RUTHENIUM, [6-[[BIS(1,1-DIMETHYLETHYL)PHOSPHINO-κP] METHYLENE] 1

Ruthenium, [6-[[Bis(1,1-dimethylethyl)phosphino-κP] methylene]-N,N-diethyl-1,6-dihydro-2-pyridinemethanaminato-κN1,κN2]carbonylhydride1

N

N

P

Ru

C

H

O

[863971-63-5] C20H35N2OPRu (MW 451.55)InChI = 1S/C19H34N2P.CO.Ru.H/c1-9-21(10-2)14-16-12-11-

13-17(20-16)15-22(18(3,4)5)19(6,7)8;1-2;;/h11-13,15H,9-10,14H2,1-8H3;;;/q-1;;+1;/b17-15-;;;

InChIKey = CYXMUFURMPCJIX-FDRCHMJRSA-N

(reagent used as efficient catalyst for (a) the preparation of estersby dehydrogenative coupling of alcohols with liberation of H2, (b)the facile hydrogenation of activated and unactivated esters intoalcohols under mild hydrogen pressure, and (c) the preparation ofamides by coupling of amines with alcohols with the liberation

of H2 and without generation of waste)

Solubility: soluble in benzene, toluene, xylene, mesitylene,tetrahydrofuran, and dioxane.

Form Supplied in: red–brown solid; commercially available fromStrem Chemicals, USA.

Analysis of Reagent Purity: 31P{1H} NMR (C6D6): 94.7 (s). 1HNMR (C6D6): −26.45 (d, JPH = 25.5 Hz, 1H, Ru-H), 0.78(t, JHH = 7.3 Hz, 3H, N(CH2CH3)2), 0.94 (t, JHH =7.0 Hz, 3H, N(CH2CH3)2), 1.43 (d, JPH = 6.0 Hz, 9H,P(C(CH3)3)2), 1.46 (d, JPH = 5.5 Hz, 9H, P(C(CH3)3)2),2.13 (m, 1H, N(CHHMe)2), 2.35 (m, 1H, N(CHHMe)2),2.48 (m, 1H, N(CHHMe)2), 2.66 (d, JHH = 13.5 Hz, 1H, -CHHN), 2.76 (m, 1H, N(CHHMe)2), 3.49 (d, JHH = 13.5Hz, 1H, -CHHN), 3.66 (s, 1H, = CHP), 5.34 (d, JHH =7.5 Hz, 1H, pyridine-H3), 6.50 (d, JHH = 8.0 Hz, 1H,pyridine-H5), 6.59 (vt, JHH = 8.0 Hz, JHH = 7.5 Hz, 1H,pyridine-H4). 13C{1H}NMR (C6D6): 10.87 (s, N(CH2CH3)2),11.30 (s, N(CH2CH3)2), 29.14 (s, P(C(CH3)3)2), 35.25(d, JPC = 27.7 Hz, P(C (CH3)3)2), 38.08(d, JPC = 26.4 Hz,P(C(CH3)3)2), 50.63 (s, N(CH2Me)2), 55.31 (s, N(CH2Me)2),64.44 (s, CH2N), 65.25 (d, JPC = 50.3 Hz, = CHP), 96.52(s, Py-C5), 114.27 (d, JPC = 16.4 Hz, Py-C3), 132.09 (s, Py-C4), 156.88 (d, JPC = 2.5 Hz, Py-C6), 169.12 (d, JPC = 15.1Hz, py-C2), 206.90 (d, JPC = 11.3 Hz, Ru-CO) ppm; IR (KBr,pellet): 1899 (vCO) cm−1. Anal. Calcd. for C20H35N2OPRu: C,53.20; H, 7.82. Found: C, 53.31, H, 7.94.

Handling, Storage, and Precautions: air and moisture sensitive.However, it can be handled safely under argon or nitrogen. Itcan also be stored for a long time under inert atmosphere at lowtemperature. Avoid skin contact.

