Novel access to N,N′-diaryl-trans-1,2-diaminocyclohexane ligands. A cheap and easy way to prepare ligand for asymmetric transfer hydrogenation

Article abstract of DOI:10.1016/j.molcata.2015.10.030

N,N′-diaryl-trans-1,2-diaminocyclohexane ligands were prepared from 1,2-diaminocyclohexane and cyclohexanone derivatives via a heterogeneous palladium catalysis. In one step an alkylation followed by an aromatisation is performed under air or in the presence of an hydrogen trap. The interest of the synthesized ligands were evaluated in the reduction of aromatic ketones. The alcohols were efficiently and selectively obtained with an iridium complex and a mixture of formic acid and sodium formate.

Full text of DOI:10.1016/j.molcata.2015.10.030

Journal of Molecular Catalysis A: Chemical 411 (2016) 196–202
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Novel access to N,Nꢀ-diaryl-trans-1,2-diaminocyclohexane ligands. A
cheap and easy way to prepare ligand for asymmetric transfer
hydrogenation
Bilal El-Asaada,b, Boris Guichereta, Estelle Métaya,∗, Iyad Karaméb, Marc Lemairea,∗
a Equipe Catalyse Synthèse et Environnement, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, Université Claude Bernard
Lyon 1, Bâtiment Curien, 43 boulevard du 11 novembre 1918, 69622 Villeurbanne Cedex, France
b Laboratory of OrganoMetallic Catalysis and Coordination Chemistry, Lebanese University (UL)-Faculty of Sciences 1, Department of chemistry, Raffic
Al-Harirri Campus, Al-Hadath, Lebanon
a r t i c l e i n f o
a b s t r a c t
N,Nꢀ-diaryl-trans-1,2-diaminocyclohexane ligands were prepared from 1,2-diaminocyclohexane and
cyclohexanone derivatives via a heterogeneous palladium catalysis. In one step an alkylation followed
by an aromatisation is performed under air or in the presence of an hydrogen trap. The interest of the
synthesized ligands were evaluated in the reduction of aromatic ketones. The alcohols were efficiently
and selectively obtained with an iridium complex and a mixture of formic acid and sodium formate.
© 2015 Elsevier B.V. All rights reserved.
Article history:
Received 11 September 2015
Received in revised form 20 October 2015
Accepted 28 October 2015
Available online 2 November 2015
Keywords:
Diamine ligand
Dehydrogenative alkylation
Reduction
Ketones
Iridium
1. Introduction
dine with aniline allows the access to similar diarylamines
[9]. Dimeric bidentated NHC were also synthezised from these
Chiral molecules have found
a
variety of applications in
intermediates [10]. Dihydroxyderivatives were prepared from
3-N-hydroxy-aminoprop-1-enes via a copper catalyzed oxida-
tive dimerization [11]. Quinoline based ligands were studied
as chaperone molecules in cycloaddition reactions [6(c)]. Nitro
derivatives have shown useful application in nonlinear optics
[7].
pharmaceutical, agrochemical, flavor and flagrance industries.
In addition, around 85% of new drugs are chiral, this can be
explained by the development of asymmetric catalysis, specifi-
cally the interest for chiral ligands access and applications [1].
From the birth of asymmetric catalysis, plethora of molecules,
most of them inspired by the seminal work of Knowles, Kagan,
Sharpless and Noyori, have been designed and synthesized [2].
Nowadays, a wide library of ligands has been available [3].
Among them, N,Nꢀ-trans-1,2-diaminocyclohexane is the chiral
platform of different family of diaza ligands such as SALEN,
notably well-known in the epoxidation [4] or the preparation of
Trost ligands [5]. N,Nꢀ-diaryl-trans-1,2-diaminocyclohexane have
been less investigated [6]. From literature data, these com-
pounds were prepared in Buchwald coupling conditions from
aromatic halides [7] or via a Meisenheimer type nucleophilic
aromatic substitution. [8] The ring-opening of N-phenyl aziri-
One report mentioned their evaluation as ligand in asymmetric
transfer hydrogenation with isopropanol but with a poor efficiency
[6(a)]. The asymmetric transfer hydrogenation has already been
established as a real alternative of hydrogenation with molec-
ular hydrogen. From the pioneer works with isopropanol, large
quantity of data was collected and offer to organic chemists use-
ful tools [12–16]. [Ruthenium, rhodium and iridium complexes
are the most studied ones in this domain [17]. The most con-
ventional hydrogen sources in ATH are 2-propanol, formic acid,
and sodium format which are cheap and green reducing agents.
