2,2',5,5'-tetramethyl-4,4'-bis(diphenylphoshino)-3,3'-bithiophene: A new, very efficient, easily accessible, chiral biheteroaromatic ligand for homogeneous stereoselective catalysis

Article abstract of DOI:10.1021/jo991533x

The four-step straightforward synthesis of enantiopure (+)- and (-)- 2,2',5,5'-tetramethyl-4,4'-bis(diphenylphoshino)-3,3'-bithiophene (tetraMe- BITIOP), anew C₂-symmetry chelating ligand for transition metals, is described, starting from 2,5-dimethylthiophene. The complexes of this electron-rich diphosphine with Ru(II) and Rh(I) were used as catalysts in some homogeneous hydrogenation reactions of prostereogenic carbonyl functions of α- and β-ketoesters, of prostereogenic carbon-carbon double bonds of substituted acrylic acids, and of N-acetylenamino acids. The enantiomeric excesses were found to be excellent in all the experiments and comparable with the best results reported in the literature for the same reactions, carried out under similar experimental conditions, with the metal complexes of the most popular chiral diphosphine ligands as catalysts.

Full text of DOI:10.1021/jo991533x

J . Org. Chem. 2000, 65, 2043-2047
2043
2,2′,5,5′-Tetr a m eth yl-4,4′-bis(d ip h en ylp h osh in o)-3,3′-bith iop h en e: A
New , Ver y Efficien t, Ea sily Accessible, Ch ir a l Bih eter oa r om a tic
Liga n d for Hom ogen eou s Ster eoselective Ca ta lysis
Tiziana Benincori,*,† Edoardo Cesarotti,*,‡ Oreste Piccolo,*,§ and Franco Sannicolo`*,|
Dipartimento di Chimica Organica e Industriale dell’Universita`, via Golgi 19-20133-Milano, Italy,
Dipartimento di Scienze Chimiche, Fisiche e Matematiche dell’Universita` dell’Insubria, via Lucini
3-22100-Como, Italy, Dipartimento di Chimica Inorganica, Metallorganica e Analitica dell’Universita`,
via Golgi 19-20133-Milano, Italy, and Chemi S.p.A., via dei Lavoratori 54-20092-Cinisello Balsamo, Italy
Received September 30, 1999
The four-step straightforward synthesis of enantiopure (+)- and (-)-2,2′,5,5′-tetramethyl-4,4′-bis-
(diphenylphoshino)-3,3′-bithiophene (tetraMe-BITIOP), a new C2-symmetry chelating ligand for
transition metals, is described, starting from 2,5-dimethylthiophene. The complexes of this electron-
rich diphosphine with Ru(II) and Rh(I) were used as catalysts in some homogeneous hydrogenation
reactions of prostereogenic carbonyl functions of R- and â-ketoesters, of prostereogenic carbon-
carbon double bonds of substituted acrylic acids, and of N-acetylenamino acids. The enantiomeric
excesses were found to be excellent in all the experiments and comparable with the best results
reported in the literature for the same reactions, carried out under similar experimental conditions,
with the metal complexes of the most popular chiral diphosphine ligands as catalysts.
In tr od u ction
formylation, hydrosilylation, and hydrocyanation reac-
tions have also attained sufficient maturity levels. How-
ever, it was found that each reaction (and substrate)
requires that the steric and electronic properties of the
metal complex be tailored according to its needs: electron-
rich diphosphines are known to give very active com-
plexes in carbon-oxygen double-bond hydrogenation,6
while low phosphorus electronic availability is much more
favorable in olefin hydroformylation.7 Small bite angle
values are crucial for attaining high stereoselectivity
levels in the former reaction, while larger values are
preferable in the latter.8
Our previous work on chiral diphosphines character-
ized by an atropisomeric backbone composed of two
interconnected five-membered heteroaromatic rings9 dem-
onstrated that the supporting heterocycle is crucial in
determining phosphorus electronic availability and the
geometric properties of the ligand.
The recent trends in organic reaction development are
oriented toward synthetic efficiency, which is mainly re-
lated to selectivity (chemo-, regio-, and stereoselectivity),
productivity, and atom economy; it goes without saying
that a reaction should be environmentally responsible by
design.
