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Cite this:Chem. Commun., 2014,

50, 9661

An efficient ruthenium(IV) catalyst for the selectivehydration of nitriles to amides in water under mildconditions†

Eder Tomas-Mendivil, Francisco J. Suarez, Josefina Dıez and Victorio Cadierno*

A Ru(IV) catalyst able to promote the selective hydration of nitriles to

amides in water, at low metal loadings and under mild conditions, is

presented.

Amide bond forming reactions are among the most important andwidely studied transformations in organic chemistry,1 but they alsopresent a contemporary challenge because of the industrial needfor cleaner and more atom-economical protocols.2 Nitrile hydrationideally represents the simplest method for the sustainable prepara-tion of primary amides. However, strong acids and bases combinedwith harsh reaction conditions have been traditionally employed topromote the process, lowering its selectivity and applicability.1,3

In the search of more attractive and selective protocols, greatimprovements have been achieved using enzymes4 and metalcatalysts.5 In this context, significant efforts have been devoted inrecent years to the search of homogeneous catalysts able topromote the selective conversion of nitriles to amides directlyemploying water as a solvent.6 We must note down this point that,although water is the most obvious solvent for this transformation,the vast majority of catalysts reported to date operate in organicmedia on grounds of solubility and stability.5

Ruthenium complexes are particularly effective nitrile hydrationcatalysts, and promising results in water have been described withthe help of hydrophilic phosphine ligands.7 However, high tempera-ture regimes (Z100 1C) and metal loadings (5 mol%) are typicallyneeded to achieve good conversions.8 As a significant improvement,herein we present a new Ru(IV) complex able to catalyze the selectivehydration of a large number of organonitriles in water underremarkably milder conditions (60 1C), and featuring a high activityat a low metal loading (1 mol%).9,10

As shown in Scheme 1, the new complexes [RuCl2(Z3:Z3-C10H16){PR2(OH)}] (R = Ph (2a), Me (2b)) were synthesized inhigh yield by treatment of the commercially available dimer{RuCl(m-Cl)(Z3:Z3-C10H16)}2 (1) with two equivalents of the corres-ponding secondary phosphine oxide R2P(QO)H, via tautomeriza-tion of R2P(QO)H into the phosphinous acids R2P(OH) andcleavage of the chloride bridges of 1.11,12 Compounds 2a,b werecharacterized by means of elemental analysis and multinuclearNMR spectroscopy, the data obtained being fully consistent withthe proposed formulations (see ESI†). In particular, coordinationof the phosphinous acids in the equatorial position was readilyevidenced in the 1H and 13C{1H} NMR spectra by the appearanceof a single set of signals for the two allylic moieties of the2,7-dimethylocta-2,6-diene-1,8-diyl ligand, i.e. the two halves ofthe hydrocarbon chain are in equivalent environments.12 Thispoint was further confirmed by means of a single-crystal X-raydiffraction study on complex 2a (Fig. 1).† An intramolecularH-bonding interaction of moderate intensity (mostly electro-static)13 between the OH unit of the phosphinous acid and oneof the chloride ligands was found in the crystal structure of thiscomplex (distance and angle of the O1–H1O� � �Cl2 contact of2.00(3) Å and 163.9(2)1, respectively).14

The ability of complexes 2a,b to promote the catalytichydration of nitriles in water was evaluated employing benzo-nitrile (3a) as a model substrate (Table 1). Thus, using 5 mol%of 2a, quantitative formation of benzamide (4a) was observedby GC after only 15 min of heating at 100 1C (entry 1). Reductionof the catalyst loading to 1 mol% still produced 4a in 98% yieldwithout a drastic increase in the reaction time (2 h; entry 2).This latter result could be improved using 2b, which led to the

Scheme 1 Synthesis of the bis(allyl)-Ru(IV)-phosphinous acid complexes2a,b.

Laboratorio de Compuestos Organometalicos y Catalisis (Unidad Asociada al CSIC),

Centro de Innovacion en Quımica Avanzada (ORFEO-CINQA), Departamento de

Quımica Organica e Inorganica, IUQOEM, Universidad de Oviedo, 33006 Oviedo,

Spain. E-mail: vcm@uniovi.es

† Electronic supplementary information (ESI) available: Experimental section,characterization data and copies of the NMR spectra of all compounds. CCDC989910 (2a). For ESI and crystallographic data in CIF or other electronic formatsee DOI: 10.1039/c4cc04058a

