Electronic tuning in C1-symmetric chelating diphosphane ligands supported on stereogenic aryl-heteroaryl templates

Article abstract of DOI:10.1055/s-2001-18429

The syntheses of a wide range of novel C₁-symmetric chelating diphosphanes with stereogenic axes are reported. These ligands feature identical or different phosphanyl groups supported on diverse atropisomeric templates based on the interconnection of five-membered heteroaromatic and six-membered carbocyclic rings. Easy synthetic accessibility, independent tunability of the electronic and steric properties of the two phosphane donors, the low cost and the good stereoselection ability of some of them obtained in an enantiopure state are the main advantageous features of this class of ligands.

Full text of DOI:10.1055/s-2001-18429

SPECIAL TOPIC
2327
Electronic Tuning in C1-Symmetric Chelating Diphosphane Ligands
Supported on Stereogenic Aryl–Heteroaryl Templates
Electronic
T
unringin 1
C
a
-Symmetr
n
c
iphosphan
o
e
L
igands Sannicolò,*a Tiziana Benincori,b Simona Rizzo,a Serafino Gladiali,*c Sonia Pulacchini,c Gianni Zottid
a
Dipartimento di Chimica Organica e Industriale dell’Università e Centro CNR per la Sintesi e la Stereochimica di Speciali Sistemi
Organici, Via Golgi 19, 20133 Milano, Italy
Fax +39(02)58354139; E-mail: staclaus@icil64.cilea.it
b
c
d
Dipartimento di Scienze Chimiche, Fisiche e Matematiche dell’Università dell’Insubria, Via Valleggio 11, 22100 Como, Italy
Dipartimento di Chimica dell’Università, Via Vienna 2, 07100 Sassari, Italy
Istituto di Polarografia ed Elettrochimica Preparativa, C. N. R., c.so StatiUniti 4, 35020, Padova Italy
Received 31 July 2001
most illustrative of this trend and has contributed to draw-
ing attention to the aspects of asymmetric catalysis perti-
nent to the design of new ligands.4 Also, it should be noted
that metalloenzymes, which are all devoid of C2-symme-
Abstract: The syntheses of a wide range of novel C1-symmetric
chelating diphosphanes with stereogenic axes are reported. These
ligands feature identical or different phosphanyl groups supported
on diverse atropisomeric templates based on the interconnection of
five-membered heteroaromatic and six-membered carbocyclic try, are nevertheless highly efficient in the chirality trans-
rings. Easy synthetic accessibility, independent tunability of the
fer processes.
electronic and steric properties of the two phosphane donors, the
low cost and the good stereoselection ability of some of them ob-
Atropisomeric chelating diphosphanes are among the
most efficient chiral chelating ligands for asymmetric hy-
drogenation. The stereogenic axial cores of these deriva-
tives are in general C2-symmetric and they are built up by
introducing the chelating phosphorus functions onto ho-
motopic sites of a C2-symmetric scaffold.5 Atropisomeric
C1-symmetric diphosphanes have been prepared in the
biphenyl6 and in the binaphthyl families (BINAPP’,
Figure 1),7 by stepwise introduction of two non equivalent
phosphanyl groups. The BINAPP’ ligand is a chiral in-
ducer more efficient than the relevant C2-symmetric coun-
terpart, BINAP, in the Rh-catalyzed asymmetric
hydrogenation of acrylic acid derivatives and in Pd-cata-
lyzed allylic alkylation.7 It should be stressed that the dif-
ferent substitution pattern at the phosphorus termini does
not affect symmetry only, but induces substantial changes
in the electronic properties and in the steric enviroment at
the donor center as well. Thus, the performances of BI-
NAPP’ is the result of both of these effects which cannot
be independently considered.
tained in an enantiopure state are the main advantageous features of
this class of ligands.
Key words: diphosphane ligands, heterocyclic diphosphanes,
chiral ligands, C1 ligands, asymmetric hydrogenation
Introduction
For a long time C2-symmetry has been assumed to be a
prerequisite for a chiral ligand to provide high enantiose-
lectivity levels in asymmetric catalysis.1 For this reason,
and for the easier modeling of the ligands and of the reac-
tion intermediates, until recently ligand design for asym-
metric hydrogenation has been largely dominated by C2-
symmetric diphosphanes.2 However, it has been pointed
out3 that C2-symmetry does not necessarily need to be
maintained in the relevant complexes and that the origi-
nally homotopic P-donors can play different roles in the
catalytic cycle. Thus, ligand asymmetry may result in an
advantage rather than a drawback in a stereoselective re-
action and the stereochemical outcome of the process ba-
sically depends upon effective matching between the
catalytic complex and the substrate, which is ultimately
modulated by the steric and the electronic properties of
the ligand. Thus, it is not a paradox that C2-symmetric
controllers are highly efficient since they produce C1-
symmetric catalysts, which are, in turn, the enantioselec-
tive origin for C1-symmetric products.
Figure 1 Chemical structures of BINAPP’ and new atropisomeric
chelating diphosphanes
This conclusion finds support in the results obtained with
diphosphanes carrying constitutionally heterotopic
chelating functions; the success of the ferrocenyl diphos-
phanes of the JOSIPHOS family is probably one of the
We have recently described the synthesis of the ligand 1a
featuring two identical constitutionally heterotopic phos-
phanyl substituents.8 This was obtained by attaching two
diphenylphosphane groups onto a C1-symmetric scaffold
constituted by a 3-phenylnaphtho[2,1-b]thiophene back-
bone (Figure 1).
Synthesis 2001, No. 15, 12 11 2001. Article Identifier:
1437-210X,E;2001,0,15,2327,2336,ftx,en;C03801SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2328
F. Sannicolò et al.
SPECIAL TOPIC
Ligand 1a is the first diphosphane featuring a C1-symmet- ligands described in this paper are reported in Figure 2,
ric atropisomeric scaffold and it is the prototype of a new but it is evident that the choice for new scaffolds is unlim-
class of chiral ligands possessing the general structure ited.
schematically represented in Figure 1, in which the elec-
They are naphthothiophene-, naphtho- and benzofuran-
tronic properties of the donor centers are modulated by the
and indole-based ligands and express the structural poten-
inherently differentiated electronic demand or supply of
tial connected with this class of ligands. Diphosphane 1b
the supporting heteroaromatic ring and of the phenyl sys-
was obtained in an enantiopure state and submitted to pre-
tem onto which suitable substituents can easily be intro-
liminary catalysis tests as a ligand of Ru (II) in the stereo-
duced. This electronic fine-tuning possibility can be
selective hydrogenation of prostereogenic ketonic
fruitfully combined with very easy synthetic accesses,
functions.
which are merely reduced to the preparation of aryl sub-
stituted five-membered aromatic heterocycles. Further-
more, since the two phosphanyl groups are introduced
through different methodologies (acid-base lithiation on
Synthesis of the Ligands
the heterocyclic ring and transmetalation on the carbocy-
The synthetic approach to the heterocyclic-carbocyclic
clic ring), it becomes easy to introduce two differently
backbone of all the ligands is very simple; according to
substituted phosphane groups on the two rings.