Stereoselective homogeneous catalysis, promoted by
complexes of transition metals with chiral ligands car-
rying electron-donor chelating functions, represents a
methodology that perfectly meets all of these require-
ments.1 In this light, the multitude of new chiral ligands
for transition metals presented in recent literature2 is
amply justified when considering the enormous variety
of reactions that, at least in theory, can be satisfactorily
carried out in a catalytic manner.3 The hydrogenation
reactions of olefinic and carbonyl (Pro)1-chiral and con-
figurationally labile (Pro)0-chiral substrates are today
widely applied even for the preparation of products of
industrial interest.4 Also, the single and cascade stereo-
selective Heck reaction has recently attracted a great deal
of attention due to its versatility and efficiency in
carbon-carbon bond formation.5 Stereoselective hydro-
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P. S.; Tschoerner, M. J . Am. Chem. Soc. 1997, 119, 6315. Hii, K. K.;
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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 .
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tognazza, P.; Cesarotti, E. J . Chem. Soc., Chem. Commun. 1995, 685.
Antognazza, P.; Benincori, T.; Brenna, E.; Cesarotti, E.; Sannicolo`, F.;
Trimarco, L. Eur. Pat. 0770085 to Chemi S.p. A.. Benincori, T.; Brenna,
E.; Sannicolo`, F.; Trimarco, L,; Antognazza, P.; Cesarotti, E.; Demartin,
F.; Pilati, T. J . Org. Chem. 1996, 61, 6244.
† Dipartimento di Scienze Chimiche, Fisiche e Matematiche dell’
Universita` dell’Insubria.
‡ Dipartimento di Chimica Inorganica, Metallorganica e Analitica
dell’Universita` di Milano.
§ Chemi S.p.A.
| Corresponding author. Dipartimento di Chimica Organica e In-
dustriale dell’Universita` di Milano.
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metric Catalysis, I-III; Springer-Verlag: Berlin, 1999 and references
therein. Blaser, H.-U., Pugin, B.; Spindler, F. In Applied Homogeneous
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A., Eds.; VCH: Weinheim, 1996; p 992. Noyori, R.; Hashiguchi, S. In
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10.1021/jo991533x CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/09/2000

2044 J . Org. Chem., Vol. 65, No. 7, 2000
Benincori et al.
F igu r e 1.
The basic aim of this research was to prepare a new
chiral ligand in the biheteroaromatic series endowed with
high electronic density at phosphorus, low bite-angle
value,10 and tailor-made for stereoselective homogeneous
hydrogenation of functionalized carbonyl and olefinic
double bonds. This paper reports the synthesis and
characterization of enantiopure (+)- and (-)-2,2′,5,5′-tetra-
methyl-4,4′-bis(diphenylphosphino)-3,3′-bithiophene (tetra-
Me-BITIOP) (+)-(1a ) and (-)-(1a ) and the preliminary
results of its application as a ligand for Ru(II) and Rh(I)
in homogeneous stereoselective hydrogenation of func-
tionalized carbonyl and olefinic substrates.
known 3-bromo-2,5-dimethylthiophene12 with tert-butyl-
lithium, gave known 2,2′,5,5′-tetramethyl-3,3′-bithiophene13
in a 65% yield. Dibromination of the latter with NBS,
in acetic acid-chloroform solution, in the presence of
hydroquinone, afforded known 4,4′-dibromo-2,2′,5,5′-tetra-
methyl-3,3′-bithiophene14 in a 90% yield. Reaction with
2 equiv of butyllithium, followed by quenching of the
resulting dianion with 2 equiv of chlorodiphenylphos-
phine, afforded the racemic diphosphine (()-1a , which
was oxidized in situ with diluted hydrogen peroxide to
give the diphosphine oxide (()-1b, in an 85% yield.
