methyl formate and dihydrogen (7 atm) catalysed by 1 (0.1 mol%) at 145 8C in 1,4dioxane yielded 71% of methanol after 30 h (Table 3, entry 1). Performing the reaction under 9 atm of H2 resulted in complete conversion of methyl formate to methanol after 36 h with complete selectivity (Table 3, entry 2). Using a lower temperature, complex 1 (0.01 mmol) was heated with methyl formate (15 mmol) and dihydrogen (10 atm) at 110 8C in THF for 48 h to yield 77% of methanol (Table 3, entry 3). With catalyst 2, under the same conditions (methyl formate/2 ¼ 1,500/1, 10 atm of H2 , 110 8C in THF for 48 h), 96% conversion of methyl formate into methanol was observed (Table 3, entry 4). Importantly, GC analysis of the reaction mixtures indicated the absence of CO, which is a problematic by-product in heterogeneously catalysed hydrogenation of methyl formate35–39. Using 50 atm of H2 , even higher TONs (Table 3, entries 5 and 6) were achieved (up to 4,700) using complex 2. Notably, the air-stable hydrido chloride complex7 4 in the presence of one equivalent of base (relative to Ru) also efficiently catalysed the hydrogenation of methyl formate; in this reaction the actual catalyst 2 is generated in situ by deprotonation of 4. Thus, upon heating a THF solution of complex 4 (0.01 mmol) with KOtBu (0.01 mmol) and methyl formate (15 mmol) at 110 8C under H2 (10 atm) for 48 h, methanol was formed in 91% yield (Table 3, entry 8). No reaction took place in the absence of base (Table 3, entry 9). Importantly, hydrogenation of methyl formate is efficiently catalysed by 2 under solvent-free conditions, as in the case of dimethyl carbonate. Thus, heating a solution of methyl formate (10 mmol) and a catalytic amount of 2 (0.01 mmol) at 80 8C under H2 (10 atm) resulted in quantitative conversion of methyl formate selectively to methanol after 8 h, with the corresponding consumption of dihydrogen (Table 3, entry 10). Like in the case of dimethyl carbonate, this is an ultimate green transformation—no solvent, no waste, complete selectivity, quantitative yield, and under very mild conditions. Under the same solvent-free conditions, catalyst 1 is less effective and affords only 16% conversion of methyl formate. Hydrogenation of other formate esters also proceeds efficiently. Thus, reaction of ethyl formate with H2 (10 atm) at 110 8C in THF for 48 h catalysed by 2 (formate/2 ¼ 1,500/1) resulted in 92% of ethanol and 91% of methanol without formation of CO or ethyl acetate. In the same way, hydrogenation of n-butyl formate catalysed by 2 resulted in 86% conversion and selectively yielded methanol (82%) and n-butanol (84%). Homogeneous hydrogenation of alkyl formates. Finally, we examined the possibility of homogeneous hydrogenation of alkyl formates to methanol and the corresponding alcohols using Mechanistic studies of the hydrogenation of organic carbonates and formates. The mechanism of these unusual hydrogenation reactions is of interest. As we reported, the trans-dihydride 3 is O Cat. 2 a O Ph O 3H2 Ph CH2OH + + MeOH N H N O b O Pd/C H2 Ph CH3 + + CO2 N H Figure 2 | Hydrogenation of a benzyl carbamate. a, Unprecedented hydrogenation to methanol, amine and benzyl alcohol catalysed by 2. b, A common amine deprotection by heterogeneous hydrogenation of benzyl carbamate with cleavage of the benzyl–O bond and liberation of free CO2. reaction was performed under solvent-free conditions under mild pressure ( pH2 ¼ 10 atm) and low temperature (100 8C). In none of these hydrogenations did we observe any formation of alkyl formates. Table 3 | Homogeneously catalysed hydrogenation of methyl formate to methanol. O H Entry 1 2 3 4 5† 6† 7 8‡ 9 10§ Cat. 1 1 1 2 2 2 3 4 4 2 Solvent 1,4-dioxane 1,4-dioxane THF THF THF THF THF THF THF Neat OMe + 2H2 Temp. (88 C) 145 145 110 110 110 110 110 110 110 80 pH2 7 9 10 10 50 50 10 10 10 10 Cat. Δ 2 MeOH Time (h) 30 36 48 48 8 14 48 48 48 8 Conv. (%)* 72 .99 78 96 87 94 84 93 – 99 Yield (%)* 71 99 77 96 85 94 81 91 – 98 TON 710 990 1,155 1,440 4,250 4,700 1,215 1,365 – 980 Complexes 1, 2, 3 or 4 (0.01 mmol), methyl formate (10 mmol for entries 1–2; 15 mmol for entries 3–4, 7–9), H2 and dry solvent (2 ml) were heated in a Fischer-Porter tube at the specified (oil bath) temperature. *Yields of methanol and conversion of methyl formate were analysed by GC using m-xylene as an internal standard. †Complex 2 (0.005 mmol), methyl formate (25 mmol), and THF (5 ml) were heated under H2 pressure in an autoclave. ‡One equiv (relative to Ru) of KOtBu was used. §Complex 2 (0.01 mmol) and methyl formate (10 mmol) were used neat. NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry © 2011 Macmillan Publishers Limited. All rights reserved. 611 ARTICLES NATURE CHEMISTRY dimethyl carbonate to deliver methyl formate, the in situ generated complex 1 (in the absence of dihydrogen) reacts further with excess of dimethyl carbonate, leading to 5 (see Supplementary Information for reaction of 1 with dimethyl carbonate) by the decomposition of dimethyl carbonate to methanol, CO and H2 (note that no CO was observed in the catalytic hydrogenation reactions, because 1 reacts with H2 to form 3). Analogous stepwise hydrogenation was also observed for the case of methyl formate. Upon reaction of methyl formate (2.5 equiv.) with 3 at room temperature, formation of methanol and a complex tentatively assigned as a formaldehyde Ru(II) intermediate 6 was observed after 10 min (Fig. 4b)51. The aldehyde proton of 6 appears as a singlet at 9.21 ppm (0.5 ppm downfield relative to free formaldehyde, which appears at 8.73 ppm in toluene-d8). After prolonged standing at room temperature (6 h), the signal of 6 slowly diminished, together with the formation of the fully characterized, methoxy Ru(II) species 7, which was independently prepared by the addition of methanol to complex 1 (see Supplementary Information). On the basis of the above results and the metal–ligand cooperation by aromatization–dearomatization prevalent in the chemistry of pincer complexes 1 (ref. 44) and 2 (ref. 7), we propose a possible mechanism for the hydrogenation of dimethyl carbonate and methyl formate catalysed by 1 (Fig. 5), although more studies are needed for mechanistic interpretation. Initially, dihydrogen addition by metal–ligand cooperation to complex 1 results in aromatization, to form the coordinatively saturated, trans-dihydride complex 3, as previously observed4. Subsequent hydride transfer to the carbonyl group of the carbonate ligand can lead to intermediate A. This process may involve direct hydride attack on the ester or alternatively dissociation of the pyridyl arm to provide a site for dimethyl carbonate coordination. Deprotonation of the benzylic arm by the adjacent methoxy group can result in liberation of methanol and the formation of a dearomatized intermediate B, bearing a coordinated methyl formate. Dihydrogen addition to B (which may also involve amine arm opening), followed by hydride transfer to methyl formate, can generate a intermediate C. Deprotonation of the benzylic arm by the methoxy group can generate the product methanol and a formaldehyde intermediate 6, which undergoes hydrogenation to the characterized methoxy intermediate 7. Methanol liberation from complex 7 regenerates catalyst 1. Similarly, in the case of hydrogenation of methyl formate, reaction with the dihydride 3 can give intermediate C. Deprotonation P3 1HB O1 C1 RU1 N1 DOI: 10.1038/NCHEM.1089 1HA N2 Figure 3 | X-ray structure of complex 3 (50% probability level). Hydrogen atoms (except hydrides) are omitted for clarity. Selected bond distances (Å) and angles (deg): Ru1–N1 2.101 (3), Ru1–N2 2.251 (3), Ru1–P3 2.252 (1), Ru1–C1 1.821 (4), H1A–Ru1 1.71 (4) Å, (H1B–Ru1 was not refined). N1–Ru1–C1 175.0 (2), N1–Ru1–P3 82.6 (1), N1–Ru1–N2 78.0 (1), N2–Ru1–P3 160.6 (1), N2–Ru1–C1 104.8 (2), C1–Ru1–P3 94.6 (1). formed by treatment of the dearomatized 1 with dihydrogen4. A single-crystal X-ray diffraction study of 3 (Fig. 3) reveals a distorted octahedral geometry around the ruthenium centre, with the CO ligand coordinated trans to the pyridyl nitrogen atom. Complex 3 also catalyses the hydrogenation of methyl formate to methanol (Table 3, entry 7). Reaction of the trans-dihydride 3 with dimethyl carbonate (2.5 equiv.) in toluene-d8 in a sealed NMR tube at 50 8C resulted in the formation of free methyl formate and methanol in 5 min, as observed by 1H NMR, together with the fully characterized, new dearomatized dicarbonyl complex 5 (Fig. 4a and Supplementary Information). Presumably, after reaction with one equivalent of a tBu H N P tBu Ru N H CO O 2 MeO O OMe Δ, –H2, –CO H N H + OMe 2MeOH + tBu P tBu Ru N CO CO 5 3 H b H N tBu Ru N H 3 CO tBu O N P H CH3 H O tBu OMe tBu Ru N H tBu CO O N P + MeOH P tBu Ru N H MeOH 1 CO 7 6 Figure 4 | Reactivities of the saturated Ru(II)–trans-dihydride complex 3, suggesting its intermediacy in the catalytic hydrogenation mechanism. a, Reaction with dimethyl carbonate leads to methyl formate, methanol and complex 5. b, Reaction of complex 3 with methyl formate resulted in methanol, formaldehyde intermediate 6 and methoxy intermediate 7. 