Rhodium complex with unsymmetrical vicinal diamine ligand: excellent catalyst for asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1039/c5ra08220j

New unsymmetrical vicinal diamine ligands with systematic variation in the regio and stereo positions in the amine and sulphonamide groups were synthesized from cheap starting material such as norephedrine. Catalytic Asymmetric Transfer Hydrogenation (ATH) of aromatic alkyl ketones has been investigated using transition metal complexes and new derivatives of monotosylated unsymmetrical vicinal diamine ligands using sodium formate as the hydrogen source, in water and methanol. Chiral secondary alcohols were obtained with excellent enantioselectivity (>95% ee) and conversion of ketones (>95%) with [Rh(Cp)Cl₂]₂ and ligand 4 as a catalyst. Enantioselectivity was found to be slightly higher with the use of methanol as a solvent for ATH of ketones with sodium formate as the hydrogen source compared to water as a solvent and was found to be consistent with all the ketones investigated. The reaction mixture is homogeneous in methanol unlike in water, where substrate and product are insoluble in water and form separate phase, sodium formate being soluble in water. The activity and enantioselectivity obtained for ATH of ketones using [Rh(Cp)Cl₂]₂ and unsymmetrical vicinal diamine ligand as catalyst was comparable with the C2 symmetric benchmark ligands like TsDPEN ((1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenylethylene-diamine), and TsCYDN ((1R,2R)-N-(p-tolylsulfonyl)-1,2-cyclohexyl,diamine) under similar reaction conditions. To the best of our knowledge, this is first example of the ATH of ketones with good activity and high enantioselectivity with [Rh(Cp)Cl₂]₂ and unsymmetrical vicinal diamine ligands as catalyst systems.

Full text of DOI:10.1039/c5ra08220j

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Journal Name
RSCPublishing
ARTICLE
Rhodium complex with Unsymmetrical
VicinalDiamine Ligand: Excellent Catalyst for
Asymmetric Transfer Hydrogenation of Ketones
Cite this: DOI: 10.1039/x0xx00000x
Sudhindra H. Deshpandea, Vaishali S. Shendea, Savita Shingotea,
Debamitra Chakravartyb, Vedavati G. Puranik,Raghunath V.
Chaudharic, Ashutosh A. Kelkara*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract.New unsymmetrical vicinal diamine ligands with systematic variation in regio and stereo positions in amine
and sulphonamide groups were synthesized from cheap starting material such as norephedrine. Catalytic Asymmetric
Transfer Hydrogenation (ATH) of aromatic alkyl ketones has been investigated using transition metal complexes and
new derivatives of monotosylated unsymmetrical vicinal diamine ligands using sodium formate as the hydrogen
source, in water and methanol medium. Chiral secondary alcohols were obtained with excellent enantioselectivity
(>95% ee) and conversions of ketones (>95%) with [Rh(Cp*)Cl2]2 and ligand 4 as a catalyst. Enantioselectivity was
found to be slightly higher with the use of methanol as a solvent for ATH of ketones with sodium formate as the
hydrogen source compared to water as a solvent and was found to be consistent with all the ketones investigated. The
reaction mixture is homogeneous in methanol unlike in water, where substrate and product are insoluble in water and
form separate phases, sodium formate being soluble in water. The activity and enantioselectivity obtained for ATH of
ketones using [Rh(Cp*)Cl2]2 and unsymmetrical vicinal diamine ligand as catalyst was comparable with the C2
symmetric benchmark ligands like TsDPEN (1R,2R)ꢀNꢀ(pꢀtolylsulfonyl)ꢀ1,2ꢀdiphenylethyleneꢀdiamine),and
TsCYDN (1R,2R)ꢀNꢀ(pꢀtolylsulfonyl)ꢀ,1,2ꢀcyclohexyl,diamine) under similar reaction conditions. To the best of our
knowledge, this is first example on the ATH of ketones with good activity and high enantioselectivity with
[Rh(Cp*)Cl2]2 and unsymmetrical vicinal diamine ligands as catalyst systems.
Keywords: Asymmetric Transfer Hydrogenation, Rhodium, Unsymmetrical Vicinal Diamine, ketones
.
1. Introduction
Catalytic asymmetric transfer hydrogenation (ATH) of ketones is
one of the important transformations in organic chemistry and a
large number of catalytic methods are available to achieve this goal1ꢀ
4.One of the most significant breakthroughs in transfer
hydrogenation was reported by Noyori et al. with the use of
Ruthenium, Rhodium and Iridium complexes with chiral
Transition metal complex/ligand combination used is important for
achieving good activity and enantioselectivity in ATH of ketones17.