Resolution was performed by fractional crystallization
from tetrahydrofuran of the diastereomeric adducts of 1b
with (+)- and (-)-dibenzoyltartaric acids. Alkaline de-
complexation of the adducts afforded 90% enantiomer-
ically enriched antipodes, which were obtained in their
enantiopure forms by crystallization from a 1:1 benzene-
hexane mixture, from which the racemate separates
first. Enantiomeric purity was checked by chiral HPLC.15
(+)-1b: [R]25 ) +66 (c ) 0.49, C6H6). (-)-1b: [R]25
)
D
D
-68 (c ) 0.50, C6H6). The CD spectra of (+)-1b and
(-)-1b are reported in Figure 1. Reduction of enantio-
merically pure phosphine oxides 1b to phosphines 1a was
performed by reaction with an excess of trichlorosilane
in the presence of triethylamine in refluxing toluene
solution. Dextrorotatory (+)-1b gave levorotatory (-)-1a ,
The structural choice was dictated by the necessity of
locating the diphenylphosphino group in the electron-
richest position (the â-position) of an inherently electron-
rich heterocyclic ring (the thiophene ring). To guarantee
configurational stability to the ligand through consistent
hindrance to rotation around the interanular bond, the
latter necessarily had to occupy the free â′ position of
the thiophene ring. While the methyl group adjacent to
the interanular bond gives direct contribution to the
atropisomeric stability of 1a , the other methyl group was
introduced in order to develop a consistent buttressing
effect on the phosphine group. This design avoiding
benzocondensation turned out to be very useful, since
atropisomeric diphosphines with a biphenyl backbone
are known to have a definitely lower bite-angle than
binaphthalene-based ones.11
[R]25 ) -27 (c ) 0.48, C6H6), and levorotatory (-)-1b
D
gave dextrorotatory (+)-1a , [R]25D ) +27 (c ) 0.51, C6H6).
Enantiomeric purity was checked by chiral HPLC, per-
formed on the phosphine oxides, which were obtained by
hydrogen peroxide oxidation. Alternatively, for the same
purpose, 31P NMR spectroscopy could be employed. The
spectra of the diastereomeric aminopalladium complexes
of (+)-1a and (-)-1a with enantiopure, commercially
available di-µ-chlorobis[(S)-dimethyl(R-methylbenzyl)-
aminato-C2N]palladium(II) were prepared directly in an
NMR tube according to a known method16 and showed
Resu lts a n d Discu ssion
(10) Bonifacio, F.; Piccolo, O. Chiratech ’97, Nov 11-13, 1997,
Philadelphia, PA.
Synthesis of racemic (()-2,2′,5,5′-tetramethyl-4,4′-bis-
(diphenylphosphinyl)-3,3′-bithiophene (tetraMe-BITIO-
PO) (()-(1b), the phosphine oxide corresponding to 1a
on which the resolution process had to be carried out, is
rather simple and involves very inexpensive starting
materials and known products as intermediates. Oxida-
tive coupling (CuCl2) of 2,5-dimethyl-3-thienyllithium,
obtained by transmetalation of the very easily accessible,
(11) Zhang, X. ChiraSource ’99, Nov 15-17, 1999, Philadelphia, PA.
(12) Yoshida, K.; Saeki, T.; Fueno, T. J . Org. Chem. 1971, 36, 3673.
Kannappan, V.; Nanjan, M. J .; Ganesan, R. Indian J . Chem. Sect. A.
1980, 1183.
(13) v. Steinkopf, W.; Barlang, T.; Petersdorff, H. J . J ustus Liebigs
Ann. Chem. 1940, 543, 119. Davies, A. G.; J ulia, L.; Yazdi, S. N. J .
Chem. Soc., Perkin Trans. 2 1989, 239.
(14) Hakansson, R. Acta Chem. Scand. 1971, 1313.
(15) Ferretti, R.; Gallinella, B.; La Torre, F.; Zanitti, L.; Bonifacio,
F., Piccolo, O. J . Chromatogr. A 1998, 795, 289.

2,2′,5,5′-Tetramethyl-4,4′-bis(diphenylphoshino)-3,3′-bithiophene
J . Org. Chem., Vol. 65, No. 7, 2000 2045
well-separated AB systems at 34.3-8.80 and 33.3-8.30
ppm, respectively. The signals attributable to one dia-
stereoisomer were completely absent in the spectrum of
the other. The CD spectra of (+)-1a and (-)-1a are
reported in Figure 1.