612 NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry © 2011 Macmillan Publishers Limited. All rights reserved. NATURE CHEMISTRY ARTICLES DOI: 10.1038/NCHEM.1089 Me O MeO H2 H N OMe MeOH PtBu2 N Ru N Et2 H O PtBu2 H2 Ru CO N Et2 CO H 3 7 H H OMe N O H OMe PtBu2 N N Et2 CO H PtBu2 N Ru Ru N Et2 H H N MeOH CO N Et2 PtBu2 N H O B CO OMe PtBu2 MeOH Ru CO H HH Ru N Et2 PtBu2 6 OMe O O Ru 1 A H H2 N Et2 CO H C Figure 5 | Postulated mechanism for novel, homogeneous hydrogenation of dimethyl carbonate and methyl formate to methanol catalysed by complex 1. The mechanism involves metal–ligand cooperation by aromatization–dearomatization of the heteroaromatic pincer ligand and hydride transfer to the carbonyl group. of the benzylic arm by the methoxy group (as with intermediate B in the case of dimethyl carbonate) leads to methanol and intermediates 6 and 7, as indicated experimentally (Fig. 4b). Further mechanistic studies are in progress. In conclusion, for the first time, selective hydrogenations of the CO2 (and CO)-derived organic carbonates, formates and carbamates to methanol were demonstrated using soluble, well-defined metal complexes as catalysts. The reactions, catalysed by PNN complexes 1–3, proceed efficiently and selectively under mild, neutral conditions using mild hydrogen pressure, without the generation of any waste or by-products (such as CO) and with high TONs. Moreover, the reactions proceed very well also in absence of solvent, as demonstrated for the cases of dimethyl carbonate and methyl formate, representing ultimate ‘green’ reactions. A postulated mechanism involving metal–ligand cooperation is supported by stoichiometric reactions of dimethyl carbonate and methyl formate with dihydride complex 3. 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Discovery of environmentally benign catalytic reactions of alcohols catalyzed by pyridine-based pincer Ru complexes, based on metal–ligand cooperation. Top. Catal. 53, 915–923 (2010). 45. Langer, R., Leitus, G., Ben-David, Y. & Milstein, D. Efficient hydrogenation of ketones catalyzed by an iron pincer complex. Angew. Chem. Int. Ed. 50, 2120–2124 (2011). 46. Gnanaprakasam, B. & Milstein, D. Synthesis of amides from esters and amines with liberation of H2 under neutral conditions. J. Am. Chem. Soc. 133, 1682–1685 (2011). 47. Gunanathan, C. & Milstein, D. Selective synthesis of primary amines directly from alcohols and ammonia. Angew. Chem. Int. Ed. 47, 8661–8664 (2008). 48. Gunanathan, C., Shimon, L. J. W. & Milstein, D. Direct conversion of alcohols to acetals and H2 catalyzed by an acridine-based ruthenium pincer complex. J. Am. Chem. Soc. 131, 3146–3147 (2009). 49. Kohl, S. W. et al. Consecutive thermal H2 and light-induced O2 evolution from water promoted by a metal complex. Science 324, 74–77 (2009). 50. Olah, G. A., Geoppert, A. & Surya Prakash, G. K. Beyond Oil and Gas: The Methanol Economy (Wiley-VCH, 2006). 51. Huang, Y. H. & Gladysz, J. A. Aldehyde and ketone ligands in organometallic complexes and catalysis. J. Chem. Educ. 65, 298–303 (1988). Acknowledgements This research was supported by the European Research Council under the FP7 framework (ERC no. 246837), by the Israel Science Foundation, and by the MINERVA Foundation. D.M. is the Israel Matz Professorial Chair of Organic Chemistry. Author contributions E.B. carried out catalytic experiments, mechanistic studies and contributed to writing the manuscript. C.G. carried out catalytic experiments and contributed to writing the manuscript. J.Z. prepared and crystallized complex 3. L.J.W.S. conducted the X-ray structural study of complex 3. D.M. carried out the design and direction of the project and contributed to writing the manuscript. Additional information The authors declare no competing financial interests. Supplementary information accompanies this paper on www.nature.com/naturechemistry, including synthesis and X-ray structural determination of 3, mechanistic stoichiometric reactions, general procedures for the catalytic hydrogenation reactions, and cif file for 3 (CCDC #826775) and chemical compound information accompanies this paper at www.nature.com/ naturechemistry. Reprints and permission information is available online at http://www. nature.com/reprints. Correspondence and requests for materials should be addressed to D.M. NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry © 2011 Macmillan Publishers Limited. All rights reserved. Communications DOI: 10.1002/anie.201106612 Hydrogenation Unprecedented Catalytic Hydrogenation of Urea Derivatives to Amines and Methanol** Ekambaram Balaraman, Yehoshoa Ben-David, and David Milstein* Catalytic hydrogenation of polar bonds, in particular organic carbonyl groups, has captured considerable attention, because it provides environmentally benign approaches to synthetically important building blocks, such as alcohols and amines.[1] The ease of hydrogenation of carbonyl groups, in which hydride transfer to the carbonyl carbon is involved, generally corresponds to the electrophilicity of this carbon. The lower electrophilicity of the carbonyl group, as a result of resonance effects involving alkoxy or amido groups, makes hydrogenations of esters,[2] amides,[3] and even more so, carbonic acid derivatives, such as organic carbonates, carbamates and urea derivatives, very difficult (Figure 1). The common trend in the reactivity of polar carbonyl groups towards hydrogenation reactions is RC(O)H > RC(O)R’ @ RC(O)OR’ > RC(O)NR2’ @> ROC(O)OR’ > ROC(O)NR2’ > Figure 1. Resonance forms of urea derivatives. R2NC(O)N2R’,[3d] urea derivatives being the most challenging. Indeed, as far as we know, catalytic hydrogenation of urea derivatives has never been reported, be it under heterogeneous or homogeneous catalysis. In fact, alkyl urea compounds have been used as solvents in catalytic hydrogenation reactions. For example, rhodium-catalyzed hydrogenation of carbon monoxide to ethylene glycol under very high pressure (p(H2) = 200 bar) and at elevated temperature (200 8C) using N,N,N’,N’-tetramethylurea (TMU) as an inert solvent was reported.[4] In addition, sugar-urea-salt melts were used as “green solvents” for Rh-catalyzed hydrogenation reactions and found to be sustainable reaction media.[5] [*] Dr. E. Balaraman, Y. Ben-David, Prof. D. Milstein Department of Organic Chemistry The Weizmann Institute of Science, 76100 Rehovot (Israel) E-mail: [email protected] Homepage: http://www.weizmann.ac.il/Organic_Chemistry/milstein.shtml [**] This research was supported by the European Research Council under the FP7 framework, (ERC number 246837), by the Israel Science Foundation, by the MINERVA Foundation, and by the Kimmel Center for Molecular Design. D.M. is the holder of the Israel Matz Professorial Chair of Organic Chemistry. Supporting information, including the general procedure for the catalytic hydrogenation reactions and spectroscopic data for synthesized urea derivatives, for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201106612. 11702 Notably, alkyl and aryl urea compounds are readily synthesized from reactions of amines with CO2 in the presence of various catalysts, such as 1,8-diazabicyclo[5.4.0]undec-7-ene,[6] CsOH,[7] Cs2CO3,[8] Au/polymers,[9] [Bmim]OH[10] or KOH/PEG1000,[11] and by using ionic liquids, N-methylpyrrolidone, and supercritical carbon dioxide as solvents. Transition-metal-catalyzed synthesis of urea derivatives was also reported.[12] Recently, Zhao et al. reported the synthesis of dialkyl urea derivatives from CO2 and amines in the absence of any catalysts, organic solvents, or other additives.[13] In this context, mild hydrogenation of urea derivatives to methanol is very attractive, as it would represent a mild, two-step hydrogenation of CO2 to methanol, which is of intense current interest with regard to hydrogen storage and “methanol economy”.[14, 15] Direct, heterogeneously catalyzed hydrogenation of CO2 to methanol requires harsh conditions of temperature and pressure and suffers from the formation of byproducts such as CO, hydrocarbons, and higher alcohols, making this approach difficult.[16] Moreover, the direct hydrogenation of urea derivatives to the corresponding amines and methanol can also provide an alternative approach for amine protection chemistry,[17] because amines can be protected as urea derivatives by treatment with nontoxic, abundant CO2 under mild conditions. We have developed several unique reactions catalyzed by tridentate PNN and PNP Ru(II) pincer complexes based on pyridine[2a, 18–19] and acridine[20] backbones. These complexes show a new mode of metal–ligand cooperation based on ligand aromatization–dearomatization, which has led to a number of bond activation processes.[21] Recently, hydrogenation of amides[3c] to the corresponding alcohols and amines by selective cleavage of the C N bond under homogeneous conditions, catalyzed by the bipyridine-based pincer complex 1 (Figure 2) was developed. An analogous NHC complex is effective in hydrogenation of nonactivated esters Figure 2. Bipyridylbased PNN Ru(II) to the corresponding alcohols under pincer complex 1. mild conditions.[2f] Complex 1 effectively catalyzes also the novel hydrogenation of organic carbonates to alcohols, organic carbamates to methanol and amines, and alkyl formates to methanol and alcohols, which are of current interest with regard to mild stepwise CO2 hydrogenation to methanol.[22] Here we report the first example of catalytic hydrogenation of urea derivatives. Selective formation of methanol and the corresponding amines takes place by the double cleavage of the robust C N bonds under mild, neutral 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50, 11702 –11705 Scheme 1. Hydrogenation of urea derivatives to methanol and amines. conditions and with no generation of waste, using catalyst 1 (Scheme 1). 