3,3'-bis(diphenylphosphino)-1,1'-disubstituted-2,2'-biindoles: Easily accessible, electron-rich, chiral diphosphine ligands for homogeneous enantioselective hydrogenation of oxoesters

Article abstract of DOI:10.1021/jo001207d

Racemic (±)-3,3'-bis(diphenylphosphinyl)-1,1'-dimethyl-2,2'-biindole (1c) (N-Me-2-BINPO) and (±)-3,3'-bis(diphenylphosphinyl)-1,1'-bis(methoxymethyl)-2,2'-biindole (1d) (N-MOM-2-BINPO) were synthesized in satisfactory yields following a three-step reaction sequence, starting from indole. Resolution of racemic 1c and 1d was achieved through fractional crystallization of their diastereomeric adducts with optically active dibenzoyl tartaric acids, followed by alkaline decomplexation of the diastereomerically pure salts. Their trichlorosilane reduction gave enantiopure phosphines (+)- and (-)-(1a) (N-Me-2-BINP) and (+)- and (-)-(1b) (N-MOM-2-BINP). The electrochemical oxidative potential of 1a and 1b was found to be 0.52 and 0.60 V, respectively. Both the enantiomers of (1a) were tested as ligands of Ru(II) in asymmetric hydrogenation reactions of α- and β-oxoesters. Reactions were found to be outstandingly fast and enantioselection quite good. Comparative kinetic experiments on the hydrogenation reaction of methyl acetoacetate carried out with 1a, 1c, BINAP, and other biheteroaromatic diphosphines as ligands of Ru(II) demonstrated that all the reactions follow a first-order kinetic. A linear relationship was found between the kinetic constant log and the electrochemical oxidative potential of the diphosphine ligand.

Full text of DOI:10.1021/jo001207d

8340
J . Org. Chem. 2000, 65, 8340-8347
3,3′-Bis(d ip h en ylp h osp h in o)-1,1′-d isu bstitu ted -2,2′-biin d oles:
Ea sily Accessible, Electr on -Rich , Ch ir a l Dip h osp h in e Liga n d s for
Hom ogen eou s En a n tioselective Hyd r ogen a tion of Oxoester s
Tiziana Benincori,*† Oreste Piccolo,‡ Simona Rizzo,§ and Franco Sannicolo`*,§
‡Dipartimento di Chimica Organica e Industriale, Universita` di Milano e Centro CNR Sintesi e
†
Stereochimica Speciali Sistemi Organici, Via Golgi 19, I-20133 Milano, Italy, Dipartimento di Scienze
Chimiche, Fisiche e Matematiche, Universita` dell’Insubria, Via Lucini 3, I-22100 Como, Italy, and Chemi
S.p.A., Via dei Lavoratori, I-20092 Cinisello Balsamo, Italy
staclaus@icil64.cilea.it
Received August 7, 2000
Racemic (()-3,3′-bis(diphenylphosphinyl)-1,1′-dimethyl-2,2′-biindole (1c) (N-Me-2-BINPO) and (()-
3,3′-bis(diphenylphosphinyl)-1,1′-bis(methoxymethyl)-2,2′-biindole (1d ) (N-MOM-2-BINPO) were
synthesized in satisfactory yields following a three-step reaction sequence, starting from indole.
Resolution of racemic 1c and 1d was achieved through fractional crystallization of their
diastereomeric adducts with optically active dibenzoyl tartaric acids, followed by alkaline decom-
plexation of the diastereomerically pure salts. Their trichlorosilane reduction gave enantiopure
phosphines (+)- and (-)-(1a ) (N-Me-2-BINP) and (+)- and (-)-(1b) (N-MOM-2-BINP). The
electrochemical oxidative potential of 1a and 1b was found to be 0.52 and 0.60 V, respectively.
Both the enantiomers of (1a ) were tested as ligands of Ru(II) in asymmetric hydrogenation reactions
of R- and â-oxoesters. Reactions were found to be outstandingly fast and enantioselection quite
good. Comparative kinetic experiments on the hydrogenation reaction of methyl acetoacetate carried
out with 1a , 1c, BINAP, and other biheteroaromatic diphosphines as ligands of Ru(II) demonstrated
that all the reactions follow a first-order kinetic. A linear relationship was found between the kinetic
constant log and the electrochemical oxidative potential of the diphosphine ligand.
In tr od u ction
the backbone. This strategy provides a viable alternative
to the introduction of electron-donating or electron-
withdrawing groups on the biaryl backbone4 or on the
nonstereogenic substituents at phosphorus.5 This tradi-
tional approach is synthetically very demanding, par-
ticularly in C2 symmetry systems. (b) It is possible to vary
the steric properties of the ligands by introducing suitable
substituents on the biaryl backbone. (c) The synthetic
routes to five-membered biheteroaryl systems are simpler
and more flexible than those available for the six-
membered carbocyclic biaryls.
The search for easily accessible chiral ligands for
transition metals, showing high enantioselection ability
in homogeneous catalysis, is an ongoing challenge in
chemical research. Chelating diphosphines, supported by
an atropisomeric biaryl scaffold, are currently rated as
very efficient chiral inducers in many asymmetric trans-
formations, and BINAP1 and BIPHEMP2 are the proto-
types of this family. A few years ago we presented a class
of chiral diphosphines structurally characterized by an
atropisomeric backbone consisting of two interconnected,
five-membered, heteroaromatic units.3 The advantages
of these ligands over the more traditional biaryl carbocy-
clic systems are numerous: (a) It was possible to accede
to a highly modular, homogeneous class of diphosphine
ligands having different electronic properties at phos-
phorus. In fact, it is possible to modulate electronic
phosphorus availability through the inherent electron-
releasing capacity of the heterocyclic system constituting
The examples of biheteroaromatic diphosphines we
have published so far have 3,3′-bibenzo[b]thiophene
(BITIANP) and 4,4′,6,6′-tetramethyl-3,3′-bibenzo[b]thio-
phene
(tetraMe-BITIANP),3,6
3,3′-bibenzo[b]furan
(BICUMP),6 3,3′-dimethyl-2,2′-biindole (BISCAP),7 1,1′-
bibenzimidazole (BIMIP),7 and 2,2′,5,5′-tetramethyl-3,3′-
(4) Schmid, R.; Cereghetti, M.; Heiser, B.; Scho¨nholzer, P.; Hansen,
H.-J . Helv. Chim. Acta 1988, 71, 897; Sudan, H.; Motoi, M.; Fujii, M.;
Kanoh, S.; Yoshida, H. Tetrahedron Lett. 1979, 4566. Motoi, M.