Preparation.1 (a) Synthesis of 2-Diethylaminomethyl-6-methylpyridine 4: To a dry 500 mL round-bottom flask were added20 mL (172 mmol) 2,6-dimethylpyridine, 30.61 g (172 mmol)NBS (N-bromosuccinimide), and 300 mL CCl4 (Scheme 1). Themixture was heated at reflux under N2 for 7 h during which 0.5 gAIBN (2,2′-azobisisobutyronitrile) was added every hour. Aftercooling to room temperature, the mixture was filtered and thesolvent was removed under vacuum, yielding crude 2-bromo-methyl-6-methylpyridine as a pink-red oil. It was pure enoughfor the next step. A solution of the pink-red oil in 120 mL of dryTHF was cooled to 0 ◦C under nitrogen atmosphere and a pre-cooled solution (0 ◦C) of 40 mL diethylamine (386 mmol) in THF(120 mL) was added dropwise. The mixture was allowed to slowlywarm to room temperature and stirr overnight. The solvent wasremoved under vacuum and the residue was dissolved in 1.2 Lof diethyl ether and washed with 2 × 200 mL of a 10% aque-ous KOH solution. The ethereal solution was dried over Na2SO4

and the ether was removed under vacuum. The residue was dis-tilled under vacuum, yielding 17.5 g of 2-diethylaminomethyl-6-methylpyridine (66% yield) as a yellow oil, bp 76 ◦C (0.3 mmHg).

N

1. NBS, CCl4 AIBN, 7h

2. Et2NH, THF 12 h

N

N

1. n-BuLi

2. ClP(But)2

N

N P

66%70%

RuH(Cl)(PPh3)3(CO) N

N

P

Ru

C

H

OCl

THF, 26 h89%

KOBut/THF

98%

N

N

P

Ru

C

H

O

N

N

P

Ru

C

H

OH

+ H2

(1) (6)

(2)(3)

(4)(5)

– H2

Scheme 1.

(b) Synthesis of 2-(Di-tert-butylphosphinomethyl)-6-diethyl-aminomethyl)pyridine (PNN, 3): To an oven-dried, argon-flushed,three-neck round-bottom flask equipped with an argon-inlet tube,an ‘egg’ magnetic bar, and a rubber septum was added 3.85 g(20 mmol) of 2-diethylaminomethyl-6-methylpyridine in 70 mLdry ether. The solution was cooled to 0 ◦C and a solution ofn-BuLi (22 mmol) in hexane was added with a syringe duringa few minutes. The mixture was stirred under argon for 2 h at 0 ◦Cand then cooled to −78 ◦C and a solution of 3.96 g (22 mmol)di-tert-butylchlorophosphine in 25 mL dry ether was added

2 RUTHENIUM, [6-[[BIS(1,1-DIMETHYLETHYL)PHOSPHINO-κP] METHYLENE]

dropwise. The mixture was allowed to slowly warm to roomtemperature and stirr overnight. To this mixture was added 50 mLof degassed water and the ether phase was separated underargon atmosphere. The aqueous phase was extracted with ether(2 × 100 mL). The combined ether solutions were dried over anhy-drous Na2SO4, filtered under argon, and the solvent wasremoved under vacuum. The residue was distilled under highvacuum (0.02 mmHg), yielding 4.5 g (70%) of PNN as a paleyellow oil, bp 130 ◦C (0.02 mmHg).

(c) Synthesis of [RuH(Cl)(PNN)(CO)] 2: HClRu(PPh3)3(CO)(2.95 g, 3.1 mmol), the ligand PNN (1 g, 3.1 mmol), and THF(40 mL) were placed in a Schlenk tube in the N2 glove box.The Schlenk tube was removed and assembled with a refluxcondenser under argon. The reaction mixture was stirred andheated at 65 ◦C for 26 h under argon (oil bath temperature75 ◦C; oil bath preheated). Yellow solids separated during thereaction. The reaction was allowed to stand at room temperatureovernight under argon after which the solution was decanted ina N2 glove box. The yellow crystalline solids were washed withether (5×10 mL). The residue was dried under vacuum and thecomplex was obtained as a yellow solid (1.35 g, 89%).