Rhꢀcomplexes were found to be a better catalyst than Ruꢀcomplexes
(of TsDPEN andTsCYDN ligands) in theseconditions with very
high activity and enantioselectivity for various ketones.(Scheme
1).15,16,18
This key development has led to intense exploration of catalyst
systems with the aim of designing more efficient ligands, improving
catalytic activity and broadening the scope of asymmetric transfer
hydrogenation reaction. However; there are limited reports on
structurally versatile monosulfonated diamine ligands. Importantly,
most of these reports are restricted to modifying the substitution on
either sulphonamide group or on the phenyl group without disturbing
the real C2 symmetric backbone of TsDPEN or TsCYDN7,ꢀ10
(Scheme 2a A-D).
monoarylsulfonylatedꢀ1, 2ꢀdiamine5ꢀ10 or βꢀamino alcohols11, as
12
ligands.
Majority of work on ATH of ketones has been carried out using
TsDPEN and TsCYDN (1R, 2R)ꢀNꢀ(pꢀtolylsulfonyl)ꢀ1,2ꢀ
cyclohexyl,diamine) ligands in organic media (formic acidꢀ
triethylamine (FA/TEA) as hydrogen donor) as well as in water and
under aerobic conditions (FA/TEA or sodium formate as hydrogen
donors).13ꢀ16
a
There are very few examples on the synthesis and use
ofunsymmetrical diamine ligands with transition metal catalysts for
ATH of ketones.19ꢀ22 Wills et al.19 synthesized new unsymmetrical
monosulfonated vicinal diamines from cis 2 amino indanol (Scheme
Chemical Engineering and Process Development Division, CSIR-National
Chemical Laboratory, Pune 411 008, India
[aa.kelkar@ncl.res.in,Tel: 91 20 25902544)]
Centre For Materials Characterization, CSIR-National Chemical
b
2
b, E) and observed good results for ligandwith syn
Laboratory, Pune 411 008, India
Chemical and petroleum Engineering Department, Centre for
Environmentally Beneficial Catalysis, University of Kansas, 1501
Wakarusa, Dr. Building B, Room 112 B Lawrence, KS 66047-1803, USA
Phone: 001-785-864-1634, Fax: 001-785-864-6051, E-mail:
rvc1948@ku.edu
c
orientation.19Though,it was proposed later that antiꢀsubstitution of
amine and sulphonamide groups is important for activity and
enantioselectivity.20 Very recently Mingꢀhuaꢀxu and coꢀworkers21
synthesized new analogues of unsymmetrical vicinal diamines and
showed that it is essential to have one phenyl group attached to
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carbon bearing the sulphonamide group and a bulky substituent on
the carbon bearing amine for high activity andenantioselectivity for
ATH of ketones21(Scheme 2 b, F). Roszowski etal. synthised
derivatives of unsymmetrical vicinal diamines from limonene and
HN
Ts
Ligand 1
NH2
HN
Ts
NH2
H2N
HN Ts
H2N
HN Ts
Ligand 4
Ligand 3
Ligand 2
used in ATH of ketones with [Ru(pꢀcymene)Cl2]2, (Scheme 2 b,
G).22
Careful observation of these resultsindicated that there is no clear
view on the type of substituent and its position in the ligand and
itsinfluence on the activity andenantioselectivity. Further, these
reports were restrictedto the useof [Ru(pꢀcymene)Cl2]2 as the metal
complex for ATH and no other transition metal complex was
explored.
HN
NH2
HN
Ts
NH2
H2N
HN Ts
H2N
HN Ts
Ts
Ligand 5
Ligand 6
Liagnd 7
Ligand 8
With this background in mind, unsymmetrical vicinal diamine
ligands starting from cheap and easily available norephedrine were
prepared and tested in ATH of ketones. Diamine derivatives with
different stereo and regio positions of amine and sulphonamide
groups, along with different positions of phenyl and other methyl
group were synthesized (Scheme 3). For this purpose a synthesis
strategy was designed and ligands were synthesized using three
different reaction schemes (Schemes 4, 5 and 6). To the best of our
knowledge this is the first report on use of Rhodium complex with
unsymmetrical vicinal diamine ligands for ATH of ketones with
good activity and enantioselectivity.
