Simple 1,3-diamines and their application asligands in ruthenium(II) catalysts for asymmetrictransfer hydrogenation of aryl ketones†
Giorgio Facchetti, Raffaella Gandolfi, Marco Fuse, Daniele Zerla, Edoardo Cesarotti,Michela Pellizzoni and Isabella Rimoldi*
In this research work simple unsymmetrical 1,3-diamines were studied. The synthesis of the diamines started
from non-commercial available compounds. S-5a and S,S-5c were obtained by biocatalysis with non
conventional yeast, Rhodotorula rubra MIM 147, with excellent 99% e.e. and d.e. up to 90%. Different
approaches of synthesis were applied to the same backbone to study both the steric and electronic effects
of the ligands. The reactivity of the corresponding ruthenium complexes was evaluated in the asymmetric
hydrogen transfer reduction of acetophenone as a standard substrate and of other different aryl ketones,
highlighting the flexibility of the six membered chelating ring. A screening of the reaction conditions indicated
aqueous media in the presence of HCOONa as a hydrogen donor to be the best system for overcoming the
lack of stereocontrol thus allowing us to obtain 56% e.e. in the reduction of acetophenone with the complex
in which the ligand was diamine 1, revealed as the best in terms of reactivity and stereoselectivity also in the
reduction of the other different aryl ketones, in particular for a-tetralone, i (63% e.e.).
Introduction
In the last decade asymmetric transfer hydrogenation (ATH)has been revealed as a valid alternative to the use of molecularH2 in obtaining enantiomerically pure alcohols which can beapplied to the synthesis of many fine chemicals, pharmaceuticalsand agrochemical products.1
It is well known that the performance of the catalytic systemis strictly related to a synergistic effect between the solventnature and the hydrogen donor. In recent years the develop-ment of ATH in aqueous media has been emerged as a validalternative to the use of organic solvents for its non-toxic,economic and environmental compatible profile.
Since the pioneering work reported by Noyori and Ikariyagroups in 1995,2,3 the catalysts of choice in ATH reductions ofketones have been established to be the ruthenium(II) complexeschelating different substituted 1,2-diamines such as DPEN andits derivatives, among them the monotosylated compounds wererevealed as the most efficient ones.3–11
All these types of catalysts were based on the presence ofligands forming five membered rings when chelated to the
metal centre. Some examples of symmetric 1,4-diamines and fewexamples of 1,3-diamines were reported in the literature,12–17 mainlyused as a typical ruthenium complex [(diphosphine)-RuCl2-(diamine)] for hydrogenation of simple aromatic and aliphaticketones, in the catalytic addition of diethylzinc to aldehyde orin the Cu-catalyzed enantioselective Henry reaction.18–21
Considering the wide range of 1,2-diamines used as ligandsand their utility in asymmetric catalysis, this work reported thesynthesis of simple asymmetric monotosylated 1,3-diamines,up to now poorly investigated in ATH (Fig. 1), and the evaluationof their catalytic performances.
Results and discussion
The starting material for the synthesis of these 1,3-diamines wasthe reduction products of benzoylacetonitrile and its ethylatedderivative.
Different approaches using either asymmetric transfer hydro-genation for the reduction of benzoylacetonitrile 5 withiridium(III)22 and/or ruthenium(II) diamines complexes23 or
Fig. 1 Monotosylated 1,3-diamines.
Dipartimento di Scienze Farmaceutiche, Sez. Chimica Generale e Organica
‘‘A. Marchesini’’, Universita degli Studi di Milano, Via Venezian 21, 20133 Milano,
whole-cell catalysts24,25 were studied. Recently our group dis-played the reduction of the substrate 5 and its correspondingethylated derivative 5b using Carreira’s [Cp*Ir(diamine)(H2O)]SO4
complexes in which the diamine ligand CAMPY and its derivativeswere used as a source of chirality26 with good stereoselectivity.Unfortunately it was not enough to use these products as startingmaterials for the synthesis of enantiomerically pure diamines.Good results were obtained by a biotransformation reaction whichhas been studied especially by Gotor and Dehli27–29 employing thefungus Curvularia lunata. In these studies they underlined theproduction of the expected side product, 2-(1-hydroxy-1-phenyl-methyl)butanenitrile 5c, during the biotransformation occurringon benzoylacetonitrile 5.
