Diastereoselectivity and catalytic activity in ruthenium complexes chiral at the metal centre

Article abstract of DOI:10.1016/j.jorganchem.2014.06.016

Cis-RuCl₂(diphosphine)(CAMPY) complexes, chiral at the metal centre with matching or mismatching chiralities between diphosphine and CAMPY were prepared and the configuration at the metal was determined in solution by a complete set of NMR investigations; CAMPY is (R)-(-) or (S)-(+)-8-amino-5,6,7,8-tetrahydroquinoline. The complexes were used in ATH reactions of different aryl ketones with 2-propanol as hydrogen source. The effects of the chirality at the metal were studied and enantiomeric excesses up to 99% were obtained.

Full text of DOI:10.1016/j.jorganchem.2014.06.016

Journal of Organometallic Chemistry xxx (2014) 1e7
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Diastereoselectivity and catalytic activity in ruthenium complexes
chiral at the metal centre
Daniele S. Zerla, Isabella Rimoldi, Edoardo Cesarotti, Giorgio Facchetti, Michela Pellizzoni,
*
Marco Fuseꢀ
DISFARM, Sezione di Chimica Generale ed Organica “A. Marchesini”, Universit aꢀ degli Studi di Milano, via Venezian 21, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 March 2014
Received in revised form
Cis-RuCl (diphosphine)(CAMPY) complexes, chiral at the metal centre with matching or mismatching
chiralities between diphosphine and CAMPY were prepared and the configuration at the metal was
2
determined in solution by a complete set of NMR investigations; CAMPY is (R)-(ꢀ) or (S)-(þ)-8-amino-
17 June 2014
5,6,7,8-tetrahydroquinoline. The complexes were used in ATH reactions of different aryl ketones with 2-
Accepted 18 June 2014
Available online xxx
propanol as hydrogen source. The effects of the chirality at the metal were studied and enantiomeric
excesses up to 99% were obtained.
©
2014 Elsevier B.V. All rights reserved.
Keywords:
Ruthenium
Metal chirality
ATH
8-Amino-5,6,7,8-tetrahydroquinoline
Introduction
2
On the contrary ATH is simpler and it avoids handling H gas.
The ATH has been studied in details and a great number of catalytic
systems have been developed; the most advanced and used are
The enantioselective reduction of C]O double bonds is a key
synthetic transformationproved as fundamental for the preparation
of fine chemicals [1,2], mainly drugs, fragrances and insecticides
6
6
those based on
h -arene Ru bis-amido and on h -arene Ru H
aminoamido; these complexes are devoid of phosphine ligands and
the chiral information is located on an aminoalcohol or a diamine
[8,20].
[3e7]; the reaction has been largely reviewed and a huge bibliog-
raphy exists. The ketones' reduction can be realized by asymmetric
transfer hydrogenation (ATH) based on the use of hydrogen donors,
The very active catalysts generated by the addition of diamines
usually secondary alcohols or formic acid, or with molecular H
2
as
2
to RuCl phosphines in 2-propanol in presence of a base have been
reducing agent (asymmetric hydrogenation, AH) [8e10].
The most outstanding results have been obtained by Noyori's
group who discovered and developed the catalyst [RuCl (dipho-
essentially studied as hydrogenation catalysts but they have
received less attention as catalysts for ATH [21].
2
An improvement in ATH with this type of complexes was real-
spine)(diamine)] [11] in which the ruthenium complexes in trans
geometry [12,13].
The action mechanism of these catalysts has been studied in
details and elucidated by several research groups, first of all by
Noyori's one [14,15] and deeply in all its aspects by Morris's one
2
ized by Rigo using cis-Ru(II) complexes, [RuCl (PP)(NN)] [22,23],
where NN is the 2-(aminomethyl)pyridine. Many strategies have
been developed to increase the level of enantioselectivity, partic-
ularly by exploring the matching combination between two
different chiral ligands but when complexes are in a cis arrange-
ment the role of the chirality at the metal centre must be taken in
consideration.
[16e18].
Metal-catalysed hydrogenation of ketones and imines [19] has a
great attraction because it replaces the use of stoichiometric hy-
drides, usually difficult to handle and with amounts of basic by-
products to be disposed off; one of the few counter-indications of
this technique is the high pressure vessels necessary.
Experimental
General considerations
Commercially reagent grade solvents were dried according to
standard procedure and freshly distilled under nitrogen before
*
Corresponding author. Tel.: þ39 (02)50314367.
E-mail addresses: marco.fuse@unimi.it, fuse.marco@gmail.com (M. Fus eꢀ ).
http://dx.doi.org/10.1016/j.jorganchem.2014.06.016
022-328X/© 2014 Elsevier B.V. All rights reserved.
0
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j.jorganchem.2014.06.016

2
D.S. Zerla et al. / Journal of Organometallic Chemistry xxx (2014) 1e7
using. All synthesis of ruthenium complexes were carried out under
nitrogen atmosphere using standard Schlenk techniques. Unless
otherwise stated, materials are obtained from commercial source
and used without further purification; optically pure (R)-(ꢀ) and
carbon), 59.0, 32.7, 27.2, 21.7. C45
63.98 H 5.01 N 3.32; found C 63.51 H 5.40 N 3.01.
2 2 2
H42Cl N P Ru, PM 844, calc. C
t,c-[RuHCl ((S)-CAMPY)(PPh
[RuHCl(PPh ] (57.8 mg, 0.062 mmol) was dissolved in ben-
zene-d (2 ml), and (S)-CAMPY (10 mg, 0.067 mmol) dissolved in
benzene-d (1 ml) was added into the solution, the colour change
immediately to orange. The solution was stirred at room temper-
3 2
) ] (5)
(
S)-(þ)-8-amino-5,6,7,8-tetrahydroquinoline (CAMPY) were ob-
3 3
)
tained as described previously [24], [RuCl
RuHCl(PPh
] [26] (4) and (2R,5R)-(ꢀ)-2,5-bis-Diphenilphosphin-
-exene (ZEDPHOS) [27] were synthesized according to literature
procedures.