Scheme 1, syntheses of 1a–e were easily achieved starting
Since, the stereoselectivity obtained with ligand 1a in from inexpensive, commercially available, -thionaph-
asymmetric catalysis was often similar to those obtained thol, -naphthol or 3,5-dimethylphenol and the suitable
with C2-symmetric analogues,8 we decided to pursue fur-
,2-dibromoacetophenones. Compounds 4a–d resulting
ther efforts to increase the variety of the atropisomeric C1- from the nucleophilic substitution were cyclized to the
symmetric scaffolds for chelating diphosphanes. The new corresponding arylthiophenes 5a,b or furans 5c,d in acid-
Figure 2 Chemical structures of new atropisomeric chelating diphosphanes synthesized in the present study
Scheme 1
Synthesis 2001, No. 15, 2327–2336 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Electronic Tuning in C1-Symmetric Chelating Diphosphane Ligands
2329
ic medium. Introduction of the phosphinyl groups in 6a–e through their electrochemical oxidative potential E°. Only
was performed by lithiation of the -position of the in the case of diphosphane 2 were two oxidation peaks
thianaphthene or benzofuran system and simultaneous found, while in all the others, voltammetric experiments
transmetalation of the ortho-bromine atom with butyllith- showed only one peak, since degradative evolution of the
ium, followed by quenching of the bis-anion with diphe- radical cation took place before a further electron could be
nyl- or dicyclohexylchlorophosphane and oxidation in abstracted from the second phosphane group. The peak is
situ with hydrogen peroxide. Reduction with trichlorosi- attributable to the more electron-rich phosphane group,
lane of diphosphine oxides 6a–e produced the corre- namely the one located on the phenyl ring. In these cases,
sponding diphosphanes 1a–e in high yields.
the oxidation potential values of the diphenylphosphane
groups on the heterocyclic moieties were inferred from
those shown by structurally similar monophosphanes.9a
The electrochemical oxidative potentials of all the ligands
described are reported in Table 1.
For the preparation of 2 (Scheme 2), the 3-(2-bromophe-
nyl)naphtho[2,1-b]thiophene (5a)8 was selectively meta-
lated with LDA in the -position of the thiophene ring and
the resulting anion quenched with chlorodiphenylphos-
phane and the crude product oxidized to the 3-(o-bro-
mophenyl)-2-(diphenylphosphinyl)naphthothiophene (7)
in 82% isolated yields. Introduction of the dicyclohex-
ylphosphinic group on the aromatic carbocyclic ring was
performed by lithiation with t-BuLi, followed by quench-
ing of the resulting anion with chlorodicyclohexylphos-
phane. Oxidation of the reaction mixture, followed by
column chromatography allowed isolation of 3-(2-dicy-
clohexylphosphinyl)phenyl-2-(diphenylphosphinyl)[2.1-
b]naphthothiophene (8) in 74% yield. Reduction with
trichlorosilane of diphosphine oxide 8 produced the corre-
Table 1 Electrochemical Oxidative Potentials E° of the Ligands
Ligand
1a
E° of Hetaryl P (V)
E° of Aryl P (V)
0.91a
0.91a
-
0.74
0.75
0.68
0.72
0.67
0.64
0.70
1b
1c
1d
1e
0.9–0.95b
-
sponding diphosphane
(Scheme 2).
2
in satisfactory yields
2
1.01
0.90c
3
Straightforward is also the synthesis of the indole-based
ligand 3 involving a simple Fischer indolization to pro-
duce the backbone. Double metalation followed by reac-
tion with two equivalents of diphenylphosphinyl chloride
affords diphosphine oxide 10, which was reduced to
diphosphane 3 in the usual way (Scheme 3).
a E° (V) of 2-diphenylphosphino-3-phenylnaphto[2,1-b]thiophene.8,
b E° (V) of 2,2’-bis(diphenyl)phosphino-4,4’,6,6’-tetramethyl-3,3’-
bibenzo[b]furan.10,
c E° (V) of 1,1’-bis(diphenyl)phosphino-3,3’-dimethyl-2,2’-biin-
dole.9a
E° values for the phosphane groups located on heteroaro-
matic rings are in good agreement with those we have
found for diphenylphosphino groups in -position of a
3,3’-bithianapthene system (BITIANP).11 E° values for
the phosphane groups on the phenyl moiety are compara-
ble to those shown by BIPHEP and BINAP. The E° values
Evaluation of the Electronic Availability of the
Ligands at Phosphorus
We evaluated the different electronic properties of the
phosphanyl groups of all the ligands by voltammetry9
Scheme 2
Scheme 3
Synthesis 2001, No. 15, 2327–2336 ISSN 0039-7881 © Thieme Stuttgart · New York

2330
F. Sannicolò et al.
SPECIAL TOPIC
of heterocyclic phosphane groups are also influenced by is compatible only with a kinetic resolution process of
the nature of the heterocyclic scaffold and by their posi- configurationally labile antipodes.9a
tion on it.
A much more complex pattern is expected in the case of
As expected, dicyclohexyl substituted phosphane groups C1-symmetric diphosphanes displaying constitutionally
are more electron-rich than the diphenylsubstituted ones, heterotopic phosphorus atoms. In these cases either of the
as demonstrated by their constantly lower E° values.
antipodes produces two diastereoisomers, generally in
different amounts. Thus, four couples of doublets are ex-
pected. If the free ligand is configurationally stable, the
sum of the integrals of the signals attributable to the com-
plexes formed from one enantiomer must be equal to the
sum of the integrals of the signals related to the complexes
formed from the antipode. The 31P NMR spectrum of the
mixture of diastereomeric complexes generated from
naphthothiophene-based diphosphane ( )-1a is repro-
duced in Figure 3.
Interestingly, the presence of the electron-releasing meth-
oxy substituent on the phenyl ring in 1b does not influence
the oxidative potential value shown by 1a. This observa-
tion is in agreement with the observation that the methyl
groups present in 4-Tol-BINAP (E° = 0.65 V)10 do not ex-
ert any effect on the electrochemical oxidative potential of
BINAP (E° = 0.63 V).9a A possible interpretation of these
data involves conformational effects in solution which do
not allow the phosphorus lone pair to conjugatively align
and overlap the -system of the substituted phenyl ring.
