(S,S)-1,2-Diphenylethylenediamine

[35132-20-8] [(R,R)-form] [29841-69-8] [(S,S)-form]  · C14H16N2  · (MW 212.29)

(chiral diamine ligand for transition1,2 and main-group3 metals; optical resolution agent;4 chiral solvating agent in NMR analysis;5,6 precursor of chiral auxiliaries7)

Alternate Name: (S,S)-DPEN; (S,S)-1,2-diphenyl-1,2-ethanediamine; (S,S)-1,2-diamino-1,2-diphenylethane; (S,S)-stilbenediamine; (S,S)-a,b-diaminodihydrostilbene.

Physical Data: mp 85-86.5 °C;8 [a]23D -106 ± 1 (c 1.1, MeOH).9

Solubility: soluble in benzene, chloroform, dichloromethane, ethanol, diethyl ether, methanol, THF; modestly soluble in hot hexane, hot water.

Form Supplied in: colorless solid.

Analysis of Reagent Purity: 1H-NMR analysis of its salt with L-mandelic acid.9,10

Preparative Methods: (i) preparation of racemic DPEN and its optical resolution:8,9 Reaction of benzil and cyclohexanone in the presence of ammonium acetate and acetic acid at reflux temperature gives a cyclic bis-imine (1) (1).9 Stereoselective reduction of the bis-imine with lithium in THF-liquid ammonia at -78 °C followed by addition of ethanol, then hydrolysis with hydrochloric acid and neutralization with sodium hydroxide produces the racemic diamine (2). Recrystallization of the L-tartaric acid salt from a 1:1 water-ethanol mixture followed by neutralization with sodium hydroxide, recrystallization from hexane results in (S,S)-DPEN (3) as colorless crystals.

(ii) Transformation from (R,R)-diphenylethyleneglycol: (R,R)-Diphenylethyleneglycol prepared by Sharpless dihydroxylation11 of trans-stilbene is treated with 2.4 equiv of p-tosyl chloride, and the resulting ditosylate is converted with 2.6 equiv of sodium azide to the S,S-configured diazide without racemization. The diazide is reduced by lithium aluminum hydride to afford (S,S)-DPEN (2).12 This transformation is also achieved via its cyclic sulfate13 or sulfite.14 Asymmetric borane reduction of a bisiminodiphenylethane derivative15 and asymmetric imino pinacol-type coupling16 are also reported.

Purification: recrystallization from hexane.8,9

Handling, Storage, and Precautions: DPEN is substantially stable. No special handling care is required.

BINAP/DPEN/Ru(II)-catalyzed Asymmetric Hydrogenation of Simple Ketones1

Ru(II) complexes having a formula of trans-RuCl2(diphosphine)(dpen) are most conveniently obtained by treatment of oligomeric RuCl2(diphosphine)(dmf)n with 1.1 equiv of DPEN in DMF at room temperature17 [diphosphine = 2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP),18 2,2-bis(di-4-tolylphosphino)-1,1-binaphthyl (TolBINAP), 2,2-bis(di-3,5-xylylphosphino)-1,1-binaphthyl (XylBINAP),19 2,2-bis(di-3,5-xylylphosphino)-1,1-biphenyl (DM-BIPHEP)20]. The molecular structures of diastereomeric trans-RuCl2[(R)-tolbinap][(R,R)- or (S,S)-dpen] have been elucidated by X-ray crystallographic analysis.17 These chiral diphosphine/diamine/Ru(II) complexes act as excellent precatalysts for the asymmetric hydrogenation of simple ketones.1 A range of aromatic, hetero-aromatic, amino, and a,b-unsaturated ketones are hydrogenated to the corresponding chiral alcohols quantitatively with excellent optical purity.