HPLC analysis were performed with Merck-Hitachi L-7100
2
(PPh
3
)
3
]
[25](1),
6
[
3
)
3
6
3
31
ature for 1 h before NMR analysis. P NMR (121.5 MHz, CDCl3,
298 K): ), 69.6 (d, J ¼ 37.0 Hz, 1P,
ppm 74.3 (d, J ¼ 37.0 Hz, 1P, P
); H NMR (400.1 MHz, CDCl3, 298 K):
ppm 8.62 (d, J ¼ 5.5 Hz,1H,
d
a
1
13
1
equipped with Detector UV6000LP and Chiralpak AD. H, C, and
P
H
b
d
31
2N
P
a
/
b
Pa
P NMR spectra were recorded in CDCl
3
on Bruker DRX Advance
), 8.24e8.08 (m, 10H, Ph
), 7.11e7.03 (m, 10H, Ph ),
P
b
4N
3
4
00 MHz equipped with a non-reverse probe or Bruker DRX Avance
00 MHz. Chemical shifts (in ppm) were referenced to residual
7.02e6.93 (m, 10H, Ph ), 6.41 (d, J ¼ 7.7 Hz, 1H, H ), 6.05 (dd,
N
8N
N
2
J ¼ 7.7, 5.5 Hz, 1H, H3 ), 4.03 (m, 1H, H ), 3.11 (m, 1H, NH
),
),
N
N
N
2
solvent proton/carbon peak or using external standard 85% H
for P NMR. Signal multiplicity was assigned as s (singlet),
d (doublet), t (triplet), q (quartet) or m (multiplet).
3
PO
4
2.38 (m, 1H, NH
2
), 2.01e1.91 (m, 2H, CH
2
), 1.17e1.07 (m, 2H, CH
31
N
1.02e0.9 (m, 2H, CH
2
), ꢀ16.7 (dd, J ¼ 29.6, 23.1 Hz, iH).
Polarimetry analyses were carried out on Perkin Elmer 343 Plus
equipped with Na/Hal lamp. UveVis were recorded on Jasco V-530
UV/Vis Spectrophotometer and CD spectra on a Jasco J500
Spectrophotometer.
c-[RuCl
2
((S)-CAMPY) ((2R,4R)-(ꢀ)-2,4-bis-(diphenylphosphine)
pentane)] ((S),(R,R)-8)
Complex 3 (50 mg, 0.059 mmol) was added into a solution of
(BDPP) in
((2R,4R)-(ꢀ)-2,4-Bis-(diphenylphosphine)pentane)
Catalytic activity was monitored by GC, Carlo Erba HRGC 5160
dichloromethane (0.059 mmol in 8 ml). After stirring at room
temperature for 30 min, solvent was evaporated under reduced
pressure. Toluene (8 ml) was added to the solid and the yellow
mega series using a capillary chiral column, (MEGA DMT
internal diameter 0.35 mm).
b, 25 m,
ꢁ
solution was heated to 110 C for 24 h. A yellow solid was obtained
Synthesis of ruthenium complexes
upon partially elimination of the solvent under reduced pressure to
about 2 ml and by adding 10 ml of degassed hexane (40 mg; yield
1
31
In order to simplify the comprehension of H NMR spectra the
88%). P NMR (121.5 MHz, CDCl3, 298 K):
d
ppm 65.05 (d,
1
following labels were used: the phosphorous trans to the pyridine
J ¼ 44.5 Hz,1P, P
CDCl , 298 K): ppm 8.71 (m,1H, H ), 7.69 (m, 5H, Ph ), 7.60e7.49
(m, 5H, Ph ), 7.47e7.37 (m, 5H, Ph ), 7.18 (t, J ¼ 7.90 Hz, 1H, H ),
b
), 45.30 (d, J ¼ 44.5 Hz,1P, P
a
). H NMR (400.1 MHz,
2
N
Pa
nitrogen is defined as P
a
, the cis one as P
b
; in chelating diphosphine
b
considering the symmetry
plane of the molecule perpendicular to the PeRueP plane; all the
protons belonging to the diamine ligand were labelled with a
superscripted N.
3
d
P
a
P
b
4N
ligands the labels were split in P
a
and P
P
b
3N
7.12e7.04 (m, 5H, Ph ), 6.74 (t, J ¼ 6.60 Hz, 1H, H ), 3.74 (t,
N Pb
J ¼ 10.8 Hz, 1H, NH
2
), 3.50e3.34 (m, 1H, CH ), 3.16e3.01 (m, 1H,
P
a
8N
N
CH ), 2.91e2.78 (m, 1H, H ), 2.66e2.59 (m, 2H, CH
2
), 2.30e2.26
), 1.60e1.50 (m, 2H,
), 1.19 (dd, J ¼ 13.6, 7.2 Hz, 3H,
P
N
P
(
CH
CH
2 2 2
m, 1H, CH ), 1.83e1.74 (m, 2H, CH , CH
N
N
N
t,c -[RuCl
RuCl
10 ml), and (S)-CAMPY was added to the solution (100 mg,
.67 mmol), dissolved in CH Cl (5 ml), the colour immediately
2
((S)-CAMPY)(PPh
3
)
2
] (2)
2
P
3
),1.30e1.25 (m, 2H, CH
2
, NH
), 0.83 (dd, J ¼ 11.6, 7.0 Hz, 3H, CH
ppm 148.8, 136.2e123.9 (aromatic carbons), 59.6,
38.3, 34, 27.57, 22.1, 20.5, 19.3, 18.2. C38 Ru, PM 760, calc.