Evaluation of Configurational Stability of the
Ligands
Configurational stability of naphthofuran-based ligand 1c
was evaluated through a 31P NMR experiment carried out
in parallel with diphosphane 1a for which high configura-
tional stability had been previously demonstrated through
successful resolution. We took advantage of the spectra of
the complexes which are formed by reaction of racemic
diphosphanes with an excess of enantiopure (+)- or ( )-
di- -chloro-bis[(S)-dimethyl( -methylbenzyl)amminato-
C2N] palladium(II) (Scheme 4).
Figure 3 31P NMR spectrum of the mixture of the four diastereome-
ric amminopalladium complexes generated from ( )-1a
The 31P NMR spectra of the diastereomeric complexes ob-
tained from enantiopure (+)-1a and (–)-1a are reported in
Figures 4 and Figure 5, respectively. They demonstrate
that enantiopure (+)-1a affords two complexes in a 1.1:1
ratio, while two diastereoisomers in very different
amounts (1:2.2 ratio) are formed from (–)-1a.
When a C2-symmetric diphosphane is employed, two di-
astereomeric complexes are produced in which the origi-
nally homotopic phosphorus atoms of the free ligand
become diastereotopic (anisochronous). If the starting
ligand is configurationally stable, a couple of double
doublets is produced (generally after chloride for perchlo-
rate anion exchange) with identical integrals. Different in-
tegrals indicate a diastereomeric excess in solution which
Scheme 4
Synthesis 2001, No. 15, 2327–2336 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Electronic Tuning in C1-Symmetric Chelating Diphosphane Ligands
2331
other one gives a rather unbalanced diastereomeric coup-
le.
It was, however, impossible to find any combination of
signals, which could be assigned to two diastereomeric
couples in a good 1:1 ratio. This situation suggests that
ligand 1c is not configurationally stable at the complex-
ation temperature (25 °C). In agreement with this conclu-
sion, all the attempts performed to resolve the
corresponding phosphane oxide 6c by crystallization of
its’ adducts with different chiral acids and from several
solvents failed.
Figure 4 31P NMR spectrum of the mixture of the two diastereome-
ric amminopalladium complexes generated from (+)-1a
This result matches a previous observation about the con-
figurational stability of analogous bi-benzofuran- and bi-
thianaphthene-based atropisomeric diphosphanes: the
former was found configurationally labile at room tem-
perature, while the latter did not racemize up to 150 °C.
No changes were observed in all the above reported spec-
tra by heating the solution of the complexes at 80 °C for 3
hours.
Preparation of Enantiopure Diphosphanes (+)- and
(–)-1b
Figure 5 31P NMR spectrum of the mixture of the two diastereome-
ric amminopalladium complexes generated from (–)-1a
Resolution of racemic ( )-3-(2-diphenylphosphinyl-5-
methoxyphenyl)-2-(diphenylphosphinyl)naphtho[2,1-
b]thiophene [( )-(6b)] was achieved following a known
methodology involving fractional crystallization of its di-
astereomeric adducts with chiral dibenzoyltartaric acids
(DBTA).12
Careful integration of the signals present in the spectrum
of the mixture of the four diastereomeric amminopalladi-
um complexes generated from ( )-1a demonstrates that
the two diastereomeric couples generated from (+)-1a and
(–)-1a are present in a nearly perfect 1:1 ratio, thus giving
clear support to the configurational stability of the ligand.
Alkaline decomplexation of the diastereomerically pure
complexes gave enantiopure phosphane oxides (+)- and
(–)-6b, which were reduced with trichlorosilane to the
corresponding enantiopure diphosphanes (–)-and (+)-1b,
respectively. The enantiomeric purity of resolved phos-
phane oxides was checked by HPLC chromatography on
a chiral stationary phase, while the enantiomeric purity of
diphosphanes was controlled under the same analytical
conditions after their reoxidation to phosphane oxides
with hydrogen peroxide.
A mixture of four diastereomeric amminopalladium com-
plexes was generated also from ( )-1c and its 31P NMR
spectrum (Figure 6) was found very similar to that just
discussed for the analogous complexes obtained from ra-
cemic ( )-1a.
Preliminary Catalytic Experiments with Ru(II)
Complexes of Enantiopure Diphosphane (+)-1b
Preliminary catalysis experiments on enantiopure (+)-1b
were carried out on substrates, which are in standard use
for the evaluation of stereoselection ability and catalytic
activity of all new ligands presented in literature. Ru(II)
complexes 11a,b (Figure 7) were employed in catalytic
hydrogenation of -keto esters 12a,b to hydroxyesters
13a,b (Figure 8).
As expected, the 31P NMR spectroscopy showed that the
complex 11b consists of a mixture of two diastereomeric
species in a ratio of ca 3:1.
Figure 6 31P NMR spectrum of the mixture of four diastereomeric
amminopalladium complexes generated from ( )-1c
In this case, it is difficult to assign the signals to the dias-
tereomeric couples arising from the same enantiomer,
even though it is rather evident that one enantiomer gen-
erates two complexes in very similar amounts, while the
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2332
F. Sannicolò et al.
SPECIAL TOPIC
conformational barriers in the free ligand, is activated by
metal complexation, which reasonably involves a consis-
tent conformational rearrangement.
We considered it important to verify the kinetic behavior
of catalytic complex 11a in the hydrogenation reaction of
two different substrates, namely the acetoacetic and the
benzoylacetic esters 12a and 12b, in order to obtain any
possible information on the reaction mechanism.
Figure 7 Chemical structures of Ru(II) complexes of 11a,b
We found that acetoacetic ester hydrogenation (Figure 9)
follows a zero order kinetic in the substrate (linear depen-
dence of substrate concentration upon time, k = 11.57
10–2 m l–1 sec–1), while benzoylacetic ester reduction
(Figure 10) follows a first order kinetics in the substrate
(k = 4.63 10–5 sec–1). These results demonstrate that in
these multi-step reactions the reactants are involved in dif-
ferent steps of the whole sequence. In particular, 12a is in-
volved in the late step, which does not restrict the overall
rate.
Figure 8 Chemical structures of -keto esters 12a,b and hydroxy
esters 13a,b
Table 2 summarizes stereoselection data and some char-
acteristic experimental parameters. The enantiomeric ex-
cesses are quite high and comparable to those obtained
with diphosphane 1a8 and with some efficient C2-sym-
metric ligands.9a There is a rather negative temperature ef-
fect in the hydrogenation of 12a with complex 11a, which
is, however, overcome by using complex 11b.