Tetrahedron Lett. 1983, 24, 1513. Laue, C.; Schro¨der, G.; Arit, D.;
Grosser, R. Eur. Pat. Appl. 0529 444. Smuda, H. GIT Fachz Lab 1995,
672.
(5) (a) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki,
K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.;
Takaya, H. J . Org. Chem. 1994, 59, 3064. (b) Schmid, R.; Broger, E.
A.; Cereghetti, M.; Crameri, Y.; Foricher, J .; Lalonde, M.; Mueller, R.
K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure Appl. Chem. 1996, 68,
131. Trabesinger, G.; Albinati, A.; Feiken, N.; Kunz, R. W.; Pregosin,
P. S.; Tschoerner, M. J . Am. Chem. Soc. 1997, 119, 6315. Sollewijn
Gelpke, A. E.; Veerman, J . J . N.; Goedheijt, M. S.; Kamer, P. C. J .;
van Leeuwen, P. W. N. M.; Hiemstra, H. Tetrahedron 1999, 55, 6657.
(6) Benincori, T.; Brenna, E.; Sannicolo`, F.; Trimarco, L.; An-
tognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J . Org. Chem. 1996,
61, 6244.
† Universita` dell’Insubria.
‡ Chemi S.p.A.
§ Universita` di Milano e Centro CNR Sintesi e Stereochimica
Speciali Sistemi Organici.
(1) Akutagawa, S, Appl. Catal. A 1995, 128, 171. Naota, T.; Takaya,
H.; Murahashi, S. Chem. Rev. 1998, 98, 2599.
(2) Mezzetti, A.; Consiglio, G. J . Chem. Soc., Chem. Commun. 1991,
1675. Geneˆt, J . P.; Pinel, C.; Ratovelomanana-Vidal, V.; Mallart, S.;
Pfister, X.; Biscoff, L.; Can˜o De Andrade, M. C.; Darses, S.; Galopin,
C.; Laffitte, J . A. Tetrahedron: Asymmetry 1994, 5, 675.
(3) Antognazza, P.; Benincori, T.; Brenna, E.; Cesarotti, E.; Sanni-
colo`, F.; Trimarco, L. Ital. Pat. Appl. MI94 A 001 438. Int. Pat. Appl.:
PCT/EP95/02647 to CHEMI. Benincori, T.; Brenna, E.; Sannicolo`, F.;
Trimarco, L.; Antognazza, P.; Cesarotti E. J . Chem. Soc., Chem.
Commun. 1995, 685.
10.1021/jo001207d CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/08/2000

Chiral Diphosphine Ligands for Hydrogenation
J . Org. Chem., Vol. 65, No. 24, 2000 8341
Sch em e 1
a
Reagents and conditions: (i) MeMgCl, Ph2PCl, THF, rt, 12 h; H2O2, CH2Cl2, rt, 30 min; (ii) KOH, EtOH, reflux, 2.5 h; (iii) RX, NaH,
THF, rt, 1 h; (iv) BuLi, TMEDA, THF, CuCl2, 3 h, rt; (v) HSiCl3, TEA, xylene, 100-140 °C, 5 h.
Since high electronic density at phosphorus is known,
though only qualitatively, to be a favorable parameter
in ruthenium-catalyzed hydrogenation reactions of ke-
tonic carbonyl of ketoesters,8,11 we decided to focus our
attention on the synthesis of 3,3′-bis(diphenylphosphino)-
1,1′-dimethyl-2,2′-biindole (1a ) (N-Me-2-BINP) and 3,3′-
bis(diphenylphosphino)-1,1′-bis(methoxymethyl)-2,2′-bi-
indole (1b) (N-MOM-2-BINP), where the phosphino
groups are located in â position, the most electron-rich
position, of the indole ring which is, per se, one of the
most electron-rich heterocycles. The structure of N-MOM-
2-BINP appeared attractive, since cleavage of the meth-
oxymethyl group would afford 3,3′-bis(diphenylphosphino)-
2,2′-biindole, an excellent scaffold upon which to attach
functions capable of conferring special properties to the
F igu r e 1. Some biheteroaromatic diphosphines.
catalytic metal complexes.
bithiophene (tetraMe-BITIOP)8 backbones (Figure 1).
Furthermore, to gain quantitative evidence of the
Very successful results have been obtained so far in the
influence of the electronic availability of phosphorus on
hydogenation of prostereogenic functionalized ketonic
the kinetics of hydrogenation of oxoesters, we considered
and olefinic double bonds and in the Heck synthesis by
the comparison of kinetic data drawn from the hydroge-
employing the first and the last ligands of this series.9
nation of ethyl acetoacetate promoted by the ruthenium-
We found electrochemical oxidative potential (E°),
determined by voltammetry, to be a very significant probe
of the electronic availability of the phosphorus atoms in
(II) complexes of the biheteroaromatic diphosphines cited
above and BINAP, taken as a reference ligand.
these compounds: the higher its value, the more electron-
poor the phosphine.7 Oxidative potential increases along
Resu lts a n d Discu ssion
the series in the following order: tetraMe-BITIOP (E° )
0.57 V), tetraMe-BITIANP (E° ) 0.76 V),10 BITIANP (E°
Syntheses of racemic diphosphines N-Me-2-BINP (1a )
and N-MOM-2-BINP (1b) and of the corresponding
phosphine oxides N-Me-2-BINPO (1c) and N-MOM-2-
BINPO (1d ) were achieved through a straightforward
reaction sequence, starting from indole (Scheme 1).
) 0.83 V), BISCAP (E° ) 0.90 V), BICUMP (E° ) 1.03
V), BIMIP (E° ) 1.15 V).10
This order is in accordance with the expected decrease
in the electronic availability of the supporting heterocycle
and with a decrease in the electronic density of the
position in which the diphenylphosphino group is carried.
Preferential introduction of phosphorus in position 3
on the indole ring was performed by reaction of N-
indolylmagnesium iodide with diphenylchlorophosphine
(7) Benincori, T.; Brenna, E.; Sannicolo`, F.; Trimarco, L.; An-
tognazza, P.; Cesarotti, E.; Zotti, G. J . Organomet. Chem. 1997, 529,
445.
(8) Benincori, T.; Cesarotti, E.; Piccolo, O.; Sannicolo`, F. J . Org.
Chem. 2000, 65, 2043.
(11) Tani, K.; Suwa, K.; Tanigawa, E.; Yoshida, T.; Okano, T.;
Otsuka, S. Chem. Lett. 1982, 261. Tani, K.; Suwa, K.; Yamagata, T.;
Otsuka, S. Chem. Lett. 1982, 265. Tani, K.; Suwa, K.; Tanigawa, E.;
Ise, T.; Yamagata, T.; Tatsuno, Y.; Otsuka, S. J . Organomet. Chem.