C 60.00H 5.57 N 3.68; found C 59.87 H 5.52 N 3.60.
2
a
P
b
13
[
2
(PPh ] (640 mg, 0.67 mmol) was dissolved in CH
3
)
3
2
Cl
2
3
). C NMR (100.6 MHz,
(
0
CDCl3, 298 K): d
2
2
2 2 2
H42Cl N P
changes to orange. The solution was stirred at room temperature
for 30 min. Solvent was partially evaporated to about 5 ml then
diluted with 20 ml of degassed hexane to give the product as an
c-[RuCl
pentane)] ((S),(S,S)-8)
2
((S)-CAMPY) ((2S,4S)-(ꢀ)-2,4-bis-(diphenylphosphine)
31
orange powder (401 mg; yield 71%). P NMR (121.5 MHz, CDCl3,
1
2
98 K):
d
ppm 43.1 (d, J ¼ 31.5 Hz,1P, P
b
), 39.2 (d, J ¼ 31 Hz,1P, P
a
). H
Complex ((S),(S,S)-8) was synthesized as described for ((S),(R,R)-
31
NMR (400.1 MHz, CDCl3, 298 K):
d
ppm 8.46 (dd, J ¼ 3.4 Hz, 1H,
8), using (S)-CAMPY as diamine (36 mg; yield 80%). P NMR
(121.5 MHz, CDCl3, 298 K): , P ), 44.14
ppm 67.13 (d, J ¼ 44.3 Hz, P
). H NMR (400.1 MHz, CDCl , 298 K): ppm
8.29e8.23 (m, 1H, H ), 7.79e7.66 (m, 5H, Ph ), 7.52e7.50 (m, 2H,
2
N
P
b
Pa
H
1
3
1
1
), 7.58 (m, 6H, Ph ), 7.47 (t, J ¼ 8.5 Hz, 6H, Ph ), 7.35e7.08 (m,
d
b
b
9H, PhP , H ), 6.57 (dd, J ¼ 7.4 Hz, 1H, H ), 5.12 (m, 1H, H ),
a
/b
4N
3N
8N
(d, J ¼ 44.3 Hz, 1P, P
1
d
a
3
N
N
N
2N
Pa
.38 (m, 1H, NH
.88 (m, 4H, CH
2
), 3.10 (m, 1H, NH
2
), 2.76 (d, J ¼ 6.7 Hz, 2H, CH
2
),
ppm 155.9,
Ru,
PM 844, calc. C 63.98 H 5.01 N 3.32; found C 64.09 H 5.32 N 3.15.
N
13
P
b
P
a
P
b
4N
2
). C NMR (100.6 MHz, CDCl3, 298 K):
d
Ph ), 7.49e7.41 (m, 5H Ph ), 7.22e7.08 (m, 4H, Ph , H ),
P
3N
8N
36e127 (aromatic carbon), 56.5, 33.2, 27.7, 21.2. C45
H42Cl
2
N
2
P
2
6.98e6.81 (m, 5H, Ph b), 6.53 (t, 1H, H ), 4.69e4.56 (m, 1H, H ),
P
b
Pa
3.47e3.33 (m, 1H, CH ), 3.10e2.98 (m,1H, CH ), 2.67e2.48 (m, 3H,
N
N
P
), 1.94e1.81 (m, 2H, CHP
), 1.17 (dd, J ¼ 13.3, 7.2 Hz, 3H, CH
Pb 13
N
NH
2
, CH
2
), 2.19e2.05 (m, 1H, CH
2
2
, CH
2
),
),
C
N
Pa
c,c-[RuCl
2
((S)-CAMPY)(PPh
3
)
2
] (3)
1.78e1.69 (m, 2H, CH
2
3
N
N
Complex 2 (50 mg, 0.059 mmol) was dissolved dichloromethane
10 ml), the solution was sealed in a vial purged with nitrogen and
stirred at room temperature for 5e7 days. Solvent was partially
evaporated under reduced pressure to 2 ml and hexane (10 ml) was
1.02e0.84 (m, 2H, NH
NMR (100.6 MHz, CDCl3, 298 K):
matic carbons), 56.68, 38.07, 33.54, 33.28, 32.38, 26.96, 21.32, 18.88,
18.17. C38 Ru, PM 760, calc. C 60.00H 5.57 N 3.68; found C
60.23 H 5.63 N 3.53.
2
, CH
2
), 0.77 (dd, J ¼ 11.6, 7.0 Hz, 3H, CH
3
).