Based on the above results we decided to investigate differ-ent yeasts capable of reducing the same substrate 5 and itsderivative 5b. A screening of different genera and species ofyeasts available in our laboratory’s library was carried out (datanot reported) (Fig. 2).
Most of them resulted to produce ethylated keto-compound5b as the major product while 3-hydroxy-3-phenylpropanenitrile5 was produced in a minor amount in the presence of glucose asa co-substrate.
The group of red to pinkish yeasts is one of the most interestingbiocatalysts30–33 in the reduction of differently substituted aryl-ketones and among them Sporobolomyces salmonicolor is the bestknown for this application. As expected, this yeast was able toproduce the desired product 5a in a quantitative yield with 80%e.e. in S configuration avoiding the use of any co-substrate. In the
presence of EtOH as a co-substrate this yeast afforded 5a and 5c ina 50/50 mixture along with a decreasing enantiomeric excess.Best results were obtained when two similar yeasts were used:Rhodotorula rubra MIM 146 and Rhodotorula rubra MIM 147. Inboth cases 5a was the only product yielded in an excellent 98% e.e.in S configuration. With the aim of verifying the ability of these twoyeasts to reduce and resolve compound 5b, its racemic mixturewas quantitatively synthesised by Saccharomyces cerevisiae whichmediated non-stereoselective introduction of the ethyl group.34,35
With R. rubra MIM 146 the conversion of racemic 5b in 5c wasachieved in 48 h with 78% d.e. and 499% e.e. in S,S configuration.The best result was obtained with R. rubra MIM 147 whichproduced S,S-5c at the same time with 499% e.e. and with ad.e. up to 90% thus allowing us to completely separate the twodiastereomers using classical chromatographic techniques.
First of all, starting from linear substrate S-5a, two differenttypes of diamines were synthesised in which the tosyl-aminemoiety was set either on the aliphatic chain or on the preformedstereocentre (Scheme 1).
After obtaining the corresponding aminoalcohol 6a by reductionwith LiAlH4, the synthesis proceeded into two different pathways.The cyclisation with CDI in CH2Cl2 gave the corresponding (S)-6-phenyl-1,3-oxazinan-2-one 7a with the retention of configuration.36
Successively, the reaction with NaH and TsCl provided 6-phenyl-3-tosyl-1,3-oxazinan-2-one 10a, with an excellent yield (80% aftercrystallization). In the second pathway, after protecting the aminogroup with (Boc)2O, substrate 8a reacts with TsCl in the presence of4-DMAP and TEA directly giving 10a with the inversion of configu-ration at the chiral centre.
Indeed, under these specific conditions, the formation of TsO-on the benzylic alcohol and the tosylation of the amido moietyallowed by the 4-DMAP drove a SN2 reaction. This methodologyappears to be very appealing considering that starting from onlyone isomer we obtained both the enantiomers of 10a (Scheme 1).
Fig. 2 Biotransformation of benzoylacetonitrile by yeasts.
Substrate 10a, with the strong nucleophile NaN3 in DMF,underwent SN2 substitution on the chiral centre resulting inthe opening of the cycle and the decarboxylation. The corre-sponding azides were reduced in the presence of Pd/C tomonotosylated diamines, N-(3-amino-3-phenylpropyl)-4-methyl-benzenesulfonamides 1. For the synthesis of the analoguemonotosylated diamine 2, we planned a procedure startingfrom S-6a. The amino moiety was firstly protected with 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (Teoc-OSu).Then the classic procedure, by which the alcoholic function wasreacted with mesyl chloride in the presence of TEA,16 wasperformed unfortunately giving 9a the corresponding oxazina-none R-7a, with inversion of configuration, as observed whenBoc is used as a protecting group for the amino moiety. There-fore, an alternative starting material, (R)-(+)-3-chloro-1-phenyl-1-propanol, for the synthesis of enantiopure diamine S-2, wasstudied. The synthesis proceeded as reported in the followingscheme (Scheme 2).
The second type of diamine was synthesised starting from thereduced ethylated product 5c. The synthesis of diamine 3 vs. 1mirrored each other from the beginning to the end (Scheme 3).