(d) Synthesis of [RuH(PNN)*(CO)] 1: RuH(Cl)(CO)(PNN)complex (133 mg, 0.27 mmol, 1 equiv) was suspended in 4 mLof THF. KOBut(32 mg, 2.85 mmol, 1.05 equiv) was dissolvedin 3 mL of THF. Both solutions were cooled to −27 to −32 ◦C. TheTHF solution of KOBut was added dropwise to the yellow suspen-sion of RuH(Cl)(CO)(PNN) complex in THF. The reaction mix-ture was stirred for 4–6 h at −27 to −32 ◦C (Scheme 1). The crudereaction mixture always showed a single product peak (100%conversion of starting complex) in 31P NMR. The solventswere evaporated under vacuum. The resulting black residue wasdissolved in a benzene/pentane (3:7, 10 mL) mixture, duringwhich time KCl precipitates. The black solution was filteredthrough a celite-packed pipette and concentrated to obtain[RuH(PNN)*(CO)] (120 mg, 98%) as a red-brown solid.

(e) Synthesis of [trans-(H)2Ru(PNN)(CO)] 6: (a) To a screw-capped NMR tube was added a benzene-d6 solution of complex 6(9 mg, 0.02 mmol) under N2 atmosphere and pure hydrogen gas(99.999%) was bubbled slowly through the dark red solution forabout 20 min until the color of the solution changed to yellow.31P{1H} NMR indicated 100% conversion to the trans dihydridecomplex 6. (b) To a solution of complex 1 (49 mg, 0.1 mmol) wasadded NaHBEt3 (0.1 mL of a 1 M toluene solution; 0.1 mmol)and the mixture was stirred at room temperature for 2 h, and thenfiltered. The yellow filtrate was carefully concentrated to 0.5 mLwith H2 gas, then 5 mL pentane was added to precipitate a yellowsolid, which was filtered and washed with pentane (3×1 mL), andthen dried with H2 flow (30 mg, 63% yield). The compound isstable only under an atmosphere of H2.

Note: For catalytic reactions, complex 1 can be generated insitu from the hydrido chloride complex 2, which is air stable inthe solid state, by adding an equivalent of base.

Facile Conversion of Alcohols into Esters and Dihydrogen.1

The ruthenium complex 1 catalyzes the dehydrogenative couplingof alcohols to esters with the evolution of H2. It is an attractivemethod for the synthesis of esters as it does not involve the useof large amounts of condensing reagents and activators and

precludes the need for corresponding acid or acid derivative. Asopposed to the normal esterification of an acid and alcohol, inwhich an equilibrium mixture is generated, the evolved hydro-gen would shift the equilibrium to completion (eq 1). However,relevant reports are limited to a few nonselective heterogeneousreactions2 or homogeneous systems that utilize sacrificial hydro-gen acceptors.3 Complex 1 [RuH(PNN)*(CO)] selectively cata-lyzes the dehydrogenation of primary alcohols to esters and H2

in high turnover numbers under relatively mild and neutralconditions.

R OHR O

2R

O

toluene, reflux90–99%

1 (0.1 mol %)+ 2H2

R = alkyl, aryl

(1)

Complex 1 is the best homogeneous catalyst for acceptorlessdehydrogenative esterification of alcohols. When used as catalystwithout any base, a TOF50 > 300 h−1 at 50% conversion andTON > 900 can be obtained from the alcohols in relatively shortreaction times (4–6 h).

This reaction provides a convenient method for the synthesis ofesters because of its high efficiency, simplicity, and facile isola-tion of the desired products. In a typical example, 1-hexanol wasconverted to hexyl hexanoate in 99% yields (eq 2).