(
d ppm 147.5, 137.2e123.2 (aro-
2 2 2
H42Cl N P
31
added to obtain yellow solid (43.3 mg; yield 87%). P NMR
121.5 MHz, CDCl3, 298 K): ), 42.9 (d,
ppm 50.1 (d, J ¼ 33.0 Hz,1P, P
). H NMR (400.1 MHz, CDCl , 298 K): ppm 9.19
(
d
b
1
J ¼ 33.4 Hz, 1P, P
a
3
d
c-[RuCl
hexene)] ((S),(R,R)-9)
2
((S)-CAMPY) ((2R,5R)-(ꢀ)-2,5-bis-diphenilphosphin-3-
2
N
P
a
P
b
4N
(
1
2
CH
m, 1H, H ), 7.66 (m, 5H, Ph ), 7.36 (m, 6H, Ph , H ), 7.21 (m,
5H, PhP ), 7.04 (m, 5H, Ph ), 6.93 (m,1H, H ), 3.32 (m,1H, NH
a
/b
P
b
3N
N
),
2 2
.92 (m, 1H, H ), 2.67 (m, 2H, CH ), 1.82 (m, 1H, CH ), 1.62 (m, 2H,
Complex ((S),(R,R)-9) was synthesized as described for
((S),(R,R)-8), using (cis-(2R,4R)-(ꢀ)-2,5-bis-Diphenilphosphin-3-
hexene) (ZEDPHOS) as chelating diphosphine and refluxing for
2
8N
N
N
N
N
N
N
13
2
, NH
2
), 1.28 (m, 1H, CH
2
), 0.92 (m, 1H, CH
ppm 149.3, 135.9e128.1 (aromatic
2
); C NMR
31
(
100.6 MHz, CDCl3, 298 K):
d
24 h in 2-propanol instead of toluene (yield 38 mg; 83%). P NMR
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j.jorganchem.2014.06.016

D.S. Zerla et al. / Journal of Organometallic Chemistry xxx (2014) 1e7
3
(
121.5 MHz, CDCl3, 298 K):
d
ppm 56 (d, J ¼ 32.8 Hz, 1P, P
b
), 47.2 (d,
ppm 8.71
m, 1H, H ), 7.5 (m, 10H, Ph ), 7.3e7.15 (m, 10H, Ph ),7.07(m, 1H,
Results and discussion
1
J ¼ 32.8 Hz, 1P, P
a
). H NMR (400.1 MHz, CDCl , 298 K):
3
d
2N
Pa
Pb
(
H
We recently reported that Ru complexes with a chiral-5,6,7,8-
tetrahydro-8-amino-quinoline, (R)- or (S)-CAMPY were able to
reduce ketones in 2-propanol with good enantioselectivities [24].
This C chiral di-nitrogen ligand has a pyridine connected to a
1
primary amino group which is crucial for the catalytic activity and
the two nitrogen donors are fused in a rigid cyclohexane ring. Upon
4
N
3N
Pb
Pb
), 6.65 (t, 1H, H ), 6.45 (m, 1H, C]CH ),4.9 (m, 1H, CH ), 4.30
P
a
P
a
N
8N
(
m, 1H, C]CH ), 3.25 (m, 2H, CH , NH
2
), 2.75 (m, 1H, H ), 2.5 (m,
N
N
N
2
7
CH
H, CH
2
), 1.65 (m, 2H, CH
2
), 1.48 (m, 2H, CH
2
), 1.42 (dd, J ¼ 14.5,
P
a
N
.3 Hz, 3H, CH
3
),1.25(m, 1H, NH
2
), 1.12 (dd, J ¼ 13.0, 6.7 Hz, 3H,
Pb
13
3
). C NMR (75 MHz, CDCl
3
)
d
ppm 149.12, 141.13e123.80 (ar-
omatic carbon), 59.79, 40.65, 33.94, 33.00, 27.41, 21.96, 18.67, 18.57,
6.40. C39 Ru, PM 772.70, calc. C 60.62 H 5.48 N 3.63;
found. C 60.32 H 5.75 N 3.61.
coordination the NH
When CAMPY was the only source of chirality, complex 3 [RuCl
CAMPY)(PPh ] reduced acetophenone up to 55% e.e. and up to
0% e.e. when triphenylphosphine was replaced by an achiral
chelating diphenylphosphinopropane, DPPP. We expected that the
symmetry and the conformational rigidity of CAMPY would
generate cases of matching and mismatching when the two PPh
2
group is forced into an equatorial position.
1
H42Cl
2
N
2
P
2
2
(-
3 2
)
9
C
1
[RuCl
2
((R)-CAMPY) ((2R,5R)-(ꢀ)-2,5-bis-diphenilphosphin-3-
hexene)] ((R),(R,R)-9)
3
ligands were replaced by a chiral chelating ligand. The unique
feature of CAMPY and CAMPY-like ligands would let us to deter-
mine the stereochemistry of the complexes in solution.
Complex ((R),(R,R)-9) was synthesized as described for
31
(
(S),(R,R)-8), using (R)-CAMPY as diamine. P NMR (121 MHz,
CDCl
ppm 58.47 (d, J ¼ 32.4 Hz, 34%P), 57.54 (d, J ¼ 31.1 Hz, 4%P),
0.66 (d, J ¼ 31.3 Hz, 11%P), 47.94 (d, J ¼ 31.2 Hz, 7%P), 46.47 (d,
3
) d
5
13
J ¼ 32.5 Hz, 41%P), 42.38 (d, J ¼ 31.1 Hz, 3%P). C NMR (75 MHz,
CDCl 158.22, 136.01e123.53 (aromatic carbon), 57.23, 54.00,
0.75, 33.29, 32.71, 27.33, 21.73, 18.68, 16.37, 13.87.
Ru, PM 772.70, calc. C 60.62 H 5.48 N 3.63; found. C
0.32 H 5.75 N 3.61.
Synthesis and characterization of trans and cis complexes
3
) d
4
C
6
The complexes with CAMPY and chiral diphosphines were
prepared either with (R) or (S) ligand; the chirality is indicated only
when stereochemistry of the complexes is discussed.
39 2 2 2
H42Cl N P
The structures of trans and cis complexes were clarified by a
4
series of 2D-NMR experiments, based also on an unexpected J
General procedure for hydrogen transfer reaction
coupling between the proton a to the pyridine nitrogen and the
phosphorus atom trans [24] to the pyridine itself. These complexes
were investigated also by CD-spectroscopy in the region of the
ligand field transitions (400e700 nm) in which chiral diphosphines
and CAMPYs do not show any CD effect [28,29].