Scheme 3. Various Unsymmetrical vicinal diamine ligands synthesized.
During the isolation 10, it was partially converted to Ligand 1.
Subsequent deprotection of BOc group in compound 10 with HCl in
dioxane gave the ligand1 with overall retention of the configuration.
1H NMR spectrum showed the coupling constant of the vicinal
hydrogen to be 4 Hz, indicating the sulfonamide and amine
geometry to be cis with respect to each other. Similar observation
with inversion of configuration at hydroxyl carbon for Mitsunobu
reaction of amino alcohols and ephedrine was reported by Jules
Freedman and others.24, 25
O
OH
OH
HCOONa
Metal Ligand complex
NaHCO3
+
+
ii)
O
N
O
i)
HN
S
NH2
+
S
S
O
NH2
O
O
HO
NH2
O
O
O
O
Ligand = 1,2 Monotosylated diamines
O
HN
Scheme 1: Asymmetric transfer hydrogenation of ketones using
unsymmetrical vicinal diamines
9
Ligand 1
10
a)
9aintermediate aziridine
NaO3S
SO3Na
HN Ts
H2N
NH2
HN Ts
Scheme 4: Synthesis of ligand 1
Reaction conditions i) DEAD,(Diethyl azodicarboxylate) Triphenyl
phosphine in Dichloromethane, ii) 4N HCl in Dioxane
H2N
H2N
H2N
HN Ts
H2N
HN Ts
:
A
B
C
D
b)
Synthesis of ligand 2 has been carried as per the literature
procedures26, 27 (Scheme 5) andreduction using triphenyl phosphine
and water. In the first step, norephedrine (compound 9) was
tosylated using pꢀtoluene sulfonyl chloride to get compound 11.
Mitsunobu reaction was carried out with compound 11 to get
compound 12. Intramolecular cyclisation occurs with inversion of
configuration at the hydroxyl carbon as observed and reported in the
literature.26, 27
N
Ts
H
TsHN
NH2
Ts NH
F
NH2
NH2
E
G
Scheme 2. Structure of Different Monotosylated vicinal diamines a) with
C2 symmetry b) Unsymmetrical diamines
Ring opening of tosylated aziridine (compound12) was carried out
using sodium azide in a mixture of water and acetonitrile (20:80
volume ratio) to obtain compound 13 as the product.26 The ring
opening of this tosylated aziridine occurs with complete inversion at
the phenyl carbon resulting in overall retention of the configuration
(w.r.t starting norephedrine configuration, compound 9).Reduction
of compound 13 with triphenyl phosphine and water gave ligand 2.
The sulfonamide and amine geometry in ligands 1 and 2is cis with
respect to position of amine and sulfonamide groups.
To prepare the isomers with trans geometry, synthetic
methodology as shown in Scheme 6 was followed. Chlorination of
norephedrine (Compound 9) was carried out using thionyl chloride
as per the procedure described in literature.28
2. Results and Discussion
1R, 2S norephedrine and its enantiomer 1S, 2R norephedrine were
used as key starting materials to synthesize various regio and stereo
isomers (Scheme 3) of unsymmetrical vicinal dimaine ligands.
Ligand 1 was synthesized using the reaction of NꢀBOc (tertꢀ
butyloxycarbonyl) sulfonamide with 1R, 2S norephedrine under
Mitsunobu conditions23 (Scheme 4).Intermediate aziridine (9a) is
formed with intramolecular cyclisation and inversion at the hydroxyl
carbon.The ring opening of intermediate is caused by the NꢀBOc
sulfonamide again with inversion of configuration to get the
compound 10 (efforts on the isolation of the intermediate 10 in pure
form failed).
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Cl
S
O
O
.HCl
i)
iii)
ii)
+
i)
ii)
N
N
S
+
HO
NH
S
O
S
O
Cl
NH2
HO
NH2
O
S
O
N
H
O
O
O
O
HO
NH2
Cl
14
15
9
16
12
9
11
iv)
iv)
+
N
iii)
HN
N3
N3
NH
S
O
S
O
O
S
O
H2N
NH
S
O
O
N3
NH
S
N
S
O
O
O
O
O
O
16
17
18
12
Ligand 2
13
Scheme 5: Synthesis of ligand 2
v)
v)
HN
S
N3
N3
NH
S
H2N
NH
S
Reaction conditions: i) Triethyl amine in tꢀButyl methyl ether ii)
DEAD,(Diethyl azodicarboxylate) Triphenyl phosphine in THF(
Tetrahydrofuran) iii) Sodium azide in Acetonitrile: water, iv) Triphenyl
phosphine in THF and water
HN
S
NH2
O
O
O
O
O
O
O
O
The chloro norephedrine, compound 14 was formed with the
inversion of configuration at the carbon bearing hydroxyl group.28
The chloro norephedrine hydrochloride (compound 14) was treated
with sodium hydroxide, resulting in the formation of compound 15.