It is evident that when designing biheteroaromatic
diphosphines it is possible to fine-tune the electronic
properties on phosphorus either by changing the sup-
porting heterocycle or the position of phosphorus on it.
Asym m etr ic Hyd r ogen a tion of F u n ction a lized
Ca r bon yl a n d Olefin ic Su bstr a tes. Catalytic hydro-
genation experiments were carried out on substrates that
are in standard use for evaluation of the catalytic activity
(kinetics) and stereoselection ability of all new chiral
ligands appearing in the literature. Ruthenium(II) com-
plexes 3a , 3b, and 3c were used in the reduction of R-
Absolute configuration to the antipodes of 1a and 1b
was assigned by comparison of their CD curves with
those shown by other biheteroaromatic diphosphines,
including the one for which absolute configuration was
known through single-crystal X-ray diffractometric anal-
ysis:17 the R configuration was assigned to (+)-1b and
(-)-1a , while the S configuration was assigned to (-)-1b
and (+)-1a . This is further supported by the correlation
between the optical rotatory power sign of the ligand and
the absolute configuration of the hydrogenation products.
Evaluation of electronic availability at phosphorus in
1a was effected as usual by cyclic voltammetry under
standardized experimental conditions.18 The electro-
chemical oxidative potential of 1a was found to be 0.57
V, which is, so far, the lowest value in the whole class of
biheteroaromatic diphosphines. TetraMe-BITIOP, there-
fore, not only is the most electron-rich ligand in that
series but it is also more electron-rich than BINAP
(0.63 V). Such a low value of electrochemical oxidative
potential was mainly attributed to the location of the
diphenylphosphino groups on the thiophene ring. The
phosphine groups in the â position are expected to be
more electron-rich than those bonded to R carbons, where
sulfur exerts more consistent inductive effects. To give
clearer evidence of the effects on the electronic properties
of phosphorus related to its position on a given hetero-
cyclic ring, we synthesized 2,2′-bis(diphenylphosphino)-
5,5′-dimethyl-3,3′-bithiophene (diMe-BITIOP) (2), even
though we were aware that it could not be configuration-
ally stable.
and â-oxoesters 4a -h to the corresponding hydroxyesters
5a -h . Methallyl groups were used as ancillary ligands
of ruthenium(II) (complex 3d ) in the hydrogenation of
acrylic acid derivatives 6a ,b to tiglic (7a ) and atropic (7b)
acids. Rhodium(I) complex 3e was employed in the
Synthesis was achieved by double lithiation of known
2,2′-dimethyl-3,3′-bithiophene,19 followed by reaction with
2 equiv of chlorodiphenylphosphine. The electrochemical
oxidative potential of 2 was found to be 0.70 V. The
comparison of the redox potentials of 1a and 2 confirms
that phosphine groups bound to the R position of a
thiophene ring are definitely more electron-poor than
those situated in â. The observed difference of 0.13 V
cannot be exclusively attributed to the extra methyl
group present on the thiophene ring of 1a , since the
decrease in the electrochemical oxidative potential fol-
lowing the introduction of a second methyl group on the
3-methylthiophene ring is known to be 0.10 V.20
(16) Roberts, K. N.; Wild, S. B. J . Chem. Soc., Dalton Trans. 1979,
2015.
(17) Antognazza, P.; Benincori, T.; Mazzoli, S.; Sannicolo`, F.; Zotti,
G. Phosphorus, Sulfur, Silicon 1999, 146, 405.
(18) Benincori, T.; Brenna, E.; Sannicolo`, F.; Trimarco, L.; An-
tognazza, P.; Cesarotti, E.; Zotti, G. J . Organomet. Chem. 1997, 529,
445.
hydrogenation of the carbon-carbon double bond of
N-acetyl-R-enamino acids or esters 6c,d to the corre-
(19) Gronowitz, S.; Frostling, H. Tetrahedron Lett. 1961, 17, 607.