In a Schlenk tube sealed with a rubber septum under argon
atmosphere the base (potassium tert-butoxide, 0.04 mmol) was
added to a solution of precatalyst 4e7 (0.8 mmol) in 4 ml of 2-
ꢁ
ꢁ
propanol and the system thermostated at 40 C or 82 C; then
the ketone (0.8 mmol in 1 ml of 2-propanol) was added in one
portion ([sub] ¼ 0.16 M). GC analysis was performed taking 0.3 ml
of reaction mixture, the sample was treated with ammonium
chloride.
(S)-CAMPY reacts rapidly with [RuCl
room temperature to give the kinetic favoured OC-6-14, 2 [30], [t,c-
[RuCl ((S)-CAMPY)(PPh ]) which in turn evolvs to the chiral-at-
metal optically pure OC-6-42-C, (S)-3 [c,c,-[RuCl ((S)-CAM-
PY)(PPh ] (Scheme 1).
2 3 3 2 2
(PPh ) ] 1 in CH Cl at
2
3 2
)
2
3 2
)
Scheme 1.
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4
D.S. Zerla et al. / Journal of Organometallic Chemistry xxx (2014) 1e7
Fig. 1a shows the CD-spectra of (S)-2 (t,c-[RuCl
PY)(PPh ]), (S)-3 c,c-[RuCl ((S)-CAMPY)(PPh ] and (S)-5 t,c-
RuHCl((S)-CAMPY)(PPh ] (vide infra); as expected the CD spectra
of (R)-2, (R)-3 and (R)-5 show a complete mirror image shape
2
((S)-CAM-
is completely superimposable to that of (S)-3, directly obtained
from 1 (Scheme 1).
Any attempt to transform 5 into the dihydride 6 and to syn-
3
thesize 7 by exchange of PPh with a chelating diphosphine failed.
3
)
2
2
3 2
)
[
3
)
2
(
omitted for clarity).
Fig. 1b shows the CD evolution of the kinetically favoured (S)-2
As the ATH is usually performed at temperatures higher than
room temperature and in 2-propanol which strongly accelerates
the isomerization from 2 to 3, we focused our attention on
matching and mismatching and their effects on enantioselectivities
only for cis complexes 3 (Scheme 2).
into the thermodynamically more stable (S)-3; the direct trans-
formation from 2 to homochiral 3 is supported by the presence of
two isodichroic [31] points at 358 nm and 478 nm and it confirms
previous NMR observations that the reaction proceeds completely
stereoselective.
2 3 3
(S)-CAMPY reacts with [RuCl (PPh ) ] 1 and (R,R)-BDPP ((R,R)-
2,4-bisdiphenylphosphinopentane) in refluxing toluene to give 8
31
(S)-CAMPY reacts with [RuHCl(PPh
3
)
3
], 4 to give [RuHCl((S)-
almost quantitatively; the P NMR shows an AB system at 65.05
and 45.30 ppm (J ¼ 44.6 Hz). There is a second AB system at
59.78 ppm and 43.28 ppm (J ¼ 49.7 Hz) less than 1%, presumably
belonging to trans intermediate that rapidly disappears by adding
few drops of 2-propanol.
CAMPY)(PPh ], 5 almost quantitatively in 30 min. The mono-
3 2
)
hydride 5 had been characterised by 2D-NMR experiments; 5
presents hydrogen and chloride mutually trans, the hydridic proton
resonates at ꢀ16.62 ppm as a doublet of doublets (J(HeP) ¼ 29.57,
4
2
3.12 Hz). There is a second doublet of doublets at ꢀ16.21 ppm
In 2D-NMR experiments the J correlation between the pyridine
31
(
J(HeP) ¼ 26.8, 21.9 Hz) less than 1% of the major one. The P NMR
a-proton with the phosphorus signal at 45.30 ppm indicates that
shows an intense AB system at 74.30 and 69.65 ppm (J ¼ 36.9 Hz)
and a second AB system, less than 1% of the former, at 67.01 ppm
being the second doublet hidden by the doublet at 69.65 ppm.
phosphorus and pyridine nitrogen are mutually trans; furthermore
COSY cross peaks among the aryl phosphine protons at 7.36 and
7.09 ppm with the phosphorus atom at 65.05 ppm and a strong NOE
between the aforementioned aryl protons and H* on the chiral
carbon of (S)-CAMPYat 2.85 ppm, indicate that the stereochemistry
The unambiguous identification of the phosphorous trans to the
4
pyridine nitrogen by the J coupling, the strong NOE between NH
2
and the aryl protons on phosphorus trans to the pyridine, the strong
NOE between the H* on the stereogenic carbon and the Ru hydride
indicate that 5 (t,c-[RuHCl((S)-CAMPY)(PPh ) ]) is the diastereomer
3 2
OC-6-54-a, 99% optically pure at the metal centre .
of (S),(R,R)-8 is
Similarly (S)-CAMPY reacts with [RuCl
in refluxing toluene to give 8; in a complete set of 2D-NMR ex-
D-OC-6-42-a (Fig. 2).