Received 27th May 2014,Accepted 7th July 2014

DOI: 10.1039/c4cc04058a

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quantitative formation of 4a in 1 h (TOF = 100 h�1; entry 3).Even at 60 1C, a rapid conversion of 3a into 4a was observed byemploying 1 mol% of 2b (entry 4). The reaction could also becompleted at r.t., but 3 days were required in this case (entry 5).It is also worthy of note that a respectable TON of 500 could beachieved using 0.2 mol% of 2b, and performing the hydrationreaction at 60 1C, conditions under which complete transformationof 3a into 4a was again observed (entry 6).15

The scope and functional group tolerance of the most activecatalyst [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b) was subsequentlyexplored. Thus, as shown in Table 2, by performing the reactionsat 60 1C with 1 mol% of this complex, a large variety of aromatic,heteroaromatic, a,b-unsaturated and aliphatic organonitriles 3a–zcould be selectively transformed into the corresponding primaryamides 4a–z without the assistance of any acidic or basic co-catalyst.Concerning the aromatic substrates, a slight influence of theelectronic properties of the aryl rings was observed, with thesubstrates containing electron-donating groups showing a lowerreactivity (e.g., entry 10 vs. 6). Substitution in the ortho position alsoled to a less efficient hydration (e.g., entry 8 vs. 9). The influence ofthe electronic properties of the substrates in the activity of 2b wasalso evidenced with aliphatic substrates. Thus, in comparison withacetonitrile 3v (entry 22), chloroacetonitrile 3w (entry 23) andphenoxyacetonitrile 3x (entry 24) were hydrated much faster as a

result of the higher electrophilicity of the nitrile carbon atom inthese substrates, due to the inductive effects of the chlorine atomand the phenoxy group, respectively. For 3x, an impressive TOF valueof 1188 h�1 was attained at this mild temperature. We would alsolike to stress that, in no case, traces of the corresponding carboxylicacids were detected by GC in the crude reaction mixtures.16

The outstanding performance of complex [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b) was further exploited in the catalyticsynthesis of the antiepileptic drug rufinamide 4aa (marketedunder the trade name Inovelons),17 which could be generatedin 83% isolated yield by hydration of 4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole 3aa (Scheme 2).18

An additional proof of the synthetic utility of [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b) is its ability to promote the challenginghydration of cyanohydrins (a-hydroxynitriles), substrates that arevery difficult to hydrate because they degrade in aqueous mediainto the corresponding carbonyl compounds and HCN. The vastmajority of nitrile hydration catalysts reported to date are inactive

Fig. 1 ORTEP view of the structure of 2a (thermal ellipsoids are drawn at30% probability level). Hydrogen atoms, except that on O1, have beenomitted for clarity. Selected bond distances (Å) and angles (1): Ru–P1 2.3784(7),Ru–Cl1 2.4178(6), Ru–Cl2 2.4540(6), P1–O1 1.6040(18), Ru–C* 2.0065(2), Ru–C** 1.9997(2), Cl1–Ru–Cl2 172.41(2), Cl1–Ru–P1 86.48(2), Cl1–Ru–C* 95.53(2),Cl1–Ru–C** 88.20(2), Cl2–Ru–P1 86.11(2), Cl2–Ru–C* 88.92(2), Cl2–Ru–C**93.51(2), P1–Ru–C* 113.33(2), P1–Ru–C** 115.56(2), C*–Ru–C** 131.11(1). C*and C** denote the centroids of the allyl units (C1, C2 and C4, and C7, C8 andC9, respectively).

Table 1 Catalytic hydration of benzonitrile (3a) to benzamide (4a) in waterusing the ruthenium(IV) complexes 2a,ba

Entry Cat. mol% Ru T (1C) t (h) Yieldb (%) TOF (h�1)

1 2a 5 100 0.25 499 80.02 2a 1 100 2 98 49.03 2b 1 100 1 499 100.04 2b 1 60 3 499 33.35 2b 1 20 72 499 1.46 2b 0.2 60 24 499 20.8

a Reactions were performed under a N2 atmosphere starting from1 mmol of 3a (0.33 M in water). b Determined by GC (uncorrected GC areas).