2046 J . Org. Chem., Vol. 65, No. 7, 2000
Ta ble 1. Asym m etr ic Hyd r ogen a tion of r- a n d â-Ketoester s
Benincori et al.
substrate
catalysta
solvent
additive
P (kg/cm2)
S/C
T (°C)
t (h)b
eec (de) (%)
confgn
4a
4a
4a
4a
4b
4c
4d
4e
4f
4f
4f
4f
4g
4h
(+)-3a
(+)-3a
(+)-3b
(+)-3b
(+)-3d
(+)-3b
(-)-3a
(-)-3b
(+)-3a
(+)-3a
(+)-3b
(+)-3b
(+)-3c
(+)-3c
EtOH
EtOH
EtOH
EtOH
C7H16
EtOH
MeOH,H2O
CH2Cl2
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH, H2O
100
100
50
25
100
40
100
100
100
100
100
100
96
1000
1000
1000
1000
1000
200
40
70
30
30
80
110
45
50
80
80
70
80
25
50
3
1
24
68
94
98
97
97
S
S
S
S
94 (82)d
85
1
2
0.3
R
S
257
200
93c
RSO3H
99 (94)
50 (77)d
99 (84)d
62 (88)d
99 (88)d
89
3S,2R
S,S
S,S
S,S
S,S
R
1000
1000
1000
1000
516
CF3COOH
CF3COOH
HBF4
HBF4
75
100
462
91
S
a
b
The optical rotatory power sign refers to that of the corresponding phosphine. At 95% conversion. c Unless otherwise specified, ee
d
and dd were determined by chiral HPLC analysis. Chiral GC analysis.
Ta ble 2. Asym m etr ic Hyd r ogen a tion of Olefin ic
Su bstr a tes
resolution is possible, since they have a configurationally
labile stereocenter in R position to the reactive carbon.
sub-
cata-
P
T
t
eec
(kg/cm2) S/C (°C) (h)b (%) confgn
strate lysta
solvent
(-)-3d MeOH
(-)-3d MeOH
Con clu sion s
6a
6b
6c
6d
8
50
10
160 20
3000 25
90 25
94d
94d
87
R
R
R
R
R
TetraMe-BITIOP (1), presented in this paper, is one
of the most efficient diphosphine chiral chelating ligands
available today for use in enantioselective homogeneous
hydrogenation. A great advantage offered by tetra-
Me-BITIOP over its competitors is its very good synthetic
accessibility: this ligand can be easily obtained in 10 g
batches through a simple and reliable six-step synthetic
scheme (including resolution), carried out with an ap-
proximately 30% overall yield starting from inexpensive
2,5-dimethylthiophene. Attempts are currently under
way to improve yields and to simplify the synthetic
scheme so as to make it suitable for industrial develop-
ment.
(-)-3e EtOH
3
(-)-3e THF/MeOH
(+)-3a MeOH
20
100
80 10 18 94
160 25 0.5 92e
a
The optical rotatory power sign refers to that of the corre-
sponding phosphine. b At 95% conversion. c Unless otherwise speci-
d
fied, ee was determined by chiral HPLC analysis. Chiral GC on
the methyl ester (diazomethane). e Determined by polarimetric
analysis.
sponding N-acetyl-R-amino acids or esters 7c,d . Complex
3a was also employed in the hydrogenation of the allylic
double bond of geraniol (8) to citronellol (9).
The results of this research also provide further
evidence of a property peculiar to the class of five-
membered biheteroaromatic diphosphines, that is the
possibility of modulating the electronic availability on
phosphorus. Electronic tuning can be done either by
choosing heterocyclic rings with different inherent elec-
tronic richness, or, given the same heterocycle, by locat-
ing the phosphino groups in different positions with
respect to the heteroatom(s).
Even though each substrate requires a custom-de-
signed catalyst and the reaction conditions need to be
adjusted to obtain cost-effective procedures, we are
convinced that tetraMe-BITIOP can be successfully
utilized and give significant results even on an industrial
scale.21
Table 1 summarizes the stereoselection data found in
carbon-oxygen double bond reduction of R- and â-keto-
esters and the experimental conditions.
Table 2 summarizes the enantioselection data found
in carbon-carbon double bond reduction and the experi-
mental conditions.