In the case of diamine 4, the methodology was the same asthat initially thought for diamine 2 but in this case the formationof oxazinanone 7c did not take place and after removing the Teoc
protecting group with ZnBr2,37 diamine 4 was obtained in aquantitative yield.
The so synthesised diamines were reacted with [Ru( p-cymene)Cl2]2 to give the corresponding ruthenium(II) complexesassuming a six membered ring conformation. The synthesis ofthe ruthenium(II) complexes here reported was realised by reflux-ing in toluene for 3 h and utilised without further purification asa pre-catalyst in ATH. Different reaction conditions were evalu-ated using acetophenone as a test substrate. With regard tosolvents, water was revealed to be the best choice, as when iPrOHor MeOH was employed, the reaction conversion resultedsignificantly decreased.5,38 In the same way the selection ofhydrogen donors39 (HCOOH, HCOONa, azeotropic mixture5 : 2 = TEA:HCOOH and iPrOH) proved HCOONa among others,in a ratio of 10 : 1 with the substrate, as the best in terms of theenantioselectivity achieved. In fact by using a different hydro-gen donor, a racemic mixture of the product was obtained in allcases. Conversely the temperature variation (20 1C, 40 1C or60 1C) did not show any significant effect on enantioselectivity.Results obtained for the four diamine ligands under the setreaction conditions: water as a solvent and HCOONa as ahydrogen donor at 40 1C are reported in Table 1.
Unexpectedly the presence of an additional chiral centre inposition 2 of the ligands 3 and 4 did not improve the enantio-selectivity but in contrast it negatively influenced the stereo-selectivity of the catalysts along with a significant decrease in thereaction rate (entries 3 and 4 vs. 1 and 2). The results obtained bychanging the position of the tosyl moiety confirmed the impor-tance of the stereogenic centre to be in proximity of the amineinvolved in the catalytic cycle contributing to increase boththe reaction conversion and enantioselectivity through a stericand/or an electronic effect (entries 1 vs. 2 and 3 vs. 4).
The reactivity and selectivity of the complexes carrying thelinear diamines 1 and 2 were studied in ATH of different arylketones (Table 2).
The best results both in terms of the reaction rate and enantio-selectivity were achieved with the catalyst bearing diamine ligandScheme 2 Synthesis of linear diamines 2.
R-1 when compared to catalyst carrying S-2 diamine (entries 1–9 vs.10–18). In particular in the reduction of a-tetralone, an appreciable63% e.e. was achieved with a yield of 70% in 48 h (entry 9).40–42
Conclusions
Easily prepared 1,3-diamines were developed starting fromchiral substrates. The production of the starting material wasrealised by a biocatalytic approach using a non-conventionalyeast, Rhodotorula rubra MIM 147, achieving very good resultsin terms of stereoselectivity, yield and recovery.
The catalytic data showed that when a six membered ringwas formed by employing 1,3-diamines as a source of chirality,
enlarged when compared to the one obtained by using 1,2ligands, a lower optical induction was observed due to theflexibility of the chelating ring as already underlined forthe diphosphine ligands.43 Nevertheless the right combina-tion between the hydrogen donor and the solvent proved todrastically influence the catalytic performance of this type ofcatalyst as well as the electronic and steric properties of thesubstrate.
Experimental sectionGeneral1H and 13C NMR spectra were recorded in CDCl3 or CD3OD on aBruker DRX Avance 300 MHz equipped with a non-reverseprobe at 25 1C. Chemical shifts (in ppm) were referenced tothe residual solvent proton/carbon peak. FTIR spectra werecollected by using a Perkin Elmer (MA, USA) FTIR Spectrometer‘‘Spectrum One’’ in a spectral region between 4000 and 450 cm�1
and analysed using the transmittance technique with 32 scans perion and 4 cm�1 resolution. Polarimetry analyses were carriedout on a Perkin Elmer 343 Plus equipped with a Na/Hal lamp.ESI-MS analyses were performed by using a Thermo Finnigan(MA, USA) LCQ Advantage system MS spectrometer with anelectronspray ionisation source and an ‘Ion Trap’ mass analyser.The MS spectra were obtained by direct infusion of a samplesolution in MeOH under ionisation, ESI positive. Catalytic reac-tions were monitored by gas chromatography analysis using achiral stationary phase column (MEGA DMT b, 25 m, internaldiameter 0.25 mm) or by HPLC analysis with Merck-HitachiL-7100 equipped with Detector UV6000LP and chiral column(OD-H Chiralcel or AD Chiralpak) and with JASCO PU-2080 Plus(OJ-H Chiralcel). Commercially reagent grade solvents weredried according to standard procedures and freshly distilledunder nitrogen before use.
