Hydrogenation of Carboxylic Acid Derivatives with Bifunctional Ruthenium Catalysts

Pure Appl. Chem. 2014; 86(6): 933–943

Conference paper

Takao Ikariya* and Yoshihito Kayaki Hydrogenation of carboxylic acid derivatives with bifunctional ruthenium catalysts

Abstract: This paper focuses on recent advances in the chemistry of bifunctional Ru catalysts with chelate protic amine ligands effective for hydrogenation of polar carbonyl compounds. The rational design of the cooperating amine ligand that adjusts the balance of the electronic factors on the M/NH units in the bifunctional catalysts is crucial to exploit the characteristic catalytic performance with a wide scope and high practicability. These bifunctional molecular catalysts offer a great opportunity to develop new fundamental processes for the straightforward hydrogenation of carboxylic acid derivatives as a powerful alternative for classical reduction using stoichiometric amounts of metal hydride reagents.

Keywords: amides; bifunctional catalysts; carbonyl groups; carboxylic acid derivatives; chemical synthesis; homogeneous catalysis; hydrogenation; IUPAC Congress-44; ruthenium.

DOI 10.1515/pac-2014-0103

Introduction

Molecular hydrogen (H2), the most atom-efficient reducing chemical agent, is a component of the larg- est-volume human-made chemical reactions, hydrogenation of organic compounds [1]. Reduction of functional groups with molecular hydrogen is one of the fundamental reactions in organic chemistry. A great breakthrough was made through Noyori’s discovery of bifunctional ruthenium catalysts for direct hydrogenation and transfer hydrogenation of ketones [2]. Significant efforts have been continuously undertaken to design bifunctional molecular catalysts having the combination of two or more active sites working in concert, to attain highly efficient molecular transformation of polar substrates via H+ and H– transfer processes [3]. Detailed experimental and theoretical analyses of the real catalysts revealed that both an amidoruthenium complex having a square-planar geometry and a coordinatively saturated hydrido(amine)ruthenium complex are involved in the catalytic cycle. These reactions proceed via two steps, an enantio-determining hydride transfer and proton transfer, through a contact ion-pair intermediate, as depicted in Fig. 1 [4].

In 2001, we reported an effect of alcoholic solvent facilitating the heterolytic cleavage of H2 bound to the + 16-electron [Cp*Ru{L(CH2)2NH2}] fragment as shown in Fig. 2 [5]. Further systematic study of catalytic hydro- genations of polar substrates showed that the replacement of the tertiary amino group in the ligand with a

Article note: A collection of invited papers based on presentations at the 44th IUPAC Congress, Istanbul, Turkey, 11–16 August 2013.

*Corresponding author: Takao Ikariya, Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, O-okayama 2-12-1-E4-1, Meguro-ku, Tokyo 152-8552, Japan, Tel.: +81-3-5734-2636, Fax: +81-3-5734-2637, E-mail: [email protected] Yoshihito Kayaki: Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, O-okayama 2-12-1-E4-1, Meguro-ku, Tokyo 152-8552, Japan

Ts Rn Ph N Ru Ph N H H H Ar Rn Amine hydrido Ar O complex O Ts + H Ru C N H H N O Ar Ph H H OH OH Ph Ts R n Acontact ion-pair intermediate Ph N Ru Ph N H Amido complex

Fig. 1 Interconversion between amido and amine(hydrido)Ru complex.

+ Me2 N Ru OR H2 N ROH H H

Me2 Me2 N N Ru Ru H N N H H H H O H OH R Me2 R1 R2 N Ru ROH O N H R1 R2 H H

Fig. 2 A possible mechanism of H2-activation by a cationic Ru fragment.