OH O

O

toluene, reflux6 h, 99%

1 (0.1 mol %)+ 2H22

(2)

Efficient Homogeneous Catalytic Hydrogenation of Estersto Alcohols.4 The reduction of esters to the correspondingalcohols is an important reaction in organic synthesis. Comparedwith traditional procedures using stoichiometric amounts of metalhydride reagents (e.g., LiAlH4),5 the catalytic hydrogenation ofesters to alcohols, which generates no waste, is attractive envi-ronmentally and economically (eq 3). Heterogeneous hydrogena-tion of some fatty esters is practiced industrially at relatively hightemperatures (200–300 ◦C) and high hydrogen pressures (50–300 atm) using transition-metal catalysts,6 while homogeneoussystems capable of hydrogenation of esters are very scarce7–11

and mostly limited to activated esters. In these systems, largeamounts of additives, such as an organic base,7 inorganic acids,7

salts,9,10 zinc,11 and fluorinated alcoholic solvents,7 were neededto obtain high conversion of esters into alcohols. Activated andnon-activated esters were hydrogenated to the correspondingalcohols in the presence of catalyst 1 under relatively mild, neutralconditions, with no additives being required.4

R1 OHR1 O

O

dioxane, refluxH2 (5.3 atm)

7–100%

+ R2OH1 (1 mol %)

R2 (3)

R1 = alkyl, arylR2 = alkyl

The ester, catalyst 1, and dioxane were taken in a Fischer–Portertube. The tube was charged with 5.3 atm of H2 and heated atreflux for 4–12 h to obtain the corresponding alcohols in goodyields (eqs 4–6). The activated esters reacted rapidly (ca. 4 h),

RUTHENIUM, [6-[[BIS(1,1-DIMETHYLETHYL)PHOSPHINO-κP] METHYLENE] 3

while the unactivated esters required longer heating. The reactionis sensitive to steric hindrance of the esters. Thus, after a prolongedreaction time (24 h), only a minimal conversion (10.5 %) wasobtained when the t- butyl acetate was subjected to hydrogenation.

OHO

O

dioxane, refluxH2 (5.3 atm)

4 h

+1 (1 mol %)

MeOH

97% 100%

(4)

O

O

dioxane, refluxH2 (5.3 atm)

4 h

+1 (1 mol %)

EtOH

98% 97%

OH (5)

O

O

dioxane, refluxH2 (5.3 atm)

5 h

1 (1 mol %)

82%

OH (6)

Direct Synthesis of Amides from Alcohols and Amines.12

Amide formation is a fundamental reaction in chemical synthe-sis.13 Although several methods are known for the synthesisof amides, preparation under neutral conditions and withoutgeneration of waste is a challenging goal.13,14 Direct catalyticconversion of alcohols and amines into amides and dihydrogen(eq 7) is a desirable method for the synthesis of amides. Usingthis environmentally benign reaction,12 an assortment of simplealcohols and amines was converted into the amides, with highatom economy. The reaction required no stoichiometric activat-ing agents and generated no waste. The liberated hydrogen gasshifts the equilibrium toward the completion of the reaction.

R1CH2OH R2NH2+ R2NHCOR1 +catalyst, ∆

2H2

R1 = alkylR2 = alkyl, aryl

toluene58–99 %

(7)

The reaction mixtures were heated at reflux under a flow ofargon to facilitate the formation of product amides by the hy-drogen removal (eqs 8 and 9). When simple linear alcoholssuch as 1-hexanol and 1-pentanol were used, traces of secondaryamines were observed along with the main amide product. 2-Methoxyethanol reacted with diverse amines to generate theamides in almost quantitative yields.

NH2 +toluene, reflux, 7 h

+NH

O

2H2

OH

96%

1 (0.1 mol %)

(8)

OHO NH2

HN

O

O + 2H2

toluene, reflux, 9 h

1 (0.1 mol %)+

(9

99%

)

The amidation reactions are sensitive to steric hindrance at thealcohol or the amine. Thus, when 2-methyl-1-butanol reacted withbenzyl amine, the corresponding amide was obtained in 70% yield,the rest of the alcohol being converted to the ester 2-methylbutyl-2-methylbutanoate (eq 10). A similar pattern was also observedwhen 2-heptylamine was reacted with hexanol, leading to 72%yield of the corresponding amide.