Enzymatic synthesis of rac-2-benzoylbutanenitrile 5b
Commercial Baker’s yeast (50 g L�1) was suspended in aphosphate buffer (200 mL, 0.1 M, pH 7) containing 50 g L�1
of glucose and 5 g L�1 of substrate 5. The biotransformationsystem was shaken using a mechanic stirrer at 28 1C. Whenthe total conversion was achieved, the cells were separated bycentrifugation. Both the aqueous phases and the cell mixturewere extracted with diethyl ether (3 � 50 mL), dried withNa2SO4 and the solvent was removed in vacuo. The crudeproduct was purified by flash chromatography (CH2Cl2/hexane/ethyl acetate = 4 : 1 : 1) to give 860 mg of 5b (86% yield). 1H NMR(300 MHz, CDCl3): d = 1.16 (t, J = 7.7 Hz, 3H, –CH3), 2.02–2.15(m, 2H, –CH2–), 4.30 (dd, J = 6.2, 4.3 Hz, 1H, –CH–), 7.49–7.56(m, 2H, arom), 7.65 (d, J = 7.6 Hz, 1H, arom), 7.95 (d, J = 6.7 Hz,2H, arom) ppm; 13C NMR (75 MHz, CDCl3): d = 190.88, 170.91,134.63, 133.93, 130.38, 129.31, 128.92, 128.68, 41.38, 23.77, 11.89ppm; IR n = 3467, 2975, 2936, 2249, 1694, 1597, 1449, 1265, 1233,1208, 1000, 696 cm�1; elemental analysis for C11H11NO: C, 76.28;H, 6.40; N, 8.09; found: C, 76.13; H, 6.34; N, 7.98; MS (ESI) ofC11H11NO m/z 196.1 ([M + Na]+).
Table 1 ATH of acetophenone using [Ru(p-cymene)(L)Cl] complexes
a Reactions were carried out at 40 1C using 0.5 mmol of the substratewith 0.5 mol% of the ruthenium complex in 3 mL of water in thepresence of 10 equiv. HCOONa as a hydrogen donor. b Conversion wasdetermined by NMR and e.e. was determined by HPLC after 48 h.
Table 2 ATH of different aryl ketones
Entrya Ligand Substrate Conversionb (%) e.e.b (%)
1 R-1 a 40 02 b 70 41 (S)3 c 95 40 (S)4 d 46 18 (S)5 e 43 23 (S)6 f 50 35 (S)7 g — —8 h — —9 i 70 63 (S)
10 S-2 a 5 011 b 15 34 (R)12 c 35 24 (R)13 d 8 15 (R)14 e — —15 f 15 5 (R)16 g — —17 h — —18 i 10 0
a Reactions were carried out at 40 1C using 0.5 mmol of the substratewith 0.5 mol% of the ruthenium complex in 3 mL of water in thepresence of 10 equiv. HCOONa as a hydrogen donor. b Conversion wasdetermined by NMR and e.e. was determined by HPLC after 48 h.
General procedure of biotransformation with Rhodotorularubra MIM 147
Rhodotorula rubra MIM 147 was routinely maintained on maltextract slants (8 g L�1, yeast extract 5 g L�1, agar 15 g L�1, pH 5.6).The strain, grown on malt extract slants for 72 h at 28 1C, wasinoculated into 1000 mL Erlenmeyer flasks containing 150 mL ofthe same liquid medium and incubated on a reciprocal shaker(100 spm) for 48 h at 28 1C. Cells obtained by centrifugation(4000� g for 15 min at 4 1C) of the culture broth (1 L) were washedwith deionised water (3� 200 mL). After lyophilisation 20 g L�1 ofyeast was suspended in 500 mL of 0.1 M phosphate buffer pH = 7containing 50 g L�1 of glucose. The substrates dissolved in DMSOwere added to the biotransformation system in 2 g L�1 (5) or1 g L�1 (rac-5b) of substrate concentration and 1% of the solvent.The biotransformation system was shaken using a mechanicstirrer at 28 1C for 48 h. The cells were separated by centrifugationand broth were extracted with diethyl ether (3 � 150 mL), driedwith Na2SO4 and the solvent was removed in vacuo. The crudeproduct was purified by flash chromatography (ethyl acetate/cyclohexane = 7 : 3) to give 786 mg of S-5a (78% yield) or 287 mgof S,S-5c (57% yield).