1989, 370, 203. Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.;
Nozaki, k.; Kumobayashi, H.; Hori, Y.; Ishizaki, T.; Akutagawa, S.;
Takaya, H. J . Org. Chem. 1994, 59, 3064.
(9) Tietze, L. F.; Thede, K.; Sannicolo`, F. Chem. Commun. 1999,
1811.
(10) Electrochemical oxidative potentials are referred to Ag/Ag+
electrode in acetonitrile.

8342 J . Org. Chem., Vol. 65, No. 24, 2000
Benincori et al.
in THF solution.12 We found that harder reactants, such
as N-indolylsodium or diphenylphosphinyl chloride, ex-
clusively orient the attack of phosphorus at the nitrogen
atom.
resolution methodology.13 Fractional crystallization of the
diastereomeric adducts produced by reaction of (()-1c
and (()-1d with equimolar amounts of enantiopure (-)-
O,O′-dibenzoyl-L-tartaric acid gave, in both cases, the
dextrorotatory diastereoisomer as the less-soluble adduct.
Evaluation of product distribution was performed by
careful column chromatography of the phosphine oxides
obtained by oxidation of the crude reaction mixture with
33% hydrogen peroxide, in dichloromethane solution, at
0 °C. 3-(Diphenylphosphinyl)indole (2a ) was obtained in
a 55% yield, together with N-(diphenylphosphinyl)indole
(2b) and 1,3-bis(diphenylphosphinyl)indole (2c) in 7%
and 25% yields, respectively. Treatment of the mixture
of crude phosphine oxides 2a , 2b, and 2c with the cal-
culated amount of alcoholic sodium hydroxide produced
cleavage of the phosphorus-nitrogen bond in 2b and 2c,
converting 2b into indole, and the useless diphosphine
oxide 2c into the desired monophosphine oxide 2a .
Following this procedure, the latter was isolated in a pure
state in a 78% overall yield.
[Adduct from 1c: mp ) 233 °C (CHCl3); [R]25 ) +6.2 (c
D
) 0.50, EtOH); (yield: 60% of the theoretical amount).
Adduct from 1d : mp ) 234 °C (CHCl3/AcOEt 3:1); [R]25
D
) +18.5 (c ) 0.51, EtOH); (yield: 57% of the theoretical
amount)]. The mother liquors were treated with 0.75 M
sodium hydroxide solution to effect the decomplexation
of the soluble adduct and to remove the resolving agent.
The residue was treated in turn, with (+)-O,O′-dibenzoyl-
D-tartaric acid, according to the procedure described
above, to give the levorotatory adduct [Adduct from 1c:
mp ) 236 °C; [R]25D ) -6.0 (c ) 0.51, EtOH) (yield: 86%
of the theoretical amount). Adduct from 1d : mp ) 236
°C; [R]25 ) -17.6 (c ) 0.51, EtOH) (yield: 86% of the
D
theoretical amount)].
Repetition of this procedure on the crystallization
residues allowed quantitative resolution of the racemates.
Alkaline decomplexation of the dextrorotatory complex
obtained from 1c gave dextrorotatory phosphine oxide
(+)-N-Me-2-BINPO, (+)-1c, [mp ) 301 °C (MeOH/H2O
Methylation of the anion of 2a with methyl iodide in
THF solution gave 3-(diphenylphosphinyl)-1-methylin-
dole (2d ) in a quantitative yield. The oxidative coupling
reaction (CuCl2) of the 2-lithium derivative of 2d gave
racemic (()-3,3′-bis(diphenylphosphinyl)-1,1′-dimethyl-
2,2′-biindole, (()-N-Me-2-BINPO (1c) in a 51% yield.
13:5); [R]25 ) +67,6 (c ) 0.50, EtOH)]; the levorotatory
D
adduct correspondingly gave levorotatory (-)-N-Me-2-
Alternative quenching of the anion of 2a with chlo-
romethoxymethane gave 3-(diphenylphosphinyl)-1-meth-
oxymethylindole (2e) in an 89% yield. The oxidative
coupling reaction of its 2-lithium derivative, under the
same experimental conditions employed for the synthesis
of 1c, gave racemic (()-3,3′-bis(diphenylphosphinyl)-1,1′-
bis(methoxymethyl)-2,2′-biindole, (()-N-MOM-2-BINPO
(1d ), again in a 51% yield. Overcrowding around the
incipient interannular bond probably is the yield-limiting
factor impeding these coupling reactions. However, owing
to the availability of inexpensive starting materials and
the simplicity of the experimental procedures, we were
able to scale-up both the reaction sequences, so as to
prepare more than 10-g batches of racemic 1c and 1d .
They could be converted into the corresponding racemic
phosphines 1a and 1b, in an about 90% isolation yield,
by reaction with trichlorosilane, in the presence of
triethylamine, in refluxing xylene solution.
BINPO, (-)-1c [mp ) 302 °C; [R]25 ) -65.6 (c ) 0.51,
D
EtOH)].
In the case of the adducts obtained from 1d , alkaline
treatment of the dextrorotatory complex afforded the
dextrorotatory phosphine oxide (+)-N-MOM-2-BINPO,
(+)-1d , [mp ) 351 °C (2-propanol/H2O-1:1); [R]25D ) +77.1
(c ) 0.51, EtOH)]. The levorotatory adduct analogously
gave levorotatory (-)-N-MOM-2-BINPO, (-)-1d [mp )
351 °C; [R]25 ) -76.6 (c ) 0.52, EtOH)].
D
Enantiomeric purity of (+)- and (-)-1c and 1d was
confirmed by chiral HPLC analysis (Supelcosil LC-(R)-
phenylurea, eluant: hexane:2-propanol:CH2Cl2 50:5:45
(v/v/v), 0.5 mL.min-1).14 The CD spectra of the antipodes
were also perfect mirror images (Figure 2 and Figure 3).
Reduction of (+)-1c to (+)-N-Me-2-BINP, (+)-1a [mp
) 321 °C; [R]25D ) +119.5 (c ) 0.51, C6H6)] was performed
with trichlorosilane in excess, in the presence of triethyl-
amine, in a refluxing xylene solution, under argon
atmosphere. Analogous reduction of (-)-1c, gave (-)-N-
Me-2-BINP, (-)-1a [mp ) 322 °C; [R]25D ) -121 (c ) 0.50,
C6H6)].
Parallel results were obtained in the reduction of (+)-
and (-)-1d which respectively gave (+)-N-MOM-2-BINP,
(+)-1b [mp ) 179 °C; [R]25D ) +133 (c ) 0.42, C6H6)] and
(-)-N-MOM-2-BINP, (-)-1b [mp ) 179 °C; [R]25D ) -135
(c ) 0.42, C6H6)] in 90% yields.