Table 2 Catalytic hydration of nitriles to amides in water using theruthenium(IV) complex [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b)a

Entry Substrate 3 t (h) Yield of 4b (%) TOF (h�1)

1 R = Ph (3a) 3 499 (89) 33.32 R = C6F5 (3b) 0.5 98 (85) 196.03 R = 2-C6H4Cl (3c) 7 98 (80) 14.04 R = 3-C6H4Cl (3d) 2 499 (74) 50.05 R = 4-C6H4Br (3e) 2 97 (75) 48.56 R = 4-C6H4(COMe) (3f) 1 98 (80) 98.07 R = 3-C6H4NO2 (3g) 0.5 99 (75) 198.08c R = 2-C6H4Me (3h) 16 89 (71) 1.89 R = 4-C6H4Me (3i) 3 95 (87) 31.710 R = 4-C6H4OMe (3j) 8 97 (81) 12.111 R = 4-C6H4OH (3k) 7 95 (73) 13.612 R = 4-C6H4SMe (3l) 4 99 (75) 24.813 R = 2-pyridyl (3m) 6 97 (74) 16.214 R = 3-pyridyl (3n) 0.5 98 (84) 196.015 R = 4-pyridyl (3o) 1 98 (90) 98.016 R = 2-thienyl (3p) 0.5 99 (71) 198.017 R = 3-thienyl (3q) 1 97 (79) 97.018 R = 5-Me-2-furyl (3r) 0.5 499 (72) 200.019 R = 3-furyl (3s) 0.5 499 (76) 200.020 R = CHQCH2 (3t) 3 499 (83) 33.321 R = n-C6H13 (3u) 6 97 (65) 16.222 R = CH3 (3v) 6 499 (87) 16.723 R = CH2Cl (3w) 0.25 499 (80) 400.024 R = CH2OPh (3x) 5 min 99 (92) 1188.025 R = CH2-2-thienyl (3y) 1 499 (87) 100.026 R = CH2CH2OPh (3z) 6 499 (80) 16.7

a Reactions were performed under a N2 atmosphere starting from1 mmol of the corresponding nitrile (0.33 M in water). b Determinedby GC (uncorrected GC areas); isolated yields after the work-up aregiven in brackets. c Reaction performed with 3 mol% of 2b.

Scheme 2 Catalytic synthesis of rufinamide 4aa using complex 2b.

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towards cyanohydrins due to their poisoning by cyanide.19 Asshown in Scheme 3, using 5 mol% of 2b and performing thereactions at r.t. to minimize the decomposition of the substrates,complete conversion of lactonitrile 3ab and 2-hydroxybutyronitrile3ac into the corresponding a-hydroxyamides 4ab,ac could beachieved after 72 h of stirring. In the case of 3ab, a 92% conversionis already reached after 7 h.20

Another remarkable aspect of complex [RuCl2(Z3:Z3-C10H16)-{PMe2(OH)}] (2b) is that it can be easily separated from the reactionproducts. Thus, in most cases, after completion of the reaction,selective crystallization of the amide takes place by cooling themixture at r.t., or at 0 1C in an ice bath, remaining 2b completelydissolved in water.21 As an illustrative example, the reaction mixtureresulting from the hydration of the model benzonitrile substrate 3abefore and after cooling is shown in Fig. 2. Clean and extensivecrystallization of the formed benzamide readily took place at r.t.

This easy catalyst/product separation allowed us to evaluate thelifetime and level of recyclability of 2b, which are the key factors forpractical applications of this catalyst.22 To our delight we foundthat, using the hydration of pentafluorobenzonitrile (3b) intopentafluorobenzamide (4b) as a model (entry 2 in Table 2), theaqueous phase containing 2b could be reused 10 consecutive times,with loss of activity being observed only after the sixth cycle(cumulative TON after the 10 cycles = 853; see Fig. 3).

In summary, we have designed a new metal catalyst for theselective hydration of nitriles into primary amides in water, displayinga broad substrate scope and functional compatibility. The followingfeatures of complex [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b) merit high-lighting: (i) it is readily accessible in high yield from a commerciallyavailable ruthenium precursor. (ii) It operates in pure water withoutthe assistance of any acidic or basic co-catalyst.23 (iii) The reactionsproceed efficiently and cleanly under remarkably mild conditions

(60 1C) and with low metal loadings (1 mol%). (iv) It is able to hydratethe challenging cyanohydrins. And (v) it can be easily recycled. Inshort, complex [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b) represents themost active homogeneous catalyst reported to date for the catalytichydration of nitriles employing environmentally friendly water as thesolvent. Although studies to elucidate the mechanism of action of 2bare still in progress in our lab, we can assume, based on previousstudies by Tyler,20 that the excellent activity shown by this complex isrelated to the activating effect that the OH group of the phosphinousacid ligand Me2P(OH) exerts on the water molecules by H-bonding. Inthis way, the key nucleophilic attack of water on the coordinatednitrile is favoured (see Fig. 4).

Financial support from MINECO of Spain (CTQ2010-14796/BQU) is acknowledged. E.T.-M. also thanks the Spanish Govern-ment and the ESF for the award of a FPU fellowship.