This transformation again takes place with the inversion of
configuration at benzylic carbon to form aziridine25, 29 (compound
15). The aziridine was reacted withpꢀtoluene sulfonyl chloride and
pyridine to get compound 16. The ring opening of sulfonated
aziridine (compound 16) was carried out using 1,4ꢀ
Ligand 4
17
18
Ligand 3
Scheme 6: Synthesis of ligand 3 and 4
Reaction conditions: i) SOCl2, ii) 4N NaOH, in Methanol, iii) Pyridine in tꢀ
butyl methyl ether iv) 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO) and
Trimethylsilyl azide (TMS azide), v) Triphenyl phosphine in THF and H2O
In compound 18azide is attached to the carbon having phenyl group
(formed due to ring opening of the sulfonated aziridine 16from
phenyl side) and sulfonamide group is attached to carbon having
methyl group and showed coupling constant of 5.8 Hz. Thetrans
geometry of azide and sulfonamide in azide (compound 18a
enantiomer of 18) was confirmed by X ray single crystal structure.
ORTEP diagram for the azide intermediate compound 18a is
presented in Figure 1. (details in supporting information, page
number 39 section 5).The reduction of azide compounds (17 and 18)
was carried out using triphenyl phosphine/water. Acid base work up
was used to isolate ligand 3as a white solid. In case of ligand 4
however, this purification procedure gave gummy mass which on
standing for two days became off white sticky solid. Therefore,
ligand 4 was prepared as hydrochloride salt using 4N HCl in dioxane
to obtain free flowing solid. Enantiomers of these ligands (Ligands
5-8) were prepared by using the same procedure using 1S, 2R
norephedrine as a starting material.
diazabicyclo[2.2.2]octane(DABCO) in
2
equivalence and
Trimethylsilyl azide(TMS azide) as a nucleophile and azide source.
Two compounds (compound 17 and compound 18) were formed
during this reaction (in a 60:40 ratio checked by NMR).
Please note that in Scheme 5, aziridine with trans geometry gave
only one product (compound 12).26, 27 Phenyl and methyl groups in
sulfonated aziridine (Scheme 5, compound 12) are trans with respect
to each other. Thus, ring opening of compound 12 produces only one
compound with complete regio and stereo specificity. In compound
16, (Scheme 6), geometry of phenyl and methyl is cis w.r.t each
other. The ring opening of aziridine and activated aziridine in
ephedrine type compounds is governed by the stereochemistry of the
phenyl and methyl groups. Compound with cis geometry is known to
produce regioisomers because of attack from both the sides.24, 25This
probably results in attack of nucleophile from both the sides
producing 2 compounds( compounds 17 and 18). These two
compounds were found to be very difficult to separate by column
chromatography or crystallization methods. The purification by flash
chromatography was developed for the separation of these two
compounds. The detailed structural analysis of these compounds was
carried out. The NMR spectrum of compound 17clearly showed that
benzylic proton had an additional coupling constant (8 Hz) and is
coupled to the NH proton of the sulfonamide group. (Confirmed
with 2D 1Hꢀ1H COSY (Correlation Spectroscopy) and 1Hꢀ
15NHMBC) (Supporting Information, page number, 38 section 4).
This indicated the ring opening of sulfonated aziridine (compound
16), is proceeding from methyl side also.
2.1 ATH of ketones in water
ATH of acetophenone using sodium formate as hydrogen donor and
water was investigated using Ru, Rh and Ir metal complexes as
catalyst precursors with eight monosulfonated diamine
ligandsprepared as described. The results are presented in Table 1.