tertiary phosphino group results in the expansion in the scope of the Ru/NH bifunctionality [6]. Whereas the half-sandwich bifunctional precatalysts Cp*RuCl[(CH3)2N(CH2)2NH2], 2, are only effective for ketone reductions, Cp*RuCl(P–N) (P–N: (C6H5)2P(CH2)2NH2), 1 combined with a base efficiently promote hydrogenation of either ketones, imides or epoxides [7]. Presumably, the back-bonding properties of the phosphorus atom might enhance the Lewis acidity of the NH2 protons, thus facilitating the hydrogen transfer to various polar functionalities. Although the original bifunctional amido–Ru catalysts, Ru[Tsdpen](η6-arene) (Tsdpen = N-(p- toluenesulfonyl)-1,2-diphenylethylenediamine), cannot efficiently promote hydrogenation of ketonic substrates, some isolable cationic amine Ru and Ir complexes, Ru(OTf)[Tsdpen](η6-p-cymene) [8] and + – [Cp*Ir(Tscydn)(CH3CN)] SbF6 [9] are highly effective for the asymmetric hydrogenation of either ketones or imines. Similarly to the mechanism in Fig. 2, a key step is the heterolytic H2 cleavage, which is promoted by cationic species [10]. It generates an active hydride complex such as RuH(Tsdpen)(η6-p-cymene) with simultaneous release of HOTf in a polar solvent like methanol. After the hydride/proton transfer from the amine hydrido complex, the regenerated 16-electron amido Ru complex reacts with HOTf to complete the catalytic cycle. These experimental results prompted us to develop new chiral hydrogenation catalysts, [η6:η1- 5 1 C6H5(CH2)nNTf]Ru[(S,S)-Tsdpen] and [η :η -(CH3)4C5(CH2)nNTf]M[(S,S)-Msdpen] (M = Rh and Ir) in which the NTf unit is linked to a η6-arene or η5-tetramethylcyclopentadienyl ring [11]. The introduction of a suitable tether unit dramatically facilitates the heterolytic cleavage of H2 suggesting that the hemilabile NTf group on the tether participates in the proton transfer processes as shown in Fig. 3. T. Ikariya and Y. Kayaki: Hydrogenation with bifunctional Ru catalysts 935

+ Ru H H2N H NTf NTs C6H5 O H

C6H5 CH3

Fig. 3 Heterolytic H2-cleavage by NTf tethered-Ru complex.

Ph Me H 2 2 H P N N N PPh2 Ru Ru Ru Ru N Cl N Cl N Cl P CO Cl H H H H H H Ph2 1 2 3 4a

Fig. 4 Bifunctional Ru precursors for catalytic hydrogenation.

Significant progress in the field of selective hydrogenation of C–O double bonds of ketones with both chiral and achiral catalysts has been made in the branch of homogeneous transition metal-based molecular catalysis. Until now only limited progress was observed in the hydrogenation of the polar functionalities bearing less electrophilic carbonyl groups, such as carboxylic acids and their derivatives [12]. The recent progress in the hydrogenation of esters and lactones exploits the conceptually new bifunctional molecular catalysts originating from the metal/NH synergy effect or aromatization-dearomatization concept [13]. In addition to the half-sandwich chelate amine complex, several pincer ligands involving a metal/NH group have been developed for powerful hydrogenation systems. For example, Takasago Int. Corp. released an efficient precatalyst, RuHCl(CO)(dpa) (4a; dpa = HN(CH2CH2PPh2)2), which has high potential industrial application. Hence, our further efforts were directed towards these synthetically important transformations by using a series of bifunctional Ru catalysts depicted in Fig. 4.

Hydrogenation of imides and N-acylcarbamates with bifunctional

Ru catalysts bearing P–NH2 ligands

The Cp*RuCl(P–N) catalyst allows the straightforward catalytic hydrogenation of carboxyimides and N-acylcarbamates yielding N-protected amines and alcohols selectively [14]. Prochiral cyclic imides such as 4-sub- stitued glutarimides and cyclic meso-imides, such as 3,4-disubstituted succinimides, are important starting compounds in asymmetric synthesis. The known carbonyl-selective reductions of N-substituted cyclic imides affording lactams or carboxamide alcohols, mostly rely on the stoichiometric amount of metal hydride reagents in organic synthesis [15]. We found that a variety of imides are chemoselectively reduced to the corresponding alcohols and carb t oxamides in 2-propanol containing bifunctional Ru precatalyst, Cp*RuCl(P–N) 1, and the base KO C4H9 as the catalytic system under mild conditions, as shown in Scheme 1 [14a]. Only the catalysts with P–N ligands are 2 effective in these reactions, whereas the analogous Cp*RuCl[k (N,N)-(CH3)2N(CH2)2NH2] catalyst 2 exhibits no catalytic activity toward the imide hydrogenation. Notably, the tertiary amine variant (C6H5)2P(CH2)2N(CH3)2 as the ligand is completely ineffective, indicating the crucial importance of the NH group in the ligand for the M/NH bifunctional activation of the carbonyl compounds. The hydrogenation method is characterized by its excellent chemoselectivity and a wide substrate scope. A less substituted acyl group in the 3,3-dimethyl substituted glutarimide was exclusively hydrogenated to give the corresponding amide alcohol, as shown in Scheme 1. The orientation of the two carbonyl groups possibly plays a key role in the selectivity. This chemoselective hydrogenation is applicable to the deprotection of primary amines 936 T. Ikariya and Y. Kayaki: Hydrogenation with bifunctional Ru catalysts