This technology has been used notably to reduce enantioselec-
tively ketones. In this case, preparations of chiral ligands have
a determining role rendering, development of simple method-
ology to prepare enantioselective molecules, are still in great
demand.
∗
Corresponding authors. Fax: +33 4 72431408.
E-mail addresses: estelle.metay@univ-lyon1.fr (E. Métay),
marc.lemaire.chimie@univ-lyon.fr (M. Lemaire).
http://dx.doi.org/10.1016/j.molcata.2015.10.030
1381-1169/© 2015 Elsevier B.V. All rights reserved.

B. El-Asaad et al. / Journal of Molecular Catalysis A: Chemical 411 (2016) 196–202
197
Table 1
Transfer hydrogenation of acetophenone using Ru and Ir metal with ligand 1 and 6.
2.2. General method for preparation of ligands
Procedure A: Dehydrogenative alkylation of functionalized
␣-tetralone with (1R, 2R)-cyclohexane-1, 2-diamine: In a pres-
sure tube were successively added under inert atmosphere, 1eq of
diamine (2 mmol, 0.23 g), 3eq of ␣-tetralone (6 mmol, 0.9 g) and
2.5 mol% of Pd/C (5%) (0.05 mmol, 107 mg). Then, the tube was
sealed and placed in preheated oil bath (T = 150 ◦C). After 24 h of
stirring at 800 rpm the crude was cooling down and diluted in a
mixture (50/50) of CH2Cl2 and CH3OH then filtered off on Milli-
pore filter (Durapore filter 0.01 ␮m). The solvents were removed
under vacuum and the crude material was purified by flash col-
umn chromatography on silica gel (Eluent cyclohexane (500 mL),
then cyclohexane/ethyl acetate 90:10)
Entry
Metal complex
L
KOtBu(mol%)
Conva(%)
e.eb (%)
1
2
3
4
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[Ir(COD)2] BF4
1
6
1
1
5
5
5
5
90
35
0
Rac
11 (S)
–
[IrCp*Cl2]2
76
Rac
a
% Conversion of acetophenone in alcohol was determined by GC.
% Determined by GC chiral column.
b
Procedure B: Dehydrogenative alkylation of functionalized
␤-tetralone with (1R, 2R)-cyclohexane-1, 2-diamine: In a pres-
sure tube were successively added under inert atmosphere, 1eq
of diamine (2 mmol, 0.23 g), 2.5eq of ␤-tetralone (5 mmol, 0.75 g)
and 2 mol% of Pd/C (5%) (0.04 mmol, 85 mg). Then the tube was
sealed and placed in preheated oil bath (T = 130 ◦C). After 24 h of
stirring at 800 rpm the crude was cooling down and diluted in a
mixture of (50/50) of CH2Cl2 and CH3OH, then filtered off on Mil-
lipore filter (Durapore filter 0.01 ␮m). The solvents were removed
under vacuum and the crude material was purified by flash col-
umn chromatography on silica gel (Eluent cyclohexane (500 mL)
then cyclohexane/ethyl acetate 90:10).
In the laboratory, we previously developed the palladium cat-
alyzed dehydrogenative alkylation of cyclohexanone derivatives to
prepare aromatic ethers [18] and amines [19]. The aromatic amines
were prepared by heating an amine with cyclohexanone deriva-
tives in the presence of palladium on charcoal and 1-octene as
hydrogen scavenger in a pressure tube. The formation of the imine
was followed by a tautomerisation into enamine leading to the con-
comitant aromatization, the release of hydrogen is adsorbed on the
palladium surface which hydrogenated 1-octene. With this useful
tool in hand, the access to chiral aryl amine was studied.