Comparison of the catalytic efficiency of the Ru(II) com-
plexes produced from 1a and 1b clearly demonstrated that
the latter gives kinetically more active catalysts. The reac-
tion time required to complete the hydrogenation reaction
of acetoacetic ester 12a, with 11a as a catalyst, at 40 °C
(110 min), was about one half of the time required to com-
plete the same reaction (210 min) when the catalyst was
prepared from 1a, under identical experimental condi-
tions. This holds true also in benzoylacetic ester 12b hy-
drogenation: the reaction requires 3.75 hours when
promoted by 11b, while 6 hours are necessary when an
analogous 1a Ru(II)-complex is employed. Since it is well
documented that electron-rich ligands foster the hydroge-
nation reaction of -keto esters,13 it appears that diphos-
phane 1b behaves as a more electron rich promoter than
1a, even though the E° values of these ligands are nearly
the same. A tentative interpretation of these findings hy-
pothesizes that the conjugative electron-releasing effect
of the methoxy group to phosphorus, which is inhibited by
Figure 9 Hydrogenation of ethyl acetoacetate 12a in the presence
of 11a as a catalyst (100 atm, 40 °C, S/C 300)
Figure 10 Hydrogenation of methyl benzoylacetate 12b in the
presence of 11a as a catalyst (100 atm, 55 °C, S/C 240)
Table 2 Hydrogenation of -Keto Esters with Ru(II) Complexes of (+)-1b as Catalysts
Substrate
12a
Catalyst
11a
Substrate/Catalyst
P (Atm)
100
T (°C)
40
T (h)
1.8
5
ee(%)a
84
Conf.
k (sec–1)
1.57 10–2
-
300
300
300
240
R
R
R
S
12a
11a
100
25
>99.9
>99.9
70
12a
11b
100
40
40
6.18 10–4
4.63 10–5
12b
11a
100
55
3.75
a Evaluated by chiral HPLC.
Synthesis 2001, No. 15, 2327–2336 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conclusions
Electronic Tuning in C1-Symmetric Chelating Diphosphane Ligands
2333
3-(2-Bromo-5-methoxy)phenylnaphtho[2,1-b]thiophene (5b)
Compound 4b (5.48 g, 14 mmol) was added under stirring to poly-
phosphoric acid (PPA, 45 g) at 80 °C. The mixture was stirred for 1
h, then poured onto ice, neutralized with 20% NH4OH solution and
extracted with CH2Cl2. The organic layer was dried (Na2SO4) and
evaporated to dryness to give 5b as a solid, which was purified by
triturating with diisopropyl ether (5.18 g, 94%).
1H NMR (CDCl3): = 7.68 (m, 6 H), 7.37 (s, 1 H, 2-H of thianaph-
thene ring), 7.28 (m, 1 H, 3-H of phenyl ring), 7.05 (d, 1 H, 6-H of
phenyl ring), 6.94 (dd, 1 H, 4-H of phenyl ring), 3.8 (s, 3 H).
Research developed in this work has produced a series of
C1-symmetric ligands for homogeneous stereoselective
catalysis belonging to a new class of diphosphanes dis-
playing a mixed aryl–heteroaryl atropisomeric backbone.
The synthetic access to these systems is very simple being
reduced to that of an aryl-substituted aromatic heterocy-
cle.
Electrochemical characterization of the ligands has
proved the flexibility that these systems offer in tuning the
electronic properties at phosphorus, which ranges from
modest to high electron availability.
3-[2-(Diphenylphosphinyl-5-methoxy)phenyl]-2-(diphenyl-
phosphinyl)naphtho[2,1-b]thiophene (6b)
BuLi (1.6 M in hexane, 19.5 mL, 31 mmol) was added dropwise to
a solution of 5b (5.18 g, 14 mmol) and TMEDA (5 mL) in THF (130
mL) at –70 °C under N2. The temperature was allowed to warm to
20 °C, then diphenylphosphinous chloride (6.2 mL) was added and
the mixture stirred for 12 h. The solvent was evaporated under re-
duced pressure, the residue treated with CH2Cl2 (140 mL) and 35%
H2O2 solution (38 mL), and then stirred for 2 h. The organic layer
was separated, dried (Na2SO4), and the residue obtained after evap-
oration of the solvent was chromatographed (SiO2, eluant: EtOAc–
CH2Cl2, 3:7, v/v). The last fractions eluted were evaporated under
reduced pressure to give 6b (2.9 g, 30%); mp 360 °C.
Naphthofuran-based diphosphane 1c has been found to be
configurationally unstable at room temperature, while the
analogous naphthothiophene-based diphospanes 1a and
1b were obtained in an enantiopure form on a preparative
scale and they did not racemise even at 130 °C tempera-
ture. They have been successfully experimented as Ru(II)-
ligands in the homogeneous stereoselective hydrogena-
tion of keto esters, displaying good face-selection capaci-
ty and remarkable kinetic activity.
1H NMR (CDCl3): = 7.9–6.5 (m, 29 H), 3.35 (s, 3 H).
31P NMR (CDCl3): = 28.02 (s, 1 P), 20.42 (s, 1 P).
MS: m/z = 690 (M+).
A concluding consideration involves the economic advan-
tages related to this class of ligands for which the prelim-
inary cost estimate is about one tenth of DuPHOS, one
fifth of BINAP and one third of tetraMe-BITIOP13 and, in
some cases, even less. Thus diphosphanes 1a and 1b de-
serve consideration for a immediate application also on an
industrial scale level.
3-[2-(Diphenylphosphino-5-methoxy)phenyl]-2-(diphenyl-
phosphino)naphtho[2,1-b]thiophene (1b)
In a three-necked flask equipped with a thermometer and a reflux
condenser connected to an argon inlet tube were placed 6b (0.2 g,
0.32 mmol), anhyd xylene (10 mL), Et3N (0.45 mL, 3.32 mmol) and
trichlorosilane (0.36 mL, 3.6 mmol). The mixture was stirred for 3
h at 110 °C. The solvent was removed under reduced pressure, then
a 10% aq NaOH solution (18 mL) wad added to the residue and the
mixture stirred at 60 °C for 15 min. The organic layer was extracted
with degassed CH2Cl2, washed with degassed H2O, dried (Na2SO4)
and evaporated to dryness to give a solid which was triturated with
MeOH to give 1b (0.16 g, 85%); mp 243 °C.
Chiral HPLC analyses were performed with
a DAICEL
CHIRACEL OD column (210 nm). Electrochemical experiments
were performed in a three-electrode cell at 25 °C under N2. The
working electrode was a platinum microelectrode (0.003 cm2); the
counter electrode was platinum; the reference electrode was silver/
0.1 M AgClO4 in MeCN (0.34 V vs. SCE). The voltammetric appa-
ratus (Amel, Italy) included a 551 potentiostat modulated by a 568
programmable function generator. MeCN for voltammetric mea-
surements was distilled twice over P2O5 and once over CaH2.