O O Cp*RuCl(P N) KOtBu N R +H2 NHR 2-propanol 10 atm 80 C OH O Ph2 Imide:Ru:base =100:1:1 R=CH3 (72%) P Bn (>99 %) Ru C6H5 (>99 %) N Cl O O H H Cp*RuCl(P N) KOtBu Cp*RuCl(P N); 1 NBn +H2 NHBn 2-propanol 10 atm 80 C O OH >99%yield

Scheme 1 Chemoselective hydrogenation of imides catalyzed by a binary catalyst system composed of Cp*RuCl(P–N) 1 with base.

from N-phthaloyl-protected amino acid ester derivatives in Gabriel amino acid synthesis. Thus, N-phthaloyl-l- Phe methyl ester undergoes hydrogenation under neutral conditions to generate N-(o-hydroxymethylbenzoyl)- l-Phe methyl ester without any loss of the ee value after acid hydrolysis, as shown in Scheme 2. The chiral version of the Cp*RuCl(P–N) catalyst bearing the chiral P–N ligand derived from l-proline promoted the enantioselective hydrogenation of prochiral 4-arylglutarimides to provide the corresponding hydroxyamides with excellent enantiomeric excesses and in high yields, as shown in Scheme 3. The resulting chiral hydroxyamides are readily converted by a ring-closing followed by deprotection to chiral piperidinone derivatives, which serve as important synthetic intermediates for a number of physiologically active chiral compounds, including the antidepressant paroxetine. Enantioselective hydrogenation of readily accessible bicyclic imides with the 3,4-(OCH2O)C6H3 group derived from cyclic dicarboxylic acids gave the corresponding hydroxyamides with excellent enantiomeric excesses as shown in Scheme 4 [14b]. Thus, the cyclic dicarb oxylic acids can be transformed to chiral cyclic compounds bearing two different functional groups on two chiral centers, which would otherwise require tedious multistep synthesis. Similarly to the hydrogenation of imides with the catalyst 1, N-acylcarbamates, N-acyloxazolidinone, and N-acylsulfonamides can be hydrogenated, as shown in Scheme 4 [14c]. tert-Butyl alcohol is the preferable solvent for the hydrogenation of these substrates because other alcohols can cause undesired alcoholysis of the substrates. The reaction of N-alkoxycarbonyl protected cyclic carboxamides (lactams) gave preferentially N-protected aminoalcohols in almost quantitative yield. The rates of the reaction strongly rely on the electron-withdrawing nature of substituents on nitrogen in the substrates, the rate increasing in the order of

Cbz < Boc < CO2CH3 < Ts. Notably, the hydrogenation was applicable to the reductive transformation of chiral N-acyloxazolidiones, which are useful synthetic intermediates in the asymmetric synthesis. The resulting chiral alcohol and the

Cp*RuCl(P N) O O KOtBu + H2 N CO2CH3 2-propanol HN CO2CH3 10 atm O 80 C, 2h HO CH2C6H5 CH2C6H5

Ph O 2 Cl H N CO CH P HCl 3 2 3 O Ru + 1,4-dioxane CH2C6H5 N Cl 30 C, 1h H H >99%yield>99 %yield Cp*RuCl(P N); 1

Scheme 2 Deprotection of N-phthaloyl amino acid derivative. T. Ikariya and Y. Kayaki: Hydrogenation with bifunctional Ru catalysts 937

O Cp*Ru(proP N)Cl O t KO Bu 1) CBr4,PPh3 2) NaH Ar NR +H2 Ar NHR 2-propanol 3) CAN 30 atm O 80 C OH R=3,4-methylenedioxyphenyl >99%yield, >99%ee O O Ph2 P O O Ru Ar NH p-FC6H4 NH2Cl NH Cl ( )-Paroxetine HCl Ar =4-FC H Cp*Ru(proP N)Cl 6 4

O Cp*Ru(proP N)Cl CONHR KOtBu * NR +H2 2-propanol 30 atm * 80 C, 24 h O CO2H R=3,4-methylenedioxyphenyl O O O O

NR NR NR NR n n O O O O >99%conv >99 >99>99 94 %ee(n =1,2)9776 91 %ee(n =1) 93 %ee(n =3) 82 %ee(n =2) 92 %ee(n =3)

Scheme 3 Enantioselective hydrogenation of prochiral cyclic and bicyclic imides with bifunctional chiral Cp* RuCl(P–N) catalysts.