Procedure C: In a pressure tube were successively added, under
inert atmosphere, 3eq of diamine (9 mmol, 1.03 g), 1eq of ␣-
tetralone (3 mmol, 0.4 g) and 3 mL of toluene as a solvent. The
tube was sealed and placed in a preheated oil path (110 ◦C) for
64 h. Thereafter 2 mol% of Pd/C (5%) (0.06 mmol, 127 mg) and 2eq
of Octene (6 mmol, 0.67 g) were added to the mixture under inert
atmosphere, The tube was sealed again and placed in a preheated
oil path (150 ◦C) After 24 h of stirring at 800 rpm the crude was cool-
ing down and diluted in a mixture of (50/50) CH2Cl2 and CH3OH
then filtered off on Millipore filter (Durapore filter 0.01 ␮m). The
solvents were removed under vacuum and the crude material was
purified by flash column chromatography on silica gel (Eluent DCM
(500 mL) then DCM/MeOH 95:5).
2. Experimental
2.1. Methods and materials
All reagents were obtained from commercial sources and used as
received. Cyclohexane-1, 2-diamine, cyclohexanone and tetralone
derivatives were purchased from Sigma–Aldrich®. Pd/C 5 wt% on
active carbon, reduced and dry (EScatTM 1431) was purchased from
Strem Chemicals Inc. All reactions were performed under an inert
atmosphere (argon). Silica gel (40–63 micron) was used for column
chromatography. Thin layer chromatography (TLC) was performed
on pre-coated silica gel 60−F 254 plates. UV light, phosphomolibdic
acid and ninhydrine were used as Revelator for analysis of the TLC
plates. All compounds were characterized by spectroscopic anal-
ysis. The NMR spectra were recorded with a Bruker ALS or DRX
300 (1H: 300 MHz, 13C: 75 MHz), chemical shifts are expressed in
ppm, J values are given in Hz; CDCl3, CD3OD and dimethyle sulfox-
2.3. Characterization data for chiral amine ligand
(1R,2R)-N1,N-di(naphthalen-1-yl)cyclohexane-1,2-diamine
[640276–57–9]: The compound obtained by following the typical
procedure A starting from (1R,2R)-cyclohexane-1, 2-diamine (0.23
g, 0.24 mL, 1eq) and ␣-tetralone (0.9 g, 0.8 mL, 3eq). HREIMS cal-
ide DMSO-d6 were used as solvent and internal standard (CDCl3:
,
7.26 ppm in 1H and 77.1 ppm in 13C. CD3OD: 4.87 ppm, 3.31 in 1
H
and 49.1 ppm in 13C. DMSO: 2.5 ppm in 1H and 39.5 ppm in 13C).
The peak patterns are indicated as follows: (s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet, and br, for broad).
culated for C26H26N2 = 366.2096 and found m/z = 366.2081, [a]20
D
= −305 (c 1.02, CHCl3); Mp: 116 ◦C; 1H NMR (300 MHz, CDCl3): ı
= 1.38–1.44 (m, 2H, CH2), 1.54–1.60 (m, 2H, CH2), 1.88–1.91 (m,
2H, CH2), 2.59 (d, J = 15.0 Hz, 2H, CH2), 3.64–3.67 (m, 2H, CH2),
4.65 (s, 2H, NH), 6.81, (d, J = 6.0 Hz, 2H, CHarom), 7.43–7.29 (m, 8H,
CHarom), 7.67 (d, J = 6.0 Hz, 2H, CHarom), 7.78 (d, J = 9.0 Hz, 2H,
CHarom). 13C NMR (75 MHz, CDCl3): ı = 24.8 (2CH2), 32.1 (2CH2),
57.6 (2CH), 105.4 (2CHarom), 117.9 (2CHarom), 120.2 (2CHarom),
124.2 (2Cqarom), 124.9 (2CHarom), 125.9 (2CHarom), 126.4 (2CHarom),
128.6 (2CHarom), 134.5 (Cqarom), 142.8 (Cqarom).
Chiral GC was performed on Shimadzu Gas Chro-
matograph GC−14A coupled with an integrator Shimadzu
C−R6A Chromatopac using
a
Rt®−␤DEXm capillary column
(30.0 m × 0.25 mm × 0.25 ␮m) purchased from Restek Chromatog-
raphy Products and an FID (flame ionisation detector). N2 gas
was used as a carrier at 1.75 kg/cm2. Chiral HPLC was performed
on a PerkinElmer Series 200 (pump, UV/VIS detector at 254 nm,
Vacuum degasser) with a chiral column Chiralcel OJ−H column
0.46 × 25 cm (Daicel Chemical Ind., Ltd.).