The results showed that the catalysts prepared with
monosulfonateddiamine ligands (Table 1, Sr. No. 1ꢀ8) were active
and selective for asymmetric transfer hydrogenation of
acetophenone.It was also observed that ligandꢀmetal complex
combination
was
important
for
high
activity
and
enantioselectivity.Rh catalyst showed excellent conversion (>97%)
and enantioselectivity (>90%) with ligands 3 and 4 (Table 1 entry
3,4,7,8) and very low conversion with ligands 1 and 2,while Ru (10
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to 36%) and Ir (10 to 22 %) catalysts showed lower activity with all 30The position of amine and sulfonamide groups with respect to each
the ligands.
other had significant impact on conversion, but lower effect on
enantioselectivity.Best results (99 % conversion in 1.25 h with 92 %
ee) were obtained using Rhꢀligand
4 catalyst systemwith
[Rh(Cp*)Cl2]2.and further screening of ketones was done withRhꢀ
ligand 4 catalyst system.
Comparison of the results obtained with [Rh(Cp*)Cl2]2 and ligand 4
in the present work with literature reports with[Rh(Cp*)Cl2]2
TsDPEN, and TsCYDN, indicated that enantioselectivity was
slightly lower (97 % for TsDPEN,15 94 % for TsCYDN18 vs 92 %
for ligand 4, Table 1 entry 4).
2.2 Screening of ketones using [Rh(Cp*)Cl2]2ligand 4 complex
Various ketones were screened for ATH using Rhꢀligand
4
catalyst system with sodium formate as the hydrogen donor in
water. The results are presented in Table 2. With acetophenone;
95 % conversion was observed with 91 % ee in 1 h. With the
presence of electron withdrawing groups in para position (
pꢀ
chloro acetophenone and ꢀbromo acetophenone), the
p
conversions as well as enantioselectivity were slightly lower
compared to acetophenone, (Table 2, entry 2 and 3). With
electron donating groups in para position (methyl and isobutyl
acetophenone), conversions were significantly lower, 90 % and
87 % in 2 h and 6 h respectively. The enantioselectivity
however was higher for methyl acetophenone (97 %) compared
to acetophenone (91 %) (Table 2 entry 5). For isobutyl
acetophenone the enantioselectivity was found lower ( 89%).4ꢀ
methoxy acetophenone is known to be a challenging substrate
for ATH reaction, probably because of its low redox potential5.
In the present work 4ꢀmethoxy acetophenone was also reduced
with very good conversion (82 % in 2h) and excellent
enantioselectivity (97%). Although to reach more than 90 %
conversion it took nearly 12 h (Table 2 entries 6). Cyclic
ketones like indanone and tetralone were reduced at much faster
rate but lower than acetophenone and with significantly lower
enantioselectivity (98 % conversion in 1.5 h with 84 % ee for
indanone, 95 % conversion in 2 h with 88 % ee for tetralone)
(Table 2, entry 8 and 9). For 6ꢀmethoxyꢀ2ꢀacetyl naphthalene
(Table 2, entry 10), however only 5 % conversion was observed
with 98 % ee even after prolonged reaction time of 12 h. For
this reaction it was observed that, substrate is insoluble in water
and floats on water.
Figure 1. ORTEP diagram of compound 18a Ellipsoids are drawn at 50%
probability (CCDC Depositary number CCDC 1018428, Details supporting
information page number 38)
Enantioselectivity for all the metal complexes and all ligands was
good to excellent and was in a range of 68 to 92%. Relative
stereochemistry of the amine and sulfonamide group of ligand was
found to be critical in deciding the activity of the catalyst system.
For example Ligand 1 and 2 having syn geometry of the amine and
sulfonamide groups were less reactive irrespective of the metal
complex used. Thus, ruthenium, rhodium and iridium complexes
used in this study showed < 30 % conversion with moderate to good
ee. (67ꢀ90%.).Similar observation is noted by other research groups
for compounds having syn or cis geometry. However, indane based
sulfonamide ligands showed high conversion and ee (96%, and 83%
ee),19though amine and sulfonamide configuration in these ligands
was cis w.r.t each other. Ligands having anti or trans geometry
(ligands 3 and 4) showed high conversions and ee (>90%) for the
[Rh(Cp*)Cl2]2 catalyst (Table 1, Sr. No. 3 and 4).