S-5a. All characterization data are in agreement with thepreviously reported literature.22,23,44,45 [a]20
D = �63.8 (c = 1,CHCl3); HPLC data: HPLC data for 5a: OJ-H Chiralcel, eluent:hexane : 2-propanol = 90 : 10, flow = 1.0 mL min�1, l = 216 nm;rt: (S) = 24.5 min, (R) = 30.8 min.
To a solution of 5a or S,S-5c (1.72 mmol) in anhydrous THF (10 mL),LiAlH4 was added (100 mg, 2.6 mmol) and the resulting mixture wasstirred under a nitrogen atmosphere at 0 1C. After 1 hour, somewater was carefully added in order to quench the excess LiAlH4 andthe solution was then reduced in volume and extracted withdichloromethane (3 � 15 mL). The organic layers were dried onNa2SO4, filtered and evaporated to give the product.
(S)-3-Ammino-1-phenylpropan-1-ol S-6a. Pale yellow oil(200 mg, 77% yield). [a]20
N,N0-Carbonyldiimidazole (204 mg, 1.35 mmol) was added to asolution of 6a or S,S-6c in CH2Cl2 at room temperature and theresulting mixture was stirred for 12 h. Then, the solvent wasevaporated and the residue solved in ethylacetate and washedwith aqueous HCl (0.1 M) and water. After drying and elimina-tion of the solvent, crystallization by diffusion of hexane intothe acetone solution afforded the product.
(S)-6-Phenyl-1,3-oxazinan-2-one S-7a. White solid (179 mg,75% yield). [a]20
General synthesis of tosyl-oxazinanones S-10a or S,S-9c
To a solution of S-7a or S,S-7c (1.69 mmol) in anhydrous THF at0 1C the stoichiometric amount of NaH was added (68 mg,1.69 mmol). After thirty minutes the solution of tosyl chloridein THF (387 mg, 2.03 mmol) was dropped into the formersolution and stirred at room temperature overnight. The resultingsolution was quenched with water and extracted with trichloro-methane (3 � 10 mL). The collected organic layers were driedon Na2SO4, filtered and evaporated to give a yellow oil thenpurified by crystallization in dichloromethane–hexane to pro-vide the product.
(S)-6-Phenyl-3-tosyl-1,3-oxazinan-2-one S-10a. White solid(440 mg, 80% yield). [a]20
Synthesis of (R)-6-phenyl-3-tosyl-1,3-oxazinan-2-one R-10a
To a solution of 8a (270 mg, 1.08 mmol) in fresh-distilleddichloromethane, 4-dimethylaminopyridine (99 mg, 0.81 mmol)and triethylamine (2 mL, 14.04 mmol) were added. The reactionmixture was then cooled to �10 1C and stirred for half an hour.A solution of tosyl chloride (267 mg, 1.4 mmol) in dichloro-methane was then dropped into the former solution and stirredovernight allowing the reaction mixture to reach room tempera-ture. The reaction was monitored by TLC using dichloromethane/diethyl ether 1 : 1 as an eluent. After 24 h the reaction is com-pleted. The desired product was obtained as a white solid by slowdiffusion of hexane into the acetone solution (152 mg, 43% yield).[a]20
D = +24.7 (c = 0.25, CHCl3). All characterization data are inagreement with that previously reported for S-10a.
General synthesis of azido benzenesulfonamides 11a or S,R-10c
To a solution of 10a or S,S-9c in anhydrous DMF (0.30 mmol),NaN3 was added (98.2 mg, 1.51 mmol). The solution was refluxedat 120 1C for 3.5 h under a N2 atmosphere. After cooling to roomtemperature, water was added and the solution was extracted withdiethyl ether (3 � 10 mL). The collected organic layers were driedon Na2SO4, filtered and evaporated to give the product.