(1R,2R)-N1,N2-bis(5-methylnaphthalen-1-yl)cyclohexane-
1,2-diamine: The compound obtained by following the typical
Optical rotations were determined at 589 nm (sodium D line) at
20 ◦C by using a PerkinElmer−343 MC digital polarimeter. Optical
rotations are reported as follows [␣]TD (concentration c = g/100 mL
of solvent) and solvent. Configurations were determined by com-
procedure
A starting from (1R,2R)-cyclohexane-1, 2-diamine
(0.69 g, 0.72 mL, 6eq) and 4-methyl-1-tetralone (2.9 g, 2.7 mL, 9eq).
HREIMS calculated for C28H30N2 = 394.2409 found m/z = 394.2392.
[a]20D = −201.98 (c 1.01, CHCl3). Mp: 130 ◦C. 1H NMR (300 MHz,
CDCl3): ı = 1.31–1.34 (m, 2H, CH2), 1.45–1.52 (m, 2H, CH2),
1.80–1.82 (m, 2H, CH2), 2.47–2.52 (m, 2H, CH2), 2.54 (s, 6H, 2CH3),
3.54–3.56 (m, 2H, CH2), 4.3–4.76 (s, 2H, NH), 6.73 (d, J = 7.62 Hz, 2H,
CHarom), 7.18–7.45 (m, 8H, CHarom), 7.71 (d, J = 8.34 Hz, 2H, CHarom),
parison of the measured [␣]T with the one reported in the
D
literature.
Melting points were recorded on a Heizbank system Kofler Type
WME (Wagner & Munz).

198
B. El-Asaad et al. / Journal of Molecular Catalysis A: Chemical 411 (2016) 196–202
Scheme 1. Our approach compare to literature.
Scheme 2. Synthesis of aromatic amines by alkylation and dehydrogenation starting from (1R, 2R)-1,2-diphenylethanediamine.
Scheme 3. Synthesis of aromatic amines by alkylation and dehydrogenation.
Scheme 4. (a) Synthesis of Ligand 5. (b) Synthesis of monoarylated ligand 6.

B. El-Asaad et al. / Journal of Molecular Catalysis A: Chemical 411 (2016) 196–202
199
Table 2
Transfer hydrogenation of acetophenone using [Ir(COD)2] BF4/ligand 1 system and formic acid.
1- [Ir(COD) ]BF ( . mol%)
2
4 0 5
OH
ligand 1, H O/MeOH mL/ mL,
O
2
1
1
RT, h under argon,
1
2- Reducing agent
70 °C
Entry
Ligand 1 (mol%)
HCO2X (equiv.)
Time (h)
Conva (%)
TON
60
130
48
98
52
TOFc (h−1
)
e.eb (%) (S)
1
2
3
4
5
6
0.5
1
1
1
1
HCO2H, 5eq
HCO2H, 5eq
HCO2H, 10eq
HCO2Na 5eq
HCO2H 5eq
HCO2H 2.5eq/HCO2Na 2.5eq
40
40
40
48
40
23
30
65
24
49
26
1.5
3.25
1.2
2.45
1.3
8.7
77
78
70
50
82
85
1
>99
≈200
a
Conversion was determined by GC.
Determined by chiral GC.
Minimum TOF.
b
c
Table 3
Chiral diamine ligands for transfer hydrogenation of acetophenone.
Entry
Ligand
Time (h)
Conva(%)
TON
TOFc (h−1
12.5
8.33
8.33
12.5
)
e.eb(%)
1
2
3
4
5
2
3
4
5
6
16
24
24
16
24
100
200
200
200
200
192
86
83
83
83
52
100
100
100
96
8
a
Conversion was determined by GC.
Determined by GC chiral column.