Enantiomeric purity of all the optically pure diphos-
phines was confirmed by oxidation with hydrogen per-
oxide which gave enantiopure diphosphine oxides (HPLC).
This result demonstrates that the ligands are configu-
rationally stable up to 140 °C, which is the reaction
temperature at which they are prepared by reduction of
the corresponding diphosphine oxides.
We first checked the electronic availability at phos-
phorus in N-Me-2-BINP (1a ) and N-MOM-2-BINP (1b).
Voltammetric experiments showed the anodic peak,
corresponding to a nonreversible monoelectron abstrac-
tion, at 0.52 and 0.60 V, respectively.10 The value found
for 1a is the lowest observed for a bis(diphenylphosphino)
chelating ligand, including all our biheteroaryl diphos-
phines, BINAP (E° ) 0.63 V) and other popular ones, like
DIOP (E° ) 0.97 V), CHIRAPHOS (E° ) 0.97 V),
NORPHOS (E° ) 0.83 V), and BPPM (E° ) 0.99 V).
MeDuPHOS was found to be, as expected, the most
electron-rich diphosphine (E° ) 0.39 V).
N-MOM-2-BINP (1b), was found to be slightly more
electron-poor than N-Me-2-BINP (1a ), on account of the
electron-withdrawing inductive effect exerted by the
oxygen atom of the methoxymethyl group on the indole
ring.
The CD spectra of enantiomeric diphosphines showed
perfectly specular shapes (Figure 2 and Figure 3).
Resolution of N-Me-2-BINPO (1c) and N-MOM-2-
BINPO (1d ) was successfully achieved following a known
(13) Takaya, H.; Mashima, K.; Koyano, K. J . Org. Chem. 1986, 51,
629.
(12) Reinecke, M. G.; Sebastian, J . F.; J ohnson, W.; Pyun, C. J . Org.
Chem. 1972, 37, 3066.
(14) Ferretti, R.; Gallinella, B.; La Torre, F.; Zanitti, L.; Bonifacio,
F. J . Chromatogr. A 1998, 795, 289.

Chiral Diphosphine Ligands for Hydrogenation
J . Org. Chem., Vol. 65, No. 24, 2000 8343
F igu r e 2. CD spectra (CH2Cl2) of (+)- and (-)-1a and (+)-
and (-)-1c
the case of BITIANP and BINAP.6 This observation
provides support for the following configurational assign-
ment: (-)-N-Me-2-BINP, (-)-1a , and (-)-N-MOM-2-
BINP, (-)-1b, should be the S enantiomers and dextroro-
tatory (+)-N-Me-2-BINP, (+)-1a , and (+)-N-MOM-2-
BINP, (+)-1b , the R antipodes. Consequently, dextro-
rotatory (+)-N-Me-2-BINPO, (+)-1c, and (+)-N-MOM-2-
BINPO, (+)-1d , should have R configuration, while S
configuration should be assigned to levorotatory (-)-N-
Me-2-BINPO, (-)-1c, and (-)-N-MOM-2-BINPO, (-)-1d .
Comparison of the shape of the CD curves with those
shown by BINAP13 and by the only biheteroaromatic
diphosphine with known configuration BIMIP16 lends
further support to these conclusions.
As for the enantioselection levels observed in acetoace-
tic ester (4a ) (entries 1 and 9) and benzoylacetic (4b)
(entries 4 and 10) hydrogenation, they were found to be
rather good (92-93%) and comparable to those obtained
with many popular commercially available chiral diphos-
phines.5a,15 In the case of substrate 4a , enantiomeric
excess does not decrease when hydrogen pressure is
halved (entry 2) and when the substrate-catalyst ratio
is more than doubled (entry 3).
F igu r e 3. CD spectra (CH2Cl2) of (+)- and (-)-1b and (+)-
and (-)-1d
We focused our tests of enantioselection ability and
catalytic activity of the ruthenium (II) complexes 3 of (+)-
and (-)-1a ,b on the hydrogenation of Pro1-chiral R- and
â-ketoesters 4a -e and Pro0-chiral â-ketoester 6, which
has a configurationally labile stereocenter.
These reactions were chosen as reference reactions for
two main reasons: first of all they are well described in
the literature in tests employing the ruthenium com-
plexes of many popular chiral diphosphines as catalysts.15
Second, as anticipated, it had been previously observed
that the kinetic behavior of these reactions is strongly
influenced by the electronic availability of the ligand at
phosphorus. These reactions appeared therefore to be a
very good testing ground for evaluating the above-
mentioned effects. The experimental results are sum-
marized in Table 1.
The ligands exhibited satisfactory enantioselection
ability also in the carbonyl hydrogenation of R-oxoesters,
such as phenylglyoxylic (4c) (entry 5 ee ) 76%) and
benzylpyruvic (4d ) (entries 6 and 7) esters. In the former
case enantiomeric excess was improved by employing a
lower substrate-catalyst ratio value (entry 7; ee ) 89%).
Very good diastereo- (92%), but unsatisfactory enanti-
oselectivity (64%), were found in the case of ethyl
cyclopentanonecarboxylate 6 (entry 8) hydrogenation.
The relationship between the configuration of the
hydrogenation products and the rotatory power sign of
the ligand was found to be identical to that observed in
(15) Kitamura, M.; Ohkuma, T.; Tokunaga, M.; Noyori, R. Tetrahe-
dron Asymmetry 1990, 1, 1. Kitamura, T.; Tokunaga, M.; Ohkuma,
M.; Noyori, R. Org. Synth. 1993, 71, 1.
(16) Antognazza, P.; Benincori, T.; Mazzoli, S.; Pilati, T.; Sannicolo`,
F. Phosphorus, Sulphur Silicon 1999, 146, 405.

8344 J . Org. Chem., Vol. 65, No. 24, 2000
Ta ble 1. Asym m etr ic Hyd r ogen a tion of r- a n d â-Ketoester s
Benincori et al.
entry
cat.a
sub
solvent
S/C
H2 (kg/cm2)
T (°C)
t (h)
25
30
4.5
0.80
24
12
26
3
de (%)
ee (%)
conf
1
2
3
4
5
6
7
8
9
(-)-3a
(-)-3b
(-)-3b
(-)-3a
(-)-3c
(-)-3c
(+)-3c
(+)-3a
(-)-3d
(-)-3d
4a
4a
4a
4b
4c
4d
4d
6
MeOH-H2O
MeOH-H2O
MeOH-H2O
MeOH-H2O
MeOH-HBF4
MeOH-HBF4
MeOH-HBF4
MeOH-H2O
MeOH-H2O
MeOH-H2O
1000
1000
2490
251
245
560
100
50
10
10
32
45
35
30
30
45
40
45
-
-
-
93b
95b
94b
93b
76c
81b
89b
64b
92b
93b
S
S
S
R
S
S
R
100
100
104
100
100
100
100
100
-
200
-
92
1000
1000
250
1R,2R
S
R
4a
4b
2.7
3
10
a
b
The optical rotatory power sign refers to that of the corresponding diphosphine. HPLC analysis (CHIRACEL OD, eluant: hexane/
2-propanol 90:10, 1 mL/min). c HPLC analysis (CHIRACEL OJ , eluant: hexane/ethanol 90:10, 1 mL/min).