2 3 3
(PPh ) ] 1 and (S,S)-BDPP
4
periments the J correlation between the pyridine a-proton with
Inspite ofasmall hypsochromicshift, the CDspectra of(S)-5 shows
the phosphorus signal at 44.14 ppm indicates that this phosphorus
is trans to the pyridine; furthermore the presence of COSY cross
peaks among the aryl phosphine protons at 7.13 and 6.93 ppm with
the phosphorus at 67.13 ppm and the lack of the NOE between the
aforementioned aryl protons and the hydrogen on the chiral carbon
of (S)-CAMPY at 4.63 ppm, indicate that the stereochemistry of
(S),(S,S)-8 is L-OC-6-42-a (Fig. 2). Fig. 3 shows the CD spectra of
(S),(R,R)-8 and (S),(S,S)-8 complexes in the LF region; the spectra of
(S),(R,R)-8 is almost the mirror image of (S),(S,S)-8 indicating a local
enantiomeric relationship between the metallic ruthenium
a positive CD band at 410 nm and (S)-2 (t,c-[RuCl
2
((S)-CAM-
PY)(PPh ]) evinces an analogous CD positive band at 420 nm. CD
3 2
)
active transition in this region is obvious for 5 in which the metallic
chromophore is chiral not racemic but it should be true also for (S)-2;
X-ray structures of analogous dichloride complexes always show a
distorted octahedral geometry [32,33] and it is likely that this distor-
tion should be the origin of the CD active transitions in the LF range.
The (S)-5, dissolved in chlorinated solvents (CH
2 2 3
Cl or CHCl ),
gives the optically pure OC-6-42-c, (S)-3 for which the CD spectrum
Fig. 1. a) CD spectra of complexes: 2 (____), 3(-<-) and 5 (-o-). b) Isomerisation of complex 2(____) to complex 3(-<-) followed via CD spectroscopy: 1 h (*), 2 h (
h( ) and 3 days (x) .
◊
), 3 h(B), 4 h(,),
5
D
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D.S. Zerla et al. / Journal of Organometallic Chemistry xxx (2014) 1e7
5
cromofores, in spite of the complexes are distereoisomers. This
behaviour implies that the chirality at the metal atom is dictated
essentially by the chelating phosphine; as confirmed by the almost
superimposable CD spectra of (S),(S,S)-8 and (R)-(S,S)-8.
Cis-(R,R)-2,5 bis(diphenylphosphino)-3-hexene, (R,R)-ZEDPHOS
[
27], is a ligand that combines the easiness of synthesis of ligands
3
based on stereogenic sp carbon atoms with the tendency to
chelate metal in an octahedral geometry, typical of the aromatic di-
2
aryl and diheteroaryl diphosphines [34,35] with C axial chirality.
As expected (R,R)-ZEDPHOS is flexible enough to evolve to cis
complexes. This ligand was used to reduce the precursor of 4-
acetoxy-2-azetidinone with good enantioselectivity [36].
2 3 3
(S)-CAMPY reacts with [RuCl (PPh ) ] 1 and (R,R)-ZEDPHOS in
refluxing toluene to give (S)-(R,R)-9 as a single diastereomer; the
31
Scheme 2.
P NMR shows only an intense AB system at 56.00 and 47.20 ppm
13
1
1
31
(
J ¼ 32.8 Hz). Ce H HSQC, He P HMBC, and NOE between the H*
at 2.75 ppm and the aryl proton at 7.35 ppm (phosphorus trans to a
chloride atom), unambiguously indicate that (S)-(R,R)-9 is -OC-6-
D
42-a (Fig. 2).
On the contrary the reaction of (R)-CAMPY with 1 and (R,R)-
31
ZEDPHOS leads to the formation of a mixture of complexes; in
P
NMR spectra there are three AB systems at 58.38 and 46.38 ppm
(
J ¼ 32.4 Hz) (ca. 75%), 50.57 and 47.85 ppm (J ¼ 31.2 Hz) (ca. 20%)
and 57.45 and 42.29 ppm(J ¼ 31.1 Hz)(ca. 5%). The 7.5:2:0.5 ratio
does not change even after prolonged reflux in 2-propanol. The
1
13
complexity of H and
appointment of the stereochemistry. Fig. 3 shows the CD spectra of
S)-(R,R)-9 and (R)-(R,R)-9; (S)-(R,R)-9 (or -OC-6-42-a) presents a
strong negative CD at 370 nm while the thermodynamic mixture of
R)-(R,R)-9 gives an almost flat CD confirming that it is a mixture of
C spectra does not allow a certain
(
D
(
distereoisomers of opposite configuration at the metal.
Asymmetric transfer hydrogenation (ATH)
Fig. 2. Complexes configuration assigned by NMR spectroscopy.
The results of ATH of different aryl ketones are summarized in
Table 1; generally (S) chirality of CAMPY and diphosphines in (R,R)
configuration gives the better matching; (R) and (R,R) chiralities
give rise to a more or less pronounced mismatching .
Fig. 3. a) CD spectra of complexes (S),(R,R)-8 ( -^- ) and (S),(S,S)-8 (___). b) CD spectra of complexes (S)-(R,R)-9 (- -) and (R)-(R,R)-9 (___).
◊
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6
D.S. Zerla et al. / Journal of Organometallic Chemistry xxx (2014) 1e7
(
R,R)-BDPP gives a single diastereomeric precatalyst either with
even the inversion of configuration with the (R),(R,R)-9 precatalyst
could be due to the variation of the composition of the hydridic
intermediates or to a different influence of the temperature on the
ATH rates of the different hydrides.
(
S) or (R)-CAMPY and the precatalyst composition reflects the cat-
alytic activity: (S),(R,R)-8 reduces acetophenone 10a to (R)-1-
phenylethanol 11a in 90% e.e.(entry 1); (R),(R,R)-8 gives (R)-1-
phenylethanol 11a in 88% e.e.(entry 3). At 82 C (refluxing 2-
propanol) (S),(R,R)-8 maintains almost the same stereoselectivity
88%); (R),(R,R)-8 gives also (R)-11a but in 76% e.e. (entries 1,3 vs
,4). The same matching/mismatching operates also in the reduc-
tion of o-tolylacetophenone 10a; (S),(R;R)-8 gives o-tolyl-1-ethanol
1b in 97% e.e. while (R),(R,R)-8 gives (R)-11b in 40% e.e. (entries 11
and 12).