The structure activity relationship showed that along with
stereochemistry of the amine and sulfonamide groups, their regio
position is also important. In ligand 3 sulfonamide group is attached
to the carbon having phenyl group and amino group is attached to
the carbon having methyl group. In ligand 4 the amino group is
attached to the carbon having the phenyl group and sulfonamide
group is attached to the carbon having the methyl group. The results
showed that ligand 4 and its enantiomer (Table 1, entry 4 and 8)
were most active for all the catalysts screened and best results were
observed with [Rh(Cp*)Cl2]2 (99% conversion with 92 % ee in 1.25
h). The activity was marginally higher than ligand 3 and its
enantiomer for [Rh(Cp*)Cl2]2(97 % conversion with 92 % ee in
2h,entry 3 and 7). The difference in activity between ligand 3 and 4
was probably because of the different positions of the amine and
sulfonamide group. The enantioselectivity using both the ligands 3
and 4 was same, indicating that methyl and phenyl group attached to
the carbon having sulfonamide group do not influence
enantioselectivity. It was found that the configuration of the resultant
alcohol was having the same configuration as that of the carbon
bearing sulfonamide group. Thus, for all the entries it was observed
that irrespective of the activity shown by ligand, configuration is
driven by the carbon bearing sulfonamide group. These observations
were found to be consistent with the observed literature reports.20ꢀ22,
Since 6ꢀmethoxyꢀ2ꢀacetyl naphthalene is a solid, it is not
forming a separate layer along with the catalyst as found in the
case of other ketones. Because of this the reaction cannot take
place at the interface of aqueous phase and organic phase
(ketone)13.The use of appropriate solvent to solublise such
substrates and make a homogeneous phase would be helpful in
driving the reaction forward. With this idea in mind ATH of
ketones was investigated with methanol as a solvent( Scheme
7
). Before initiating this activity, the role methanol only as
solvent was confirmed using deutarated methanol as solvent
and reactant. (Supporting info
16).
rmation, section 2.1, page number
O
OH
OH
O
O
Sodium Formate /Methanol
Metal Ligand complex
O
+
+
Na
Scheme 7: ATH of ketones using Sodium formate in methanol
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Table 1: ATH of acetophenone using monosulfonated unsymmetrical diamines and transition metal complexes
Entry
Ligand
([Ru(p-cymene)Cl2]2
[Rh(Cp*)Cl2]2
[Ir(Cp)*Cl2]2
Conv. [%]
Conv. [%]
ee %
Config
conv. %
ee
Config.
ee
Config.
%
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
12
68
70
90
85
70
72
91
83
R
S
R
S
S
R
S
R
23
78
82
92
92
80
83
92
92
R
S
10
86
75
82
90
85
77
80
88
R
S
R
S
S
R
S
R
<10
22
18
<10
22
97
R
S
S
36
99*
21
22
10
10
<10
21
15
R
S
R
<10
20
97
32
99*
20
Reaction conditions
2 h, * 1.25 h
:
Metal complex, 0.005mmol; Ligand,0.01mmol; sodium formate 5 mmol; acetophenone, 1mmol;water 2cm3 ; Temperature: 250C; Time
Table 2: ATH of various ketones using [Rh (Cp*)Cl2]2and ligand 4
Entry
Ketone
Reaction
time (h)
Conv. %
FinalTO
F,h-1
%ee
1
2
Acetophenone
4ꢀBromo Acetophenone
4ꢀChloro Acetophenone
2,4 Dichloro acetophenone
4ꢀmethyl acetophenone
4ꢀisobutyl acetophenone
4ꢀMethoxy acetophenone
1 Indanone
1
1.5
1.5
2
95
99
94
66
66
48
46
12
28
66
48
ꢀ
91
88
88
86
97
89
97
84
88
98
3
99
4
95
5
2
90
6
6
87
7
3(12)
1.5
2
82(95)
98
8
9
1ꢀtetralone
95
10
6ꢀmethoxy2ꢀAcetylnaphthalene
12
5
Reaction conditions:Rh(Cp*)Cl2]2, 0.005 mmol; Ligand, 0.01 mol; ketone,1 mmol; sodium formate 5 mmol; water,2 cm3; Temperature: 250C
2.3 ATH of ketones with methanol as a solvent
ATH of acetophenone in methanol as a solvent (Scheme7) was complex which is a catalyst precursor in ATH of ketones
as
investigated in detail using [Rh (Cp*)Cl2]2 as a catalyst precursor reported by Noyori.8(For details see supporting information page
and ligands 1-8 (Table 3). The trends for activity observed were number 15 section 2).Ligand4 showed better activity than