1,3-Dimethylurea was selected as a benchmark substrate for the study of hydrogenation of alkyl ureas catalyzed by complex 1. Treatment of 1,3-dimethylurea (1 mmol) and a catalytic amount of complex 1 (1 mol %) with H2 (10 atm) at 110 8C in anhydrous THF resulted in 41 % conversion of dimethylurea to yield methanol (35 % by GC) and methylamine after 48 h (Table 1, entry 1). The gaseous amine was characterized by GC-MS of the gas phase of the reaction mixture and not quantified. A longer reaction time and higher Table 1: Hydrogenation of 1,3-dimethylurea to methanol and methylamine catalyzed by 1. Entry Catalyst 1 [mol %] Reaction conditions[a] p(H2) [atm] t [h] Conversion [%][b] Yield of MeOH [%][b,c] 1 2 3 4 1 1 1 2 10 10 13.6 13.6 48 72 72 72 41 53 61 96 35 52 57 93 [a] Complex 1, 1,3-dimethylurea (1 mmol), H2, and anhydrous THF (2 mL) were heated in a Fischer–Porter tube (100 mL) at 110 8C (bath temperature) for the specified time. [b] Conversion of 1,3-dimethylurea and yields of methanol were determined by GC using m-xylene as an internal standard. [c] MeNH2 was detected in the gas phase (as well as in liquid phase) by GC-MS and not quantified. hydrogen pressure resulted in improved conversion of dimethylurea and yield of methanol (Table 1, entries 2 and 3). Performing the same reaction under 13.6 atm of H2 and 2 mol % of catalyst resulted in a 93 % yield of methanol after 72 h (Table 1, entry 4). Various alkyl and aryl urea derivatives were subjected to hydrogenation at 13.6 atm of hydrogen (Table 2). Hydrogenation of 1,3-dihexylurea yielded methanol and 1-hexylamine in 83 and 87 % yields, respectively, after 72 h (Table 2, entry 2). As expected, the activated urea, 1,3-bis(2-methoxyethyl)urea gave almost quantitative conversion to methanol and 2-methoxyethylamine upon hydrogenation (Table 2, entry 3). Dibenzylurea derivatives underwent hydrogenation in moderate yields (Table 2, entries 5–7), giving methanol, benzyl amines, as well as trace amounts of the corresponding benzyl formamides (detected by GC-MS). Fluoro-dibenzylurea did not undergo defluorination during the hydrogenation (Table 2, entry 7). The hydrogenation of 1,3-diarylurea Angew. Chem. Int. Ed. 2011, 50, 11702 –11705 derivatives proceeded very smoothly to yield methanol and the corresponding aniline derivatives (Table 2, entries 8 and 9). Thus, upon heating a THF solution of 1 (0.02 mmol) and 1,3-diphenylurea (1 mmol) at 110 8C under H2 (12 atm), complete conversion took place to selectively form methanol and aniline in 90 % and 95 % yields, respectively (Table 2, entry 8). Performing the same reaction with a lower catalyst loading (1 mol % of 1) gave moderate yields of methanol (63 %) and aniline (69 %). Even the more sterically hindered tetra-substituted urea derivatives were selectively hydrogenated to yield methanol and the corresponding secondary amines. Thus, heating a THF solution containing 1,1’,3,3’tetramethylurea (1 mmol) and a catalytic amount of complex 1 (2 mol %) under hydrogen pressure (13.6 atm) at 110 8C for 72 h resulted in a 53 % conversion of tetramethylurea (TMU) to methanol (46 %) and N,N’-dimethylamine (Table 2, entry 10); the lower conversion is probably a result of steric reasons. In the case of bis(pentamethylene)urea, 63 % yield of methanol, and 57 % of piperidine (Table 2, entry 11) were obtained. Traces of the corresponding dialkyl formamides were also observed in these cases. Although moderate yields were obtained for the hydrogenation of tetrasubstituted urea, these compounds have been used as inert polar solvents for hydrogenation reaction under very high hydrogen pressure, without undergoing hydrogenation.[4] The observation of traces of formamides (Table 2, entries 5–6 and 10–11) suggests a stepwise hydrogenation reaction, in which a formamide along with one equivalent of amine is initially formed by the cleavage of a C N bond, followed by fast hydrogenation of the formamide, which does not accumulate.[23] In support of faster hydrogenation of formamides as compared with the starting urea derivatives, heating a THF solution of complex 1 (0.02 mmol), bis(pentamethylene)urea and N-formylmorpholine (1 mmol each) at 110 8C for 12 h under H2 (13.6 atm), resulted in almost complete conversion of N-formylmorpholine (to 89 % yield of morpholine and 93 % yield of methanol) and very low conversion (< 2 %) of bis(pentamethylene)urea (to piperidine and methanol; Scheme 2). In addition, partial hydrogenation of bis(pentamethylene)urea did not lead to accu- Scheme 2. Competitive hydrogenation of formamide- and urea- derivatives (conversion of N-formylmorpholine = 95 %, conversion of bis(pentamethylene)urea 2 %). mulation of the corresponding formamide; only methanol and piperidine (31 % and 37 % yields, respectively) were formed after 36 h under 13.6 atm of H2 and 2 mol % of catalyst 1. Stepwise hydrogenation was also observed by us in the hydrogenation of organic carbonates to methanol.[22] In conclusion, hydrogenation of urea derivatives to the corresponding amines and methanol was achieved for the first time. The reaction is selectively catalyzed by a bipyridine- 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 11703 Communications Table 2: Hydrogenation of urea derivatives to amines and methanol catalyzed by complex 1.[a] Entry Urea derivative MeOH (yield [%][b]) Product Amine Yield [%][b] 1[c] 89 2 83 87 3 94 97 4 73 79 5[d] 61 60 6[d] 67 71 7 58 59 8[e] 90 63[f ] 95 69[f ] 9[e] 93 87 10[c,d] 46 11[d] 63 (CH3)2NH 57 [a] Complex 1 (0.02 mmol), urea derivative (1 mmol), H2 (13.6 atm) and anhydrous THF (2 mL) were heated in a Fischer–Porter tube (100 mL) at 110 8C (bath temperature) for 72 h (most of the reactions were repeated twice). [b] Yields of products were determined by GC (using 1 mmol of mxylene as an internal standard). [c] The amines n-propylamine and Me2NH (entries 1 and 10, respectively) were analyzed in the gas phase (as well as in the liquid phase) by GC-MS and not quantified. [d] The corresponding formamides (entries 5–6 and 10–11) were observed by GC-MS and not quantified. [e] p(H2) = 12 atm. [f] Complex 1 (0.01 mmol), 1,3-diphenylurea (1 mmol), H2 (13.6 atm), and anhydrous THF (2 mL) were heated at 110 8C for 72 h. based PNN Ru(II) pincer complex under mild hydrogen pressure and neutral reaction conditions. As alkyl and aryl urea derivatives are readily obtained from CO2 and amines, their hydrogenation offers an environmentally benign, mild, atom economical approach to the indirect transformation of CO2 to methanol, which is of intense current interest with regard to hydrogen storage and “methanol economy”. Received: September 17, 2011 Published online: November 3, 2011 11704 www.angewandte.org . Keywords: catalysis · hydrogenation · methanol · pincer complexes · urea derivatives [1] a) S. E. Clapham, A. Hadzovic, R. H. Morris, Coord. Chem. Rev. 2004, 248, 2201 – 2237; b) M. Ito, T. Ikariya, Chem. Commun. 2007, 5134 – 5142; c) O. W. W. N, A. J. Lough, R. H. Morris, Chem. Commun. 2010, 46, 8240 – 8242. [2] a) J. Zhang, G. Leitus, Y. Ben-David, D. Milstein, Angew. 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J. W. Shimon, Y. Ben-David, M. A. Iron, D. Milstein, Science 2009, 324, 74 – 77 (consecutive light-induced splitting of water to dihydrogen and dioxygen); b) E. Khaskin, M. A. Iron, L. J. W. Shimon, J. Zhang, D. Milstein, J. Am. Chem. Soc. 2010, 132, 8542 – 8543 (N H activation of amines and ammonia); c) C. Gunanathan, B. Gnanaprakasam, M. A. Iron, L. J. W. Shimon, D. Milstein, J. Am. Chem. Soc. 2010, 132, 14763 – 14765 (activation of H2 and NH3 by an acridine-based PNP Ru(II) complex). [22] E. Balaraman, C. Gunanathan, J. Zhang, L. J. W. Shimon, D Milstein, Nat. Chem. 2011, 3, 609 – 614. [23] Heating a THF solution containing N-formylmorpholine (1 mmol) and a catalytic amount of complex 1 (2 mol %) under hydrogen pressure (13.6 atm) using a pressure vessel at 110 8C for 12 h resulted in quantitative conversion of N-formylmorpholine to methanol (91 %) and morpholine (95 %) without decarbonylation of the formyl group. Thus, under our reaction conditions the formamides undergo hydrogenation more readily than urea derivatives. See also Ref. [3b]. 