O O Cp*RuCl(P N) O KOtBu + CH OH N OCH + H2 HN OCH 3 3 2-propanol 3 30 atm Bn 80 C Bn S/C=100 >99%yield

O Cp*RuCl(P N) KOtBu N R + H2 HO NHR 2-propanol n R' n 30 atm R' 80 C n =0 3 >99%yield

O O R N R N R=Boc, CO2CH3,Ts R=CO2CH3,R'=H R=Boc, R' =H R' R=Boc, R' =CO2CH2C6H5 O O R N R=Boc, CO2CH3,Ts N R R=Boc, CO2CH3,Ms, Ts

O O O Cp*RuCl(P N) OH t O N KO Bu O NH + H2 + CH C H 2 6 5 2-propanol CH C H C H CH 30 atm 2 6 5 6 5 3 80 C C6H5 CH3 S/C=33 89 %yield 90 %yield >99%ee

Ph2 P Ru N Cl H H Cp*RuCl(P N); 1

Scheme 4 Catalytic hydrogenation of N-acylcarbamates and related compounds with Cp*Ru(P–N) catalyst 1. 938 T. Ikariya and Y. Kayaki: Hydrogenation with bifunctional Ru catalysts original chiral auxiliary can be obtained without any loss in the optical purity as shown in Scheme 4. This method may be an environmentally benign catalytic alternative to the method using LiAlH4, which some- times causes difficulty in the recovery of the chiral auxiliaries.

Hydrogenation of esters and lactones with bifunctional Ru catalysts

Bifunctional catalyst 1, Cp*RuCl(P–N), in the presence of a large amount of base promotes the hydrogenation of lactones and simple esters, leading to the corresponding diols and alcohols, respectively [16, 17]. For example, phthalide was cleanly hydrogenated to oxylyleneglycol under 50 atm of H2 at 100 °C in the presence of catalyst 1, as shown in Scheme 5. A variety of aprotic solvents, including THF, dioxane, and toluene, can be equally used as alcoholic solvents under similar conditions. The amount of base has a significant influ- ence on the reaction rate, and the addition of more than 25 equiv of NaOCH3 as the base to the Cp*RuCl(P–N) complex resulted in an improvement of its catalytic performance, although the reason for this is still unclear. Structural modification of the protic chelating amine ligand of the Cp*Ru catalyst system caused marked improvement in the catalytic performance and provided efficient access to diols from lactones, as shown in Scheme 5 [18]. Thus, Cp*RuCl(N–N) (N–N: 2-C5H4NCH2NH2) 3 bearing a pyridyl amine chelating ligand is more effective for hydrogenation of lactones than Cp*RuCl(P–N) catalyst. The precatalyst 3 combined with

25 mol% of NaOCH3 was efficient for hydrogenation of several kinds of lactones at 100 °C under 50 atm of

H2 in 2-propanol to give the corresponding diols in reasonably good to excellent yields. The catalytic activity of Cp*RuCl(N–N) catalyst is comparable with Milstein’s RuH(NNP)(CO) pincer complex, although the latter works without any base additive and under lower H2 pressure [19]. A variety of esters and lactones can be reduced to the corresponding alcohols and diols, respectively. Since the discovery of Milstein’s pincer catalyst for the hydrogenation of esters, modified pincer catalysts have been designed by their group and others [13]; namely, a pincer-type bifunctional complex, RuHCl(CO)

(dpa) 4a (dpa = [(C6H5)2P(CH2)2]2NH) serves as more efficient catalyst for ester hydrogenation [20]. In particular, the commercially available catalyst 4a effects hydrogenation of α-fluorinated esters with S/C = 4000–5000 in methanol containing NaOCH3 under 10 atm of H2 at 40 °C giving fluorinated alcohols in almost quantitative

