PHANE-TetraPHOS, the First D2 Symmetric Chiral Tetraphosphane. Synthesis, Metal Complexation, and Application in Homogeneous Stereoselective Hydrogenation

Article abstract of DOI:10.1002/ejoc.202100109

PHANE-TetraPHOS, a new D₂ symmetric tetraphosphane based on the [2.2]paracyclophane scaffold, has been synthesized and characterized. The peculiarity of this system is the presence of four homotopic diphenylphosphane groups, exchangeable through C₂ symmetry operations and consequently indistinguishable. Their spatial arrangement allows the simultaneous complexation of two metal atoms. Enantiomeric purity was attained at tetra-phosphane oxide level by fractional crystallization of the diastereomeric adducts obtained from the racemate with enantiopure dibenzoyltartaric acids. Alkaline treatment of diastereomerically pure adducts followed by exhaustive P?O groups reduction with HSiCl₃ gave both PHANE-TetraPHOS antipodes in an enantiopure state. They were tested as rhodium ligands in the homogeneous enantioselective hydrogenation of some benchmark unsaturated compounds. Catalytic activity and enantiodiscrimination ability were found comparable to those exhibited by the complexes of the parent bidentate ligand PHANEPHOS, but only half a mole of precious chiral ligand was employed.

Full text of DOI:10.1002/ejoc.202100109

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PHANE-TetraPHOS, the First D2 Symmetric Chiral
Tetraphosphane. Synthesis, Metal Complexation, and
Application in Homogeneous Stereoselective
Hydrogenation
Luca Vaghi,*[a] Roberto Cirilli,[b] Marco Pierini,[c] Simona Rizzo,[d] Giancarlo Terraneo,[e] and
Tiziana Benincori*[f]
Dedicated to Professor Franco Cozzi on the occasion of his 70th birthday
PHANE-TetraPHOS, a new D2 symmetric tetraphosphane based
on the [2.2]paracyclophane scaffold, has been synthesized and
characterized. The peculiarity of this system is the presence of
four homotopic diphenylphosphane groups, exchangeable
through C2 symmetry operations and consequently indistin-
guishable. Their spatial arrangement allows the simultaneous
complexation of two metal atoms. Enantiomeric purity was
attained at tetra-phosphane oxide level by fractional crystalliza-
tion of the diastereomeric adducts obtained from the racemate
with enantiopure dibenzoyltartaric acids. Alkaline treatment of
diastereomerically pure adducts followed by exhaustive PÀ O
groups reduction with HSiCl3 gave both PHANE-TetraPHOS
antipodes in an enantiopure state. They were tested as rhodium
ligands in the homogeneous enantioselective hydrogenation of
some benchmark unsaturated compounds. Catalytic activity
and enantiodiscrimination ability were found comparable to
those exhibited by the complexes of the parent bidentate
ligand PHANEPHOS, but only half a mole of precious chiral
ligand was employed.
Introduction
represented by achiral ligands, generally designed to “double”
the catalytic activity of diphosphanes, to lower the catalyst
loading and to prepare heterobimetallic complexes widening
the applicative scope of a catalyst.[2] Chirality was introduced in
tetraphosphane ligands in 2003, when the group of Mikami
designed a tropos tetraphosphane based on a 1,3-terphenyl
Chiral tetraphosphanes have deserved too scarce consideration
so far as potential ligands of transition metals for asymmetric
homogeneous catalysis. This area has been worthily dominated
by chiral diphosphane ligands that have been employed with
enormous success for a long time, even though also chiral
monophosphanes have found important specific applications.[1]
A reason for such a modest appeal could be the multiple
complexation modes offered by four, generally non-equivalent,
phosphorous centres which could generate different, possibly
antagonist, complexes. The history of tetraphosphanes is mainly
backbone exhibiting
a C2 symmetric helical arrangement
following double metal complexation (Figure 1).[3] The reaction
of the racemic dipalladium complex with two equivalents of an
enantiopure diamine gave a one to one diastereomeric mixture
°
of complexes. Heating the latter at 80 C caused total
conversion of the less stable diastereoisomer into the more
[a] Dr. L. Vaghi
[e] Prof. Dr. G. Terraneo
Dipartimento di Scienza dei Materiali
Università degli Studi di Milano-Bicocca
Via R. Cozzi 55, 20125 Milano, Italy
E-mail: luca.vaghi@unimib.it
Laboratory of Supramolecular and Bio-Nanomaterials (SupraBioNanoLab)
Department of Chemistry, Materials, and Chemical Engineering “Giulio
Natta”
Politecnico di Milano
[b] Dr. R. Cirilli
Via Mancinelli 7, 20131 Milano, Italy
[f] Prof. Dr. T. Benincori
Centro Nazionale per il Controllo e la Valutazione dei Farmaci
Istituto Superiore di Sanità
Viale Regina Elena 299, 00161 Roma, Italy
[c] Prof. Dr. M. Pierini
Dipartimento di Scienza ed Alta Tecnologia
Università degli Studi dell’Insubria
Via Valleggio 11, 22100 Como, Italy
Dipartimento di Chimica e Tecnologie del Farmaco,
Università La Sapienza
P.za Aldo Moro 5, 00185 Roma
[d] Dr. S. Rizzo
E-mail: tiziana.benincori@uninsubria.it
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100109
Part of the “Franco Cozzi’s 70th Birthday” Special Collection.