Ta ble 2
E° (V)
kobs (s-1
The kobs value found in the case of the electron-richest
diphosphine is about 50 times that observed in the case
of the electron-poorest ligand.
BINAP
ligand (L)
)
kobsi/kobs
ee %
(+)-N-Me-2-BINP
(+)-tetraMe-BITIOP
(+)-N-MOM-2-BINP
(+)-BINAP
0.52 3.47 × 10-5
2.67
2.89
95
98
91
99
99
-
0.57 3.76 × 10-5
We also found a strong linear correlation between the
electrochemical oxidative potential value E° of the free
ligands and the logarithm of kobs of the reactions in which
they are employed, as reported in Figure 4.
0.60 3.33 × 10-5 2,56
0.63 1.3 × 10-5
1
0.83
(+)-tetraMe-BITIANP 0.76 1.08 × 10-5
(()-BISCAP
(()-BICUMP
0.90 2.17 × 10-6
1.03 2.17 × 10-7
1.7 × 10-1
1.7 × 10-2
-
This relationship is fully comparable to a Hammet-type
relationship, valid since the activity of systems with
different electronic properties but rather similar geom-
etry of the chelate core, is being compared. It could be
inferred that the ratios between the energy differences
involved in electrochemical monoelectron abstraction
from the phosphine group of the free ligands in voltam-
metric experiments are maintained at the level of the
catalytic complexes in the hydrogenation reaction of
acetoacetic ester. The step of the catalytic cycle involving
the displacement of the reaction product from the metal
center, effected by ethyl acetoacetate, accounts for the
observed first order in the substrate rate equation. The
more basic the metal center, the easier the detachment
of the ethyl hydroxybutyrate, which is removed as an
anion.
The general conclusions which can be drawn regarding
these results is that the stereoselection ability of N-Me-
2-BINP and N-MOM-2-BINP does not stray from the
limits of many good, commercially available diphos-
phines. On the other hand, catalytic activity, in terms of
reaction times, shown by the complexes of N-Me-2-BINP,
seems to be undeniably enhanced when compared with
the data drawn from analogous reactions carried out with
all the other bis(diphenylphosphino) chelating ligands
which are more electron-poor.
To shed some light on this point, comparative kinetic
experiments of the hydrogenation of ethyl 3-oxobutanoate
(4a ) were carried out with enantiopure (+)-N-Me-2-BINP
(1a ), (+)-N-MOM-2-BINP (1b), (+)-tetraMe-BITIOP, (+)-
tetraMe-BITIANP, (+)-BINAP, and with racemic BIS-
CAP and BICUMP (Table 2) as ligands of ruthenium(II),
under identical experimental conditions (solvent: 95%
aqueous ethanol; temperature: 40 °C; hydrogen pres-
sure: 100 kg/cm2; substrate-catalyst ratio: 1000; sub-
strate concentration: 0.41 M). All the catalytic complexes
were prepared according to the same experimental
procedure.18 Progress of the reaction was evaluated by
GLC, after determination of the response factor between
starting material and reaction product 5a . In all the
reactions where enantiopure ligands were used, we found
that the enantiomeric excess of the product was constant
throughout the entire reaction.
Kinetic data demonstrated that the reaction rate is
first order in substrate in all cases. This homogeneity of
kinetic behavior is a crucial prerequisite for comparison,
since it suggests mechanistic homogeneity. A very good
fitting was found when the reagent (or product) concen-
tration log was plotted against time: straight lines were
obtained (correlation coefficient R from >0.999 to 0.979),
the slope of which gave the observed kinetic constant
values (kobs). These data demonstrate that the reaction
rate found in the case of BINAP is nearly tripled when
electron-rich diphosphines are used and reduced to about
one twentieth when electron-poor ligands are employed.
Con clu sion s
The results reported above provide evidence of the
crucial role played by the electronic properties of phos-
phorus in determining the hydrogenation rate of the
ketonic function of ethyl acetoacetate. We found a free
energy linear correlation between the electrochemical
oxidative potentials of ligands exhibiting different elec-
tronic availability at phosphorus and the log of the
observed rate constant (kobs). In the case in point,
electron-rich diphosphines facilitate the reaction, but we
have recently given qualitative evidence that an opposite
situation works in the intramolecular Heck reaction,
which seems to be favored by electron-poor ligands.17
Easy synthesis, a simple resolution process, and suc-
cessful application of the two BINPs as ruthenium
ligands in hydrogenation reactions of R- and â-ketoesters
all provide a convincing demonstration of the advantages
offered by the biheteroaromatic scaffold. This simple
architecture behaves effectively in tuning the electronic
properties of the phosphorus atom bonded to it, while a
proper substitution on it could afford chelating species
endowed with suitable steric properties. This strategy
looks very promising for tailoring synthetically accessible
and efficient ligands, capable of satisfying all the stereo-
electronic needs imposed by reaction and substrate.
(17) Tietze, L. F.; Thede, K.; Schimpf, R.; Sannicolo`, F. Chem.
Commun. 2000, 583.
(18) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Tetrahe-
dron Lett. 1991, 4163.

Chiral Diphosphine Ligands for Hydrogenation
J . Org. Chem., Vol. 65, No. 24, 2000 8345
F igu r e 4. Ligand (L) electrochemical oxidative potential (E°)-observed kinetic constant (kobs) relationship in ethyl acetoacetate
hydrogenation catalyzed by [(L)RuCl2(DMF)n]
P r ep a r a tion of 3-(Dip h en ylp h osp h in yl)-N-m eth ylin -
d ole (2d ). NaH (3.37 g, free-flowing powder, moistened with
oil, 55-65%) was added portionwise to a suspension of 2a
(17.65 g) in dry THF (300 mL) under N2. After the mixture
was stirred 30 min, a solution of MeI (3.5 mL) in THF (50 mL)
was added; the mixture was stirred for 1 h and then concen-
trated in vacuo. The residue was treated with water and CH2-
Cl2; the organic layer was separated, dried (Na2SO4), and
concentrated in vacuo. The crude reaction product was tritu-
rated with isopropyl ether to give 2d (17.5 g, 95%): mp 218
Exp er im en ta l Section
Gen er a l. Chiral HPLC analyses were performed with a
DAICEL CHIRACEL OD (254 nm) column. The CD spectra
were recorded in CH2Cl2 solution and plotted as mdeg/A, where
A is the UV absorption of the same solution at 300 nm.