NH2 OHtoluene, reflux, 12 h

1 (0.1 mol %)+

NH

O

70%

+ 2H2 (10)

Secondary amines do not react. Thus, heating dibenzylaminewith 1-hexanol under the experimental conditions resulted in aquantitative yield of hexyl hexanoate. The scope of this methodwas extended to the bis-acylation processes with diamines. Uponheating a slight excess of a primary alcohol and catalyst 1 withdiamines (500 equiv relative to 1) in toluene at reflux under argon,bis-amides were produced in high yields. The high selectivity ofthe dehydrogenative amidation reaction to primary amine func-tionalities enabled the direct bis-acylation of diethylenetriaminewith 1-hexanol to provide the bis-amide in 88% yield without theneed to protect the secondary amine functionality (eq 11).

H2N

HN

NH2OH+

toluene, reflux, 8 h

1 (0.1 mol %)

NH

HNNH

88%O O

(11)

1. Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein, D., J. Am. Chem. Soc.2005, 127, 10840.

2. (a) Ishihara, K.; Ohara, S.; Yamamoto, H., Science 2000, 290, 1140. (b)Corma, A.; Nemeth, L. T.; Renz, M.; Valencia, S., Nature 2001, 412,423. (c) Hoydonckx, H. E.; De Vos, D. E.; Chavan, S.; Jacobs, P. A.,Top. Catal. 2004, 27, 83.

3. (a) Murahashi, S.-I.; Naota, T.; Ito, K.; Maeda, Y.; Taki, H., J. Org. Chem.1987, 52, 4319. (b) Blum, Y.; Shvo, Y., J. Organomet. Chem. 1984, 263,93. (c) Blum, Y.; Shvo, Y., Isr. J. Chem. 1984, 24, 144. (d) Meijer, R.H.; Ligthart, G. B. W. L.; Meuldijk, J.; Vekemans, J. A. J. M.; Hulshof,L. A.; Mills, A. M.; Kooijman, H.; Spek, A. L., Tetrahedron 2004, 60,1065.

4 RUTHENIUM, [6-[[BIS(1,1-DIMETHYLETHYL)PHOSPHINO-κP] METHYLENE]

4. Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein, D., Angew. Chem., Int.Ed. 2006, 45, 1113.

5. Ege, S. N. Organic Chemistry; D. C. Heath and Company: Lexington,1989, p 596.

6. Pouilloux, Y.; Autin, F.; Barrault, J., Catal. Today 2000, 63, 87 andreferences therein.

7. Teunissen, H. T.; Elsevier, C. J., Chem. Commun. 1998, 1367.

8. (a) Grey, R. A.; Pez, G. P.; Wallo, A., J. Am. Chem. Soc. 1981, 103, 7536.(b) Mechanistic studies revealed that the actual catalyst in this process is[RuH4(PPh3)3]: Linn, D. E.; Halpern, J., J. Am. Chem. Soc. 1987, 109,2969.

9. (a) Matteoi, U.; Bianchi, M.; Menchi, G.; Frediani, P.; Piacenti, F., J. Mol.Catal. 1984, 22, 353. (b) Matteoi, U.; Menchi, G.; Bianchi, M.; Frediani,P.; Piacenti, F., J Organomet. Chem. 1986, 299, 233. (c) Matteoi, U.;Menchi, G.; Bianchi, M.; Frediani, P.; Piacenti, F., J. Organomet. Chem.1995, 498, 177, and references therein.

10. (a) Hara, Y.; Inagaki, H.; Nishimura, S.; Wada, K., Chem. Lett. 1992,1983. (b) Teunissen, H. T.; Elsevier, C. J., Chem. Commun. 1997, 667.

11. Nomura, K.; Ogura, H.; Imanishi, Y., J. Mol. Catal. A 2002, 178,105.

12. Gunanathan, C.; Ben-David, Y.; Milstein, D., Science 2007, 317, 790.

13. Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH: New York, 1999.

14. Smith, B. Compendium of Organic Synthetic Methods; Wiley: New York,2001. Vol. 9, pp 100–116.

Chidambaram Gunanathan & David MilsteinThe Weizmann Institute of Science, Rehovot, Israel