Istituto di Scienze e Tecnologie Chimiche “Giulio Natta”, CNR
Via Golgi 19, 20133 Milano, Italy
© 2021 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original work is
properly cited, the use is non-commercial and no modifications or adap-
tations are made.
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tetrasubstituted p-cyclophane, and the new tetradentate ligand
3, which is the protagonist of the present paper, is endowed
with an architecture displaying three orthogonal C2 axes
interchanging all the four phosphane groups and conferring to
the ligand the unusual D2 symmetry. The nickname we assigned
to 3 is PHANE-TetraPHOS (Figure 2), considering that PHANE-
PHOS 4 (Figure 2), which is a quite popular C2 symmetric
diphosphane ligand, displays the same p-cyclophane scaffold.[6]
Experimental support to the structural design of 3 was
given by the single-crystal XRD analysis of the dichloropalla-
dium complex of PHANEPHOS, showing that the planes of the
two phenylene rings are perfectly parallel,[7] suggesting that the
double metal complexation in tetraphosphane 3 should easily
occur without any steric constraint.
As for synthetic accessibility, p-cyclophane is a commercially
available rather inexpensive starting material. Furthermore, its
tetrabromination was expected to lead, as the main product, to
the bis-pseudo-ortho isomer, namely the 4,7,12,15-tetrabromo-
p-cyclophane (5), which is the natural starting material for the
preparation of tetraphosphane 3 (Figure 2).[8]
Figure 1. Known chiral tetraphosphanes.
The access to PHANEPHOS is much more difficult, since
dibromination of p-cyclophane does not afford the necessary
pseudo-ortho-dibromo derivative 6b, but the achiral S2 sym-
metric pseudo-para-diastereoisomer 6a. The latter must be
submitted to thermal diastereoselective equilibration to give a
1:1 mixture of 6a and 6b, from which the latter was isolated
by solubility difference and chromatography.[6]
stable one 1, which, applied as Lewis acid catalyst in
asymmetric carbonyl-ene reaction of ethyl glyoxylate with
methylenecyclohexane, showed slightly better, even though
very similar, enantioselectivity and yields than those obtained
by using a double molar amount of the analogous catalysts
prepared from BINAP and BIPHEP.
In 2006,
a P-stereogenic tetraphosphane 2 (Figure 1)
combining two 1,2-bis(alkylmethylphosphino)ethane (BisP*)-like
units,[4a] was applied as Rh(I) ligand in asymmetric hydro-
genation of prostereogenic CÀ C double bonds giving results
comparable with those obtained using t-Bu-BisP-rhodium
complex.[4b] The Authors suggested that only one diphosphane-
rhodium unit participated to the hydrogenation catalytic cycle,
underlying the crucial structural restrictions for the synchronous
operation of two adjacent metal centres. As a matter of fact,
when one of the rhodium atoms undergoes oxidative addition
followed by coordination of the substrate, the resulting
octahedral moiety creates such a steric hindrance that coordi-
nation of a second substrate molecule is inhibited. This research
case demonstrates that geometrical structural parameters must
be carefully considered in designing tetradentate ligands as
precursors of bimetallic catalytic systems.
We developed in the past two classes of electronically
tunable C1 and C2 symmetric diphosphanes based on atropiso-
meric biheteroaromatic scaffolds that were employed as chiral
ligands of transition metals producing excellent results in the
hydrogenation of prostereogenic CÀ C and CÀ O double bonds
even at an industrial scale level.[5] We decided to resume our
work in this field by designing a new chiral tetraphosphane
ligand featured by four homotopic phosphane groups, organ-
ized on a scaffold granting the complexation of two metal
atoms by two selected phosphane pairs and the complete steric
independence of the two units after complexation. All these
structural requirements are fully satisfied by a suitably 4,7,12,15-
Figure 2. Comparison between synthetic routes to PHANE-TetraPHOS (�)-3
and PHANEPHOS (�)- 4.
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Results and Discussion
bromine.[8b] The best results were obtained by using the last
two methodologies, affording (�)-5 in 40% and 42% yield,
Synthesis of (À )-3
respectively.
Preliminary experiments for the functionalization of the
paracyclophane scaffold with diphenylphosphinyl groups were
based on a stepwise double substitution of the bromine atoms,
effected by double lithiation of tetrabromoderivative (�)-5 with
t-BuLi, followed by addition of two equivalents of diphenyl-
phosphinylchloride.
Chromatographic analysis demonstrated the presence of a
multitude of compounds among which the most interesting
one, isolated in 15% yield, was the C2 symmetric diphosphane
oxide (�)-8, whose structure was determined by single-crystal
X-ray diffraction analysis (Figure 3).
As anticipated, the synthetic route (Scheme 1) to the tetraphos-
phane (�)-3 involves the exhaustive bromination of commer-
cially available [2.2]paracyclophane, which affords racemic (�)-5
and the achiral constitutional isomer 7 in comparable amounts.