Et4NClO4 was dried at 70 °C under vacuum before use. All other
chemicals were reagent grade and were used as such.
1H NMR (CDCl3): = 8–6.6 (m, 32 H), 3.4 (s, 3 H)
31P NMR (CDCl3): = 6.3 (s, 1 P), –2.6 (s, 1 P).
1-(2-Bromo)phenyl-2-(2-naphthyloxy)ethanone (4c)
A solution of 1-(2-bromophenyl)-2-bromoethanone15 (21 g, 75.5
mmol) in DMF (50 mL) was rapidly added to a DMF solution of an-
hyd sodium 2-naphtholate [from 2-naphthol (15 g, 104 mmol) and
NaOMe]. The mixture was stirred for 3 d and concentrated under re-
duced pressure. The residue was diluted with H2O (100 mL) and ex-
tracted with CH2Cl2 (2 100 mL). The organic layer was dried
(Na2SO4) and concentrated to dryness to give a residue, which was
chromatographed (SiO2, eluent: CHCl3). The last fractions eluted
were evaporated to dryness to give 4c (16 g, 62%) as an oil.
Hydrogenation reactions were carried out in a stirred (550 rpm) and
thermostated 100 mL, Hastelloy Parr autoclave, equipped with a
sampling pipe, which extended to the bottom of the vessel.
1-(2-Bromo-5-methoxy)phenyl-2-(2-naphthylthio)ethanone
(4b)
A solution of 1-(2-bromo-5-methoxyphenyl)-2-bromoethanone14
(7.05 g) in EtOAc (7 mL) was added dropwise into a mixture of H2O
(10 mL), EtOH (30 mL), KOH (1.28 g, 23 mmol) and 2-thionaph-
thol (3.67 g, 23 mmol), keeping the temperature below 25 °C. The
mixture was stirred for 12 h and then concentrated under reduced
pressure. The residue was diluted with H2O (50 mL) and extracted
with EtOAc (2 50 mL). The organic layer was dried (Na2SO4),
concentrated to dryness and the residue was chromatographed
(SiO2, eluant: CHCl3–hexane, 6:4 v/v). The last fractions were
evaporated to dryness to give 4b (5.48 g, 62%) as an oil.
1H NMR (CDCl3): = 7.39 (m, 11 H), 5.22 (s, 2 H).
3-(2-Bromo)phenyl-naphtho[2,1-b]furan (5c)
Compound 4c (16 g, 47 mmol) was added under stirring to PPA
(100 g) at 80 °C. The mixture was stirred for 1.5 h, then poured onto
ice, neutralized with 20% NH4OH solution and extracted with
CH2Cl2. The organic layer was dried (Na2SO4) and evaporated to
dryness to give 5c (11g, 72%) as a viscous oil.
1H NMR (CDCl3): = 7.72 (m, 4 H), 7.48 (m, 4 H), 6.78 (dd, 1 H,
J = 8.72, 3.07 Hz, 3-H of the phenyl ring), 6.73 (d, 1 H, J = 3.07 Hz,
6-H of the phenyl ring), 4.4 (s, 2 H), 3.6 (s, 3 H).
1H NMR (CDCl3): = 7.96 (d, 1 H, J = 8 Hz), 7.77 (m, 3 H), 7.48
(m, 7 H).
MS: m/z = 644 (M+).
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2334
F. Sannicolò et al.
SPECIAL TOPIC
3-[2-(Diphenylphosphinyl)phenyl]-2-(diphenylphosphinyl)-
naphtho[2,1-b]furan (6c)
warm to 20 °C, then diphenylphosphinous chloride (2.16 mL, 11.6
mmol) was added and the mixture stirred for 3 h. The solvent was
evaporated under reduced pressure, the residue treated with CH2Cl2
(100 mL) and 35% H2O2 solution (5 mL) and the mixture was
stirred for 2 h at 25 °C. The organic layer was separated, dried
(Na2SO4) and the residue chromatographed (SiO2, eluent: EtOAc–
CH2Cl2, 3:7, v/v). The last fractions eluted were evaporated under
reduced pressure to give 6d in a pure state(1 g, 42%); mp 218 °C.
1H NMR (CDCl3): = 7.89 (m, 4 H), 7.7 (m, 6 H), 7.48 (m, 14 H),
7.02 (s, 1 H, 7-H of the benzofuran ring,), 6.61 (s, 1 H, 5-H of the
benzofuran ring), 2.17 (s, 3 H), 1.97 (s, 3 H).
BuLi (1.6 M in hexane, 25 mL, 40 mmol) was added dropwise into
a solution of 5c (5.78 g, 18 mmol) and TMEDA (6 mL) in THF (100
mL) at –70 °C under N2. The temperature was allowed to warm to
20 °C and the mixture stirred for 30 min. Diphenylphosphinous
chloride (7.4 mL, 39.9 mmol) was added and the mixture stirred for
1 h. The solvent was evaporated under reduced pressure, the residue
treated with CH2Cl2 (100 mL) and 35% H2O2 solution (20 mL), and
then the mixture was stirred for 2 h. The organic layer was separat-
ed, dried (Na2SO4) and the residue was chromatographed (SiO2,
eluant: EtOAc–CH2Cl2, 3:7, v/v). The last fractions eluted were
evaporated under reduced pressure to give 6c (6.0 g, 52%) as a crys-
talline solid; mp 162–165 °C.
31P NMR (CDCl3): = 31.31 (s, 1 P), 17.72 (s, 1 P).
3-[2-(Diphenylphospino)phenyl]-2-(diphenylphosphino)-4,6-
dimethylbenzo[b]furan (1d)
1H NMR (CDCl3): = 7.78 (m, 8 H), 7.35 (m, 20 H), 6.63 (m, 2 H).
31P NMR (CDCl3): = 31.85 (s, 1 P), 18.90 (s, 1 P).
In a three-necked flask equipped with a thermometer and a reflux
condenser connected to an argon inlet tube were placed 6d (1g, 1.76
mmol), anhyd xylene (23 mL), Et3N (1.7 mL, 12.5 mmol) and
trichlorosilane (1.22 mL, 12 mmol). The mixture was stirred for 2 h
at 140 °C. The organic layer was separated, washed with degassed
H2O, dried (Na2SO4) and evaporated to dryness to give a solid
which was triturated with degassed EtOAc to give 1d (0.66 g, 70%);
mp 320 °C (dec.).