It appears that the enantiofacial recognition ability of
tetraMe-BITIOP is very high, comparable to that exhib-
ited by well-known ligands, like BINAP and DuPHOS.
Also, from the standpoint of reaction rate, in experiments
comparing tetraMe-BITIOP to BINAP, it was observed
that lower reaction times were required due to its greater
electronic availability at phosphorus. Furthermore, under
extremely fast reaction conditions, variations in enantio-
meric excess were observed, as if the concentration of
available hydrogen were the limiting factor for hydrogen-
ation. A more detailed kinetic analysis will be reported
elsewhere.
Exp er im en ta l Section
P r ep a r a tion of 4,4′-Bis(d ip h en ylp h osp h in yl)-2,2′,5,5′-
tetr a m eth yl-3,3′-bith iop h en e (()-1b. BuLi (3.8 mL, 1.6 M
solution in hexane, 6.08 mmol) was dropped into a solution of
4,4′-dibromo-2,2′,5,5′-tetramethyl-3,3′-bithiophene (1.15 g, 3.0
mmol) in THF (30 mL) at -60 °C under N2. After 10 min of
stirring, diphenylphosphinous chloride (1.1 mL, 6.13 mmol)
was added; the mixture was stirred for 1 h, and the temper-
ature was allowed to warm to room temperature. The mixture
was concentrated under reduced pressure and the residue
treated with water and extracted with CH2Cl2. The organic
It is interesting to note that the use of acid cocatalysts
significantly improves both enantiomeric and diastereo-
meric excesses in hydrogenation reactions of â-ketoesters
4e and 4f, which are chiral substrates for which kinetic
(21) Chemi S.p. A. has already employed this ligand in hydrogena-
tion reactions carried out on a 50-200 kg scale level.
(22) Schenck, T. G.; Downes, J . M.; Milne, C. R. C.; Mackenzie, P.
B.; Boucher, H.; Whelan, J .; Bosnich, B. Inorg. Chem. 1985, 24, 2334.
(20) Waltman, R. J .; Bargon, J .; Diaaz, A. F. J . Phys. Chem. 1983,
87, 1459. Tourillon, G.; Garnier, F. J . Electroanal. Chem. 1984, 161, 51.

2,2′,5,5′-Tetramethyl-4,4′-bis(diphenylphoshino)-3,3′-bithiophene
J . Org. Chem., Vol. 65, No. 7, 2000 2047
layer was treated with H2O2 (10 mL, 35%) at 0 °C. The mixture
was stirred for 1 h at 0 °C and for 1 h at room temperature
and then diluted with water. The organic layer was separated,
dried (Na2SO4), and concentrated in vacuo. Chromatography
(SiO2, eluant AcOEt/CH2Cl2/Et3N 3:7:0.1) provided pure
BITIOP (2.3 × 10-2 mmol) and [RuCl2(C6H6)]2 (1.15 × 10-2
mmol) was added freshly distilled argon-degassed DMF. The
mixture was stirred at 100 °C for 15 min. The resulting orange
solution was cooled to 50 °C and concentrated under reduced
pressure to give 3a . The ruthenium complex residue was
utilized without further purification: 31P NMR (CDCl3) δ 69.4
(d, J ) 53 Hz), 62.1 (d, J ) 38 Hz), 60.2 (d, J ) 42 Hz), 58.7
(d, J ) 42 Hz), 58.0 (d, J ) 42 Hz), 55.3 (d, J ) 40 Hz), 54.3
(d, J ) 42 Hz), 53.9 (d, J ) 47 Hz).
1
(()-1b (98%): mp 140 °C; H NMR (CDCl3) δ 7.6 (m, 20H),
1.95 (d, 6H), 1.65 (s, 6H); 31P NMR (CDCl3) δ 21.19; mass
spectrum m/z 622 (M+). Anal. Calcd for C36H32S2P2O2: C, 69.44;
H, 5.18. Found: C, 69.23; H, 5.09.