Electrochemical oxidation potential of 1a and 1b were deter-
mined in a three-electrode cell, at 25 °C, under nitrogen in
acetonitrile + 0.1 M Bu4NClO4. The working electrode was a
platinum minidisk electrode (0.003 cm2); the reference elec-
trode was silver/0.1 M silver perchlorate in acetonitrile (0.34
V vs SCE). Phosphine solutions were 10-4 M, and the scan
rate was 0.1 V s-1. The voltammetric apparatus (AMEL, Italy)
included a 551 potentiostat modulated by a 568 programmable
function generator.
1
°C. H NMR (CDCl3) δ 3.8 (s, 3H), 7.07 (t, 1H), 7.25 (m, 2H),
7.35 (m, 2H), 7.43 (m, 4H), 7.52 (m, 2H), 7.78 (dd, 4H); 31P
NMR (CDCl3) δ 22.03. Anal. Calcd for C21H18NOP: C, 76.11;
H, 5.47; N, 4.23. Found: 76.46; H, 5.49; N, 4.43.
P r ep a r a tion of (()-3,3′-Bis(d ip h en ylp h osp h in yl)-N,N′-
d im eth yl-2,2′-biin d ole (1c). BuLi (0.048 mol, 1.6M solution
in hexane) was dropped into a solution of 2d (13.2 g) and
TMEDA (7.2 mL) in dry THF (300 mL), at room temperature.
After the mixture was stirred 1 h, CuCl2 (8 g) was added; the
mixture was stirred for 3 h, quenched with 2 N HCl solution,
and stirred overnight. The mixture was concentrated in vacuo,
the residue extracted with CH2Cl2, and the organic layer dried
(Na2SO4) and concentrated in vacuo. The crude residue was
treated with warm AcOEt, and the solid obtained was collected
and crystallized (MeOH/H2O 3:1) to give 1c (6.7 g, 51%): mp
350 °C. 1H NMR (CDCl3) δ 3.40 (s, 6H), 7.68 (dd, 4H), 7.53
(dd, 4H), 7.13 (m, 6H); 31P NMR (CDCl3) δ 21.9; mass spectrum
m/z 660 (M+). Anal. Calcd for C42H34N2O2P2: C, 76.35; H, 6.81;
N, 5.55. Found: 76.46; H, 6.77; N, 5.37.
Hydrogenation reactions were carried out in a stirred (550
rpm), 100 mL, Hastelloy Parr autoclave equipped with a
sampling pipe which extended to the bottom of the vessel.
P r ep a r a tion of 3-(Dip h en ylp h osp h in yl)in d ole (2a ). A
3 M THF solution of MeMgCl (62.0 mL, 0.186 mol) was
dropped into a solution of indole (20.0 g, 0.170 mol) in dry THF
(150 mL) under N2. After being refluxed 25 min, the mixture
was cooled at -30 °C, and a solution of chlorodiphenylphos-
phine (36 mL, 0.170 mol) in THF (15 mL) was added.
The mixture was stirred at room temperature for 12 h and
then concentrated in vacuo. The residue was dissolved into
CH2Cl2 (500 mL), and H2O2 (100 mL, 30%) was added at 10
°C. After the mixture was stirred 30 min at room temperature,
the organic layer was separated, dried (Na2SO4), and concen-
trated in vacuo. The crude reaction product (45 g) was
dissolved into ethanol (250 mL) and treated with an aqueous
solution of KOH (35 g in 25 mL). The reaction mixture was
refluxed for 2.5 h, diluted with H2O, and extracted with CH2-
Cl2. The organic layer was separated, dried (Na2SO4), and
concentrated in vacuo. The crude reaction product was tritu-
rated with isopropyl ether to give 2a (78%): mp 251 °C. 1H
NMR (CDCl3) δ 6.94 (t, 1H), 7.04 (s, 1H), 7.09 (t, 1H), 7.28 (d,
1H), 7.34 (d, 1H), 7.40 (m, 4H), 7.51 (m, 2H), 7.72 (dd, 4H),
Resolu tion of (()-3,3′-Bis(d ip h en ylp h osp h in yl)-N,N′-
d im eth yl-2,2′-biin d ole [(+)-1c] w ith (-)- a n d (+)-2,3-O,O′-
Diben zoylta r ta r ic Acid [DBTA]. A mixture of (()-1c (9 g)
and (-)-DBTA monohydrate (5.1 g) was dissolved in CHCl3
(50 mL), refluxed for a few minutes, and allowed to stand at
room temperature for 24 h. The adduct between (+)-1c and
(-)-DBTA was collected, and the filtrate was stored for the
recovery of (-)-1c. The above complex (3.72 g) was further
purified by treatment with warm CHCl3. The solid collected
[3.02 g, mp 233 °C, [R]25D ) +6.2 (c ) 0.50, EtOH)] was treated
with 0.75 N NaOH solution (57 mL), and the mixture was
extracted with CH2Cl2 (3 × 25 mL). The combined organic
layers were washed with water and then dried (Na2SO4). The
solution, concentrated in vacuo, provided (+)-1c [1.5 g, mp
301.3 °C, [R]25D ) +67.6 (c ) 0.50, EtOH)]. The mother liquors
from the first resolution were concentrated to dryness to give
a solid residue (11.7 g), which was treated with 0.75 N NaOH
solution (230 mL) and extracted with two portions of CH2Cl2
(2 × 150 mL). The combined organic layers were washed with
water and then dried (Na2SO4). The solution was concentrated
10.80 (s, 1H). 31P NMR (CDCl3) δ 23.90. Anal. Calcd for C20H16
-
NOP: C, 75.69; H, 5.09; N, 4.41. Found: 75.86; H, 5.19; N,
4.43.
Column chromatography (SiO2, eluant: CH2Cl2/MeOH 10:
0.3) of the reaction mixture obtained from H2O2 oxidation,
before alkaline hydrolysis, allowed isolation of N-(diphe-
nylphosphinyl)indole (2b) and 1,3-bis(diphenylphosphinyl)-
1
indole (2c) in a pure state. 2b: mp 130 °C; H NMR (CDCl3)
δ 6.58 (t, 1H), 6.78 (t, 1H), 7.10 (m, 2H), 7.41 (m, 4H), 7.58
1
(m, 8H); 31P NMR (CDCl3) δ 25.66. 2c: mp 171 °C; H NMR
(CDCl3) δ 6.95 (t, 1H), 7.95 (m, 2H), 7.42 (m, 14H), 7.63 (m,
11H); 31P NMR (CDCl3) δ 22.2 (1P, s), 26.8 (1P, s).