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 11705 Published on Web 11/04/2010 Direct Hydrogenation of Amides to Alcohols and Amines under Mild Conditions Ekambaram Balaraman,† Boopathy Gnanaprakasam,† Linda J. W. Shimon,‡ and David Milstein*,† Department of Organic Chemistry and Department of Chemical Research Support, Weizmann Institute of Science, RehoVot, 76100, Israel Received September 5, 2010; E-mail: [email protected] Abstract: The selective, direct hydrogenation of amides to the corresponding alcohols and amines with cleavage of the C-N bond was discovered. The expected products of C-O cleavage are not formed (except as traces in the case of anilides). The reaction proceeds under mild pressure and neutral, homogeneous conditions using a dearomatized, bipyridyl-based PNN Ru(II) pincer complex as a catalyst. The postulated mechanism involves metal-ligand cooperation by aromatization-dearomatization of the heteroaromatic pincer core and does not involve hydrolytic cleavage of the amide. The simplicity, generality, and efficiency of this environmentally benign process make it attractive for the direct transformations of amides to alcohols and amines in good to excellent yields. Reduction of carboxylic acids and their derivatives plays an important role in organic synthesis, in both laboratory and industrial processes. Traditionally, the reduction is performed using stochiometric amounts of hydride reagents, generating stochiometric amounts of waste.1 A much more attractive, atom-economical approach is a catalytic reaction using H2; however, hydrogenation of carboxylic acid derivatives under mild conditions is a very challenging task,2 with amides presenting the highest challenge among all classes of carbonyl compounds. Very few examples of the important hydrogenation of amides to amines, in which the C-O bond is cleaved with the liberation of water (Scheme 1), were reported.3 C-O cleavage of amides can also be affected with silanes as reducing agents.4 In addition, the interesting hydrogenation of cyclic N-acylcarbamates and N-acylsulfonamides, which involves cleavage of the C-N bond, but does not form amines, was recently reported by Ikariya.5 On the other hand, to the best of our knowledge, selective, direct hydrogenation of amides to form amines and alcohols has not been reported.6 Amines and alcohols are used extensively in the chemical, pharmaceutical, and agrochemical industries.7 Design of such a reaction is conceptually challenging, since the first mechanistic step in amide hydrogenation is expected to be H2 addition to the carbonyl group to form a very unstable hemiaminal which, in the case of primary or secondary amides, spontaneously liberates water to form an imine; further hydrogenation of the imine then leads to amine formation (Scheme 1). This is the basis of the amide hydrogenation mentioned above. For amine and alcohol formation, cleavage of the C-N bond in preference to the C-O bond would be required. We have recently developed new catalytic reactions of alcohols, based on a new mode of metal-ligand cooperation, involving aromatization-dearomatization of pyridine-8 and acridine-derived9 pincer ligands. The dearomatized pyridine-based PNN Ru complex † ‡ Department of Organic Chemistry. Department of Chemical Research Support. 16756 9 J. AM. CHEM. SOC. 2010, 132, 16756–16758 Scheme 1. General Scheme for Hydrogenation of Amides 1 (Figure 1) efficiently catalyzes the dehydrogenative coupling of alcohols to form esters,8b,d,h the hydrogenation of esters to alcohols under mild conditions,8c,h and the novel coupling of alcohols and amines to form amides and H2.8e,h The dearomatized PNP complex 2 is an efficient catalyst for the dehydrogenative coupling of alcohols and amines to form imines.8f Complex 1 is also effective in N-H activation10 and in the unique light-induced splitting of water to hydrogen and oxygen.11 Figure 1. Dearomatized Ru-pincer complexes. We have now prepared the new, dearomatized, bipyridine-based pincer complex 3. Remarkably, 3 efficiently catalyzes the selective hydrogenation of amides to form amines and alcohols (eq 1). The reaction proceeds under mild pressure and neutral conditions, with no additives being required. Since the reaction proceeds well under anhydrous conditions, hydrolytic cleavage of the amide is not involved in this process. Reaction of the new, electron-rich tridentate ligand, BPy-tPNN (5),12 with [RuHCl(PPh3)3(CO)] in THF at 65 °C for 8 h results in substitution of the PPh3 ligands to yield the hydrido chloride pincer complex 4.12 The fully characterized 4 gives rise to a singlet at 107.01 ppm in the 31P{1H}NMR spectrum, and the hydride ligand appears as a doublet at -15.26 ppm (2JPH ) 24.6 Hz) in the 1H NMR spectrum. The “arm” methylene protons give rise to signals at 3.06 and 3.75 ppm (2JHH ) 16.8 Hz and 2JPH ) 10.2 Hz). The carbonyl ligand appears as a doublet at 207.37 ppm (JPC ) 15.0 10.1021/ja1080019 2010 American Chemical Society COMMUNICATIONS Table 1. Hydrogenation of Amides to Alcohols and Amines Selectively Catalyzed by BPy-PNN-Ru(II) Pincer Complex 3a Figure 2. X-ray structure of complex 4 (50% probability level). Hydrogen atoms (except hydride) were omitted for clarity. Selected bond distances (Å): Ru1-N1 2.124(2), Ru1-N2 2.086(2), Ru1-P1 2.2859(7), Ru1-C20 1.861(3). Selected angles (deg): N2-Ru1-C20 173.34(10), N2-Ru1-H1 86.4(9), Cl1-Ru1-H1 170.4(9), N1-Ru1-P1 159.65(6). Hz) in the 13C{1H}NMR spectrum. The structure of 4 was confirmed by a single-crystal X-ray diffraction study (Figure 2), which reveals a distorted octahedral geometry around the ruthenium center, with the CO ligand coordinated trans to the central nitrogen atom of the pincer system and the hydride trans to the chloride. Deprotonation of complex 4 with KOtBu at -32 °C gave the dearomatized, coordinatively unsaturated complex 3 in 94% yield (see Supporting Information (SI)). The hydride ligand of the resulting complex 3 exhibits a doublet at -20.93 ppm (2JPH ) 25.0 Hz) in the 1 H NMR spectrum. The “arm” vinylic proton appears as a singlet at 3.36 ppm and a doublet at 66.56 ppm (JPC ) 48.8 Hz) in the 13C{1H} NMR spectrum, indicating formation of an anionic PNN system. The CO ligand absorbs at 1907 cm-1 in the IR spectrum. We have reported the dehydrogenative coupling of alcohols with amines to form amides, catalyzed by complex 1, with liberation of hydrogen gas.8e,h,13,14 Exploring whether it might be possible to reverse this reaction by the application of H2 pressure, complexes 1-4 were tested as catalysts for the hydrogenation of amides. Thus, upon treatment of N-benzyl-2-methoxyacetamide with H2 (10 atm) at 110 °C (bath temperature) in dry THF for 48 h with a catalytic amount of 1 (1 mol %), 63% of 2-methoxyethanol and 62% of benzyl amine were obtained. Performing the reaction at 140 °C using 1,4-dioxane as solvent did not significantly improve the yield (alcohol yield 66%). Although a modest yield was obtained, it was significant that the reaction was selective and the corresponding secondary amine was not formed. Under the same conditions complex 2 was inactive.8c Importantly, employing complex 3 (1 mol %) as catalyst, hydrogenation of N-benzyl-2-methoxyacetamide under identical conditions (THF, 110 °C) resulted in considerably higher yields of 89% 2-methoxyethanol and 90% benzyl amine (Table 1, entry 1), with C-O hydrogenolysis not taking place at all. Of practical significance, the air-stable complex 4 (stable in air for at least 2 days) in the presence of 1 equiv (relative to Ru) of base also efficiently catalyzes the hydrogenation of amides to alcohols and amines, by generation of the catalyst 3 in situ. Thus, upon heating a THF solution of 4 (0.01 mmol) with KOtBu (0.01 mmol) and N-benzyl-2-methoxyacetamide (1 mmol) at 110 °C under H2 (10 atm) for 48 h, 80% of alcohol and 82% of amine were formed. No reaction took place in the absence of base. Hydrogenation of N-hexyl-2-methoxyacetamide catalyzed by 3 yielded 2-methoxy ethanol and hexyl amine in 91% and 90% yields, respectively (entry 2). Interestingly, N-hexyl-3-methyloxetane-3-carboxamide underwent hydrogenation to the alcohol and amine without hydrogenolysis of the strained oxetane ring (entry 3). The heterocyclic amide, N-hexylfuran-2-carboxamide, was hydrogenated to yield 69% of furfuryl alcohol and 68% of hexylamine (entry 4). The aromatic nonactivated amide, N-benzylbenzamide, was hydrogenated to benzyl a Complex 1, 2, or 3 (0.01 mmol), amide (1 mmol), H2 (10 atm), and dry THF (2 mL) were heated in a Fischer-Porter tube at 110 °C (bath temperature) for 48 h. b Yields of products were analyzed by GC (m-xylene as internal standard). c 1,4-Dioxane (2 mL) at 140 °C. d 1 equiv (relative to Ru) of base was used. e The amines (EtNH2 and MeNH2 for entries 6 and 7 respectively) were analyzed in the gas phase by GC-MS. f In the reactions involving anilide derivatives (entries 9-12), trace amounts of the corresponding secondary amines were detected by GC-MS. g 0.5 mmol of bis-amide was used. h Yield after 32 h. J. AM. CHEM. SOC. 9 VOL. 132, NO. 47, 2010 16757 COMMUNICATIONS alcohol and benzyl amine (entry 5) in a lower yield (57%), probably because of steric reasons. Significantly, the aliphatic nonactivated amides, N-ethylacetamide and N-methylpropionamide, also underwent hydrogenation to yield the corresponding alcohols and amines (71% of ethanol and ethylamine for entry 6 and 68% of n-propanol and methylamine for entry 7). The product gaseous amines were characterized by GC-MS of the gas phase and not quantified. Anilide derivatives were converted into their corresponding alcohols and aniline in excellent yields (91-95%; entries 9-12) along with trace amounts of the secondary amines (detected by GC-MS) under similar conditions. The reaction is also effective for bisamides. Thus, N,N′-(ethane-1,2-diyl)bis(2-methoxyacetamide) (0.5 mmol) was hydrogenated selectively to diamine (77%) and alcohol (78%) using catalyst 3 without formation of monoamine-monoamide (entry 13).15 Noteworthy, tert-amides also underwent hydrogenation almost quantitatively to yield alcohols and secondary amines in equivalent amounts (entries 14-16). Gratifyingly, heating a solution of N-formymorpholine (1 mmol) and complex 3 in THF at 110 °C yielded after 32 h 97% of methanol and 98% of morpholine, formyl decarbonylation not being observed. These results highlight the substantial scope of the selective hydrogenation of amides catalyzed by 3, or by the air-stable 4 with an equivalent of base (which generates 3 in situ). Figure 3. Postulated mechanism for hydrogenation of amides to amines and alcohols catalyzed by complex 3. On the basis of the above results and the known chemistry of the pincer complexes 1 and 28,10 we propose the mechanism depicted in Figure 3. Initially, dihydrogen addition by metal-ligand cooperation8,10,16 to complex 3 results in aromatization, to form the coordinatively saturated, trans dihydride complex A, as reported for complex 1.8c Decoordination of the pyridyl “arm” can provide a site for amide coordination, to give the intermediate B. Subsequent hydride transfer to the carbonyl group of the amide ligand leads to a hemiaminoxy intermediate C, with no formation of free hemiaminal. Deprotonation of the benzylic arm by the adjacent NH group leads to the amine product and a dearomatized intermediate D, bearing a coordinated aldehyde. H2 addition to D forms the aromatic dihydride E, followed by hydride transfer to the aldehyde to generate the alkoxy intermediate F. Deprotonation of the benzylic arm by the alkoxy ligand generates the product alcohol and regenerates catalyst 3. The overall process does not involve a change in the metal oxidation state. We postulate that key to the success of this process is that it does not involve intermediacy of free hemiaminal, avoiding water elimination to give an imine and, subsequently, a secondary amine. 