The diphosphine/diamine/Ru(II) complexes show exceptionally high catalytic activity for hydrogenation of simple ketones with an alkaline base in propan-2-ol. Acetophenone (601 g) is hydrogenated with trans-RuCl2[(S)-tolbinap][(S,S)-dpen] (2.2 mg) and t-BuOK (5.6 g) in propan-2-ol (1.5 L) under 45 atm H2 at 30 °C for 48 h to give (R)-1-phenylethanol in 80% ee quantitatively. The substrate concentration is as high as 30%. Under such conditions, the turnover number (TON) is at least 2 400 000, whereas the turnover frequency (TOF) at 30% conversion is 228 000 h-1 or 63 s-1 (3).17 The reaction can be conducted under 1 atm of H2 with a substrate/catalyst (S/C) molar ratio of 800. When (S)-XylBINAP is used as a diphosphine ligand instead of (S)-TolBINAP, the ee value is increased to 99%.21 Alkyl aryl ketones with various substituents are hydrogenated with a consistently high enantioselectivity.1,22 The reaction is tolerant of aromatic halides and CF3, OMe, COO-i-Pr, NO2, and NH2 groups. The high degree of enantioselectivity is a result of the synergistic effects of BINAPs and DPEN. In most cases, a combination of the (S)-BINAP derivative and (S,S)-DPEN or the R/R,R enantiomer results in the best enantioselectivity.

Hydrogenation of open-chain a,b-unsaturated ketones proceeds selectively at the C=O linkage to afford chiral allylic alcohols with high ee.22,23 b-Ionone, a dienone, is hydrogenated in the presence of trans-RuCl2[(S)-xylbinap][(S,S)-dpen] and t-BuOK in propan-2-ol under 8 atm H2 to give (R)-b-ionol in 93% ee (4).21 No saturation of the olefinic bond is observed. The related diamine-free BINAP/Ru complexes catalyze hydrogenation of the C=C unit of allylic alcohols,24 and thus the presence of diamine dramatically reverses the chemoselectivity preference. In the hydrogenation of less hindered, base-sensitive enones, K2CO3, a relatively weak base, should be used to avoid production of polymeric compounds. In most cases, the degree of enantioselection with the XylBINAP/DPEN/Ru(II) catalyst is slightly lower than that with the XylBINAP/DAIPEN/Ru(II) catalyst (DAIPEN = 1,1-di-4-anisyl-2-isopropyl-1,2-ethylenediamine).22,25

A catalyst prepared in situ consisting of RuCl2(diphosphine)-(dmf)n, DPEN, and a base is also usable,26 although it is less active than the diphosphine/DPEN/Ru(II) complex and base combination. Enantioselective hydrogenation of 2,4,4-trimethyl-2-cyclohexenone, a cyclic a,b-unsaturated ketone, with RuCl2[(R)-tolbinap](dmf)n, (S,S)-DPEN, and KOH under 8 atm H2 at 0 °C results in (S)-2,4,4-trimethyl-2-cyclohexenol with 96% ee quantitatively (5).27 In this case, unlike the above mentioned example, the combined use of (R)-TolBINAP and (S,S)-DPEN (or S and R,R) is necessary for the high stereoselection. Reaction using (R)-TolBINAP and (R,R)-DPEN gives the S alcohol in only 26% ee.

When the cyclic enone is hydrogenated with the racemic TolBINAP/Ru(II) complex and (S,S)-DPEN under otherwise identical conditions, the S allylic alcohol is obtained in 95% ee and 100% yield.28 The ee value is close to the 96% attained with the enantiomerically pure (R)-TolBINAP/(S,S)-DPEN system. Hydrogenation of o-methylacetophenone catalyzed by RuCl2[(±)-tolbinap](dmf)n and (S,S)-DPEN results in the R alcohol in 90% ee and 100% yield (6).28 The S/S,S catalyst gives the R product in 97.5% ee.

DM-BIPHEP, a conformationally flexible diphosphine, is converted to racemic RuCl2(dm-biphep)(dmf)n.20 Hydrogenation of 1-acetonaphthone with a mixture of DM-BIPHEP/Ru(II) complex, (S,S)-DPEN, and KOH under 40 atm of H2 at -35 °C results in the R alcohol and 92% ee in >99% yield (7).

Certain racemic ketones can be resolved kinetically through asymmetric hydrogenation. When racemic carvone is hydrogenated using an (S)-BINAP/Ru complex, (R,R)-DPEN, and KOH, it gives, at 54% conversion, the starting (S)-carvone in 94% ee (46%) together with (1R,5R)-carveol in 93% ee (50%) and some other minor alcohols (3.7%) (8).27 The extent of the enantiomer differentiation ability, kfast/kslow, is calculated to be 33.