O Cp*RuCl(L N) OH

NaOCH3 O + H2 OH 50 atm 2-propanol, 100 C 98 %yield ester:Ru:NaOCH3 =100:1:25 O O O O Ph2 P Bn O O O O Ru N Cl R H H 97 %yield R=CH ;98% 100% 79 % Cp*RuCl(P N); 1 3 n R= C5H11;98% O

C6H5 OCH3

96 %yield in (CH3)3COH

O O O N C H R Ru 6 5 O O O N Cl H H

Cp*RuCl(N N); 3 82 %yield 81 % R=C6H5;87% R=4-CH3OC6H4;98%

Scheme 5 Catalytic hydrogenation of esters and lactones with bifunctional Cp*Ru catalysts. T. Ikariya and Y. Kayaki: Hydrogenation with bifunctional Ru catalysts 939

F F 4a cat F F 2 NaOCH 1 OR 3 1 OH R + H2 R CH OH O 10 atm 3 40 C

ester:Ru:NaOCH3 =5000:1:1250

H X F F F F F F N PPh2 OCH3 OCH3 OCH3 Ru H F CH3 P CO O O O Ph X 2 >99%yield 98 %yield 96 %yield trans-RuX2(CO)(dpa) (25atm) 97 %sel X=H, Cl; 4a F F F F X=H, H; 4b OCH OC H C H 3 2 5 X=Cl, Cl; 4c 6 5 O O >99%yield 98 %yield 98 %sel >99%sel

F 4a cat F NaOCH3 OH CO CH + H2 2 3 CH OH,1M 97.3 %ee 10 atm 3 40 C, 25 h 98 %yield 95.0 %ee ester:Ru:NaOCH3 =4000:1:240

Scheme 6 Selective hydrogenation of α-fluorinated esters with bifunctional pincer-type Ru (II) catalysts.

yields as shown in Scheme 6 [21]. Notably, non-fluorinated methyl acetate and methyl trifluoropropionate bearing fluorine atoms at the β-position were hydrogenated inefficiently. Hence, the introduction of the fluorine atom at α-position of esters caused a marked increase in the rate of the reaction. This carbonyl selective hydrogenation is applicable to the synthesis of α-fluorinated unsaturated alcohols. For example, the reduction of ethyl 2,2-difluoropentenoate gave unsaturated alcohol with 99.6 % selectivity, in which the E/Z ratio (94/6) of the substrate was invariable during the reaction. Noticeably, the hydrogenation of chiral (R)-2-fluoropropionate gave the monofluorinated alcohol in almost quantitative yield although with a low ee due to racemization under basic conditions. To minimize racemization of the chiral ester, the drop-wise slow addition of the chiral ester provided the corresponding chiral monofluorinated alcohol without any serious decrease of the ee value. The catalyst precursor, RuHCl(CO)(dpa) 4a, was found to be readily converted to the real catalyst, t trans-RuH2(CO)(dpa) 4b by treatment of 4a with 1 equiv of KO C4H9 in THF-d8 under a hydrogen atmos- phere. In addition to the dihydride complex 4b, trans-RuCl2(CO)(dpa) 4c also worked well for the hydrogenation of methyl trifluoroacetate albeit under longer reaction times, as listed in Table 1. Fluorinated

Table 1 Hydrogenative transformation of α-fluorinated esters into alcohols A and hemiacetals B.

F F Ru cat F F F F OCH3 NaOCH3 OH OCH3 R + H2 R + R CH OH O 3 OH A B ester:NaOCH3 =1:0.25

Cat R S/C Time, h Temperature, °C H2, atm % Yield A:B 4a F 5000 6 40 10 92 9:91 4ba F 5000 8 40 10 89 8:92 4c F 3000 21 50 10 84 4:96 4a H 5000 6 40 10 > 99 100:0 4a H 5000 6 15 10 58 8:92 4a F 2000 6 40 20 99 81:15 a Ester:NaOCH3 = 1:0.1 940 T. Ikariya and Y. Kayaki: Hydrogenation with bifunctional Ru catalysts