16758 J. AM. CHEM. SOC. 9 VOL. 132, NO. 47, 2010 In conclusion, amides can be selectively and directly hydrogenated to alcohols and amines (including under anhydrous conditions) for the first time. The reaction proceeds under mild pressure and neutral, homogeneous conditions using a BPy-PNN-Ru(II) hydride pincer catalyst and dihydrogen by a mechanism involving metal-ligand cooperation. This new catalytic protocol exhibits a broad substrate scope providing a variety of amines and alcohols in good to excellent yields.17 The analogous Py-PNN complex 1 is less efficient. The reasons for this are being explored. Acknowledgment. This research was supported by the European Research Council under the FP7 framework (ERC No 246837), by the Israel Science Foundation, and by the Helen and Martin Kimmel Center for Molecular Design. D.M. is the holder of the Israel Matz Professorial Chair of Organic Chemistry. Supporting Information Available: Experimental procedures and X-ray data for complex 4 in CIF format. This material is available free of charge via the Internet at http://pubs.acs.org. References (1) Seyden-Penne, J. Reductions by the Alumino and Borohydrides in Organic Synthesis, 2nd ed.; Wiley-VCH: New York, 1997. (2) (a) Rylander, P. M. Hydrogenation Methods; Academic Press: London, 1985. (b) Hartwig, J. Organotransition Metal Chemistry; University Science Books: Sausalito, CA, 2010; pp 651-655. (3) (a) Hirosawa, C.; Wakasa, N.; Fuchikami, T. Tetrahedron Lett. 1996, 37, 6749. (b) Núñez Magro, A. A.; Eastham, G. R.; Cole-Hamilton, D. J. Chem. Commun. 2007, 3154. (c) Beamson, G.; Papworth, A. J.; Philipps, C.; Smith, A. M.; Whyman, R. AdV. Synth. Catal. 2010, 352, 869. (d) Beamson, G.; Papworth, A. J.; Philipps, C.; Smith, A. M.; Whyman, R. J. Catal. 2010, 269, 93. (4) (a) Fernandes, A. C.; Romao, C. C. J. Mol. Catal. A 2007, 272, 60. (b) Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132, 1770. (5) Ito, M.; Koo, L. W.; Himizu, A.; Kobayashi, C.; Sakaguchi, A.; Ikariya, T. Angew. Chem., Int. Ed. 2009, 48, 1324. (6) Catalytic hydrogenation of amides to amines (Via C-O cleavage, generating water) can be accompanied by hydrolytic C-N cleavage as a side reaction, presumably resulting from catalytic hydrolysis of the amides to acids and amines, followed by hydrogenation of the acids to alcohols: see refs 3b,c. (7) (a) Lawrence, S. A. Amines: Synthesis, Properties and Applications; Cambridge University Press: Cambridge, 2005. (b) Ricci, A. Amino Group Chemistry: From Synthesis to the Life Sciences; Wiley-VCH: Weinheim, 2008. (c) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V. P. Chem. ReV. 2009, 109, 2551. (8) (a) Zhang, J.; Gandelman, M.; Shimon, L. J. W.; Milstein, D. Organometallics 2004, 23, 4026. (b) Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein, D. J. Am. Chem. Soc. 2005, 127, 10840. (c) Zhang, J.; Leitus, G.; BenDavid, Y.; Milstein, D. Angew. Chem., Int. Ed. 2006, 45, 1113. (d) Zhang, J.; Gandelman, M.; Shimon, L. J. W.; Milstein, D. Dalton Trans. 2007, 107. (e) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790. (f) Gnanaprakasam, B.; Zhang, J.; Milstein, D. Angew. Chem., Int. Ed. 2010, 49, 1468. (g) Schwartsburd, L.; Iron, M. A.; Konstantinovski, Y.; Diskin-Posner, Y.; Leitus, G.; Shimon, L. J. W.; Milstein, D. Organometallics 2010, 29, 3817. (h) Milstein, D. Top. Catal. 2010, 53, 915. (9) (a) Gunanathan, C.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 2009, 131, 3146. (b) Gunanathan, C.; Milstein, D. Angew. Chem., Int. Ed. 2008, 47, 8661. (c) Gunanathan, C.; Gnanaprakasam, B.; Iron, M. A.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 2010, 132, 14763. (10) Khaskin, E.; Iron, M. A.; Shimon, L. J. W.; Zhang, J.; Milstein, D. J. Am. Chem. Soc. 2010, 132, 8542. (11) Kohl, S. W.; Weiner, L.; Schwartsburd, L.; Konstantinovski, L.; Shimon, L. J. W.; Ben-David, Y.; Iron, M. A.; Milstein, D. Science 2009, 324, 74. (12) See SI for full details. (13) Coupling of alcohols with amines to form amides and H2 reported after our publication (ref 8e): (a) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672. (b) Zhang, Y.; Chen, C.; Ghosh, S. C.; Li, Y.; Hong, S. H. Organometallics 2010, 29, 1374. (14) Coupling of alcohols with amines to form amides using hydrogen acceptors: (a) Zweifel, T.; Naubron, J. V.; Grützmacher, H. Angew. Chem., Int. Ed. 2009, 48, 559. (b) Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J. Org. Lett. 2009, 11, 2667. (15) The fact that the monoamine-monoamide was not observed, while some starting diamide was still present, suggests that it reacts faster than the diamide, perhaps as a result of coordination of the amine group. (16) (a) Grützmacher, H. Angew. Chem., Int. Ed. 2008, 47, 1814. (b) van der Vlugt, J. I.; Reek, J. N. H. Angew. Chem., Int. Ed. 2009, 48, 8832. (17) Complex 3 catalyzes also amide formation by dehydrogenative coupling of alcohols with amines: Balarman, E.; Milstein D. to be published. JA1080019 View Online / Journal Homepage / Table of Contents for this issue ChemComm Dynamic Article Links Cite this: Chem. Commun., 2012, 48, 1111–1113 COMMUNICATION www.rsc.org/chemcomm Efficient hydrogenation of biomass-derived cyclic di-esters to 1,2-diolsw Downloaded by Weizmann Institute of Science on 06 January 2012 Published on 31 October 2011 on http://pubs.rsc.org | doi:10.1039/C1CC15778G Ekambaram Balaraman, Eran Fogler and David Milstein* Received 18th September 2011, Accepted 12th October 2011 DOI: 10.1039/c1cc15778g The unprecedented homogeneous hydrogenation of cyclic di-esters, in particular biomass-derived glycolide and lactide, to the corresponding 1,2-diols is catalyzed by Ru(II) PNN (1) and Ru(II) CNN (2) pincer complexes under mild hydrogen pressure and (in the case of 1) neutral conditions. No racemization was observed when a chiral di-ester was used. The hydrogenation of esters to alcohols is an important transformation and remains a challenging task in the context of ‘‘green and sustainable chemistry (GSC)’’.1 There are relatively few examples of catalytic hydrogenation of esters to alcohols under mild conditions,1,2 which is a difficult process due to the relatively low hydridophilicity (electrophilicity) of the ester carbonyl functionality.2h,3 The complete catalytic hydrogenation of cyclic di-esters to the corresponding 1,2-diols, which is expected to be even more difficult, has never been reported, be it under heterogeneous or homogeneous conditions. The activated ester dimethyl oxalate (DMO) is the most widely reported benchmark substrate employed in studies of homogeneously catalyzed ester hydrogenation to produce 1,2-diols.4 The majority of these reports describe only partial hydrogenation (to methyl glutamate) rather than the complete hydrogenation (to ethylene glycol) whilst complete hydrogenation requires high pressures and high temperatures. For example, Matteoli et al.4b reported the homogeneous hydrogenation of oxalates to ethylene glycol (EG) with 82% yield under a H2 pressure of B200 atm at 180 1C using Ru(CO)2(Ac)2(PBu3) (Ac = acetate) as a catalyst. Elsevier et al. applied Ru-based homogeneous catalysts in the hydrogenation of dimethyl oxalate; an EG yield of 95% was obtained under B70 atm of H2 at 100 1C.4c Homogeneous hydrogenation of chiral methyl lactate to propylene glycol was reported by Ino et al. using ruthenium hydrido borohydride complexes based on bidentate phosphorus and diamine ligands under P(H2) E 50 atm with 30–45% yield.2f–g Ito et al. reported the Ru-catalyzed enantioselective hydrogenation of racemic lactones to chiral diols via dynamic kinetic resolution at 100 1C under 50 atm H2 in 2-propanol containing 25 mol% of KOtBu.2h A few cases of catalytic hydrogenations of lactones to diols were reported.1b,2d–e,h,5 Here we Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: [email protected]; Fax: +972 9346569; Tel: +972 9342599 w Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c1cc15778g This journal is c The Royal Society of Chemistry 2012 report the first catalytic hydrogenation of cyclic di-esters to the corresponding 1,2-diols. Glycolides and lactides are important classes of cyclic di-esters (di-lactones), produced from biomass sources such as glycolic acid (derived from