The two isomers can be easily separated by taking advantage
from the much lower solubility of the undesired isomer 7 in
dichloromethane. In order to optimize the yields, we experi-
mented several bromination methodologies: iron catalysed
reaction with bromine in CH2Cl2 solution,[8a] neat bromine as
reagent and solvent, reaction of solid [2.2]paracyclophane with
bromine vapours[8b] and iodine-catalysed bromination in neat
Compound (�)-8 could be an interesting intermediate to
obtain the 5,15-dibromo-PHANEPHOS and a series of substi-
tuted PHANEPHOS ligands endowed with different steric and
electronic properties. Considering, however, the difficulties
encountered in the preparation of diphosphane oxide (�)-8, we
discarded the possibility of using it as intermediate to accede to
tetraphosphane oxide (�)-9 and focused our attention to
experiments involving the simultaneous lithiation of the four
bromine atoms of (�)-5.
After several unsatisfactory attempts performed by varying
lithium species, solvent, reaction times and temperature, we
found that acceptable (25%) yields of (�)-9 were obtained
when the reaction was carried out with a large excess of t-BuLi
°
(8.6 eq), at À 78 C; the tetra-anion was immediately quenched
with chlorodiphenylphosphane. After the usual work-up, the
crude reaction product was oxidized with a 30% H2O2 solution.
Tetraphosphane oxide (�)-9, necessary to perform the reso-
lution process,[1,5,6] was obtained by simple treatment of the
crude reaction product with ethanol and its structure was
unequivocally confirmed by single-crystal X-ray diffraction
analysis, after crystallization from butanol (Figure 4).
The resolution of the racemate was successfully achieved by
fractional crystallization of the diastereomeric adducts obtained
by reaction of (�)-9 with enantiopure (+)-dibenzoyl-D-tartaric
Scheme 1. Synthesis and resolution of PHANE-tetraPHOS (À )-3. Reagents
and conditions: (a) Br2, I2 (0.01 equiv.), r.t., 7 days, dark; (b) t-BuLi (4.2 equiv.),
°
°
THF, À 78 C, 10 min, then ClPOPh2 (2.1 equiv.), THF, À 78 C to r.t. 12 h; (c) t-
°
°
BuLi (8.6 equiv.), THF, À 78 C, 10 min, then ClPPh2 (4.6 equiv.), THF, À 78 C to
°
r.t., 12 h, then H2O2, r.t., 12 h; (d) (+)-DBTA (1 equiv.), CH2Cl2/EtOAc, 40 C to
°
r.t., 12 h; e) HSiCl3 (118 equiv.), p-xilene, 140 C, 72 h.
Figure 3. X-ray structure of dibromo-diphosphinylderivative (�)-8; CCDC
number 1972369. Ball and stick representation. Colour code: C, grey; O, red;
P, dark yellow, Br, light brown and H, white.
Figure 4. X-ray structure of tetraphosphane oxide (�)-9; CCDC number
1972368. Ball and stick representation. Colour code as in Figure 3. The
butanol molecule is omitted for clarity.
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acid, and subsequent alkaline decomplexation. The resolution
analysis on a chiral stationary phase of the levorotatory
method was very successful, as demonstrated by the HPLC
phosphane oxide (Figure 5a), which showed an enantiomeric
25
°
excess higher than 99% ([α]D =À 48.0 , c=1% in CH2Cl2).
Treatment of the mother liquors, after alkaline decomplexation,
with (À )-dibenzoyl-L-tartaric acid and crystallization of the
adduct, gave the dextrorotatory antipode. The CD spectra of
both the antipodes are perfectly specular (Figure 5b).
Before discussing the assignment of the absolute config-
uration to the antipodes of 9, it is useful to introduce a short
recall of the CIP rules concerning the attribution of the
configurational descriptors pS and pR to such high symmetry
chiral molecules. Firstly, the stereogenic plane must be
individuated that, in this case, is indifferently one of the two
homotopic planes containing the aromatic ring, two phospho-
rous atoms and two methylene groups. Secondly, the so called
“pilot atom”, which is the first prioritary atom out of the plan
must be chosen; in the present case it is indifferently one of the
two equivalent methylene carbons of the cyclophane bridge,
indicated as P in Figure 6a.
The last step is the check of the clockwise (pR) or counter-
clockwise (pS) sequence, as seen from the pilot atom P, starting
from the atom directly connected to it (indicated as a in
Figure 6a) and moving along the two following atoms (b and c)
according to CIP priority rules.
The CD spectrum for the pS enantiomer of tetraphosphane
oxide 9 was simulated by DFT calculations (see details in
Experimental Section) and compared to the equivalent spectra
registered for the enantiomers of 9 separated by enantioselec-
tive HPLC. A good matching was found between the CD
spectrum of the second-eluted enantiomer and the calculated
one. (Figure 6b); thus, the pS configuration was assigned to the
second-eluted enantiomer of 9, and the pR configuration to the
first-eluted one.