H CF3 OR CF3 OR H H O O N PPh2 Ru H HH CO N PPh2 P H + Ph2 Ru TS2: 3.6 11.6 CO +H P 2 H Ph2 TS3: 2.4 CF3 Int3: 3.0 OR CF3 H O OR O H H H N PPh2 H + H Ru N PPh2 CO P Ru H CF OR CO Ph2 3 P Ph H Int2: 6.0 O 2 Int4: 7.7 H TS1: 7.8 H CF3 OR hydridetransfer N PPh2 (RDS) Ru O CO CF3 OR P H Ph2 OH Int1: 0.0

Fig. 5 A possible catalytic cycle for the formation of trifluoroacetaldehyde methyl hemiacetal. All the free energies –1 (ΔG°298 K, kcal·mol ) are calibrated relative to Int1.

esters, including CF2HCO2CH3, CF3CO2CH3, CClF2CO2CH3, and C2F5CO2CH3, were selectively hydrogenated with 4a or 4b in the reaction with S/C = 5000 to hemiacetal intermediates, which are among the most important synthons for organic synthesis. Notably, the outcome of the reaction was delicately influ- enced by the reaction conditions. A decrease of the reaction temperature to 15 °C in the hydrogenation of CF2HCO2CH3 caused a drastic change in the product ratio of alcohol/hemiacetal, giving preferentially the corresponding hemiacetal CF2HCH(OH)OCH3. When the H2 pressure was decreased under less than 10 atm at 40 °C, the hemiacetals (B) were obtainable preferentially. These results suggest that the highly fluorinated hemiacetal is stable enough to resist further conversion to alcohols (A) under the reaction conditions. After optimization of hydrogenation conditions, a preparative scale reaction of methyl trifluoroacetate, 128 g with S/C = 20 000 using the catalyst 4a gave fluoral hemiacetal in 89 % yield and with 96 % selectivity. Continuum methanol reaction field DFT analysis with the SMD (solvation model based on density) of the selective hydrogenation of CF3C(O)OCH3 to the hemiacetal intermediate suggests a very facile outer-sphere ‡ –1 hydride transfer (ΔG 298 K = 7.8 kcal·mol ) from the trans-RuH2(CO)(dpa) 4b to CF3C(O)OCH3 through a H-bonded complex Int1 via TS1 via a two-step process to afford the inner-sphere ion pair intermediate Int2, as shown in Fig. 5. A similar step-wise hydride and proton transfer mechanism from the bifunctional Ru hydride complex to carbonyl compound through the contact ion-pair intermediate was observed as discussed in Fig. 1 [4].

Hydrogenation of carboxamides with bifunctional Ru catalysts bearing N–NH2 ligands

Carboxamides with a less electrophilic carbonyl group are still one of the challenging targets in the hydrogenation of carboxylic acid derivatives [18, 22, 23]. Possible reaction pathways in the hydrogenation of carbox amides or lactams are presented in Scheme 7. Path A, which represents reductive cleavage of the C–O bond along with production of water, is a typical pathway for heterogeneous systems or traditional homogeneous catalysts [22], whereas path B, which represents CO reduction followed by C–N bond cleavage, is a typical pathway for bifunctional catalysts [18, 23]. T. Ikariya and Y. Kayaki: Hydrogenation with bifunctional Ru catalysts 941

heterogeneous or traditional Bifunctional catalysts homogeneous catalysts O OH Path A Path B n n NR NR n NHR

Lactam

Path APO athB OH 1 + R NR2 1 1 HNR2 R NR2 R Carboxamide

Scheme 7 Chemoselectivity in hydrogenation of carboxamides or lactams.

The Cp*RuCl(N–N) catalyst (N–N: 2-C5H4NCH2NH2) 3 combined with base catalyzes selective and direct hydrogenation of lactams and carboxamides to form amino alcohols and a mixture of amines and alcohols, respectively (path B in Scheme 7). For example, N-phenylpyrrolidinone was smoothly hydrogenated in 2-propanol containing 10 mol% of 3 to give 4-(phenylamino)butan-1-ol in 73 % isolated yield, although N-benzylpyrrolidinone was reluctant under similar conditions. Nevertheless, a wide variety of carbox amides were susceptible to the present hydrogenation as long as they had an aryl group on their nitrogen (Scheme 8). The inertness of carboxamides lacking any aryl group on the nitrogen allowed a chemoselective hydrogenation of a certain type of amide esters bearing an ester unit in the same molecule, which cleanly gave the hydroxyalkyl-substituted lactams under similar conditions. Notably, in the hydrogenation of lactams bearing no substituent on the nitrogen, the corresponding cyclic amines can be obtained via selective dehy- dration (path A in Scheme 6) [24].