sugar cane) and lactic acid (from fermentation of glucose), via self-esterification, and their efficient hydrogenation can provide a mild approach to 1,2-diols, which are important synthetic building blocks.6 Simple 1,2-diols, such as ethylene glycol (EG) and propylene glycol (PG) are utilized as high value-added specialty chemical intermediates, in the manufacture of biodegradable polyester fibers, unsaturated polyester resins, antifreeze, pharmaceuticals and other important products.7 Currently, these two vicinal diols are industrially produced from petroleum-derived ethylene and propylene via hydration of their corresponding epoxy alkanes under forcing conditions.8 However, as crude oil resources become limited, substitutes for petroleum feedstocks are increasingly sought after; as such, the synthesis of 1,2-diols from biomass-derived compounds is of great interest.9 Such alternative methods which are selective, environmentally benign, and proceed under mild reaction conditions with stable, welldefined catalysts are very desirable. In studies towards the development of ‘green’, atom-economical approaches for various catalytic organic transformations,10 we have developed the acceptorless dehydrogenation of alcohols,11a dehydrogenative coupling of primary alcohols to esters,11b,c direct amidation of alcohols with amines,11d acylation of alcohols using esters,11e amide synthesis from esters and amines,11f and imines from alcohols and amines11g with liberation of molecular hydrogen, and mild hydrogenation of non-activated esters.2c These reactions are catalyzed by pyridine-based PNN [2-(di-tertbutylphosphinomethyl)-6-(diethylaminomethyl)pyridine] and PNP [2,6-bis(di-tert- butylphosphinomethyl)pyridine] pincertype Ru(II) complexes. We have also reported the hydrogenation of ketones12a and hydrogenation of CO2 and bicarbonate to formate salts using PNP–Fe pincer complexes.12b Recently, we illustrated the selective hydrogenation of amides to the corresponding alcohols and amines by C–N bond activation under mild conditions, catalyzed by the new bipyridine-based pincer complex 1.13 Complex 1 also effectively catalyzes the hydrogenations of CO2– and CO– derived organic carbonates, formates and carbamates to form methanol.14 The recently synthesized analogous N-heterocyclic carbene complex 2 efficiently catalyzes the hydrogenation of simple esters to the corresponding alcohols.2i Here we report that the biomass-derived glycolide and lactide can selectively and efficiently be hydrogenated to the corresponding Chem. Commun., 2012, 48, 1111–1113 1111 View Online Table 2 Catalytic hydrogenation of lactide to propylene glycola Solvent p(H2)/atm Time/h Yieldb (%) Entry Catalyst Lactide 1 2 3c 4e 1 1 1 2 Meso THF Chiral (S,S) THF Chiral (S,S) THF Chiral (S,S) THF 10 10 50 50 48 48 12 12 87 82 91(73)d 67 Downloaded by Weizmann Institute of Science on 06 January 2012 Published on 31 October 2011 on http://pubs.rsc.org | doi:10.1039/C1CC15778G a Fig. 1 Bipyridine-based PNN (1) and CNN-Ru(II) (2) pincer complexes. 1,2-diols under very mild conditions, with no generation of waste. The cyclic di-ester of glycolic acid, glycolide, was chosen as a model substrate for the hydrogenation of cyclic di-esters catalyzed by complexes 115 and 22i (Fig. 1). Heating a 1,4-dioxane solution containing glycolide (1 mmol) and 1 mol% of complex 1 under mild hydrogen pressure (6 atm) at 135 1C (bath temperature) for 36 h resulted in formation of ethylene glycol (EG) as the only product in 61% yield (Table 1, entry 1), with 67% conversion of the glycolide. After removal of the solvent, the obtained crude viscous liquid was analyzed by ESI (electrospray ionization mass spectrometry), showing no formation of polymeric material. Performing the same reaction under similar conditions using 10 atm of H2 resulted after 36 h in 88% of ethylene glycol (Table 1, entry 2). Optimization studies revealed that lower reaction temperatures could be employed using THF as solvent. Thus, heating complex 1 (0.01 mmol) with glycolide (1 mmol) and dihydrogen (10 atm) at 110 1C in 3 mL of dry THF for 48 h in a Fisher–Porter tube yielded 93% of ethylene Scheme 1 Catalytic hydrogenation of glycolide to ethylene glycol. Table 1 Catalytic hydrogenation of glycolide to ethylene glycol (EG) according to Scheme 1a Entry Catalyst Solvent p(H2) Yield of Temp. (1C) (atm) Time/h EGb (%) 1 2 3 4c 5d 6 135 135 110 110 110 110 1 1 1 1 2 2 1,4-Dioxane 1,4-Dioxane THF THF THF THF 6 10 10 50 10 10 36 36 48 12 48 48 61 88 93 85 58 0 a Catalyst (0.01 mmol), glycolide (1 mmol), H2 and dry solvent (3 mL) were heated in a Fischer–Porter tube at the specified (oil bath) temperature. b Yields of ethylene glycol were determined by GC using m-xylene as an internal standard. c Complex 1 (0.02 mmol), glycolide (10 mmol) and THF (5 mL) were heated under H2 pressure in a highpressure reactor. d One equivalent (relative to Ru) of KOtBu was added. 1112 Chem. Commun., 2012, 48, 1111–1113 Catalyst (0.01 mmol), meso or chiral lactide (1 mmol), H2 and dry THF (3 mL) were heated in a Fischer–Porter tube at 110 1C (oil bath temperature). b Yields of propylene glycol were analyzed by GC using m-xylene as an internal standard. c Complex 1 (0.02 mmol), L-lactide (10 mmol) and THF (5 mL) were heated under H2 pressure in a highpressure reactor. d Isolated yield. e One equivalent (relative to Ru) of KOtBu was used. glycol (Table 1, entry 3). Higher rates were obtained at higher pressure; heating a THF solution of glycolide (10 mmol) and a catalytic amount of complex 1 (0.02 mmol) at 110 1C under H2 (50 atm) using a high pressure reactor resulted after 12 h in the selective formation of ethylene glycol in 85% yield (turnover number 425) (Table 1, entry 4). The bipyridine-based N-heterocyclic carbene complex 22i,16 in the presence of one equiv. of base (relative to Ru) also catalyzed the hydrogenation of gylcolide to ethylene glycol. Upon heating a THF solution of complex 2 (0.01 mmol) with KOtBu (0.01 mmol) and gylcolide (1 mmol) at 110 1C under H2 (10 atm) for 48 h, 58% of ethylene glycol was formed (Table 1, entry 5). The reaction likely proceeds via the in situ deprotonation of 2 to generate a dearomatized complex2i which is the actual catalyst. In the absence of base, no reaction was observed (Table 1, entry 6). Notably, in none of these hydrogenation reactions did we observe (by GC and GC-MS) any formation of partially hydrogenated products, even after shorter reaction times. The optimized catalytic conditions were employed in the hydrogenation of lactide, the ester derivative of lactic acid (a glucose fermentation product). Thus, upon hydrogenation of meso-lactide with H2 (10 atm) at 110 1C in THF for 48 h with 1 mol% of 1, propylene glycol (1,2-propanediol) was obtained selectively in 87% yield (Table 2, entry 1). Significantly, the hydrogenation of the chiral L-lactide catalyzed by complex 1 yielded optically pure (S)-(+)-1,2-propanediol as the sole product, without racemization even under high pressure (Scheme 2). Thus, treatment of a THF solution (5 mL) of L-lactide (10 mmol) with dihydrogen (50 atm) at 110 1C for 12 h with a catalytic amount of 1 (0.02 mmol) selectively yielded 91% of (S)-(+)-1,2-propanediol (Table 2, entry 3). After removal of the solvent under reduced pressure, the reaction mixture was passed through a short silica gel bed and the 1,2-diol was eluted with CH2Cl2 : MeOH (10 : 1) and concentrated under vacuum to yield 73% of the optically pure 1,2-propanediol. The optical rotation of Scheme 2 Hydrogenation of optically active L-lactide to (S)-(+)1,2-propanediol. This journal is c The Royal Society of Chemistry 2012 Downloaded by Weizmann Institute of Science on 06 January 2012 Published on 31 October 2011 on http://pubs.rsc.org | doi:10.1039/C1CC15778G View Online the isolated 1,2-propanediol (([a]D22 = +27.51, in CHCl3) was essentially the same as reported in the literature (+26.91).17 Complex 2 (0.2 mol%) in the presence of one equiv. of base (relative to Ru) also catalyzed the hydrogenation of L-lactide to optically pure 1,2-propanediol under the same conditions in 67% yield. Thus, under these experimental conditions, no racemization took place.17,18 In conclusion, for the first time, complete hydrogenation of cyclic di-esters was accomplished. The biomass-derived glycolide and lactide were selectively hydrogenated to the corresponding 1,2-diols, catalyzed by well-defined electron rich bipyridine-based PNN and CNN Ru(II) pincer complexes. This offers an environmentally benign, atom economic approach to the indirect transformation of biomass to important synthetic building blocks, ethylene glycol and propylene glycol. The reactions proceed under mild, neutral homogeneous conditions (in the case of the CNN complex, in the presence of catalytic base). Significantly, no racemization took place when a chiral di-ester was used. This research was supported by the European Research Council under the FP7 framework (ERC No 246837), by the Israel Science Foundation, by the MINERVA Foundation and by the Helen and Martin Kimmel Center of Molecular Design. D.M. holds the Israel Matz Professorial Chair of Organic Chemistry. 4 5 6 7 8 9 10 Notes and references 1 (a) S. E. Clapham, A. Hadzovic and R. H. Morris, Coord. Chem. Rev., 2004, 248, 2201–2237; (b) M. Ito and T. Ikariya, Chem. Commun., 2007, 5134–5142; (c) W. W. N. O, A. J. Lough and R. H. Morris, Chem. Commun., 2010, 46, 8240–8242. 