The different stereoselectivities are connected also to the
different catalytic activities: (S),(R,R)-8 reduces 10a an 10b with
TOF 19,000 and 1600 respectively, the mismatched (R),(R,R)-8 re-
duces the same substrates with TOF 3300 and 400.
ꢁ
It should be noted that (S),(R,R)-9 is always twenty times more
reactive than (R),(R,R)-9; TOF changes from 8100 to 500 in the
ꢁ
(
2
reduction of 10a (entry 6 and 9) at 40 C, from 6400 to 300 for 10b
(entry 13 and 15) and from 6000 to 150 for 10c (entry 18 and 20).
Noyori and co-workers proposed a well-defined metal-ligand
bifunctional catalytic mechanism which operates in hydrogenation
1
with H
hydrogen donors like 2-propanol replace H
was clarified in detail for trans-[Ru(Binap)(diamine)H
work we deal with cis-[Ru(diphesphine)(diamine)Cl ] complexes
2
but that is supposed to operate also when organic
gas. The mechanism
]; in this
2
2
2
with definite stereochemistry and diastereomeric composition that
it represents the thermodynamic fate in the synthesis of the
precatalysts.
(S),(R,R)-8 reduces 3,5-threfluoromethylacetophenone 10c to
(
R)-11c in 83% e.e. (entry 16) and m-methoxyacetophenone 10d to
the corresponding alcohol (R)-11d with a stereoselectivity higher
than 99% (entry 21).
Notwithstanding we were unable to prepare the dihydrides of
matching/mismatching complexes c-8 and c-9.
The effects of matching/mismatching are dramatically enhanced
with (R,R)-ZEDPHOS as co-ligand. (S),(R,R)-9 reduces acetophenone
The hydride OC-6-54-a (S)-5 reduces 10a to (R)-11a in 45% e.e.
with a TOF of about 11,000. An excess of t-BuOK is essential,
otherwise the monohydride is unreactive also under H atmo-
2
spheres. The structure in solution, determined by NMR shows a
strong NOE between H* and the hydride, one of the hydrogens on
ꢁ
ꢁ
1
9
0a to (R)-11a in 97% e.e. at 40 C and in 94% e.e. at 82 C; (R),(R,R)-
ꢁ
gives (R)-11a with a modest 9% e.e. at 82 C but gives the opposite
ꢁ
ꢁ
C
(S)-11a enantiomer in 63% e.e. at 40 C and in 76% e.e. at 10
entries 6e10).
(
2
the NH must be forced into an equatorial position, rather far from
(
S),(R,R)-9 reduces 10b to (R)-11b with stereoselectivity higher
than 99% (entry 13), it reduces 10c and 10d to (R)-11c and (R)-11d in
6 and 98% e.e. respectively (entries 18 and 19). The mismatched
R),(R,R)-9 reduces 10b to (S)-11b and 10c to (S)-11c in 22 and 28%
the hydride and thus inactive; as a consequence the axial proton
must overlook a chloride atom. Under these conditions a base is
necessary to convert the chloride into an hydride.
The precatalysts (S),(R,R)-8, (R),(R,R)-8, (S),(R,R)-9 are
composed by single diastereomer, the negative CD band around
400 nm (positive for (R)-(S,S)-8) indicates that the complexes are
chiral not racemic at the metal centre; on the contrary the
9
(
e.e. respectively (entries 15 and 20).
The 7.5:2:0.5 diastereomeric composition of (R),(R,R)-9 pre-
catalyst does not change with the temperature. The decrease or
Table 1
Catalytic asymmetric transfer hydrogenation of ketones.
Conv.% (min.)a
TOF (h )b
ꢀ1
e.e.% (conf.)a
Substrate
Complex
Entry
Temperature
ꢁ
1.9$104
1
0a
(S),(R,R)-8
1
2
3
4
5
6
7
8
9
40
82
40
82
10
40
82
10
40
82
40
40
40
82
40
40
82
40
82
40
40
82
40
82
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
92 (20)
94 (2)
90 (R)
88 (R)
88 (R)
76 (R)
96 (R)
97 (R)
94(R)
76 (S)
63 (S)
9 (R)
97 (R)
40 (R)
>99 (R)
93 (R)
22 (S)
83 (R)
82 (R)
96 (R)
92 (R)
28 (S)
>99 (R)
86 (R)
98 (R)
93 (R)
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
4
5.3$10
(
(
R),(R,R)-8
S)-(R,R)-9
84 (20)
85 (20)
50 (300)
94 (10)
95 (3)
3.3$103
9.5$103
8.1$103
3.6$104
(
R)-(R,R)-9
16 (300)
52 (60)
57 (60)
85 (60)
40 (60)
98 (40)
78 (20)
37 (120)
>99 (40)
>99 (3)
>99 (10)
>99 (0.9)
14 (120)
96 (200)
>99 (20)
93 (10)
94 (3)
500
10
600
10b
10c
10d
(S),(R,R)-8
11
12
13
1.6$103
400
(
(
R),(R,R)-8
S)-(R,R)-9
6.4$103
1.6$104
300
14
(
R)-(R,R)-9
15
16
(S),(R,R)-8
2.5$103
4
17
1.8$10
(
S)-(R,R)-9
18
6$103
6$104
150
19
(
R)-(R,R)-9
20
21
(S),(R,R)-8
S)-(R,R)-9
500
3
22
5.3$10
(
23
1$104
24
5.5$104
Conditions: reaction carried out at 40 or 82 ꢁC, ketone solution 0.16 M in 2-propanol, sub/base/cat ¼ 1000:50:1.
a
Determined by GC analysis.