O Cp*RuCl(N N) OH KOtBu NC6H5 + H2 NHC6H5 2-propanol 50 atm 100 C 73 % Isolated yield Substrate:Ru:KOtBu =10:1:2.5

O Cp*RuCl(N N) 2 t OH H R R2 KO Bu N 1 + H2 + R N 2-propanol R1 R3 3 50 atm R 100 C

O O O

N C6H5 CH3 C6H5 N C6H5 N C6H5 N Ru CH3 CH3 N Cl >99%yield 80 % 66 % H H Cp*RuCl(N N); 3 O O O

C6H5 n C6H5 n CH3 C6H5 N C8H17 N C8H17 N H H CH 78 % 67 % 60 % 3

O O O

NC6H5 NR NAr n

n=1; 99 % R=4-CF3C6H4;99% Ar =4-CF3C6H4;99% =2;84% =2-pyridyl;94% =4-CH3OC6H4;88% =3;99% =CH2CO2CH3;85%

O Cp*RuCl(N N) KOtBu NH + H2 NH 2-propanol 50 atm 100 C

99 %yield

Scheme 8 Catalytic hydrogenation of carboxamides and lactams with Cp*Ru(N–N) catalyst 3. 942 T. Ikariya and Y. Kayaki: Hydrogenation with bifunctional Ru catalysts

Conclusions

We demonstrated that a family of Ru catalysts with the metal/NH bifunctional moiety, such as Cp*Ru(P–N) 1 and Cp*Ru(N–N) 3, and RuHCl(CO)(dpa) 4a complexes, serves as efficient catalysts for hydrogenation of carbonyl compounds including carboxylic acid derivatives, esters and carboxamides. The amido complexes formed from chloro(amine) complexes and KOC(CH3)3, promoted heterolytic cleavage of dihydrogen in alcoholic solvents. Significant and rapid progress, particularly for the ester hydrogenation, has been achieved for the past decade by utilization of conceptually new bifunctional molecular catalysts originating from the metal–ligand cooperation effects. However, most molecular catalysts still need relatively forced reaction conditions in terms of the temperature and pressure. From a practical point of view, development of base- free catalysts for hydrogenation is also highly desirable. Therefore, the rational design of new molecular catalyst systems is crucially important to explore unprecedented catalytic performance for hydrogenation of polar functionalities. The industrial outlook for the hydrogenation with the sophisticated catalysts should be bright because of their excellent catalytic performance, operational simplicity, and economic viability as well as their suitability for the green chemistry.

Acknowledgments: This work was financially supported by a Grant-in-Aid for Scientific Research (S) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 22225004) and partly supported by the GCOE Program.