The reduction of enantiopure (À )-9 into the corresponding
phosphane (À )-3, was successfully performed using trichlorosi-
lane as reducing agent in refluxing p-xylene solution. The
complete reduction of the four diphenylphosphino groups
Figure 5. a: enantioselective HPLC analysis of the resolved (À )-9 (Chromato-
graphic conditions: column, Chiralpak IA-3 100 mm×4.6 mm, 3 μm; mobile
phase, dichloromethane:ethanol 20:100 (v/v); flow-rate, 1.5 mL/min; detec-
tor, CD at 280 nm). b: CD spectra of (+)-9 (green) and (À )-9 (red)
(acetonitrile, 0.1 mg/mL).
°
required prolonged reaction times (three days) at 140 C and a
large excess of HSiCl3, added in three portions distributed along
the whole reaction time. The 31P NMR spectrum of phosphane 3
displayed a singlet at À 1.1 ppm confirming the D2 2 symmetry
of the molecule.
Rh complexes of 3 and enantioselective catalytic
hydrogenation tests
The preliminary complexation experiments performed with (�)-
3
using two equivalents of bis(benzonitrile)palladium(II)
chloride gave such an insoluble material that we could get the
proof that the expected bimetallic complex was formed only by
mass spectrometry analysis. Thus, we redirected our investiga-
tion to enantiopure Rh(I) complexes (Scheme 2).
The reaction of 3 with one equivalent of [Rh(COD)2]BF4 gave
the mononuclear rhodium complex 10, as demonstrated by the
31P NMR showing a singlet at À 1.7 ppm corresponding to the
free phosphane groups, and a doublet at 33.1 ppm related to
Figure 6. a) assignment of configurational descriptors to the pS enantiomer;
b) comparison of experimental spectra of (+)- and (À )-9 and calculated CD
spectrum for pS enantiomer.
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Figure 7. Metal complexes (À )-12 and (À )-13 used for comparison and
Scheme 2. Rhodium complexes of (�)-3.
substrates.
the two chelating phosphorous atoms, characterized by the
typical Rh-P coupling constant (J=147.0 Hz).
Table 1. Comparison of catalytic activity and enanatioselectivity of com-
plexes (À )-12 and (À )-13.[a]
The neat formation of the mono rhodium complex 10 is of
great interest, since it demonstrates the feasibility of inserting
two quasi-homotopic different metals onto the two phosphane
couples of 3, thus pathing the access to a series of hetero-
bimetallic catalysts. Unfortunately, preliminary experiments in
this direction have been, at least for the moment, unsuccessful,
since, by adding one equivalent of bis-benzonitrilepalladium
dichloride to a solution of complex 10, the precipitation of an
intractable highly insoluble material, impossible to characterize,
was again observed.
Entry
S
Conv. [%][b]
ee [%][c]
Conv. [%][b]
ee [%][c]
(À )-12
(À )-12
(À )-13
(À )-13
1
2
3
4
5
6
14
15
16
17
18
19
100
100
100
98
96
3
>99 (R)-(À )
79 (R)-(À )
31 (S)-(À )
22 (R)-(+)
14 (R)-(+)
7 (R)-(+)
100
100
100
70
75
2
>99 (R)-(À )
78 (R)-(À )
32 (S)-(À )
22 (R)-(+)
14 (R)-(+)
8 (R)-(+)
[a] Experimental conditions: S/C (À )-12=100 (1% mol); S/C (À )-13=200
°
(0.5% mol); solvent: MeOH; temperature: 25 C; hydrogen pressure: 1 atm;
reaction time: 1 h. [b] Determined by GC for 14, 16, 17, 18, 19 and by H
NMR for 15. [c] Determined by GC on CSP for 14, 16, 17, 18, 19 and by
HPLC on CSP for 15.
1
By adding a second equivalent of [Rh(COD)2]BF4 to complex
10, both the 31P NMR signals immediately disappeared and the
contemporary growth of
a new a doublet at 27.5 ppm
confirmed the formation of the binuclear Rh complex 11. The
same complex was formed also by direct addition of two Conclusions
equivalents of [Rh(COD)2]BF4 to a solution of 3.
The Rh(COD)OTf complex of the (À )-PHANEPHOS ((À )-12),[6a]
and the bis Rh(COD)OTf complex of (À )-3 ((À )-13) were
prepared in situ to compare the performances of (À )-PHANE-
TetraPHOS (À )-3 with those exhibited by (À )-PHANEPHOS (À )-4
in the asymmetric homogeneous hydrogenation of some
benchmark unsaturated compounds (Figure 7). The two com-
plexes have been tested under identical experimental con-
ditions, with the sole difference that half a mole of complex 13
was used in order to have identical metal amounts in solution
(Table 1).
The results of this preliminary catalytic screening, summar-
ized in Table 1, show that the performances of both the
complexes (À )-12 and (À )-13 are similar. The enantioselection
levels are nearly identical, while a moderate drop in kinetics
was observed in some cases (Table 1, entry 4 and 5) when the
binuclear complex (À )-13 was used.