2 (a) H. T. Teunissen and C. J. Elsevier, Chem. Commun., 1998, 1367–1368 (aromatic and aliphatic esters were hydrogenated in hexafluoropropan-2-ol using in situ prepared ruthenium complexes at 86 atm of H2 under basic conditions); (b) K. Nomura, H. Ogura and Y. Imanishi, J. Mol. Catal. A: Chem., 2002, 178, 105–114 (methyl phenylacetate was hydrogenated to a mixture of PhCH2CH2OH and PhCH2CO2CH2CH2Ph using in situ prepared Ru catalyst and zinc under 20 atm of H2); (c) J. Zhang, G. Leitus, Y. Ben-David and D. Milstein, Angew. Chem., Int. Ed., 2006, 45, 1113–1115; (d) L. A. Saudan, C. M. Saudan, C. Debieux and P. Wyss, Angew. Chem., Int. Ed., 2007, 46, 7473–7476 (catalyzed by Ru N,P complexes, P(H2) = 50 atm under very basic conditions (catalyst/base = 1/100); (e) S. Takebayashi and S. H. Bergens, Organometallics, 2009, 28, 2349–2351; (f) W. Kuriyama, Y. Ino, O. Ogata, N. Sayo and T. Saito, Adv. Synth. Catal., 2010, 352, 92–96; (g) Y. Ino, W. Kuriyama, O. Ogata and T. Matsumoto, Top. Catal., 2010, 53, 1019–1024; (h) M. Ito, T. Ootsuka, R. Watari, A. Shiibashi, A. Himizu and T. Ikariya, J. Am. Chem. Soc., 2011, 133, 4240–4242; (i) E. Fogler, E. Balaraman, Y. Ben-David, G. Leitus, L. J. W. Shimon and D. Milstein, Organometallics, 2011, 30, 3826–3833; (j) Y. Sun, C. Koehler, R. Tan, V. T. Annibale and D. Song, Chem. Commun., 2011, 47, 8349–8351. 3 (a) A. J. McAlees and R. McCrindle, J. Chem. Soc., 1969, 2425–2435; (b) F. A. Carey and R. J. Sundberg, Advanced This journal is c The Royal Society of Chemistry 2012 11 12 13 14 15 16 17 18 Organic Chemistry, Kluwer Academic/Plenum, New York, 4th edn, 2000. (a) R. A. Grey, G. P. Pez and A. Wallo, J. Am. Chem. Soc., 1981, 103, 7536–7542; (b) U. Matteoli, G. Menchi, M. Bianchi, P. Frediani and F. Piacenti, J. Organomet. Chem., 1995, 498, 177–186; (c) M. C. van Engelen, H. T. Teunissen, J. G. de Vries and C. J. Elsevier, J. Mol. Catal. A: Chem., 2003, 206, 185–192 and references therein; (d) B. Boardman, M. J. Hanton, H. van Rensburg and R. P. Tooze, Chem. Commun., 2006, 2289–2291. Y. Hara, H. Inagaki, S. Nishimura and K. Wada, Chem. Lett., 1992, 1983–1986. Heterogeneous hydrogenation of lactic acid to propylene glycol: (a) R. D. Cortright, M. Sanchez–Castillo and J. A. Dumesic, Appl. Catal., B, 2002, 39, 353–359 (Using 10 wt% of Cu/SiO2 as catalyst at 200 1C and 0.72 MPa of hydrogen pressure, achieving 1,2propanediol with 88% selectivity, in addition to 2-hydroxy propionaldehyde (3%), propionic acid (6%) and propyl alcohol (3%) as by-products under vapor-phase conditions); (b) A. Primo, P. Concepción and A. Corma, Chem. Commun., 2011, 47, 3613–3615 (Reaction conditions: 0.4 mol% of Ru (0.64%)/TiO2, T = 150 1C, P(H2) = 32 bar, t E 18 h. The yield of propylene glycol was B87%). (a) G. H. Xu, Y. C. Li and H. J. Wang, Ind. Eng. Chem. Res., 1995, 34, 2371–2378; (b) J. Lauridsen, J. Am. Oil Chem. Soc., 1976, 53, 400–405. T. Haas, B. Jaeger, R. Weber and S. F. Mitchell, Appl. Catal., A, 2005, 280, 83–88. Heterogeneous hydrogenolysis of glycerol to propylene glycol and ethylene glycol: (a) A. Yin, X. Guo, W. Dai and K. Fan, Green Chem., 2009, 11, 1514–1516; (b) J. Zhou, L. Guo, X. Guo, J. Mao and S. Zhang, Green Chem., 2010, 12, 1835–1843. For recent reviews: see (a) D. Milstein, Top. Catal., 2010, 53, 915–923; (b) C. Gunanathan and D. Milstein, Top. Organomet. Chem., 2011, 37, 55–84; (c) C. Gunanathan and D. Milstein, Acc. Chem. Res., 2011, 44, 588–602. (a) J. Zhang, M. Gandelman, L. J. W. Shimon and D. Milstein, Organometallics, 2004, 23, 4026–4033; (b) J. Zhang, G. Leitus, Y. Ben-David and D. Milstein, J. Am. Chem. Soc., 2005, 127, 10840–10841; (c) J. Zhang, M. Gandelman, L. J. W. Shimon and D. Milstein, Dalton Trans., 2007, 107–113; (d) C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007, 317, 790–792; (e) B. Gnanaprakasam, Y. Ben-David and D. Milstein, Adv. Synth. Catal., 2010, 352, 3169–3173; (f) B. Gnanaprakasam and D. Milstein, J. Am. Chem. Soc., 2010, 133, 1682–1685; (g) B. Gnanaprakasam, J. Zhang and D. Milstein, Angew. Chem., Int. Ed., 2010, 49, 1468–1471. (a) R. Langer, G. Leitus, Y. Ben-David and D. Milstein, Angew. Chem., Int. Ed., 2011, 50, 2120–2124; (b) R. Langer, Y. DiskinPosner, G. Leitus, L. J. W. Shimon, Y. Ben-David and D. Milstein, Angew. Chem., Int. Ed., 2011, 50, 9948–9952. E. Balaraman, B. Gnanaprakasam, L. J. W. Shimon and D. Milstein, J. Am. Chem. Soc., 2010, 132, 16756–16758. E. Balaraman, C. Gunanathan, J. Zhang, L. J. W. Shimon and D. Milstein, Nat. Chem., 2011, 3, 609–614. Complex 1 also catalyzes the hydrogenation of simple non-activated esters to the corresponding alcohols. Unpublished results. Complex 2 is stable at 35 1C for about 3 months (under atmosphere of N2) and stable at room temperature for about 4 days under open air without decomposition. See ESIw for more details. See ESIw for full details. Minor racemization (B6%) was reported in the hydrogenation of methyl L-lactate (ref. 2f–g). Chem. Commun., 2012, 48, 1111–1113 1113 Communications DOI: 10.1002/anie.201105876 Homogeneous Catalysis Synthesis of Peptides and Pyrazines from b-Amino Alcohols through Extrusion of H2 Catalyzed by Ruthenium Pincer Complexes: LigandControlled Selectivity** Boopathy Gnanaprakasam, Ekambaram Balaraman, Yehoshoa Ben-David, and David Milstein* Peptides constitute one of the most important families of compounds in chemistry and biology. Short peptides have found intriguing biological and synthetic applications. For example, the conformational rigidity of cyclic peptides makes them attractive for drug discovery and biomedical research.[1] Several cyclic peptides that show intriguing biological activity are found in nature.[2] Cyclic peptides have been discovered that are novel antibiotics,[3] enzyme inhibitors,[4] and receptor antagonists. Among them are the smallest cyclopeptides, 2,5diketopiperazines derivatives, which are commonly found as natural products.[5] These compounds exhibit high-affinity binding to a large variety of receptors and show a broad range of biological acitivities,[6] including antimicrobial, antitumoral, antiviral, and neuroprotective effects. 2,5-diketopiperazine derivatives are synthesized in solution or on the solid phase from commercially available and appropriately protected chiral a-amino acids in processes that are usually not atom-economical and generate considerable amounts of waste. Large libraries of cyclic peptides are accessible through solid-phase split-and-pool synthesis,[7] and various methods were developed for their syntheses.[8] Very recently, the synthesis of diketopiperazines from amino acids under microwave irradiation was reported.[9] Green, atom-economical methods for the generation of peptides are highly desirable. We have developed several reactions catalyzed by PNN and PNP RuII pincer complexes based on pyridine,[10, 11] bipyridine,[12, 13] and acridine[14] and have discovered a new mode of metal–ligand cooperation[15] based on ligand aromatization–dearomatization.[16] For example, the PNN RuII pincer complex 1 (Scheme 1) catalyzes the direct synthesis of amides from alcohols and amines with liberation of H2[17] (Scheme 2, Eq. (1)). Several reports on amide formation by [*] Dr. B. Gnanaprakasam, Dr. E. Balaraman, Y. Ben-David, Prof. D. Milstein Department of Organic Chemistry Weizmann Institute of Science 76100 Rehovot, (Israel) E-mail: [email protected] Homepage: http://www.weizmann.ac.il/Organic_Chemistry/milstein.shtml [**] This research was supported by the European Research Council under the FP7 framework, (ERC No 246837), by the Israel Science Foundation, and by the MINERVA Foundation. D.M. is the holder of the Israel Matz Professorial Chair of Organic Chemistry. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201105876. 12240 Scheme 1. PNN- and PNP-type pincer ruthenium complexes. Scheme 2. Reactions of alcohols with amines catalyzed by complexes 1–3. dehydrogenative coupling of amines with alcohols appeared later.[18] Unlike complex 1, the analogous PNP complex 2 (or complex 3 in the presence of an equivalent of base) catalyzes the coupling of amines with alcohols to form imines rather than amides with liberation of H2 and H2O (Scheme 2, Eq. (2)).[19] Herein we report a novel method for peptide synthesis, which involves dehydrogenative coupling of b-amino alcohols with extrusion of H2 catalyzed by complex 1. This environmentally benign and atom-economical reaction proceeds under neutral reaction conditions without the use of toxic reagents, activators, condensing agents, or other additives. With the analogous PNP complex 2, a strikingly different reaction takes place, which leads to pyrazines with extrusion of H2 and H2O. Initially, we were interested to see whether coupling of bamino alcohols with amines can be accomplished and whether racemization would be involved. Reaction of (S)-2-amino-3phenylpropan-1-ol (4), benzylamine, and 1 mol % of the catalyst 1 in toluene at reflux for six hours led to (S)-2-aminoN-benzyl-3-phenylpropanamide 5 in 58 % yield[20a] after column chromatography (Scheme 3). The specific rotation of amide 5 obtained from the catalysis is essentially the same as reported[20b] (+ 16.08). The neutral reaction conditions likely help to prevent racemization. 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50, 12240 –12244 Table 1: Synthesis of cyclic dipeptides from b-amino alcohols catalyzed by complex 1.