Resolu tion of 4,4′-Bis(d ip h en ylp h osp h in yl)-2,2′,5,5′-
tetr a m eth yl-3,3′-bith iop h en e (()-1b w ith (-)- or (+)-2,3-
O,O′-Diben zoylta r ta r ic Acid (DBTA). A mixture of (()-1b
(12.5 g) and monohydrate (-)-DBTA (7.6 g) was dissolved
in THF (150 mL), refluxed for a few minutes, and allowed
to stand at room temperature for 24 h. An adduct between
(+)-1b and (-)-DBTA was collected, and the filtrate was stored
for recovery of (-)-1b. The adduct was dissolved into warm
THF (450 mL), and a pure adduct was collected [8.76 g, mp
P r ep a r a tion of (+)- a n d (-)-[(Tetr a Me-BITIOP )Ru (p-
cym en e)I]I (3b). (+)- or (-)-tetraMe-BITIOP (0.024 g), [Ru-
(p-cymene)I2]2 (0.015 g), methanol (3 mL), and CH2Cl2 (8 mL)
were stirred in a Schlenk tube under argon at 50 °C for 1.5 h.
The solution was concentrated under reduced pressure to give
3b as a red solid that was used as catalyst in hydrogenation
reactions without further purification: 31P NMR (CDCl3) δ 38.0
(d, J ) 63 Hz), 15.3 (d, J ) 63 Hz).
P r ep a r a tion of (+)- a n d (-)-[(Tetr a Me-BITIOP )Ru -
(C6H6)Cl]Cl (3c). (+)- or (-)-tetraMe-BITIOP (0.045 g),
[(C6H6)RuCl2)2 (0.019 g), ethanol (10 mL), and benzene (1.3
mL) were stirred in a Schlenk tube under argon for 1 h at
50-60 °C. The orange solution was evaporated under reduced
pressure to give 3c as an orange-yellow solid that was used
in the asymmetric catalysis experiments without further
purification: 31P NMR (CDCl3) δ 22.5 (d, J ) 62 Hz), 38.7 (d,
J ) 62 Hz).
P r ep a r a tion of (-)-[(Tetr a Me-BITIOP )Ru Bis(2-m eth -
a llyl)] [(-)-3d ]. (-)-TetraMe-BITIOP (0.0104 g), [(COD)Ru
bis(2-methallyl) (0.0054 g), and toluene (5 mL) were stirred
at 110 °C for 2 h. The solution was concentrated under reduced
pressure to give 3d . The Ru complex residue was used in
asymmetric hydrogenation without further purification: 31P
NMR (CDCl3) δ 36.25.
159-172 °C (DEC), [R]25 ) -36.9 (c ) 0.49, benzene)] after
D
standing for 10 days. The adduct was treated with 0.75 N
NaOH solution, and the mixture was extracted exhaustively
with CH2Cl2. The combined organic layers were dried
(Na2SO4) and concentrated in vacuo to give a solid that
was crystallized from a hexane/benzene 1:1 mixture to give
(+)-1b [2.1 g, mp 236 °C, [R]25 ) +62 (c ) 0.49, benzene)].
D
The mother liquors from the first resolution step were con-
centrated to dryness to give a solid that was treated with a
0.75 N NaOH solution and extracted with CH2Cl2. The organic
layer was washed with water, dried (Na2SO4), and concen-
trated in vacuo to give (-)-1b, which was crystallized from
hexane/benzene 1:1 [1.2 g, mp 236 °C, [R]25 ) -62 (c ) 0.49,
D
benzene)].
P r ep a r a tion of (+)- a n d (-)-4,4′-Bis(d ip h en ylp h os-
ph in o)-2,2′,5,5′-tetr am eth yl-3,3′-bith ioph en e [(+)- an d (-)-
1a ]. In a three-necked flask equipped with a thermometer and
a reflux condenser connected to an argon inlet tube were placed
(+)-1b (0.49 g), dry xylene (15 mL), trichlorosilane (0.52 mL),
and triethylamine (0.72 mL). The mixture was stirred and
heated at 100 °C for 1 h and then at 140 °C for 3 h. After
cooling to room temperature, the mixture was concentrated
in vacuo, and the residue was treated with water and extracted
with CH2Cl2. The residue was treated with methanol, and the
precipitate was collected to give (-)-1a [0.29 g, mp 178 °C and
P r ep a r a t ion of (-)-[(t et r a Me-BITIOP )R h (COD)]BF 4
21
[(-)-3e]. A solution of [Rh(COD)2]BF4 (0.314 g) and (-)-
tetraMe-BITIOP (0.457 g) in CH2Cl2 (18 mL) was stirred under
argon at room temperature for 1 h. The solvent was partially
removed (10 mL) under reduced pressure, and THF (15 mL)
first, then hexane (20 mL), were added. The yellow-orange
precipitate was filtered under argon and used as catalyst in
hydrogenation reactions without further purification: 31P
NMR (CDCl3) δ 20.51 (d, J ) 145.8 Hz).