The challenge of the project was the design, the synthesis and
the investigation of the complexation properties of PHANE-
TetraPHOS (3), an unusual tetradentate ligand in which all four
donor atoms are homotopic. Keystone to satisfy this require-
ment is the D2 molecular symmetry and PHANE-TetraPHOS,
based on the [2,2]-paracyclophane scaffold, is the first example
of such
a high symmetry chiral tetraphosphane. It was
synthesized according to a rather simple scheme and both
antipodes were obtained in an enantiopure state through a
classical sequence involving tetraphosphane oxide 9. The 3D
properties of the new molecules are well depicted by X-ray
diffraction analysis of 9. The complexation ability of 3 to was
investigated. While mono- and bimetallic complexes of Pd are
fully insoluble materials, the formation of mono- and bi-
rhodium complexes has been investigated by 31P NMR
spectrometry. A preliminary screening of the catalytic activity
and stereoselection ability of the binuclear Rh complex (À )-13
was carried out in the CÀ C double bond hydrogenation of
some standard (pro)1-chiral substrates in parallel with the
corresponding mononuclear PHANEPHOS complex (À )-12,
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1
7. H NMR (400 MHz, CDCl3) δ 6.99 (s, 4H, ArÀ H), 3.41-3.30 (m, 4H,
maintaining identical Substrate/Rh ratio. Similar enantioselec-
tion performances were observed for the two catalysts demon-
strating that the new D2-symmetric PHANE-TetraPHOS mirrors
the structurally related C2-symmetric PHANEPHOS. It is evident,
however, that in the former case, the amounts of the precious
ligand are halved. Research would deserve further investigation
mainly directed to the preparation of new more soluble bi- and
hetero-bimetallic complexes.
CH2), 3.16-3.05 (m, 4H, CH2); 13C NMR (101 MHz, CDCl3) δ 140.7 (C-
4,5,15,16), 129.3 (C-3,6,11,14), 128.6 (C-7,8,12,13), 34.5 (C-1,2,9,10).
4,12-Dibromo-7,15-bis(diphenylphosphinyl)[2.2]
paracyclophane (�)- (8). t-BuLi (1.6 M solution in pentane,
2.5 mL, 4.0 mmol) was added dropwise to a stirred solution of
°
(�)-5 (530 mg, 1.0 mmol) in dry THF (30 mL) at À 78 C at a rate
°
such that the temperature remains below À 70 C. Diphenylphos-
phinic chloride (400 μL, 2.1 mmol) was added via a syringe over
15 minutes and the reaction mixture was left warming to r.t.
overnight, under vigorous stirring. Water (25 mL) was added to
the suspension. The organic layer was separated, the aqueous
phase was extracted with AcOEt (3×20 mL), the combined
organic layers were washed with NaOH(aq) (32%, 50 mL), dried
(Na2SO4) and concentrated in vacuo. Chromatography (SiO2,
Experimental Section
All reactions utilizing air- and moisture-sensitive reagents were
performed in dried glassware under dry argon or nitrogen. Dry
solvents were used as received and stored under inert gas. All
reagents, if not otherwise specified, were used as received and, if
necessary, stored under inert gas. Macherey-Nagel Alugram® sil G/
UV 254 pre-coated plates were used for TLC analysis. Column
chromatography was performed on Macherey-Nagel MN Kieselgel
silica gel. Melting points were determined with a Büchi B-540
AcOEt/Exane 1/1, Rf =0.22) afforded (�)-8 (110 mg, 15%). White
1
°
solid; m.p. 270–275 C; H NMR (300 MHz, CDCl3) δ 7.75–7.32 (m,
12H, POPh2-H 5-H 13-H), 7.24 (d, J= 14.0, 2H, 8-H 16-H), 3.42–3.31
(m, 2H, CH2), 3.26–3.17 (m, 2H, CH2), 3.04–2.85 (m, 4H, CH2); 31P
NMR (121 MHz, CD2Cl2) δ 23.9; MS (EI): m/z=766 [M]+.
1
instrument. H, 13C and 31P NMR spectra were recorded with Bruker
(�)-4,7,12,15-Tetra(diphenylphosphinyl)[2.2]paracyclophane
(�)-(9). t-BuLi (1.7 M solution in pentane, 5 mL, 8.6 mmol) was
added dropwise to a stirred solution of (�)-5 (530 mg, 1.0 mmol)
AC300, AC200 or AV400 spectrometers. Chemical shifts (δ) are
expressed in parts per million (ppm), and coupling constants are
given in Hz. Splitting patterns are indicated as follows: s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet, br.=broad, dd=
doublet of doublets. Mass analyses were performed by using a VG
7070 EQ-HF instrument. Specific rotations were measured at five
wavelengths (589, 578, 546, 436 and 365 nm) by using a Perkin-
Elmer polarimeter model 241 equipped with an Na/Hg lamp. The
volume of the cell was 1 mL, and the optical path was 10 cm. The
°
in dry THF (30 mL) at À 78 C at a rate such that the temperature
°
remains below À 70 C. Chlorodiphenylphosphine (848 μL,
4.6 mmol) was added via a syringe over 15 minutes and the
reaction mixture was left warming to r.t. overnight, under
vigorous stirring. Water (25 mL) was added to the suspension.
The organic layer was separated, the aqueous phase was
extracted with CH2Cl2 (3×25 mL), the combined organic layers
were concentrated in vacuo. CH2Cl2 (15 mL), EtOH (15 mL), and
H2O2 (30% (w/w) in H2O, 1 mL) were added to the residue, the
resulting solution was stirred overnight at r.t.. The solution was
dried (Na2SO4) and concentrated under reduced pressure.