3-[2-(Diphenylphosphino)phenyl]-2-(diphenylphosphino)-
naphtho[2,1-b]furan (1c)
In a three-necked flask equipped with a thermometer and a reflux
condenser connected to an argon inlet tube were placed 6c (6.0 g,
9.3 mmol), anhyd xylene (50 mL), Et3N (12.5 mL, 92 mmol) and
trichlorosilane (10.6 mL, 106 mmol) and the mixture was stirred for
4 h at 140 °C. The organic layer was separated, washed with de-
gassed H2O, dried and evaporated to dryness to give a solid which
was triturated with MeOH to give 1c (4.2 g, 72%).
1H NMR (CDCl3): = 7.91(d, 2 H, J = 8.4 Hz), 7.75 (d, 1 H, J = 9
Hz), 7.62 (d, 2 H, J = 9 Hz), 7.32 (m, 25 H), 6.93 (t, 2 H, J = 7.5 Hz).
31P NMR (CDCl3): = –13.72 (d, 1 P, J = 7.8 Hz), –32.10 (d, 1 P,
J = 7.8 Hz).
31P NMR (CDCl3): = –13.55 (s, 1 P), –30.86 (s, 1 P).
3-[2-(Dicyclohexylphosphinyl)phenyl]-2-(dicyclohexyl-phos-
phinyl)naphtho[2,1-b]thiophene (6e)
BuLi (2.5 M in hexane, 2.6 mL, 6.5 mmol) was added dropwise into
a solution of 5a8 (1.0 g, 2.9 mmol) and TMEDA (1 mL) in anhyd
THF (40 mL) at –70 °C under N2. The temperature was allowed to
warm to 20 °C and the mixture stirred for 11 h. Then dicyclohexy-
lphosphinous chloride (1.5 g, 6.5 mmol) was added and the mixture
was stirred for 1 h. The solvent was evaporated under reduced pres-
sure, the residue treated with CH2Cl2 (25 mL) and 35% H2O2 solu-
tion (10 mL), and the mixture was stirred for 2 h. The organic layer
was separated, dried (Na2SO4) and the residue chromatographed
(SiO2, eluant: EtOAc–CH2Cl2, 1:1, v/v) to give 6e (0.7 g, 35%); mp
274 °C.
1-(2-Bromo)phenyl-2-(3,5-dimethyl)phenoxyethanone (4d)
A solution of 1-(2-bromophenyl)-2-bromoethanone15 (10 g, 36
mmol) in DMF (30 mL) was rapidly added to a DMF solution of an-
hyd sodium 3,5-dimethylphenolate [from 3,5-dimethylphenol (4.39
g, 36 mmol) and NaOMe]. The reaction mixture was stirred for 3 d
at 25 °C and concentrated under reduced pressure. The residue was
diluted with H2O (20 mL) and extracted with CH2Cl2 (2 20 mL).
The organic layer was dried (Na2SO4), concentrated to dryness and
the residue was chromatographed (SiO2, eluent: hexane–CH2Cl2,
6:4 v/v) to give 4d, which was triturated with diisopropyl ether (0.7
g, 61%); mp 74 °C.
1H NMR (CDCl3): = 7.84 (d, 1 H, J = 8.14 Hz), 7.82 (d, 1 H,
J = 8.7 Hz), 7.72 (d, 1 H, J = 8.7 Hz), 7.5 (m, 4 H), 7.34 (m, 1 H),
7.06 (m, 2 H), 0.5–2.5 (m, 44 H).
31P NMR (CDCl3): = 44.90 (s, 1 P), 43.04 (s, 1 P).
1H NMR (CDCl3): = 7.61 (d, 1 H, J = 7.2 Hz, 3-H of the phenyl
ring), 7.48 (td, 1 H, J = 4.36 Hz, 5-H of the phenyl ring), 7.4 (t, 1 H,
J = 5.45 Hz, 4-H of the phenyl ring), 7.35 (dd, 1 H, J = 7.2 Hz, 6-H
of the phenyl ring), 6.63 (s, 1 H, 4-H of the xylyl ring), 6.52 (s, 2 H,
2-H and 6-H of the xylyl ring), 5.1 (s, 2 H, CH2), 2.26 (s, 6 H, 2
CH3).
MS: m/z = 684 (M+).
3-[2-(Dicyclohexylphosphino)phenyl]-2-(dicyclohexyl-phos-
phino)naphtho[2,1-b]thiophene (1e)
In a three-necked flask equipped with a thermometer and a reflux
condenser connected to an argon inlet tube were placed 6e (0.13 g,
0.2 mmol), anhyd xylene (4 mL), Et3N (0.25 mL, 1.8 mmol) and
trichlorosilane (0.2 mL, 2 mmol). The mixture was stirred for 1 h at
120 °C and then for 2 h at 140 °C. The organic layer was separated,
washed with degassed H2O, dried and evaporated to dryness to give
a solid which was triturated with degassed MeOH to give 1e (0.01
g, 80%); mp 200 °C (dec.)
3-(2-Bromo)phenyl-4,6-dimethylbenzo[b]furan (5d)
Compound 4d (1.3 g, 4.08 mmol) was added under stirring to PPA
(13 g) at 80 °C. The mixture was stirred for 30 min, then poured
onto ice, neutralized with aq 20% NH4OH solution and extracted
with CH2Cl2. The organic layer was dried (Na2SO4) and evaporated
to dryness to give a residue, which was chromatographed (SiO2, elu-
ent: hexane) to give 5d (1.1g, 89%).
1H NMR (CDCl3): = 7.68 (d, 1 H, J = 7 Hz, 3-H of the phenyl
ring), 7.47 (s, 1 H, 2-H of the benzofuran ring), 7.29 (m, 4 H), 6.82
(s, 1 H, 5-H of the benzofuran ring), 2.43 (s, 3 H), 2.1 (s, 3 H).
31P NMR (CDCl3): = –9.54 (d, 1 P, J = 11 Hz), –17.48 (d, 1 P,
J = 11 Hz).