[a] Entry Scheme 3. Amidation of (S)-2-amino-3-phenylpropan-1-ol (4) with benzylamine catalyzed by 1. Scheme 4. Peptide formation by dehydrogenative coupling of b-amino alcohols. Next, we explored the self-reactions of b-amino alcohols. In principle, dehydrogenative coupling of b-amino alcohols can lead to formation of both cyclic and linear peptides (Scheme 4). Heating a 1,4-dioxane solution containing (S)(+)-2-amino-1-propanol (2 mmol) and 1 (1 mol %) to reflux for 19 h in argon atmosphere resulted in 90 % conversion of the amino alcohol, as determined by GC–MS. Solvent evaporation, dilution of the residue with CH2Cl2, separation of an insoluble solid by filtration, and drying under vacuum gave 72 % poly(alanine) 6 (R = Me in Scheme 4) containing a minor quantity of the cyclic dimer 3,6-dimethylpiperazine2,5-dione 7 a[21] (R = Me in Scheme 4, Table 1, entry 1). The products were characterized by NMR spectroscopy and mass spectrometry. The characteristic peak at 174.9 ppm in the 13 C{1H} NMR spectrum of 6 indicates the presence of a carbonyl group. The specific rotation of the product in acetic acid was 1058. The ESI mass spectrum revealed the formation of a linear polypeptide sequence. The peak with the highest mass-to-charge ratio found by MALDI-TOF spectrometry was at m/z 1644, which corresponds to 23 monomer units (see the Supporting Information). Interestingly, larger substituents in a-position to the amine group lead to the formation of the corresponding cyclic dipeptides as the only products under the same reaction conditions. Thus, a 1,4-dioxane solution of (S)-2-amino-4methylpentan-1-ol heated to reflux with complex 1 (1 mol %) led to isolation of the cyclic dipeptide 3S,6S-3,6-diisobutylpiperazine-2,5-dione (7 b) in 64 % yield after workup (Table 1, entry 2).[22] The product structure was confirmed by NMR spectroscopy and mass spectrometry (see the Supporting Information). The optical rotation (½a20 D ¼478) was very close to the reported value (438), thus indicating Angew. Chem. Int. Ed. 2011, 50, 12240 –12244 b-Amino alcohol Yield[b] [%] Peptide 1 6 72[c] 2 7b 64 3 7c 72 4 7d 78 5 7e 72 6 7f 92 7 7g 99 [a] Complex 1 (0.02 mmol), amino alcohol (2 mmol), and 1,4-dioxane (2 mL) were heated to reflux in argon (oil bath temperature of 135 8C) for 19 h. [b] Yield of isolated product. [c] Including a minor amount of the dipeptide 7 a. that no racemization had taken place.[23] A lower yield of 7 b (52 %) was obtained in toluene as a solvent. Similarly, the use of benzene as a solvent resulted in 48 % yield after 26 h. The melting point of the cyclic dipeptide 7 b was 272 8C, as reported.[23] In contrast to traditional peptide syntheses, which include both solid- and solution-phase methods and produce waste, during this reaction only H2 is formed as a by-product. Activated esters or carboxylic acids or the use of microwave conditions are not required. To explore the synthetic utility of this reaction, various bamino alcohols were studied. A 1,4-dioxane solution containing (2S,3S)-2-amino-3-methylpentan-1-ol (2 mmol) and catalyst 1 (0.02 mmol) was heated to reflux for 19 h and then cooled to room temperature; subsequently the solid product precipitated, was filtered off, and was dried under vacuum to give pure 3-(sec-butyl)-6-(sec-butyl)piperazine-2,5-dione 7 c in 72 % yield (Table 1, entry 3). The structure was confirmed by NMR spectroscopy and mass spectrometry. Under the same conditions, (S)-2-amino-3-methylbutan-1-ol yielded an 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 12241 Communications insoluble solid, which precipitated from the reaction mixture and was isolated by filtration and dried under vacuum to give 78 % of (3S,6S)-3,6-diisopropylpiperazine-2,5-dione 7 d (Table 1, entry 4). The optical rotation of the pure product (528) was essentially the same as reported[24] (54.88). Thus, under the described experimental conditions, no racemization took place. The reaction of (S)-2-amino-3-phenylpropan-1-ol and 1 in 1,4-dioxane at reflux led to 90 % conversion and isolation of the corresponding (3S,6S)-3,6-dibenzylpiperazine-2,5dione[24] 7 e in 72 % yield without racemization (Table 1, entry 5 and the Supporting Information). The reaction of 2amino-2-methylpropan-1-ol under the same conditions gave 100 % conversion with isolation of the corresponding cyclic dipeptide 3,3,6,6-tetramethylpiperazine-2,5-dione 7 f in 92 % yield (Table 1, entry 6). Tricyclic ring systems represent an important structural motif in many naturally existing alkaloids. Such a ring system was readily achieved when (S)-pyrrolidin-2-yl-methanol was employed in the new cyclopeptidation reaction. Thus, heating a 1,4-dioxane solution of (S)-pyrrolidin-2-yl-methanol at reflux in the presence of catalyst 1 led to 100 % conversion of the starting material as determined by GC–MS. After solvent evaporation and subsequent hexane addition to the crude solid, the solid was isolated by filtration and washed with hexane to give optically pure (5aS,10aS)-octahydrodipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione[23] 7 g in 99 % yield (Table 1, entry 7). Pyrazines are biologically important organic compounds and their synthesis[25] is of industrial significance. Interestingly, when RuII PNP complex 2 or 3 in the presence of an equivalent amount of base was used as catalyst, an entirely different reaction took place, which led to pyrazine derivatives of b-amino alcohols rather than to diketopiperazines (Scheme 5). Thus, a toluene solution of isoleucinol with Scheme 5. Synthesis of pyrazines from b-amino alcohols. complex 2 (1 mol %) was heated to vigorous reflux in argon for 24 h, while the reaction progress was monitored by GC– MS, which showed complete conversion of isoleucinol. The solvent was evaporated under vacuum and the residue was purified by silica-gel column chromatography to afford 2,6diisobutylpyrazine 8 a in 53 % yield (Table 2, entry 1). In refluxing 1,4-dioxane, 40 % conversion of the starting material was observed, yielding 15 % of the product 8 a after 24 h. The 1H NMR spectrum exhibits the characteristic aromatic CH signals at 8.27 ppm, and GC–MS confirms the expected molecular weight. The same reaction conducted in open air atmosphere in the presence of complex 2 resulted in isolation of 8 a in 48 % yield. The reaction of isoleucinol in air using complex 3 in the presence of one equivalent of base (relative 12242 www.angewandte.org Table 2: Synthesis of pyrazines from b-amino alcohols catalyzed by complex 2.[a] Entry b-Amino alcohols Yield[b] [%] Pyrazines 1 8a 53 (48)[c] 2 8b 35 3[d] 8c 38 4 8d 45 [a] Complex 2 (0.02 mmol), an amino alcohol (2 mmol), and toluene (2 mL) were heated at vigorous reflux (oil bath temperature 165 8C for 24 h). [b] Yield of isolated product. [c] Reaction performed in air (see the Supporting Information for details). [d] Heated in absence of solvent (oil bath temperature at 165 8C). to Ru) under the same reaction conditions resulted in isolation of 8 a in 50 % yield. The similar yields of 8 a obtained after reaction in argon and in air indicate that air does not play a role as oxidant in the dehydrogenation of the presumed intermediate 1,4-dihydropyrazine to form the pyrazine. Significantly, no cyclic dipeptide was obtained under these conditions. Similar results were obtained with other amino alcohols. Thus, toluene solutions of (S)-2-amino-3-methylbutan-1-ol, (S)-2-amino-4-methylpentan-1-ol, and (S)-2-amino2-phenylethanol were heated at vigorous reflux (bath temperature 165 8C) for 24 h while the reaction progress was monitored by GC–MS. After complete disappearance of the amino alcohol, the crude product was purified by column chromatography to give the corresponding pyrazine products 8 b–d[26, 27] (Table 2). Although mechanistic studies have not been carried out, we believe that first, OH activation of the alcohol by complexes 1 or 2 results in aromatization of the pincer complex. Then H2 liberation leads to the formation of a coordinated aldehyde complex. A sequence involving nucleophilic attack by the amine group of a second amino alcohol molecule on the aldehyde, which is coordinated to the PNN complex 1, would eventually result in a peptide. In the case of the bulky PNP complex 2, which lacks a hemilabile amine “arm”, dissociation of the aldehyde and attack on it by the amino alcohol take place in solution, resulting in an imine (by water liberation from a hemiaminal), eventually leading to a 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50, 12240 –12244 pyrazine after aromatization of a presumed 1,4-dihydropyrazine intermediate. In summary, a new method for peptide-bond formation, in particular selective formation of cyclic dipeptides, and of poly(alanine), was developed using dehydrogenative selfcoupling of b-amino alcohols. The reactions are catalyzed by the dearomatized PNN complex 1 and lead to a variety of biologically important cyclic dipeptides. In striking contrast, the closely related dearomatized PNP complex 2 selectively catalyzes the dehydrogenative coupling of b-amino alcohols to form pyrazines. These unprecedented reactions proceed under neutral reaction conditions and generate no waste, thereby representing a clear departure from traditional synthetic methodology. Received: August 19, 2011 Revised: October 4, 2011 Published online: October 26, 2011 [9] [10] [11] [12] . Keywords: dehydrogenation · homogeneous catalysis · peptides · pyrazines · ruthenium [13] [14] [1] S. Liu, W. Gu, D. Lo, X. 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