Crystallization (EtOH) afforded (�)-9 (257 mg, 25%). White solid;
°
system was set at a temperature of 20 C. Circular dichroism (CD)
spectra were recorded by using a Jasco J-700 spectropolarimeter.
The spectra were average-computed over three instrumental scans,
and the intensities are presented in terms of ellipticity values
(mdeg). The analytical HPLC apparatus consisted of a Perkin-Elmer
(Norwalk, CT, USA) 200 LC pump equipped with a Rheodyne (Cotati,
CA,USA) injector, a 5-μL sample loop, an HPLC Dionex CC-100 oven
(Sunnyvale, CA, USA) and a Jasco (Jasco, Tokyo, Japan) Model
CD2095 Plus UV/CD detector. Data were processed using Clarity
software (DataApex, Prague, The Czech Republic). GC analyses of
the products of the hydrogenation tests were performed by using a
Dani GC1000 instrument. HPLC analysis of the product of the
hydrogenation of methyl (Z)-2-acetamidocinnamate 15 was per-
formed by using a Waters 1525 binary HPLC pump coupled with a
Waters 2487 UV detector.
°
m.p. 354–355 C; IR (ATR): 3054, 2935, 2857, 1590, 1573, 1483,
1436, 1348, 1311, 1186, 1134, 1111, 1071, 1028, 998, 964, 914,
853, 751, 717, 694, 618, 571, 559 cmÀ 1; H NMR (300 MHz, CD2Cl2)
1
δ 7.77–7.31 (m, 44H, ArÀ H), 3.18-3.07 (m, 4H, CH2), 2.82-2.71 (m,
4H, CH2); 13C NMR (75 MHz, CD2Cl2)
δ 146.5–146.1 (m, C-
3,6,11,14), 139.5–139.0 (m, C-5,8,13,16), 134.4 (dd, J=281.5,
103.5 Hz, C-4,7,12,15), 134.4 (dd, J=102.1, 4.0 Hz, C-1 POPh2),
133.1–131.0 (m, C-2,6 POPh2), 132.1 (d, J=21.1 Hz, C-4 POPh2),
129.0–128.7 (m, C-3,5 POPh2), 35.7 (d, J=3.5 Hz, (C-1,2,9,10); 31P
NMR (121 MHz, CD2Cl2) δ 24.6; MS (EI): m/z=1008 [M]+ .
.
Resolution of (�)-4,7,12,15-tetra(diphenylphosphinyl)[2.2]
paracyclo-phane (�)-9. A solution of (+)-dibenzoyl-D-tartaric
acid (0.57, 1.6 mmol) in a mixture of CH2Cl2 (15 mL) and AcOEt
4,7,12,15-tetrabromo-[2.2]-paracyclophane (�)- (5) and 4,5,15,16-
tetra-bromo[2.2]paracyclophane (7).[8b] [2.2]Paracyclophane (5 g,
24 mmol) was slowly added in small portions to a mixture of Br2
(15 mL, 295 mmol) and I2 (75 mg, 0.3 mmol). The solution was kept
in the dark and left under stirring for one week at r.t.. The mixture
°
(15 mL) at 40 C was added rapidly to a solution of (�)-9 (1.6 g,
°
1.6 mmol) in CH2Cl2 (50 mL) at 40 C under vigorous stirring. The
reaction mixture was allowed to cool slowly overnight. The white
precipitate was filtered, dissolved in dichloromethane (50 mL)
and washed with 1 M aqueous sodium hydroxide (3×50 mL) and
water (50 mL). The organic layer was dried (MgSO4) and
concentrated to afford (À )-9 as white solid (520 mg, 65%). The
enantiomeric purity of (À )-9 was determined to be > 99% by
HPLC analisys (Chiralpak IA-3, dichloromethane:ethanol 20:100,
°
was dropped into NaOH(aq) (20%, 150 mL) at 0 C. The precipitate
was collected by filtration, washed with hot EtOH (3×25 mL), and
dried in vacuo to yield a mixture of (�)-5 and 7 in equal amount.
Dichloromethane was added to the residue, pure 7 was recovered
by filtration (4.5 g, 36%). The dichloromethane filtrate was concen-
trated under reduced pressure to afford (�)-5 as white solid (5.2 g,
42%).
1.5 ml/min, detector CD at 280 nm) (+)-9 t1 =1.0 min, (À )-9 t2 =
1
D
(�)-5. H NMR (400 MHz, CDCl3) δ 7.20 (s, 4H, ArÀ H), 3.29-3.18 (m,
°
1.6 min, [α]25 =À 48 (c 1, DCM). The mother liquors of the first
4H, CH2), 3.04-2.93 (m, 4H, CH2); 13C NMR (101 MHz, CDCl3) δ 140.3
(C-4,7,12,15), 134.4 (C-5,8,13,16), 125.3 (C-3,6,11,14), 32.7 (C-
1,2,9,10).
resolution were washed with 1 M aqueous sodium hydroxide (3 ×
50 mL) and water (50 mL). The organic layer was dried (MgSO4),
concentrated and treated with (À )-dibenzoyl-L-tartaric acid as
well as done before to afford (+)-9 as white solid (488 mg, 61%):
D
°
[α]25 = + 48 (c 1, DCM).