Hyd r ogen a tion Rea ction s. In a typical experiment (Table
1, entry 1), a solution of ethyl 3-oxobutanoate (4a ) (20 mmol)
and (+)-3a (0.020 mmol) in methanol (10 mL), previously
degassed with argon, was loaded with a syringe into a 100
mL Parr autoclave. Hydrogen was introduced (100 kg/cm2),
and the solution was stirred at 70 °C for 30 min. The autoclave
was cooled, the hydrogen pressure released, the solvent
evaporated, and the residue distilled (17 mmHg) to give ethyl
(S)-(+)-3-hydroxybutanoate (5a ) (98%).
[R]25 ) -27.4 (c ) 0.51, benzene)].
D
(-)-1b was reduced to (+)-1a by following the same proce-
dure described above for (+)-1b [mp 179 °C, [R]25 ) +27.4 (c
D
) 0.51, benzene)]: 1H NMR (CDCl3) δ 7.30 (m, 20 H), 6.85 (s,
2 H), 2.40 (s, 6 H); 31P NMR (CDCl3) δ -24.98; mass spectrum
m/z 590 (M+). Anal. Calcd for C36H32S2P2: C,73.20; H, 5.46.
Found: C,73.04; H, 5.27.
P r ep a r a t ion of 2,2′-Bis(d ip h en ylp h osp h in o)-5,5′-d i-
m eth yl-3,3′-bith iop h en e (2). BuLi (3.8 mL, 1.6 M solution
in hexane, 6.08 mmol) was dropped into a solution of 5,5′-
dimethyl-3,3′-bithiophene (0.58 g, 3.0 mmol) in THF (30 mL)
at -60 °C under N2. After 10 min of stirring, diphenylphos-
phinous chloride (1.1 mL, 6.13 mmol) was added; the mixture
was stirred for 1.5 h, and the temperature was allowed to
warm to room temperature. The mixture was concentrated
under reduced pressure and the residue treated with water
and extracted with CH2Cl2. The organic layer was dried (Na2-
SO4) and concentrated in vacuo. The residue was treated with
Ack n ow led gm en t. Dr. P. Antognazza, Dr. S. Ara-
neo, Dr. F. Bonifacio, Dr. C. Crescenzi, Dr. G. De Iase,
Dr. G. Melato, Dr. S. Tollis, Dr. U. Tuan, and Dr. A.
Turri are acknowledged for their contribution to the
experimental success of this project. Also acknowledged
is Dr. G. Zotti (CNR-IPELP, Padua, Italy) for CV
experimentation. This work was supported in part (T.B.,
F.S.) by Chemi S.p.A., holder of the patents for the
synthesis and use of all biheteroaryl-diphosphine ligands,
and MURST COFIN 1998/99 project (9803153701).
1
diisopropyl ether to give 2 (80%): mp 236-239 °C; H NMR
(CDCl3) δ 7.30 (m, 20 H), 6.85 (s, 2H), 2.40 (s, 6 H); 31P NMR
(CDCl3) δ -24.98; mass spectrum m/z 562 (M+). Anal. Calcd
for C34H28S2P2: C, 72.58; H, 5.02. Found: C, 72.47; H, 5.01.
P r ep a r a tion of [(+)- a n d (-)-Tetr a Me-BITIOP ]Ru Cl2
(3a ). To a Schlenk tube charged with (+)- or (-)-tetraMe-
J O991533X