Notes and references1 (a) The Chemistry of Amides, ed. J. Zabicky, Wiley-Interscience, New York,

1970; (b) The Amide Linkage: Structural Significance in Chemistry, Bio-chemistry and Materials Science, ed. A. Greenberg, C. M. Breneman andJ. F. Liebman, John Wiley & Sons, New York, 2000.

2 For reviews highlighting this point, see: (a) D. J. C. Constable, P. J. Dunn,J. D. Hayler, G. R. Humphrey, J. L. Leazer Jr., R. J. Linderman, K. Lorenz,J. Manley, B. A. Pearlman, A. Wells, A. Zaks and T. Y. Zhang, GreenChem., 2007, 9, 411; (b) V. R. Pattabiraman and J. W. Bode, Nature, 2011,480, 471; (c) C. L. Allen and J. M. J. Williams, Chem. Soc. Rev., 2011,40, 3405.

3 P. D. Bailey, T. J. Mills, R. Pettecrew and R. A. Price, in Comprehen-sive Organic Functional Group Transformations II, ed. A. R. Katritzkyand R. J. K. Taylor, Elsevier, Oxford, 2005, vol. 5, pp. 201–294.

4 For selected reviews, see: (a) M. Kobayashi and S. Shimizu, Curr.Opin. Chem. Biol., 2000, 4, 95; (b) S. Prasad and T. C. Bhalla,Biotechnol. Adv., 2010, 28, 725.

5 For reviews, see: (a) V. Y. Kukushkin and A. J. L. Pombeiro, Inorg.Chim. Acta, 2005, 358, 1; (b) T. J. Ahmed, S. M. M. Knapp andD. R. Tyler, Coord. Chem. Rev., 2011, 255, 949.

6 For a specific review, see: R. Garcıa-Alvarez, P. Crochet andV. Cadierno, Green Chem., 2013, 15, 46.

Scheme 3 Catalytic hydration of cyanohydrins 3ab,ac using complex 2b.

Fig. 2 Hydration of benzonitrile (3a) to benzamide (4a) in water usingcomplex [RuCl2(Z3:Z3-C10H16){PMe2(OH)}] (2b) as the catalyst. After com-pletion of the reaction at 60 1C (left) and after cooling the mixture at r.t.(right). Reaction conditions identical to those indicated in Table 2.

Fig. 3 Reuse of the aqueous solution containing 2b in the hydration reactionof pentafluorobenzonitrile (3b). Separation of pentafluorobenzamide (4b)formed by crystallization at 0 1C in an ice bath. Reaction conditions identicalto those indicated in Table 2 (0.5 h of reaction in each cycle).

Fig. 4 The activating effect of the phosphinous acid ligand Me2P(OH)during catalysis.

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7 (a) For a specific review, see: R. Garcıa-Alvarez, J. Francos, E. Tomas-Mendivil, P. Crochet and V. Cadierno, J. Organomet. Chem., 2014,DOI: 10.1016/j.organchem2013.11.042, in press: (b) For a recentexample not included in this review, see: E. Bolyog-Nagy,A. Udvardy, F. Joo and A. Katho, Tetrahedron Lett., 2014, 55, 3615.

8 Some examples showing a remarkable activity in water at 100 1C andat 1 mol% of Ru loading have been described: (a) W.-C. Lee andB. J. Frost, Green Chem., 2012, 14, 62; (b) W.-C. Lee, J. M. Sears,R. A. Enow, K. Eads, D. A. Krogstad and B. J. Frost, Inorg. Chem.,2013, 52, 1737.

9 Only the homogeneous systems [PtH{(PMe2O)2H}(PMe2OH)], [{Rh-(m-OMe)(cod)}2]/PCy3 and [RhBr(PIN)(cod)] (cod = 1,5-cycloctadiene;PIN = 1-isopropyl-3-(5,7-dimethyl-1,8-naphthyrid-2-yl)imidazol-2-ylidene), based on more expensive transition metals, have shownhigh activity and scope below 100 1C. All of them operate in organicmedia. See: (a) T. Ghaffar and A. W. Parkins, J. Mol. Catal. A: Chem.,2000, 160, 249; (b) A. Goto, K. Endo and S. Saito, Angew. Chem., Int.Ed., 2008, 47, 3607; (c) P. Daw, A. Sinha, S. M. W. Rahaman, S. Dindaand J. K. Bera, Organometallics, 2012, 31, 3790.