General synthesis of amino benzensulfonamides R-1, S-1 or S,R-3
In a stainless steel autoclave (20 mL), equipped with tempera-ture control and a magnetic stirrer, purged five times withhydrogen, a solution of 11a or S,R-10c (0.15 mmol) in methanolwith 1% of Pd/C was transferred. The autoclave was pressurisedat 20 atm and kept under stirring at room temperature for fourhours. The mixture was then filtered on Celite and the solventwas evaporated in vacuo to give the product.
(R)-N-(3-Amino-3-phenylpropyl)-4-methylbenzenesulfonamideR-1. Yellow oil, without any further purification step (43 mg,95% yield). [a]20
Synthesis of tert-butyl-(S)-(3-hydroxy-3-phenylpropyl)carbamate S-8a
To a solution of 6a (520 mg, 2.94 mmol) in a mixture of THF/water 1 : 1, Na2CO3 was added (720 mg, 6.76 mmol). Thesolution was then cooled to 0 1C and a solution of di-tert-butyl dicarbonate (770 mg, 3.53 mmol) in 5 mL THF was addeddropwise. After 1 h stirring at 0 1C, the solution was warmed toroom temperature and stirred for further 3 h. The reaction was
monitored by TLC using dichloromethane/diethyl ether 1 : 1 asan eluent. After 4 h the reaction was complete and water wasadded to the mixture and extracted with diethyl ether (3� 10 mL)to give the product as a yellow oil (575 mg, 78% yield). [a]20
A solution of S-9a (405 mg, 1.37 mmol) and triethylamine (380 mL,2.74 mmol) in anhydrous THF (10 ml) was cooled to 0 1C. Mesylchloride (130 mL, 1.64 mmol) in THF (2 mL) was added dropwise.The reaction was stirred for 2 h, filtrated and the solvent evapo-rated in vacuo. R-7a was obtained as a white solid (179 mg, 74%yield). [a]20
D = +40.0 (c = 0.5, CHCl3). All characterization data are inagreement with that previously reported for S-7a.
General synthesis for insertion of the amino group in 1 positionS-12a or S,R-11c
A solution of (R)-(+)-3-chloro-1-phenyl-1-propanol or S,S-8c(0.68 mmol) and triethylamine (190 mL, 1.36 mmol) in anhydrousTHF (5 mL) was cooled to 0 1C. Mesyl chloride (65 ml, 0.81 mmol)in THF (1 mL) was added dropwise. The reaction was stirred for2 h, filtrated and the solvent evaporated in vacuo. The mesylatedintermediate was used without any other purification step. Thecompound was dissolved in dry DMF (5 mL) and NaN3 (65 mg,
1 mmol) was added. After stirring for 12 h at room temperature,water (2 mL) was added and the solution was extracted with diethylether (3 � 10 mL). The collected organic layers were washed withan aqueous solution of NaHCO3, dried on Na2SO4, filtered andevaporated to give the azido compound. In a stainless steelautoclave (20 mL), equipped with temperature control and amagnetic stirrer, purged five times with hydrogen, a solution ofthe azido intermediate (0.67 mmol) in methanol with 1% ofPd/C was transferred. The autoclave was pressurised at 20 atmand kept under stirring at room temperature for four hours.The mixture was then filtered on Celite and the solvent wasevaporated in vacuo to give the product.
The reaction mixture was then cooled to 4 1C and stirred forhalf an hour. A solution of tosyl chloride (126 mg, 0.66 mmol)in dichloromethane was then dropped into the former solutionand stirred overnight allowing the reaction mixture to reachroom temperature. The reaction was monitored by TLC usingEtOAc/hexane 1 : 1 as an eluent.