8346 J . Org. Chem., Vol. 65, No. 24, 2000
Benincori et al.
in vacuo to give a residue enriched in the levorotatory
enantiomer. The recovered solid and (+)-DBTA (3.5 g) were
dissolved in CHCl3 (90 mL) and refluxed for a few minutes.
After 24 h an adduct between (-)-1c and (+)-DBTA was
collected and purified by treatment with warm CHCl3. The
complex [5.8 g, mp 236 °C, [R]25D ) -5.9 (c ) 0.50 EtOH)] was
treated with a 0.75 N NaOH solution (110 mL), and the
mixture was extracted with CH2Cl2 (3 × 40 mL). The combined
organic layers were washed with water and then dried (Na2-
SO4). The solution, concentrated in vacuo, provided (-)-1c [2.65
7.28 (m, 3H), 7.43 (m, 2H), 7.6 (d, 1H, J ) 8.24 Hz); 31P NMR
(CDCl3) δ -29.30. Anal. Calcd for C44H38N2O4P2: C,73.32; H,
5.31; N, 3.89. Found:73.36; H,5.73; N, 3.85.
P r ep a r a t ion of [[(+)- a n d (-)-N-Me-2-BINP ]R u Cl2-
(DMF )n ] (3a ). To a Schlenk tube charged with (S)-N-Me-2-
BINP (2.9 × 10-2 mmol) and red brown [RuCl2(C6H6)]2 (1.25
× 10-2 mmol), prepared according to the procedure reported
in the literature,18 was added freshly distilled, argon-degassed,
DMF (5 mL). The mixture was stirred at 100 °C for 10 min.
The resulting orange-yellow solution was cooled to 50 °C and
concentrated under reduced pressure. The ruthenium complex
3a obtained as residue was left under vacuum for 1 h and then
argon pressurized. It was utilized without further purification
in the enantioselective reductions of R- and â-ketoesters. The
31P NMR spectrum showed a complex set of signals, indicating
that the crude catalyst was a mixture of RuCl2 (N-Me-2-BINP)-
(DMF)n with a different number of coordinated solvent mol-
ecules.19 31P NMR (CDCl3) δ 53.41 (d, J ) 37.9 Hz), 50.79 (d,
J ) 42.7 Hz), 49.85 (d, J ) 39.8 Hz), 49.10 (d, J ) 43.6 Hz),
45.27 (d, J ) 38.2 Hz), 44.09 (d, J ) 42.9 Hz), 42.67 (d, J )
43.42 Hz), 40.67 (d, J ) 41.3 Hz), 39.13 (d, J ) 36.5 Hz), 36.04
(d, J ) 43.04 Hz), 17.65 (d, J ) 43.37 Hz).
P r ep a r a t ion of [R u I((+)- a n d (-)-N-Me-2-BINP )(p -
cym en e)]I (3b). (-)-N-Me-2-BINP (0.0207 g, 0.0325 mmol),
[Ru(p-cymene)I2]2 (0.0159 g, 0.0153 mmol), ethanol (6 mL), and
CH2Cl2 (3 mL) were stirred in a Schlenk tube, under argon,
at 50 °C, for 1.5 h. The resulting solution was concentrated
under reduced pressure, and the residue was used in the
asymmetric catalytic reductions without further purifica-
tion. 31P NMR (CDCl3) δ 36.79 (d, J ) 39.5 Hz,), 27.61 (d, J )
39.5 Hz).
P r epar ation of [Ru Cl((+)- an d (-)-N-Me-2-BINP )(C6H6)]-
Cl (3c). (+)-N-Me-2-BINP (0.0218 g, 0.0342 mmol), [RuCl2
(C6H6)]2 (0.007 g, 0.0280 mmol), ethanol (7 mL), and C6H6 (1
mL) were stirred in a Schlenk tube under argon at 55 °C for
1 h. The resulting solution was concentrated under reduced
pressure, and the residue was used in the asymmetric catalytic
reductions without further purification: 31P NMR (CDCl3) δ
36.09 (d, J ) 42.9 Hz), 17.62 (d, J ) 43.6 Hz).
P r ep a r a tion of [[(+)- a n d (-)-N-MOM-2-BINP ]Ru Cl2-
(DMF )n ] (3d ). To a Schlenk tube charged with (S)-N-MOM-
2-BINP (1.3 × 10-2 mmol) and red brown [RuCl2(C6H6)]2 (0.6
× 10-2 mmol), prepared according to the procedure reported
in the literature,18 was added freshly distilled, argon-degassed,
DMF (5 mL). The mixture was stirred at 100 °C for 15 min.
The resulting orange-yellow solution was cooled to 50 °C and
concentrated under reduced pressure. The ruthenium complex
3d obtained as residue was left under vacuum for 1 h and then
argon pressurized. It was utilized without further purification
in the enantioselective reductions of R- and â-ketoesters. The
31P NMR spectrum showed a complex set of signals clustered
around 46 and 48 ppm, indicating that the crude catalyst was
a mixture of RuCl2 (N-MOM-2-BINP)(DMF)n with a different
number of coordinated solvent molecules.19
g, mp 301.9 °C, [R]25 ) -65.6 (c ) 0.50, EtOH)].
D
P r ep a r a tion of (-)-3,3′-Bis(d ip h en ylp h osp h in o)-1,1′-
d im eth yl-2,2′-biin d ole [(-)-1a ]. (-)-1c (0.5 g), dry xylene (14
mL), trichlorosilane (0.6 mL), and triethylamine (0.8 mL) were
placed in a three-necked flask equipped with thermometer and
a reflux condenser, connected to an argon inlet tube. The
mixture was heated at 100 °C under stirring for 1 h, at 120
°C for 2 h, and finally at 140 °C for 2 h. After being cooled to
room temperature, the mixture was concentrated in vacuo; the
residue was treated with 10% NaOH solution (35 mL) and
stirred for 15 min at 60 °C. The mixture was extracted with
CH2Cl2, and the organic layer was dried (Na2SO4) and con-
centrated under reduced pressure. The residue was triturated
with methanol (5 mL) to give (-)-1a [0.38 g, mp 322 °C, [R]25
D
1
) -121.05° (c ) 0.50, C6H6)]. H NMR (CDCl3) δ 3.50 (s, 6H),
6.94 (t, 2H), 7.07 (m, 8H), 7.24 (m, 12H), 7.43 (m, 6H); 31P NMR
(CDCl3) δ -28.75. Anal. Calcd for C42H34N2P2: C, 80.23; H,
5.46; N, 4.46. Found: 80.36; H,5.73; N, 4.35.