TOF ¼ turn over frequency at 50% of conversion (mmol of product on mmol of catalyst per hour).
b
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j.jorganchem.2014.06.016

D.S. Zerla et al. / Journal of Organometallic Chemistry xxx (2014) 1e7
7
mismatching in (R),(R,R)-9 gives rise to a mixture of diastereomers
and to an almost flat CD spectrum. If the catalysts maintain the cis
configuration during the catalytic cycle, hypothesis not conflicting
with the outer sphere mechanism [14] only the chlorine trans to the
[7] A. Zanotti-Gerosa, W. Hems, M. Groarke, F. Hancock, Platin. Met. Rev. 49
2005) 7.
(
[8] T. Ohkuma, N. Utsumi, K. Tsutsumi, K. Murata, C. Sandoval, R. Noyori, J. Am.
Chem. Soc. 128 (2006) 8724e8725.
[9] V. Rautenstrauch, X. Hoang-Cong, R. Churlaud, K. Abdur-Rashid, R.H. Morris,
Chem. Eur. J. 9 (2003) 4954e4967.
2
phosphorus and closed to the axial proton of NH could give a
[
10] A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 118
catalytically active hydride but in any case the complex is chiral at
the metal centre. Asymmetric catalysis remains however a kinetic
phenomenon and differences in stereoselectivity should be
explained by the different reaction rates between a chiral config-
urationally stable hydride and the prochiral face of the substrate.
(
1996) 2521e2522.
[11] T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 117
1995) 2675e2676.
[
[
(
12] R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed. 40 (2001) 40e73.
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[
[
[
[
15] C.A. Sandoval, T. Ohkuma, K. Mu n~ iz, R. Noyori, J. Am. Chem. Soc. 125 (2003)
3490e13503.
16] S.E. Clapham, A. Hadzovic, R.H. Morris, Coord. Chem. Rev. 248 (2004)
201e2237.
17] A. Hadzovic, D. Song, C.M. MacLaughlin, R.H. Morris, Organometallics 26
2007) 5987e5999.
1
Conclusion
2
We were able to obtain diastereomer, enantiomers at metal
centre, in steterochemically pure form using BDPP and CAMPY. In
the matching combination, (S)-CAMPY/(R,R)-BDPP, the precatalysts
gave enantioselectivities from 82 to more than 99% e.e. depending
on the substrate, while in mismatching one the catalyst gave lower
enantioselectivities and the reactivity is more than twenty time
lower in respect to the matching one. With (R,R)-ZEDPHOS the
matching combination with (S)-CAMPY gave enantioselectivities
from 93 to 99% e.e., whereas in the mismatching we obtained a
diastereomeric mixture which gave lower enantioselectivities and
even opposite stereochemistry. It is likely that, with this kind of
catalyst in which the outer sphere mechanism is operating, the
stereoselectivity depends on the reaction rates between active
specie and substrate but also, and perhaps to a greater extent, on a
configurationally stable chiral metal centre. We are aware that an
answer will probably arrive only from a computational study. Work
is in progress towards this direction.
(
18] R. Abbel, K. Abdur-Rashid, M. Faatz, A. Hadzovic, A.J. Lough, R.H. Morris, J. Am.
Chem. Soc. 127 (2005) 1870e1882.
[19] N. Arai, N. Utsumi, Y. Matsumoto, K. Murata, K. Tsutsumi, T. Ohkuma, Adv.
Synth. Catal. 354 (2012) 2089e2095.
20] K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori, Angew. Chem. Int. Ed.
Engl. 36 (1997) 285e288.
[21] P. Rigo, et al., Eur. J. Inorg. Chem. 2008 (2008) 4041e4053.
[
[
[
[
[
22] K. Abdur-Rashid, R. Abbel, A. Hadzovic, A.J. Lough, R.H. Morris, Inorg. Chem. 44
(
2005) 2483e2492.
23] W. Baratta, E. Herdtweck, K. Siega, M. Toniutti, P. Rigo, Organometallics 24
(2005) 1660e1669.
24] G.F. Isabella Rimoldi, Edoardo Cesarotti, Michela Pellizzoni, Curr. Org. Chem.
1
6 (2012) 2982e2988.
25] T.A. Stephenson, G. Wilkinson, J. Inorg. Nucl. Chem. 28 (1966) 945e956.
[26] R.A. Schunn, E.R. Wonchoba, G. Wilkinson, in: Inorganic Syntheses, John Wiley
Sons, Inc., 1971, pp. 131e134.
27] E. Cesarotti, I. Rimoldi, P. Spalluto, F. Demartin, Tetrahedron Asymmetry 18
2007) 1278e1283.
[28] J.W. Faller, X. Liu, J. Parr, Chirality 12 (2000) 325e337.
&
[
(
[
[
[
[
29] E. Cesarotti, L. Prati, A. Sironi, G. Ciani, C. White, J. Chem. Soc. Dalton Trans.
(
1987) 1149e1155.
30] A. von Zelewsky, Stereochemistry of Coordination Compounds, John Wiley &
Sons Ltd., 1996.
31] J.C. Sutherland, in: Comprehensive Chiroptical Spectroscopy, John Wiley &
Sons, Inc., 2012, pp. 35e63.
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A.F. England, T. Ikariya, R. Noyori, Angew. Chem. Int. Ed. 37 (1998)
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.jorganchem.2014.06.016.
1
703e1707.
33] E. Lindner, H.A. Mayer, I. Warad, K. Eichele, J. Organomet. Chem. 665 (2003)
76e185.
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043e2047.
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012 (2012) 4365e4370.
[
[
[
[
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Please cite this article in press as: D.S. Zerla, et al., Journal of Organometallic Chemistry (2014), http://dx.doi.org/10.1016/
j.jorganchem.2014.06.016