similar to that observed in water and sodium formate for all ligands ligand3(97% in 2h, Vs 82
% in 2h respectively). The
with high activity for ligands3 and4(ligands with trans geometry of enantioselectivity obtained however was similar for both the ligands
amine and sulfonamide groups).Alsoin general the ee values (96% and 95% respectively) (Table 3, entry 3, 4, 7, 8). The activity
obtained in methanol were higher for all the ligands than for ATH of acetophenone with ligands 1 and 2 (ligands with cis
thoseobtained in water (compare results in Table 1 and Table geometry of amine and sulfonamide groups) with Rh catalyst was
3).Methanolic solution became turbid as reaction progressed due to very low. However,the reaction mixture became turbid after 2 h,
the formation of sodium methyl carbonate and 18 electron hydride
indicating the formation of sodium methyl carbonate and Rhꢀhydride
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complex(similar to that observed in case of ligands3 and 4). It was Finally the results obtained for ATH of acetophenone with Rhꢀligand
not possible to get similar observations in water as sodium hydrogen 4 were compared with benchmark ligands like RhꢀTsDPEN and Rh –
carbonate generated is water soluble. Xiao et al16, have proposed that TsCYDN (Fig.2.) with methanol as solvent. It was observed that
rate determining step may not be the one with metal hydride initial activity of RhꢀTSDPEN is slightly higher than Rhꢀligand 4
formation but transfer of hydride to ketonic substrate via six complex, but comparable with RhꢀTsCYDN (Fig. 2c TOF, hꢀ1 at 15
membered
electroncomplex could be critical in deciding the activity and observed. Rh–TsDPEN showed marginally higher ee than Rhꢀ
enantioselectivity in ATH of ketones. TsCYDN and RhꢀLigand 4 complex (98% vs 96 % receptively).
transition
states14ꢀ16.Thus
geometry
of
18 mins 213, 170 and 167 respectively). Similar effect in the ee was
Table 3: ATH of acetophenone in methanol as solvent
Entry Ligand Time (h) Conv % Final TOF,hꢀ1 ee % Config
1
1
2
3
4
5
6
7
8
2
10
ꢀ
85
85
95
96
85
85
95
96
R
S
R
S
S
R
S
R
2
3
4
5
6
7
8
2
18
ꢀ
2(4)
2
82(98)
97
24
49
ꢀ
2
10
2
18
ꢀ
2(4)
2
82(98)
97
24
49
Reaction conditions: [Rh(Cp*)Cl2]2,0.005mmol; Ligand,0.01mmol; acetophenone 1 mmol ; sodium formate 5 mmol; Temperature:
250C;Methanol, 2cm3
a)
b)
c)
Figure 2: Comparative data, for Ligand 4 with benchmark ligands TsCYDN, TsDPEN, a) conversion, b) ee c) Initial TOF, h-1 (15 mins)
Reaction conditions
acetophenone,1mmol
:
[Rh(Cp*)Cl2]2, 0.005 mmol; ligand 0.01 mmol; sodium formate 5 mmol,; Temperature, 250C; Methanol 1.88 cm3
2.4Comparison of results in water and methanol
Various ketones were screened using [Rh(Cp*)Cl2]2/ligandꢀ4 water,table 3 entry 9).Tetralone was reduced within 3 h with more
catalyst system with methanol as solvent and the results are than 98 %ee, vs 88% ee in water, table 3 entry 9.2ꢀacetylꢀ6
presented in Table 4.All theketones were reducedwith excellent methylnaphthalenegave55% conversion with 98% ee in 2 h reaction
conversion and enantioselectivity and the activity trends observed time in methanol as solvent, compared to just 5% with water as a
were similar to those observed with water as solvent, (compare solvent.Comparison of the results with Rhꢀligand 4 catalyst system
Tables2 and 4). However, consistently higher ee was observed for all showed that activity for all the ketones screened was higher with
the ketones investigated, with slightly lower activity than observed water as a solvent,(Table 2 and 4) but the enantioselectivity in
in water.Cyclic ketone like Indanone ( table 4, entry 7) was reduced methanol was consistently higher by ~5 %. For cyclic ketones like
within 2 h with 98% conversion and 97% ee, (vs 84 % ee in indanone and tetralone the enantioselectivity was higher by 10ꢀ12%
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Table 4: ATH of various ketones using ligand4 and [Rh (Cp*)Cl2]2 catalyst using methanol as solvent
Entry
Ketone
Time
(h)
Conv.