References

[1] G. J. Kubas. Chem. Rev. 107, 4152 (2007). [2] (a) T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori. J. Am. Chem. Soc. 117, 2675 (1995). (b) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori. J. Am. Chem. Soc. 117, 7562 (1995). [3] (a) T. Ikariya. Bull. Chem. Soc. Jpn. 84, 1 (2011). (b) T. Ikariya, A. J. Blacker. Acc. Chem. Res. 40, 1300 (2007). (c) T. Ikariya, K. Murata, R. Noyori. Org. Biomol. Chem. 4, 393 (2006). (d) K. Muñiz. Angew. Chem. Int. Ed. 44, 6622 (2005). [4] P. A. Dub, T. Ikariya. J. Am. Chem. Soc. 135, 2604 (2013). [5] M. Ito, M. Hirakawa, K. Murata, T. Ikariya. Organometallics 20, 379 (2001). [6] M. Ito, T. Ikariya. Chem. Commun. 43, 5134 (2007). [7] M. Ito, M. Hirakawa, A. Osaku, T. Ikariya. Organometallics 22, 4190 (2003). [8] (a) T. Ohkuma, N. Utsumi, K. Tsutsumi, K. Murata, C. Sandoval, R. Noyori. J. Am. Chem. Soc. 128, 8724 (2006). (b) C. A. San- doval, T. Ohkuma, N. Utsumi, K. Tsutsumi, K. Murata, R. Noyori. Chem. Asian J. 1–2, 102 (2006). (c) T. Ohkuma, K. Tsutsumi, N. Utsumi, N. Arai, R. Noyori, K. Murata. Org. Lett. 9, 255 (2007). [9] S. Shirai, H. Nara, Y. Kayaki, T. Ikariya. Organometallics 28, 802 (2009). [10] (a) R. M. Bullock. Chem. Eur. J. 10, 2366 (2004). (b) S. E. Clapham, A. Hadzovic, R. H. Morris. Coord. Chem. Rev. 248, 2201 (2004). [11] (a) M. Ito, Y. Endo, T. Ikariya. Organometallics 27, 6053 (2008). (b) M. Ito, Y. Endo, N. Tejima, T. Ikariya. Organometallics 29, 2397 (2010). [12] (a) P. A. Dub, T. Ikariya. ACS Catal. 2, 1718 (2012). (b) W. W. N. O, R. H. Morris, ACS Catal. 3, 32 (2013). (c) T. P. Brewster, A. J. M. Miller, D. M. Heinekey, K. I. Goldberg. J. Am. Chem. Soc. 135, 16022 (2013). (d) D. Spasyk, S. Smith, D. G. Gusev. Angew. Chem. Int. Ed. 52, 2538 (2013). (e) X.-H. Yang, J.-H. Xie, W.-P. Liu, Q.-L. Zhou. Angew. Chem. Int. Ed. 52, 7833 (2013). [13] C. Gunanathan, D. Milstein. Acc. Chem. Res. 44, 588 (2011). [14] (a) M. Ito, A. Sakaguchi, C. Kobayashi, T. Ikariya. J. Am. Chem. Soc. 129, 290 (2007). (b) M. Ito, C. Kobayashi, A. Himizu, T. Ikariya. J. Am. Chem. Soc. 132, 11414 (2010). (c) M. Ito, L. W. Koo, A. Himizu, C. Kobayashi, A. Sakaguchi, T. Ikariya. Angew. Chem. Int. Ed. 48, 1324 (2009). [15] J. Seyden-Penne. Reductions by the Alumino and Borohydrides in Organic Synthesis, 2nd Ed., Wiley-VCH, Weinheim (1997). [16] M. Ito, T. Ikariya. J. Synth. Org. Chem. Jpn. 66, 1042 (2008). [17] T. Ikariya, M. Ito, A. Shiibashi, T. Ootsuka, Tokyo Institute of Technology, Japan; Central Glass Company, Limited; Patent WO2010004883A1, p 31 (2010). [18] M. Ito, T. Ootsuka, R. Watari, A. Shiibashi, A. Himizu, T. Ikariya. J. Am. Chem. Soc. 133, 4240 (2011). [19] J. Zhang, G. Leitus, Y. Ben-David, D. Milstein. Angew. Chem. Int. Ed. 45, 1113 (2006). [20] W. Kuriyama, T. Matsumoto, O. Ogata, Y. Ino, K. Aoki, S. Tanaka, K. Ishida, T. Kobayashi, N. Sayo, T. Saito. Org. Process Res. Dev. 16, 166 (2012). T. Ikariya and Y. Kayaki: Hydrogenation with bifunctional Ru catalysts 943

[21] T. Otsuka, A. Ishii, P. A. Dub, T. Ikariya. J. Am. Chem. Soc. 135, 9600 (2013). [22] (a) A. A. N. Magro, G. R. Eastham, D. Cole-Hamilton. Chem. Commun. 43, 3154 (2007). (b) M. Stein, B. Breit. Angew. Chem. Int. Ed. 52, 2231 (2013). (c) J. Coetzee, D. L. Dodds, J. Klankermayer, S. Brosinski, W. Leitner, A. M. Z. Slawin, D. J. Cole- Hamilton. Chem. Eur. J. 19, 11039 (2013). [23] (a) E. Balaraman, B. Gnanaprakasam, L. J. W. Shimon, D. Milstein. J. Am. Chem. Soc. 132, 16756 (2010). (b) J. M. John, S. H. Bergens, Angew. Chem. Int. Ed. 50, 10377 (2011). (c) T. Miura, I. E. Held, S. Oishi, M. Naruto, S. Saito. Tetrahedron Lett. 54, 2674 (2013). [24] R. Watari, T. Otsuka, M. Ito, T. Ikariya, In 5th Kanto Branch Conference, The Chemical Society of Japan, 1B529: Tokyo, Japan, August 30–31, (2011).