(+)-1c was reduced to (+)-1a [mp 321 °C, [R]25D ) +119.50°
(c ) 0.50, C6H6)] by following the same procedure.
P r ep a r a t ion of 3-(Dip h en ylp h osp h in yl)-N-m et h oxy-
m eth ylin d ole (2e). NaH (5.6 g, free-flowing powder, moist-
ened with oil, 55-65%) was added portionwise to a suspension
of 2a (36 g) in dry THF (450 mL) under N2. After the mixture
was stirred 25 min, a solution of methoxychloromethane (9
mL) in THF (100 mL) was added; the mixture was stirred for
1 h and then concentrated in vacuo. The residue was treated
with water and CH2Cl2; the organic layer was separated, dried
(Na2SO4), and concentrated in vacuo. The crude reaction
product was triturated with isopropyl ether to give 2e (89%):
1
mp 281 °C. H NMR (CDCl3) 3.25 (s, 3H), 5.5 (s, 2H), 7.1 (t,
1H), 7.27 (t, 1H), 7.38 (m, 2H), 7.45 (m, 4H), 7.52 (m, 2H),
7.76 (m, 4H); 31P NMR (CDCl3) δ 23.80. Anal. Calcd for C22H20
-
NO2P: C, 73.12; H, 5.58; N, 3.87. Found: 73.06; H, 5.49; N,
3.63.
P r ep a r a tion of (()-3,3′-Bis(d ip h en ylp h osp h in yl)-1,1′-
d im eth oxym eth yl-2,2′-biin d ole (1d ). BuLi (40 mL, 1.6M
solution in hexane) was dropped into a solution of 2e (18 g)
and TMEDA (9.2 mL) in dry THF (400 mL), at room temper-
ature. After the mixture was stirred 30 min, CuCl2 (10.3 g)
was added; the mixture was stirred overnight, quenched with
2 N HCl solution, and concentrated in vacuo. The residue
extracted with CH2Cl2, and the organic layer was dried (Na2-
SO4) and concentrated in vacuo. The crude residue was treated
with AcOEt, and the solid obtained was treated with acetone
Asym m etr ic Hyd r ogen a tion of Eth yl 3-Oxobu ta n oa te
(4a ) w ith 3a . A 100 mL Hastelloy autoclave was purged five
times with hydrogen; a solution of ethyl 3-oxobutanoate (7.69
mmol) and (+)-3a (0.00385 mmol) in a mixture of MeOH/H2O
(20 mL/1 mL), previously degassed for 15 min with argon, was
loaded into the autoclave with a syringe. Hydrogen was
introduced (105 kg/cm2), and the solution was stirred at 45 °C
for 30 min. The autoclave was cooled, the hydrogen pressure
released, the solvent evaporated, and the residue distilled
under vacuum (18 mmHg) to give ethyl (R)-(-)-3-hydroxybu-
tanoate (5a ) (100% yield).
Hydrogenation of ethyl benzoylacetate (4b) and 2-(ethoxy-
carbonyl)cyclopentanone (6) was carried out under the same
conditions employed for ethyl 3-oxobutanoate, unless otherwise
stated.
Asym m etr ic Hyd r ogen a tion of Meth yl P h en ylglyoxy-
la te (4c). A 100 mL Hastelloy autoclave was purged five times
1
to give 1d (51%): mp 293 °C. H NMR (CDCl3) δ 3.15 (s, 3H),
5.3 (dd, 2H, J ) 10.4 Hz), 7.0 (m, 3H), 7.15 (m, 2H), 7.25 (t,
1H, J ) 7.98 Hz), 7.4 (m, 6H), 7.7 (m, 2H); 31P NMR (CDCl3)
δ 21.96; mass spectrum m/z 660 (M+). Anal. Calcd for
C
42H34N2O2P2: C, 76.35; H, 6.81; N, 5.55. Found: 76.46; H,
6.77; N, 5.37.
P r ep a r a tion of (()-3,3′-Bis(d ip h en ylp h osp h in o)-1,1′-
d im et h oxym et h yl-2,2′-b iin d ole [(()-1b ]. (()-1d (0.96 g),
dry xylene (22 mL), trichlorosilane (1.06 mL), and triethy-
lamine (1.48 mL) were placed in a three-necked flask equipped
with thermometer and a reflux condenser, connected to an
argon inlet tube. The mixture was heated at 80 °C under
stirring for 90 min. After being cooled to room temperature,
the mixture was concentrated in vacuo; the residue was treated
with 10% NaOH solution (35 mL) and stirred for 15 min at 60
°C. The mixture was extracted with CH2Cl2, and the organic
layer was dried (Na2SO4) and concentrated under reduced
pressure. The residue was triturated with methanol (5 mL)
1
to give (()-1b (90%): mp 248-250 °C. H NMR (CDCl3) δ 3.1
(19) Mashima, K.; Hino, T.; Takaya, H. J . Chem. Soc., Dalton Trans.
1992, 2099.
(s, 6H), 5.22 (dd,2H, J ) 10.48 Hz), 6.98 (m, 2H), 7.11 (m, 3H),

Chiral Diphosphine Ligands for Hydrogenation
J . Org. Chem., Vol. 65, No. 24, 2000 8347
with hydrogen, and then a solution of methyl phenylglyoxylate
(3.085 mmol) and (+)-3c (0.028 mmol) in MeOH (20 mL)
containing HBF4 (0.152 mmol), previously degassed for 15 min
with argon, was loaded into the autoclave with a syringe.
Hydrogen was introduced (100 kg/cm2), and the solution was
stirred at 30 °C for 26 h. The autoclave was cooled, the
hydrogen pressure released, and the solvent evaporated.
Chromatography (SiO2, eluant: hexane/AcOEt 7:3) provided
(R)-(+)-2-hydroxy-2-phenylmethyl acetate (5d ) (85% yield).
Asymmetric hydrogenation of ethyl 2-keto-4-phenylbutyrate
(4d ) was carried out under the same conditions as employed
for methyl phenylglyoxylate.
out through the sampling pipe by exploiting internal pressure
and GC-analyzed to evaluate conversion. After sampling, the
hydrogen pressure was restored and stirring resumed.
Ack n ow led gm en t. This work was supported by
CHEMI S.p.A., holder of the patents for the synthesis
and use of all biheteroaryl-diphoshine ligands and
MURST COFIN 1998/99 project (9803153701). We are
grateful to Mr. G. Celentano, Istituto di Chimica Or-
ganica dell’Universita` di Milano, Facolta` di Farmacia,
who performed the chiral HPLC analyses.
Kin etic Exp er im en ts. At appropriate time intervals, stir-
ring was stopped, and an aliquot of the solution was drawn
J O001207D