%
Final
TOF,
h-1
ee
%
1
Acetophenone
2
97
49
50
50
48
47
16
9
96
96
96
92
97
97
97
97
98
86
98
92
98
2
4-Bromoacetophenone
4-chloroacetophenone
2,4 Dichloroacetophnenone
4-Methyl acetophenone
4-Isobutyl acetophenone
4-Methoxy acetophenone
1-Indanone
2
99
3
2
99
4
2
95
5
2
94
6
6
97
7
8
74
8
2
98
49
46
7
9
1-Tetralone
2(3)
12
14
2
92(98)
88
10
11
12
13
2-Acetyl pyridine
3-Acetyl pyridine
98
7
p-Bromopropiophenone
88
44
28
2-Acetyl 6 Methoxy
naphthalene
2
55
Reaction Conditions:[Rh(Cp*)Cl2]2,0.005 mmol; Ligand,0.01mmol; ketone 1 mmol; sodium formate 5 mmol; Temperature: 250C; Methanol 2cm3
3Experimental Section. 4 Conclusions.
All the experiments were carried out using ovenꢀdried glassware in New unsymmetrical vicinal diamines were synthesized having
open air. All the ketones used except 2ꢀAcetylꢀ6ꢀmethoxy different regio and stereo positions of amine and sulphonamide
naphthalene were procured from Aldrich. 2ꢀAcetylꢀ6ꢀmethoxy groups. The ATH of ketones using sodium formate as a hydrogen
naphthalene was obtained as a free sample from private company source and water and methanol as solvents was studied.
and purity of the compound (>98%) was confirmed by GC and GCꢀ Unsymmetrical vicinal dimaines synthesized from norephedrine in
MS analysis. All solvents used were reagent grade. combination with [Rh (Cp*)Cl2]2 as catalyst is effective for ATH of
[Rh(Cp*)Cl2]2was purchased from Strem Chemicals. The NMR various ketones, using water as well as methanol as solvent. The
spectra were recorded on a 400 MHz Bruker spectrometer. HPLC ATH proceeds smoothly with conversion ranging between 88 to 98
analysis was carried out using Waters HPLC instrument with % and enantioselectivity between 86 %ꢀ 97%. The structure activity
quaternary gradient pump, diode array detector and auto sampler. relationship was studied and excellent enantioselectivity has
GCꢀMS analysis for conversions of ketones was carried out using beenobtained using ligand where phenyl group is attached to the
Thermo Trace GC DSQ and HPꢀ5columnpurchased from Agilent carbon bearing amine group and methyl group is attached to the
Technologies.HRꢀMS analysis was done using Agilent 6520 QꢀTOF carbon bearing sulphonamide group. Enantioselectivity for all
instrument. The analytical methods used for chiral analysis of ketones screened was consistently high except for pyrydyl ketones.
alcohols are taken from earlier available literature.6,9ꢀ11,15
The enantioselectivity was found to be consistently higher by small
but measurable amount for ATH various ketones with methanol as
3.1 Preparation of precatalyst /catalyst
solvent. The results obtained with Rhꢀligand
4
complex
The procedure described by Noyori6 and Xiao et al13ꢀ15, 18 was used
to prepare the precatalyst. In a typical experiment Rhodium complex
(5mmol, 3.09 mg) and ligand (10 mmol, 3.1 mg) were mixed in
water/methanol (2ml). The contents were heated at 400C for 1h.To
the same solution ketone 1 mmol and sodium formate 5 mmol
wereadded and reaction was initiated.
werecomparable with benchmark ligands like RhꢀTsDPENand Rh –
TsCYDN. To the best of our knowledge this is the first example of a
[Rh(Cp*)Cl2]2 and unsymmetrical vicinal diamine catalyst system
used in ATH of ketones with very high conversions and
enantioselectivity. The use of methanol makes this reaction truly
homogeneous. This homogeneity of reaction in methanol
providesfurther opportunity to study the mechanistic and kinetic
details of the
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reaction much more easily than in water. Further work on ATH ofketones is in progress in our laboratory..
15. X. Wu, X. Li, A. ZanottiꢀGerosa, A. Pettman, J. Liu, A. J.
Mills and J. Xiao, Chem. - Eur. J., 2008, 14, 2209ꢀ2222.
16. X. Wu, J. Liu, T. D. Di, J. A. Iggo, C. R. A. Catlow, J. Bacsa
and J. Xiao, Chem. - Eur. J., 2008, 14, 7699ꢀ7715.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
17. D. J. Cross, J. A. Kenny, I. Houson, L. Campbell, T.
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