Minimum TOF.
b
c
7.90 (d, J = 8.34 Hz, 2H, CHarom). 13C NMR (75 MHz, CDCl3): ı = 18.9
(2CH3), 24.8 (2CH2), 32.0 (2CH2), 57.7 (2CH), 106.0 (2CHarom), 120.8
(2CHarom), 124.0 (2CHarom), 124.70 (2CHarom), 124.78 (2CHarom),
124.9 (2Cqarom), 125.7 (2CHarom), 126.8 (2CHarom), 133.3 (Cqarom),
141.1 (Cqarom).
The compound obtained by following the typical procedure
A starting from (1R,2R)-cyclohexane-1,2-diamine (0.69 g, 0.72 mL,
6eq) and 5,7-dimethyl-1-tetralone (3.14 g, 9eq). HREIMS calucated
for C30H35N2 = 423.2722 found m/z = 423.2786. [a]20D = −262.94 (c
0.976, CH2Cl2). Mp: 134 ◦C. 1H NMR (300 MHz, CDCl3): ı = 1.36–1.39
(m, 2H, CH2), 1.52–1.58 (m, 2H, CH2), 1.86–1.89 (m, 2H, CH2), 2.32
(s, 6H, 2CH3), 2.6 (s, 6H, 2CH3), 3.63–3.66 (m, 2H, CH2), 4.63 (s, 2H,
NH), 6.68–6.81 (m, 2H, CHarom), 7.10 (s, 2H, CHarom), 7.30 (s, 2H,
CHarom), 738 (d, J = 4.5 Hz, 2H, CHarom). 13C NMR (75 MHz, CDCl3):
ı = 20.0 (2CH3), 221.9 (2CH3), 24.9 (2CH2), 32.2 (2CH2), 57.7 (2CH),
105.7 (2CHarom), 114.8 (2CHarom), 117.0 (2CHarom), 124.4 (2Cqarom),
125.2 (2CHarom), 129.9 (2CHarom), 131.8 (2Cqarom), 134.11 (2Cqarom),
134.7 (2Cqarom), 142.8 (2Cqarom).
(0.7 g, 0.72 mL, 3eq) and 2-tetralone (2.19 g, 1.98 mL, 3eq).
HREIMS calculated for C26H26N2 366,2096 found m/z = 366.2077.
[␣]20D = +348.36 (c 1.018, CHCl3). 1H NMR (300 MHz, CDCl3):
ı = 1.30–1.35 (m, 2H, CH2), 1.53–1.56 (m, 2H, CH2), 1.85–1.89
(m, 2H, CH2), 2.47–2.52 (m, 2H, CH2), 3.42–3.45 (m, 2H, CH2),
4.16 (s, 2H, NH), 6.85–6.91 (m, 4H, CHarom), 7.21–7.71 (m, 10H,
CHarom). 13C NMR (75 MHz, CDCl3): ı = 24.6 (2CH2), 32.2 (2CH2),
57.2 (2CH), 105.2 (2CHarom), 118.6 (2CHarom), 122.2 (2CHarom),
125.9 (2CHarom), 126.4 (2CHarom), 129.1 (2CHarom), 130.0 (2Cqarom),
135.1 (Cqarom), 145.1 (Cqarom).
(1R,2R)-N1-(naphthalen-1-yl) cyclohexane-1, 2-diamine
[847901–48–8]: The compound obtained by following the typical
procedure
C starting from (1R, 2R)-cyclohexane-1,2-diamine
(1.027 g, 1.08 mL, 3eq) and 2-tetralone (0.44 g, 0.4 mL, 1eq).
HREIMS calculated for C16H20N2 240,1626 found m/z = 240.1624.
[a]20D = −126.35 (c 0.2, CH2Cl2). 1H NMR (300 MHz, CDCl3):
ı = 0.97–1.01 (m, 1H), 1.29 (m, 3H), 1.71 (m, 2H), 1.99 (m, 1H),
2.22–2.27 (m, 1H), 2.54 (m, 1H), 2.77 (br. s, 2H), 3.32 (m, 1H), 4.21
(br. s, 1H), 6.72 (d, J = 9.0 Hz, 1H), 7.22 (m, 4H), 7.78 (d, J = 7.32 Hz,
1H), 7.90–7.92 (d, J = 7.98 Hz, 1H) ppm. 13C NMR (75 MHz,CD3OD):
ı = 25.8 (CH2), 26.1 (CH2), 32.2 (CH2), 33.9 (CH2), 55.8 (CH), 59.1
(CH), 106.1 (CHarom), 118.2 (CHarom), 122.14 (CHarom), 125.4
(CHarom), 126.6 (Cqarom), 126.6 (CHarom), 127.58 (CHarom), 129.4
(CHarom), 136.1 (Cqarom), 144.6 (Cqarom).