10 The heterogeneous systems CeO2 and MnO2 have also shown aremarkable reactivity below 100 1C. See: (a) M. Tamura,H. Wakasugi, K.-I. Shimizu and A. Satsuma, Chem. – Eur. J., 2011,17, 11428; (b) C. Battilocchio, J. M. Hawkins and S. V. Ley, Org. Lett.,2014, 16, 1060.

11 For reviews dealing with the use of secondary phosphine oxides asprecursors of phosphinous acids and related P-donor ligands, see:(a) L. Ackermann, Synthesis, 2006, 1557; (b) T. M. Shaikh, C.-M.Weng and F.-E. Hong, Coord. Chem. Rev., 2012, 256, 771.

12 For reviews on the coordination chemistry and catalytic applicationsof dimer 1, see: (a) V. Cadierno, P. Crochet, S. E. Garcıa-Garrido andJ. Gimeno, Curr. Org. Chem., 2006, 10, 165; (b) C. Bruneau andM. Achard, Coord. Chem. Rev., 2012, 256, 525.

13 (a) G. A. Jeffrey, An Introduction to Hydrogen Bonding, OxfordUniversity Press, Oxford, 1997; (b) T. Steiner, Angew. Chem., Int.Ed., 2002, 41, 48.

14 Metal-bound chlorine atoms are well-known H-bond acceptors:G. Aullon, D. Bellamy, L. Brammer, E. A. Bruton and A. G. Orpen,Chem. Commun., 1998, 653.

15 (a) A TOF of 10 h�1 in the hydration of 3a was recently describedusing the related Ru(II) complex [RuCl2(Z6-p-cymene){PMe2(OH)}] inpure water (quantitative formation of 4a after 2 h at 100 1C with a Ru

loading of 5 mol%). The higher activity of 2b may be reasoned interms of the more effective activation of the CRN bond uponcoordination to the stronger Lewis acid Ru(IV) center. See:S. M. M. Knapp, T. J. Sherbow, R. B. Yelle, J. J. Juliette andD. R. Tyler, Organometallics, 2013, 32, 3744(b) Complex 2b provedto be also more active than analogous [RuCl2(Z3:Z3-C10H16)(PR3)](PR3 = ‘‘cage-like’’ water-soluble phosphine) species previouslydescribed by us (TOF up to 20 h�1 at 100 1C). This fact points outthe key role played by the phosphinous acid ligand in the catalyticreaction, which could establish H-bonds with water facilitating itsapproach and addition to the coordinated nitrile. See: V. Cadierno,J. Dıez, J. Francos and J. Gimeno, Chem. – Eur. J., 2010, 16, 9808.

16 Despite the high functional group tolerance shown by complex 2b,attempts to hydrate 4-aminobenzonitrile and 6-aminohexanenitrilefailed (up to 11% conversion after 24 h).

17 See, for example: G. Coppola, Neuropsychiatr. Dis. Treat., 2011,7, 399, and references cited therein.

18 We have recently described the hydration of 3aa with different Rh(I)and Ru(II) catalysts. Higher metal loadings (5 mol%) and tempera-ture (100 1C) were needed to generate rufinamide 4aa in high yields.See: E. Tomas-Mendivil, R. Garcıa-Alvarez, C. Vidal, P. Crochet andV. Cadierno, ACS Catal., 2014, 4, 1901.

19 T. J. Ahmed, B. R. Fox, S. M. M. Knapp, R. B. Yelle, J. J. Juliette andD. R. Tyler, Inorg. Chem., 2009, 48, 7828, and references citedtherein.

20 Only two metal catalysts capable of effectively hydrating cyano-hydrins, namely [RuCl2(Z6-p-cymene){PMe2(OH)}] and [RuCl2(Z6-p-cymene){P(NMe2)3}] are currently known. Under identical reactionconditions to those employed herein, the former was able to convert3ab into 4ab in 94% yield (by 1H NMR) after 17.5 h, and the latterin 499% (by 1H NMR) after 112 h. See ref. 15a and: S. M. M. Knapp,T. J. Sherbow, R. B. Yelle, L. N. Zakharov, J. J. Juliette and D. R. Tyler,Organometallics, 2013, 32, 824.

21 Although complex 2b presents by itself a low solubility in water atr.t. (0.1 mg mL�1) or even at 60 1C (0.5 mg mL�1), under the catalyticconditions employed, i.e. in the presence of a large excess of nitrile,it readily dissolves in water at r.t.

22 Recoverable and Recyclable Catalysts, ed. M. Benaglia, John Wiley &Sons, Chichester, 2009.

23 We must note that, when dissolved in water, complex 2b generatesan acidic solution (pH of 2.8 at r.t.).

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