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doi.org/10.1002/ejoc.202100109
°
°
(À )-4,7,12,15-tetra(diphenylphosphanyl)[2.2]paracyclophane
(À )-3. Trichlorosilane (1 mL, 9.9 mmol) was added to a suspen-
sion of (À )-9 (175 mg, 0.17 mmol) in p-xilene (10 mL, degassed),
1.3 mLminÀ 1; inlet temperature: 222 C; initial temperature: 145 C;
time isotherm: 15 min; gradient: 8 CminÀ 1; final temperature:
°
°
°
200 C; detector temperature: 250 C; retention times [min]: 12.8
°
under Ar atmosphere, and heated to 140 C overnight. At
[(+)-(R)], 13.4 [(À )-(S)], 16.1 (substrate 17).
1-Phenylethyl acetate: Analysed by GC. CSP: MEGADEX DACTBSβ
24 hours intervals two further aliquots of HSiCl3 (1 mL, 9.9 mmol)
°
were added. The reaction mixture was cooled to À 10 C and
(25 m×0.25 mm i.d.); carrier gas: hydrogen; pressure: 0.55 bar; inlet
quenched by the addition of NaOH(aq) (32%, 10 mL, degassed)
(exothermic!). The organic layer was separated, and the aqueous
phase was extracted with CH2Cl2 (3×10 mL, degassed). The
combined organic layers were dried (Na2SO4) and the solvent
was removed in vacuo. MeOH (5 mL, degassed) was added to the
residue and the white precipitate was collected to give (À )-3 as
°
°
temperature: 222 C; initiaÀl 1 temperature: 80 C; time isotherm:
°
°
25 min; gradient: 20 Cmin ; final temperature: 200 C; detector
°
temperature: 250 C; retention times [min]: 22.8 [(À )-(S)], 23.9
[(+)-(R)], 28.3 (substrate 18).
Methyl 3-(acetylamino)-2-benzylpropanoate: Analysed by GC. CSP:
MEGADEX DACTBSβ (25 m×0.25 mm i.d.); carrier gas: hydrogen;
1
white solid (103 mg, 63%). H NMR (300 MHz, CD2Cl2) δ 7.80–7.21
flow: 1.4 mLminÀ 1; inlet temperature: 222 C; initial temperature:
(m, 42H, ArÀ H), 6.72 (dd, J= 9.4, 5.8 Hz, 2H, ArÀ H) 2.95–2.76 (m,
4H, CH2), 2.66–2.47 (m, 4H, CH2); 31P NMR (121 MHz, CD2Cl2) δ
À 1.0; MS (EI): m/z= 944 [M]+.
°
170 C; time isotherm: 30 min; gradient: 10 CminÀ 1; final temper-
°
°
°
°
ature: 200 C; detector temperature: 250 C; retention times [min]:
22.4 [(+)-(R)], 23.0 [(À )-(S)], 24.1 (substrate 19).
(À )-[(COD)Rh(PHANEPHOS)]OTf (À )-(12). PHANEPHOS (À )-4
(50 mg, 87 μmol) and [Rh(COD)2]OTf (41 mg, 87 μmol) were
placed in a Schlenk tube. After three argon-vacuum cycles, dry
dichloromethane (2 mL, degassed) was added, and the mixture
was left for 30 minutes under stirring. The solvent was removed
under reduced pressure, dry MTBE (2 mL, degassed) was added
to the residue, and the flask was placed in a sonicator for 15
minutes. After vigorous stirring for a further 30 minutes, the
yellow precipitate was filtered, dried in vacuum and directly used
for asymmetric hydrogenation tests.
Single crystal X-Ray diffraction analysis for 8 and 9. The single
crystal data diffraction of 8 and 9 were collected at Bruker SMART
APEX II CCD area detector diffractometer, equipped with a Bruker
KRYOFLEX low temperature device and graphite monochromator,
MoÀ Kα radiation (λ=0.71069 Å). Cell refinement and data reduc-
tion were done with Bruker SAINT. Structure solution was
performed with SHELXL and Fourier analysis and refinement were
performed by the full-matrix least-squares methods based on F2
implemented in SHELXL-2014;[9] absorption correction was per-
formed based on multi-scan procedure using SADABS.[10] Com-
pound 9 crystallized as butanol solvate. The disordered butanol
molecule was modelled over two positions fixing at 0.5 the atom
site occupancy factor. Pictures were prepared using Mercury[11]
software. Essential crystal and refinement data are reported in
Table S1 of supporting information.
(À )-{[(COD)Rh]2(PHANE-TetraPHOS)}(OTf)2
(À )-(13).
(À )-3
(50 mg, 53 μmol) and [Rh(COD)2]OTf (50 mg, 106 μmol) were
placed in a Schlenk tube. After three argon-vacuum cycles, dry
dichloromethane (2 mL, degassed) was added, and the mixture
was left for 30 minutes under stirring. The solvent was removed
under reduced pressure, dry MTBE (2 mL, degassed) was added
to the residue, and the flask was placed in a sonicator for 15
minutes. After vigorous stirring for a further 30 minutes, the
orange precipitate was filtered, dried in vacuum and directly
used for asymmetric hydrogenation tests.