(1R,2R)-N1N2-bis(6-methoxynaphthalen-1-yl)cyclohexane-
1,2-diamine: The compound obtained by following the typical
procedure A starting from (1R,2R) -cyclohexane-1, 2-diamine
(0.23 g, 0.24 mL 1eq) and 6-methoxy-1-tetralone (1.06 g,
3eq). HREIMS calculated for C28H30N2O2 = 426.2307 found
m/z = 426.2289. [a]20D =279.5 (c 1.03, CHCl3). Mp: decomposed at
72 ◦C. 1H NMR (300 MHz, CDCl3): ı = 1.40 (m, 2H, CH2), 1.49–1.53
(m, 2H, CH2), 1.85–1.86 (m, 2H, CH2), 2.52–2.56 (s, H, CH2),
3.61–3.64 (m, 2H, CH2), 3.88 (s, 2-O-CH3), 4.98 (s, 2H, NH), 6.73
(d, J = 6.0 Hz, 2H, CHarom), 7.95–7.98 (m, 2H, CHarom), 7.01 (s, 2H,
CHarom), 7.15–7.30 (m, 4H, CHarom), 7.61 (d, J = 6.0 Hz, 2H, CHarom).
13C NMR (75 MHz, CDCl3): ı = 24.7 (2CH2), 26.9 (2CH2), 55.2
(2CH3), 57.8 (2CH), 106.8 (2CHf), 117.1 (2CHarom), 119.4 (2Cq),
121.9 (2CHarom), 127.1 (2Cq), 135.9 (2Cq), 157.9 (2Cqarom).
2.4. Procedure for the reduction of ketone with [C16H24BF4Ir] and
chiral amine ligand
In a pressure tube, 0.5 mol% of metal precursor [C16H24BF4Ir]
(2.48 mg, 0.005 mol) and 1 mol% of chiral amine ligand (3.66 mg,
0.01 mmol) were dissolved in 2 mL of water and methanol (ratio
1:1) and stirred at room temperature for 1 h under argon atmo-
sphere. Then formic acid (2.5eq, 0.1 mL), sodium formate (2.5eq,
170 mg) and 1eq of ketone substrate (1 mmol) were introduced.
The reaction mixture was stirred at 500 rpm and heated at 70 ◦C for
(1R,2R)-N1,N2-di(naphthalen-2-yl)
diamine: The compound obtained by following the typical
procedure starting from (1R,2R)-cyclohexane-1, 2-diamine
cyclohexane-1,2-
B

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B. El-Asaad et al. / Journal of Molecular Catalysis A: Chemical 411 (2016) 196–202
Tables 4
Reduction of ketones derivatives.
Entry
Ketone
Product
Isolated yield
TON
TOFa(h−1
)
e.e%
1
2
3
86
70
80
172
140
160
7.2
(S)-85
(S)-85
(S)-80
6.37
7.27
4
5
79
87
168
174
7.63
7.91
(S)-84
(S)-52
6
86
172
7.2
(S)-86
7
8
9
71
31
66
142
62
6.45
2.82
6
(S)-63
(R)-25
(S)-86
132
10
81
162
7.36
(S)-93
e.e determined by GC chiral column or OD HPLC chiral column.
22 h. After that, the tube was cooled to room temperature; and the
organic compound was extracted with either with ethyl acetate or
CH2Cl2, then the solution was dried over Na2SO4, filtrated and con-
centrated under reduced pressure. The crude material was purified
by flash column chromatography on silica gel using cyclohex-
ane/ethyl acetate as gradient eluent (90:10–7:3). After evaporation,
alcohols were obtained as oil or solid. The products were identified
by NMR. The conversion and the enantioselectivity were deter-
mined by chiral GC or chiral HPLC analysis (Scheme 1).