Dynamic kinetic resolution provides a stereoselective method to convert racemic ketones having an a-stereogenic center into a single stereoisomer quantitatively among the four possible stereoisomers.29 Hydrogenation of 2-isopropylcyclohexanone with RuCl2[(S)-binap](dmf)n, (R,R)-DPEN, and KOH under 4 atm H2 at room temperature results in a 99.8:0.2 mixture of the cis (1R,2R) alcohol in 93% ee and the trans (1R,2S) isomer in 28% ee (9).30 Under the conditions, the R ketone is hydrogenated 36 times faster than the S isomer and the slow-reacting S ketone undergoes in situ stereochemical inversion 47 times faster than it is hydrogenated.

DPEN/metal-complex Catalyzed Asymmetric Reactions

A catalyst system generated in situ from Co(acac)2 and (R,R)-DPEN accelerates enantioselective Michael addition of methyl 1-oxo-2-indanecarboxylate to methyl vinyl ketone to give the R adduct in up to 66% ee (10).2

A chiral Lewis acid prepared in situ from magnesium iodide and (R,R)-DPEN efficiently catalyzes asymmetric aza-Diels-Alder reaction of a methyl glyoxylate/p-anisidine derived imine with the Danishefsky diene to give the cyclic adduct in 97% ee (11).3

Synthesis of Enantiomerically Pure C2-symmetric Vicinal Diamines via Chirality Transfer from DPEN

Several C2-symmetric vicinal diamines and their derivatives are prepared in optically pure form by chirality transfer from DPEN.31 For example, condensation of (S,S)-DPEN with butane-2,3-dione in benzene at the reflux temperature is followed by stereoselective reduction with NaBH3CN and PPTS at -20 °C to afford the (2S,3S,5R,6R)-piperazine 4 and its diastereomer in a 15:1 ratio (12). The crude product is purified by silica gel column chromatography. Formation of the biscarbamate followed by reductive cleavage of benzylic C-N bonds with lithium in liquid ammonia, and then removal of isobutyloxycarbonyl with HBr in acetic acid results in (R,R)-2,3-diaminobutane dihydrobromide 5 in 99% ee.

Optical Resolution Agent and NMR Chiral Solvating Agent

DPEN acts as an effective optical resolution agent of racemic 2,2-dihydroxy-1,1-binaphthyl (BINAPHTHOL).4 A 1:1 mixture of racemic BINAPHTHOL and (R,R)-DPEN in hot benzene produces colorless crystalline solid at room temperature. Recrystallization from benzene followed by the addition of HCl results in optically pure (R)-BINAPHTHOL (13).

In addition, DPEN is an efficient chiral solvating agent for determination of the enantiomeric excess in the 1H NMR analysis of various chiral mono- and dicarboxylic acids including a-arylpropanoic and a-halo carboxylic acids.5 The chemical-shift non-equivalence (dd) in certain diastereomeric complexes is greater than 0.05 ppm. A DPEN/Pd(II) complex can be used for determination of enantiomeric excess of the non-protected chiral amino acids by 1H and 13C NMR analysis.6 For example, {Pd[(S,S)-dpen](D2O)2}2+ and racemic alanine with a base forms the square-planar complex (14). The dd of 1H-NMR resonance in the diastereomeric complexes in D2O is 0.056 ppm, while this complex hardly dissolves in D2O.

Precursor of Useful Chiral Ligands

DPEN is widely used for the preparation of chiral ligands.7 Organometallic compounds with these ligands act as useful reagents or catalysts in asymmetric induction reactions such as dihydroxylation of olefins,32 transfer hydrogenation of ketones and imines,33 Diels-Alder and aldol reactions,34 desymmetrization of meso-diols to produce chiral oxazolidinones,35 epoxidation of simple olefins,36,37 benzylic hydroxylation,38 and borohydride reduction of ketones, imines, and a,b-unsaturated carboxylates.39

Related Reagents.

(R)- and (S)-2,2-Bis(diphenylphosphino)-1,1-binaphthyl; 1,3,2-dioxathiolane 2,2-dioxide; (R,R)-1,2-diphenyl-1,2-diaminoethane N,N-bis[3,5-bis(trifluoromethyl)benzenesulfonamide].


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Takeshi Ohkuma & Ryoji Noyori

Nagoya University, Aichi, Japan



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