Simulation of the CD spectra for the (pS) enantiomer of the
tetraphosphane oxide 9. The chiroptical properties of the
enantiomers of 9 were estimated by molecular modelling calcu-
lations. As the first step, the structure of the (pS)-9 enantiomer was
optimized and submitted to conformational search, performed at
the molecular mechanics level of theory by means of the MMFF94
force field, using the computer program SPARTAN 10v1.1.0 (Wave-
function Inc., 18401 Von Karman Avenue, Suite 370, Irvine, CA
92612, USA). This afforded just one conformation inside an energy
General procedure for asymmetric hydrogenations. A solution
of the substrate (0.36 M) in dry MeOH was deossigenated with
flowing argon for ten minutes. The catalyst was then added
(ratio stated in the text), three vacuum hydrogen cycles were
applied, and the mixture was left under vigorous stirring for
1 hour. The solution was then directly injected in the gas
chromatograph or filtrate through a short pad of silica gel when
HPLC analysis was performed.
window of 8 kcal×molÀ 1
, perfectly consistent with the one
obtained through X-ray analysis. Next, such a structure was
subjected to assessment of the Electronic Circular Dichroism (CD)
spectrum by resorting to the Amsterdam Density Functional (ADF)
package v. 2007.01. The set options were single point calculation at
the BLYP level of theory, employing the TZ2P large core basis set;
50 singlet excitations; diagonalization method: Davidson; velocity
representation; scaling factor 0.80; peak width 8.0.
Methyl 2-(acetylamino)propanoate. Analysed by GC. CSP: MEGA-
DEX DACTBSβ (25 m×0.25 mm i.d.); carrier gas: hydrogen; flow:
1 mLminÀ 1; inlet temperature: 222 C; À i1nitial temperature: 140 C;
°
°
°
°
time isotherm: 6 min; gradient: 8 Cmin ; final temperature: 200 C;
°
detector temperature: 250 C; retention times [min]: 3.7 (substrate
Deposition Numbers 1972369 (for 8), and 1972368 (for 9) contain
the supplementary crystallographic data for this paper. These data
are provided free of charge by the joint Cambridge Crystallographic
Data Centre and Fachinformationszentrum Karlsruhe Access Struc-
tures service www.ccdc.cam.ac.uk/structures.
14), 4.7 [(À )-(R)], 5.3 [(+)-(S)].
Methyl 2-acetamido-3-phenylpropanoate. Analysed by HPLC. CSP:
Chiracel® ADÀ H; eluent mixture: hexane/i-PrOH, 9:1; flow rate:
0.5 mLminÀ 1; retention times [min]: 17.1 [(À )-(R)], 21.5 [(+)-(S)], 42.0
(substrate 15).
Dimethyl 2-methylenesuccinate: Analysed by GC. CSP: MEGADEX
DACTBSβ (25 m×0.25 mm i.d.); carrier gas: hydrogen; pressure:
Acknowledgements
°
°
1 bar; inlet temperature: 222 C; iniÀti1al temperature: 60 C; time
°
°
isotherm: 10 min; gradient: 2 Cmin ; final temperature: 200 C;
We thank Dr. Tullio Pilati for preliminary X-ray experiments and
Prof. Francesco Sannicolo’ of Laboratori Alchemia S.r.l. for fruitful
discussion and suggestions. L.V., S.R. and T.B. are very grateful to
Professor Franco Cozzi for his exceptional teaching and sugges-
tions in organic stereochemistry.
°
detector temperature: 250 C; retention times [min]: 19.5 [(À )-(R)],
20.1 [(+)-(S)], 23.3 (substrate 16).
N-(1-phenylethyl)acetamide: Analysed by GC. CSP: MEGADEX
DACTBSβ (25 m×0.25 mm i.d.); carrier gas: hydrogen; flow:
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© 2021 The Authors. European Journal of Organic Chemistry published
by Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100109
[3] K. Aikawa, K. Mikami, Angew. Chem. Int. Ed. Engl. 2003, 42, 5458–5461.
Conflict of Interest
[4] a) T. Imamoto, J. Watanabe, Y. Wada, H. Masuda, H. Yamada, H. Tsuruta,
S. Matsukawa, K. Yamaguchi, J. Am. Chem. Soc. 1998, 120, 1635–1636;
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Kouchi, I. D. Gridnev, Organometallics 2006, 25, 908–914.
The authors declare no conflict of interest.
[5] a) T. Benincori, E. Brenna, F. Sannicolò, L. Trimarco, P. Antognazza, E.
Cesarotti, J. Chem. Soc. Chem. Commun. 1995, 685–686; b) T. Benincori,
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Keywords: Asymmetric catalysis · Chiral tetraphosphane · D2
symmetry · Homogeneous hydrogenation · Rhodium complexes
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Manuscript received: January 29, 2021
Revised manuscript received: March 26, 2021
Accepted manuscript online: April 6, 2021
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© 2021 The Authors. European Journal of Organic Chemistry published
by Wiley-VCH GmbH