␣-tetralone (Scheme 2). Even though a better isolated yield was
obtained in this case (up to 70%) a complete racemization has been
observed. In both cases the acidity of the benzylic proton could be
responsible of the chirality loss as the non rigidity of the structure
(Scheme 3).
Based on these observations, (1R,2R)-cyclohexanediamine
which is a rigide diamine was then considered. The dehydrogena-
tive alkylation was occurred with ␣-tetralone in the presence of
2.5 mol% of Pd/C and 1-octene in a pressure tube at 150 ◦C. The
enantioselective dinaphtyl derivative was isolated in 93% yield
showing only one peak in HPLC analysis. To confirm the retention
of configuration, both racemic 1,2-cyclohexanediamine and (1S,2S)
cyclohexanediamine were arylated and isolated in 95% yields. The
HPLC analysis reveals for the racemic mixture two peaks within
10 min between each. This very large difference of retention time
supposes that enantiomers are well differenciated by the cyclodex-
trines. As a result we were curious to evaluate their utilization in
asymmetric transformation (Scheme 4).
3. Results and discussions
At first, one reaction was performed with enantiopure ␣-
methylbenzylamine and ␣-tetralone at 130 ◦C in the presence of
palladium on charcoal and octene in a pressure tube. 46% of the
desired product was isolated but unfortunately the HLPC analysis
showed that a complete racemisation was observed. (1R, 2R)-1,2-
Diphenylethane-1,2-diamine was also engaged in the reaction with

B. El-Asaad et al. / Journal of Molecular Catalysis A: Chemical 411 (2016) 196–202
201
Table 5
Reduction of ketone derivatives.
1- C16H24BF4Ir] (0.5 mol%)
ligand 1, 1 %mol
H2O/MeOH 1ml/ 1ml,
RT, 1h, argon,
OH
R'
O
R
R'
2- 2.5 equiv. of HCO2H
2.5 equiv. of HCO2Na
R
22h, 70 °C
Entry
Ketone
Product
Isolated yield
TON
TOFa (h−1
)
e.e%
1
71
144
6.55
(S)-43
2
3
86
41
172
82
7.82
3.73
(R)-59
(R)-15
4
47
92
4.18
>99 d.e: 67%
e.e determined by GC chiral column or OD HPLC chiral column.
a
Minimum TOF.
Following the same procedure, substituted napthyl from ␣-
tetralone derivatives were synthesized with good isolated yields.
In each case, only one enantiomer was observed. The conditions
were adapted for the dehydrogenative alkylation with ␤-tetralone
to reach ligand 5 high yield, with the successful preparation of the
diaryl ligands, we were curious to selectively prepare the monoaryl
derivative. In the above conditions, the desired monoarylated prod-
uct was obtained with the diarylated one as well as some of starting
materials. Therefore, the reaction was realized stepwise with at
first the formation of the imine followed by the aromatization in
the presence of palladium. By this way, 62% of the monoarylated
molecule 6 was isolated and no racemization of the chiral center
was detected through HPLC analysis.
tified as S isomer by comparison with the literature. An addition of
formic acid 10equiv. (instead of 5) was not beneficial for the reduc-
tion since the conversion was lower (Table 2, entry 3) this maybe
due to the dilution effect and a modification of the pH. Sodium for-
mate was also examined and no improvement was observed for
both conversion and enantiomeric excess (Table 2, entry 4). Fur-
thermore, the reaction was investigated under air and gave low
conversion (26%) with a good improvement of the e.e (82%) (Table 2,
entry 5). Then a mixture of formic acid and sodium formate of ratio
1:1 was used and showed a complete conversion with 85% e.e in
22 h (entry 6). The [(COD)2Ir]BF4/ligand 1 system using a mixture
of formic acid and sodium formate (with pH 3.5 at the beginning
of the reaction) as a reductant gave the best results for this reduc-
tion (conversion >99%). This pH-dependant reactivity with formic
derivatives was previously observed by Ogo [23].
The convenient synthesis of these ligands prompts us to eval-
uate their interest in asymmetric transformation. Inspired by the
literature data, transfer hydrogenation of ketones was considered
and Ru or Ir complexes was associated to isopropanol in the pres-
ence of potassium tert-butoxide [20,21].