3-(o-Bromo)phenyl-2-(diphenylphosphinyl)naphtho[2,1-b]-
thiophene (7)
LDA (1.5 M solution in THF, 7.5 mL, 0.0117 mol) was added drop-
wise dropped into a solution of 5a (4.0 g, 11.6 mg) in anhyd THF
(170 mL) at –70 °C under N2. After stirring for 15 min, the temper-
ature was allowed to warm at –40 °C and then diphenylphosphinous
chloride (2.16 mL, 11.6 mmol) was added. The mixture was stirred
for 30 min, then the solvent was removed under reduced pressure
3-[2-(Diphenylphospinyl)phenyl]-2-(diphenylphosphinyl)-4,6-
dimethylbenzo[b]furan (6d)
BuLi (1.6 M in hexane, 5.2 mL, 8.3 mmol) was added dropwise to
a solution of 5d (1.15 g, 5.7 mmol) and TMEDA (1.2 mL) in THF
(100 mL) at 70 °C under N2. The temperature was allowed to
Synthesis 2001, No. 15, 2327–2336 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Electronic Tuning in C1-Symmetric Chelating Diphosphane Ligands
2335
and the residue treated with CH2Cl2 (80 mL) and 35% H2O2 solution
(15 mL). The mixture was stirred for 2 h at r.t. and then diluted with
H2O. The organic layer was separated, dried (Na2SO4) and concen-
trated in vacuo to give a solid, which was triturated with diisopropyl
ether to give 7 in a pure state (1.26 g, 82%); mp 193 °C.
1H NMR (CDCl3): = 7.84 (m, 4 H), 7.68 (m, 2 H), 7.55 (m, 2 H),
7.45 (m, 4 H), 7.31 (m, 6 H), 7.18 (m, 2 H).
mL) at –60 °C under N2. The temperature was allowed to warm to
r.t. and the mixture stirred for 1 h, then diphenylphosphinous chlo-
ride (0.74 mL, 3.99 mmol) was added and the mixture stirred for 1
h. The solvent was removed under reduced pressure and CH2Cl2 (50
mL) and 35% H2O2 solution (5 mL) were added. The solution was
kept at r.t. for 2 h, then the organic layer was separated, dried
(Na2SO4) and evaporated to dryness to give a residue which was
chromatographed (SiO2, eluant: EtOAc–CH2Cl2, 7:3, v/v). The last
fractions eluted were collected and evaporated to give 10 (0.76 g,
72%); mp 137–140 °C.
31P NMR (CDCl3): = 19.15 (s, 1 P).
MS: m/z = 539 (M+).
1H NMR (CDCl3): = 8.05 (m, 1 H), 7.43 (m, 23 H), 7.06 (t, 1 H,
J = 8.1 Hz), 6.95 (m, 1 H), 6.87 (m, 1 H), 6.58 (t, 1 H, J = 6.81 Hz),
1.38 (s, 3 H).
31P NMR (CDCl3): = 29.01 (s, 1 P), 25.31 (s, 1 P).
MS: m/z = 607 (M+).
3-[2-(Dicyclohexylphosphinyl)phenyl]-2-(diphenylphosphinyl)-
naphtho[2,1-b]thiophene (8)
t-BuLi (1.5 M in pentane, 7.17 mL, 10.8 mmol) was added dropwise
into a solution of 7 (5.02 g, 9.3 mmol) in anhyd Et2O (150 mL) at –
78 °C under N2. After stirring for 15 min, the temperature was al-
lowed to warm to 10 °C and dicyclohexylphosphinous chloride (2.5
g, 10.8 mmol) was added. The mixture was stirred for 3 h and the
solvent was removed at reduced pressure. CH2Cl2 (150 mL) and
35% H2O2 solution (20 mL) were added and the mixture was stirred
for 2 h. The organic layer was separated, dried (Na2SO4) and con-
centrated under vacuo to give a residue, which was chromato-
graphed (SiO2, elution with CH2Cl2–EtOAc, 3:7, v/v) to give 8. This
was further purified by trituration with diisopropyl ether (4.6 g,
74%); mp 242 °C.
1H NMR (CDCl3): = 7.84 (dd, 2 H, J = 8 Hz, 3.1 Hz), 7.58 (m, 9
H), 7.32 (m, 2 H), 7.22 (m, 1 H), 7.05 (m, 5 H), 6.77 (m, 1 H), 0.7–
2.1 (m, 22 H).
31P NMR (CDCl3): = 44.16 (s, 1 P), 28.7 (s, 1 P).
MS: m/z = 672 (M+).
1-(Diphenylphosphino)-2-[(2-diphenylphosphino)phenyl]-3-
methylindole (3)
In a three-necked flask equipped with a thermometer and a reflux
condenser connected to an argon inlet tube were placed 10 (0.2 g,
0.34 mmol), anhyd xylene (5 mL), Et3N (0.38 mL, 2.8 mmol) and
trichlorosilane (0.27 mL, 2.7 mmol). The mixture was stirred for 2
h at 80 °C. After cooling to r.t., the mixture was concentrated under
vacuo, the residue treated with aq 10% NaOH solution (15 mL) and
stirred at 60 °C for 15 min. Degassed CH2Cl2 was added (15 mL),
the organic layer separated, dried (Na2SO4) and evaporated to dry-
ness to give a residue which was triturated with degassed MeOH to
give 3 (0.12 g, 64%); mp 157 °C (dec.).
31P NMR (CDCl3): = 35.45 (d, 1 P, J = 11.69 Hz), –15.04 (d, 1 P,
J = 11.69 Hz).
3-[2-(Dicyclohexylphosphino)phenyl]-2-(diphenylphosphino)-
naphtho[2,1-b]thiophene (2)
Optical Resolution of ( )-6b with (–)- and (+)-2,3-O,O’-Di-
benzoyltartaric Acid (DBTA)
In a three-necked flask equipped with a thermometer and a reflux
condenser connected to an argon inlet tube were placed 8 (0.2 g, 0.3
mmol), anhyd xylene (6 mL), Et3N (0.35 mL, 2.6 mmol) and
trichlorosilane (0.24 mL, 2.4 mmol). The mixture was stirred at
130 °C for 4 h. After cooling to r.t, the mixture was concentrated in
vacuo, the residue treated with aq 10% NaOH solution (15 mL) and
stirred at 60 °C for 15 min. Degassed CH2Cl2 was added (15 mL),
the organic layer separated, dried (Na2SO4), evaporated to dryness
to give a residue which was triturated with degassed MeOH to give
2 (0.12 g, 64%); mp 157 °C (dec.).
1H NMR (CDCl3): = 7.82 (d, 1 H, J = 8.7 Hz), 7.78 (d, 1 H, J = 7.4
Hz), 7.67 (d, 1 H, J = 8.7 Hz), 7.43 (m, 2 H), 7.34 (m, 2 H), 7.27 (m,
1 H), 7.11 (m, 5 H), 6.93 (m, 3 H), 6.82 (m, 2 H), 6.71 (m, 2 H), 0.7–
2.0 (m, 22 H).