Synthesis of (S)-N-(3-azido-1-phenylpropyl)-4-methylbenzenesulfon-amide S-14a
Compound 13a (40 mg, 0.124 mmol) was dissolved in dryDMSO (5 mL) and NaN3 (80 mg, 1.24 mmol) was added. After24 h at 100 1C, the solution was cooled to room temperature,water (2 mL) was added and the mixture was extracted withdiethyl ether (3 � 5 mL). The collected organic layers werewashed with an aqueous solution of NaHCO3, dried on Na2SO4,filtered and evaporated to give the product S-14a as a whitesolid (40 mg, 97% yield). [a]20
Synthesis of (S)-N-(3-amino-1-phenylpropyl)-4-methylbenzenesulfon-amide S-2
In a stainless steel autoclave (20 mL) equipped with temperaturecontrol and a magnetic stirrer, purged five times with hydrogen, asolution of 14a (40 mg, 0.121 mmol) in methanol with 1% of Pd/Cwas transferred. The autoclave was pressurised at 20 atm and keptunder stirring at room temperature for four hours. The mixturewas then filtered on Celite and the solvent was evaporatedin vacuo to give the product S-2 as a yellow pale oil (35 mg,95% yield). [a]20
Typical procedure for asymmetric transfer hydrogenation(ATH). A 10 mL Schlenk tube was loaded with [RuCl2( p-cymene)]2(1 mmol), the diamine ligand (2.2 mmol) and charged withdistilled toluene (3 mL). The solution was refluxed at 110 1C for3 h. The solvent was removed in vacuo. To a solution of the keto-substrate (0.5 mmol) in water (2 mL), [Ru( p-cymene)(diamine)Cl](0.0025 mmol) in 20 mL DMSO and HCOONa as a hydrogen donor(5 mmol, 10 eq.) were added. The reaction mixture was stirred at40 1C for 48 h and extracted with ethyl acetate (2 � 5 mL). Thecombined organic layers were dried with Na2SO4 and analysedby HPLC.
1 D. J. Ager, A. H. M. de Vries and J. G. de Vries, Chem. Soc.Rev., 2012, 41, 3340–3380.
2 S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya and R. Noyori,J. Am. Chem. Soc., 1995, 117, 7562–7563.
3 K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya and R. Noyori,Angew. Chem., Int. Ed. Engl., 1997, 36, 285–288.
4 B. Zhang, H. Wang, G.-Q. Lin and M.-H. Xu, Eur. J. Org.Chem., 2011, 4205–4211.
5 Y. Tang, X. Li, C. Lian, J. Zhu and J. Deng, Tetrahedron:Asymmetry, 2011, 22, 1530–1535.
6 A. Hayes, G. Clarkson and M. Wills, Tetrahedron: Asymmetry,2004, 15, 2079–2084.
7 X. Liu, T. Zhang, Y. Hu and L. Shen, Catal. Lett., 2014,1–7.
8 J. Cossy, F. Eustache and P. I. Dalko, Tetrahedron Lett., 2001,42, 5005–5007.
9 Y. Li, Y. Zhou, Q. Shi, K. Ding, R. Noyori and C. A. Sandoval,Adv. Synth. Catal., 2011, 353, 495–500.
10 X. Wu, X. Li, W. Hems, F. King and J. Xiao, Org. Biomol.Chem., 2004, 2, 1818–1821.
11 Y. Wei, X. Wu, C. Wang and J. Xiao, Catal. Today, 2014, DOI:10.1016/j.cattod.2014.13.03.066.
12 T. Ohkuma, T. Hattori, H. Ooka, T. Inoue and R. Noyori,Org. Lett., 2004, 6, 2681–2683.
13 G. A. Grasa, A. Zanotti-Gerosa, J. A. Medlock and W. P. Hems,Org. Lett., 2005, 7, 1449–1451.
14 L. Xu, M. C. Desai and H. Liu, Tetrahedron Lett., 2009, 50,552–554.
15 G. A. Grasa, A. Zanotti-Gerosa and W. P. Hems, J. Organomet.Chem., 2006, 691, 2332–2334.
16 G. H. P. Roos and A. R. Donovan, Tetrahedron: Asymmetry,1999, 10, 991–1000.
17 J.-L. Yu, R. Guo, H. Wang, Z.-T. Li and D.-W. Zhang,J. Organomet. Chem., 2014, 768, 36–41.
18 T. Hirose, K. Sugawara and K. Kodama, J. Org. Chem., 2011,76, 5413–5428.
19 K. Kodama, K. Sugawara and T. Hirose, Chem. – Eur. J.,2011, 17, 13584–13592.
20 E. Mayans, A. Gargallo, A. Alvarez-Larena, O. Illa andR. M. Ortuno, Eur. J. Org. Chem., 2013, 1425–1433.
21 K. Csillag, Z. Szakonyi and F. Fulop, Tetrahedron: Asymmetry,2013, 24, 553–561.
22 H. Vazquez-Villa, S. Reber, M. A. Ariger and E. M. Carreira,Angew. Chem., Int. Ed., 2011, 50, 8979–8981.
23 T. Touge, T. Hakamata, H. Nara, T. Kobayashi, N. Sayo,T. Saito, Y. Kayaki and T. Ikariya, J. Am. Chem. Soc., 2011,133, 14960–14963.