The other derived ligands were evaluated in the same condi-
tions.
The substituent on the aromatic ring has no influence on the
reduction since complete conversion was observed for ligand 2, 3,
4 with similar enantiomeric excess (Table 3, entries 1,2,3). In addi-
tion, similar results were also observed with the derivative coming
from ␤-tetralone (Table 3, entry 4), while a loss of the enantiomeric
excess was noticed with the monoarylated ligand (Table 3, entry 5).
The reduction of acetophenone was studied firstly. When
[RuCl2(pcymene)]2 was used as metal precursor with ligand 1
(Table 1, entry 1), 1-phenyl-ethanol was formed with 90% con-
version in a racemic mixture, while with ligand 6 the conversion
was much lower (34%) with a poor enantiomeric excess (11%)
(Table 1, entry 2). With [Ir(COD)2]BF4 and ligand 1 no transforma-
tion was observed (Table 1, entry 3). On the other hand, when the
[IrCp*Cl2]2 was used, a good conversion was obtained but unfor-
tunately without enantioselectivity (Table 1, entry 4). In view of
these results, the nature of the reductant was modified following
Carreira conditions: [22] the reduction of acetophenone was car-
ried out with [(COD)2Ir]BF4 and ligand 1 in water/methanol (1:1)
at room temperature under argon atmosphere for one hour, before
adding formic acid as a reducing agent.
With the optimized condition,
a range of ketones has
been reduced into corresponding alcohols with high to mod-
erate isolated yields and good e.e using catalytic system
[C16H24BF4Ir]/ligand 1 as shown in Table 4.
The substitution of acetophenone with halogen did not affect
the reaction since ketones were efficiently and enantioselectively
reduced whatever the position (Table 4, entries 2–4). The reduction
of acetophenone bearing a EWG nitro group afforded the corre-
sponding alcohol with a good yield but with a poor enantiomeric
excess (Table 4, entry 5), but EWG like trifluoromethyl in the same
position, the reduction occurred with a similar conversion and
enantioselectivity compared to acetophenone (Table 4, entry 6).
Nevertheless, the meta-substitution with two CF3 groups was dele-
Initially, for 1:1 ratio metal:ligand 1 a low conversion was mea-
sured with a relatively good enantiomeric excess (e.e 77%), while
using 1:2 ratio metal-ligand the conversion reached 65% with 78%
e.e Table 2 entry 1 and 2). The configuration of the alcohol was iden-

202
B. El-Asaad et al. / Journal of Molecular Catalysis A: Chemical 411 (2016) 196–202
terious for the enantiomeric excess (Table 4, entry 7). The acidity of
the benzylic proton for the nitro and the di-trifluoromethyl deriva-
tives might be responsible for the decrease of enantiomeric excess.
Acetophenone bearing p-methoxy group was reduced with a low
yield as well as a low enantioselectivity (Table 4, entry 8). In this
particular case, the configuration of the carbon is inverted com-
pared to other, may is due to the coordination or EDG character of
methoxy group. Electron donating group as a methyl in meta give
a lower isolated yield of alcohol with only the starting material but
with similar ee. And the same group in ortho position has a positive
effect on the enantiomeric excess (Table 4, entries 9 and 10).
The reduction of more functionalized ketones was also investi-
gated (Table 5).
With activated ketone, the corresponding hydroxy ester
(Table 5, entry 1) was obtained with a modest induction 43 % (-
e.e and 71% isolated yields. Close results were observed with the
trifluoromethyl derivative (Table 5, entry 12) which was obtained
with a good isolated yield 86% in 59% ee with the opposite con-
figuration. This change is linked to the CF3 group which inverts
the priority order of the group as already well described. Dialkyl
ketones (Table 5, entry 3), gave low e.e 15% of S configuration
with moderate isolated yield. The reaction of 2,6-diacetylpyridine
afforded the corresponding diol (entry 4) in 67% d.e and >99% e.e of
S,S configuration.
trométrie de Masse (CCSM) of Université Lyon 1, for the assistance
and access to the mass spectrometry facility.
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From a very simple procedure to prepare aryl amine, conditions
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Acknowledgements
We thank the research program of the Lebanese University
for the financial and technical support. We thank F. Albrieux, C.
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