Crystallization of the diastereomeric adducts formed by the reaction
of ( )-6b (2.9 g, 4.6 mmol) with (+)-DBTA (1.58 g, 4.4. mmol)
from CHCl3 (10 mL) gave the dextrorotatory diastereoisomer as the
less soluble adduct; [ ]D25 +75.49 (c = 0.51, EtOH). Alkaline treat-
ment with aq 0.75 N NaOH solution (10.6 mL) and extraction with
25
CH2Cl2 (2 10 mL) gave (–)-6b (0.42 g); mp 260–265 °C; [ ]D
–
190.5 (c = 0.28, MeOH). The mother liquors from the first resolu-
tion step were concentrated to dryness to give a solid, which was
treated with aq 0.75 N NaOH solution (20 mL) and extracted with
CH2Cl2 (2 20 mL). The resulting diphosphine oxide (0.85 g),
treated in turn with (–)-DBTA (1.33 g) according to the procedure
described above, gave the levorotatory adduct; [ ]D25 –75.49
(c = 0.51, EtOH). Alkaline treatment gave enantiopure (+)-6b; mp
260–265 °C; [ ]D25 +189.6 (c = 0.28, MeOH). Repetition of this
procedure on the mother liquors allowed total resolution of the race-
mate.
31P NMR (CDCl3): = –18.23 (s, 1 P), –16.31 (s, 1 P).
2-(2-Bromophenyl)-3-methylindole (9)
3-[(2-Diphenylphospino-5-methoxy)phenyl)]-2-(diphenyl-
phosphino)naphtho[2,1-b]thiophene [(+)-(1b) and (–)-1b]
Reduction of the enantiopure diphosphinoxides (+)-6b and (–)-6b
to the corresponding enantiopure diphosphines (+)-1b and (–)-1b
was performed following the procedure described above for the re-
duction of ( )-6b.
A solution of 2-bromopropiophenone phenylhydrazone (8.54 g, 42
mmol) in 7 M HCl in propan-2-ol (40 mL) was left to stand for 2 h
at 25 °C. The solvent was evaporated and the residue dissolved into
CH2Cl2, washed with aq 5% NaHCO3 solution and with H2O. The
organic layer was dried (Na2SO4) and concentrated in vacuo to give
a solid, which was triturated with hexane (5.8 g, 72%).
1H NMR (CDCl3): = 8.15 (s, 1 H, NH), 7.71 (d, 1 H, J = 8 Hz, 4-
H of the indole ring), 7.62 (d, 1 H, J = 7.8 Hz, 7-H of the indole
ring), 7.44 (dd, 1 H, J = 7.62, 2.1 Hz), 7.39 (2 superimposed t, 2 H,
5-H-and 6-H of the indole ring), 7.2 (m, 3 H), 2.3 (s, 3 H).
(+)-1b
Mp 243 °C; [ ]D25 +166 (c = 0.30, benzene).
(–)-1b
Mp 245 °C; [ ]D25 –166 (c = 0.30, benzene).
1-(Diphenylphosphinyl)-2-[(2-diphenylphosphinyl)phenyl]-3-
methylindole (10)
BuLi (1.6 M in hexane, 2.5 mL, 6.5 mmol) was added to a solution
of 9 (0.5 g, 1.75 mmol) and TMEDA (0.3 mL) in anhyd THF (40
Preparation of 11a
To a Schlenk tube charged with (+)-1b (25.5 mg, 0.039 mmol) and
red brown [RuCl2(C6H6)]2 (9.66 mg, 0.019 mmol) was added fresh-
Synthesis 2001, No. 15, 2327–2336 ISSN 0039-7881 © Thieme Stuttgart · New York

2336
F. Sannicolò et al.
SPECIAL TOPIC
ly distilled and argon-degassed DMF (12.3 mL). The mixture was
stirred at 100 °C for 15 min, and the temperature was allowed to
warm to 50 °C. The solution was concentrated under reduced pres-
sure to give a residue, which was used as a catalyst in the enantiose-
lective hydrogenation of -keto esters without further purification.
References
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(b) Brunner, H.; Zettlmeir, W. Handbook of
Preparation of 11b
Compound (+)-1b (0.1 g, 0.15 mmol), [Ru(p-cymene)I2]2 (9.66 mg,
0.01 mmol), EtOH (12.3 mL) and CH2Cl2 (30 mL) were stirred in a
Schlenk tube under argon at 50 °C, for 1.5 h. The resulting red so-
lution was concentrated under reduced pressure and the residue was
used in the asymmetric catalytic reductions without further purifi-
cation.
31P NMR (CDCl3): = 39.67 (d, 0.3 P, J = 56.5 Hz), 38.05 (d, 1 P,
J = 62.4 Hz), 24.51 (d, 1 P, J = 62.4 Hz), 19.24 (d, 0.3 P, J = 56.5
Hz).
Enantioselective Catalysis with Transition Metal
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York, 1994.
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Hydrogenation Reactions; Ethyl (R)-(+)-3-Hydroxybutyrate
(13a); Typical Procedure
In a typical experiment (Table 1, entry 1), a solution of 12a (2.6 g,
20 mmol) and 11a (0.068 g, 0.07 mmol) in MeOH (10 mL), previ-
ously degassed with argon, was loaded by syringe into an autoclave.
H2 was introduced (100 Kg/cm2), and the solution was stirred at
40 °C for 110 min. The autoclave was cooled, the hydrogen pres-
sure released, the solvent evaporated, and the residue distilled (17
mmHg) to give 13a in a quantitative yield.
(9) (a) Benincori, T.; Brenna, E.; Sannicolò, F.; Trimarco, L.;
Antognazza, P.; Cesarotti, E.; Zotti, G. J. Organomet. Chem.
1997, 529, 445. (b) Benincori, T.; Piccolo, O.; Rizzo, S.;
Sannicolò, F. J. Org. Chem. 2000, 65, 8345.
(10) Unpublished results.
Kinetic Experiments
(11) Benincori, T.; Brenna, E.; Sannicolò, F.; Trimarco, L.;
Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J. Org.
Chem. 1996, 61, 6244.
(12) Takaya, H.; Mashima, K.; Koyano, K. J. Org. Chem. 1986,
51, 629.
At appropriate time intervals, stirring was stopped and samples of
the solution were drawn out through the sampling pipe by exploit-
ing the internal pressure. Conversion was evaluated through GC
analysis. After sampling operations, the H2 pressure was restored
and stirring resumed.
(13) Benincori, T.; Cesarotti, E.; Piccolo, O.; Sannicolò, F. J.
Org. Chem. 2001, 65, 2043.
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Acknowledgement
This work was supported in part (Milan) by a MURST Cofin 2000/
2001 and by Chemi S.p.A (Via dei Lavoratori, Cinisello Balsamo,
Italy), holder of the patents for the synthesis and use of all diphos-
phane ligands reported in this paper.
Synthesis 2001, No. 15, 2327–2336 ISSN 0039-7881 © Thieme Stuttgart · New York