24 D. Zhu, H. Ankati, C. Mukherjee, Y. Yang, E. R. Biehl andL. Hua, Org. Lett., 2007, 9, 2561–2563.
25 A. Kamal, M. S. Malik, A. A. Shaik and S. Azeeza, Tetrahedron:Asymmetry, 2008, 19, 1078–1083.
26 D. Zerla, G. Facchetti, M. Fuse, M. Pellizzoni, C. Castellano,E. Cesarotti, R. Gandolfi and I. Rimoldi, Tetrahedron: Asym-metry, 2014, 25, 1031–1037.
27 V. Gotor, J. R. Dehli and F. Rebolledo, J. Chem. Soc., PerkinTrans. 1, 2000, 307–309.
28 J. R. Dehli and V. Gotor, Tetrahedron: Asymmetry, 2000, 11,3693–3700.
29 J. R. Dehli and V. Gotor, Tetrahedron: Asymmetry, 2001, 12,1485–1492.
30 C.-G. Tang, H. Lin, C. Zhang, Z.-Q. Liu, T. Yang and Z.-L. Wu,Biotechnol. Lett., 2011, 33, 1435–1440.
31 A. Uzura, F. Nomoto, A. Sakoda, Y. Nishimoto, M. Kataoka andS. Shimizu, Appl. Microbiol. Biotechnol., 2009, 83, 617–626.
32 D. Zhu, Y. Yang, J. D. Buynak and L. Hua, Org. Biomol.Chem., 2006, 4, 2690–2695.
33 H. Li, D. Zhu, L. Hua and E. R. Biehl, Adv. Synth. Catal.,2009, 351, 583–588.
34 C. Fuganti, G. Pedrocchi-Fantoni and S. Servi, TetrahedronLett., 1990, 31, 4195–4198.
35 A. J. Smallridge, A. Ten and M. A. Trewhella, TetrahedronLett., 1998, 39, 5121–5124.
36 S. G. Davies, A. C. Garner, P. M. Roberts, A. D. Smith,M. J. Sweet and J. E. Thomson, Org. Biomol. Chem., 2006,4, 2753–2768.
37 S. Bijorkman and J. Chattopadhyaya, Chem. Scr., 1982, 20,201–202.
38 M. C. Carrion, M. Ruiz-Castaneda, G. Espino, C. Aliende,L. Santos, A. M. Rodrıguez, B. R. Manzano, F. A. Jalon andA. Lledos, ACS Catal., 2014, 4, 1040–1053.
39 X. Zhou, X. Wu, B. Yang and J. Xiao, J. Mol. Catal. A: Chem.,2012, 357, 133–140.
40 S. Rodrıguez, B. Qu, K. R. Fandrick, F. Buono, N. Haddad,Y. Xu, M. A. Herbage, X. Zeng, S. Ma, N. Grinberg, H. Lee,Z. S. Han, N. K. Yee and C. H. Senanayake, Adv. Synth. Catal.,2014, 356, 301–307.
41 Y. Turgut, M. Azizoglu, A. Erdogan, N. Arslan andH. Hosgoren, Tetrahedron: Asymmetry, 2013, 24, 853–859.
42 J. Li, X. Li, Y. Ma, J. Wu, F. Wang, J. Xiang, J. Zhu, Q. Wangand J. Deng, RSC Adv., 2013, 3, 1825–1834.
43 K. V. L. Crepy and T. Imamoto, Adv. Synth. Catal., 2003, 345,79–101.
44 C. Chen, L. Kong, T. Cheng, R. Jin and G. Liu, Chem.Commun., 2014, 50, 10891–10893.
45 O. Soltani, M. A. Ariger, H. Vazquez-Villa and E. M. Carreira,Org. Lett., 2010, 12, 2893–2895.
46 Y. Kita, J. Haruta, H. Yasuda, K. Fukunaga, Y. Shirouchi andY. Tamura, J. Org. Chem., 1982, 47, 2697–2700.
