Chiral Oxazolidine-Fused N-Heterocyclic Carbene Complexes of Rhodium and Iridium and Their Utility in the Asymmetric Transfer Hydrogenation of Ketones

Article abstract of DOI:10.1002/ejic.201700303

The catalytic potential of new N-heterocyclic carbene ligands, derived from a chiral fused bicyclic ring scaffold with restricted rotation along the C–N bond bearing the chiral auxiliary, has been explored in the transition-metal-mediated asymmetric transfer hydrogenation reactions of ketones. In particular, the chiral oxazolidine-fused N-heterocyclic carbene precursors (3S)-3-R-6-methyl-7-phenyl-2,3-dihydroimidazo[5,1-b]oxazol-6-ium iodide [R = sec-butyl (1f), i-butyl (2f), isopropyl (3f)] were synthesized from commercially available optically pure amino acids in a multistep sequence that avoids tedious chiral resolution. The reactions of the chiral imidazolium iodide salts 1f–3f with Ag₂O yielded the corresponding silver complexes 1g–3g, which were treated with [(COD)MCl]₂ (M = Rh, Ir; COD = 1,5-cyclooctadiene) to afford the rhodium(I) and iridium(I) complexes (1h–3h and 1i–3i, respectively). The rhodium(I) and iridium(I) complexes conveniently catalyze the asymmetric transfer hydrogenation of acetophenones for a wide variety of substrates ranging from electron-rich ones such as 4-methylacetophenone, 3,4-dimethylacetophenone, 4-tert-butylacetophenone, and 4-(methylthio)acetophenone to electron-deficient ones such as 4-bromoacetophenone, 4-chloroacetophenone, 4-fluoroacetophenone, 4-nitroacetophenone, and 3-fluoroacetophenone in moderate-to-good yields (ca. 18–95 %) but with low enantioselectivities (ca. 4–41 % ee).

Full text of DOI:10.1002/ejic.201700303

A Journal of
Accepted Article
Title: Chiral Oxazolidine fused N-heterocyclic Carbene Complexes
of Rhodium and Iridium and their Utility in Asymmetric Transfer
Hydrogenation of Ketones
Authors: Balasubramaniyam Ramasamy, Manoj Kumar Gangwar, and
Prasenjit Ghosh
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To be cited as: Eur. J. Inorg. Chem. 10.1002/ejic.201700303
Link to VoR: http://dx.doi.org/10.1002/ejic.201700303

European Journal of Inorganic Chemistry
10.1002/ejic.201700303
Chiral Oxazolidine fused N-heterocyclic Carbene Complexes of Rhodium
and Iridium and their Utility in Asymmetric Transfer Hydrogenation of
Ketones
Balasubramaniyam Ramasamy, †,‡ Manoj Kumar Gangwar and Prasenjit Ghosh*
†
,†
‡BASF Chemicals India Pvt. Ltd,
Chandivali, Mumbai 400 072
†Department of Chemistry
Indian Institute of Technology Bombay
Powai, Mumbai 400 076
Email: pghosh@chem.iitb.ac.in
Fax: +91 22 2572 3480
1
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
Keywords: oxazolidine-fused imidazole based N−heterocyclic carbenes  chiral fused
bicyclic NHC  rhodium  iridium  asymmetric transfer hydrogenation
2
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European Journal of Inorganic Chemistry
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Abstract: Catalytic potential of a new N‒heterocyclic carbene ligand derived from a chiral
fused bicyclic ring scaffold, having a restricted rotation along the C‒N bond bearing the
chiral auxiliary, have been explored in transition metal mediated asymmetric transfer
hydrogenation reactions of ketones. In particular, the chiral oxazolidine fused N‒
heterocyclic
carbene
precursors
namely,
{(3S)-3-R-6-methyl-7-phenyl-2,3-
dihydroimidazo[5,1-b]oxazol-6-ium iodide (R= sec-butyl (1f), i-butyl (2f), i-propyl (3f)}
were synthesized from commercially available optically pure amino acids in a multi-step
sequence avoiding tedious chiral resolution protocol. The reaction of the chiral imidazolium
iodide salts (1‒3)f with Ag
when treated with {(COD)MCl}
1‒3)i complexes. The rhodium(I) (1‒3)h and the iridium(I) (1‒3)i complexes conveniently
2
O yielded the corresponding silver complexes (1‒3)g, which
2
(M = Rh, Ir) gave the rhodium(I) (1‒3)h and the iridium(I)
(
carried out the asymmetric transfer hydrogenation of acetophenones for a wide variety of
substrates ranging from the electron rich ones namely, 4‒methyl acetophenone, 3,4 dimethyl
acetophenone, 4‒t-butyl acetophenone, 4‒methylthio acetophenone to the electron deficient
ones namely, 4‒bromo acetophenone, 4‒chloro acetophenone, 4‒fluoro acetophenone, 4‒
nitro acetophenone and 3‒fluoro acetophenone in moderate to good yields (ca. 18‒95 %) but
low enantioselectivities (ca. 4‒41 %).
3
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
Introduction
The development of new motifs as ligand platforms for catalysis remains an active area of
research for the phenomenally successful N-heterocyclic carbenes (NHC’s).1-3 In this regard,
the fusion of two immensely successful ligands in homogenous catalysis like that of the
4
5
oxazolidines and the imidazole based N-heterocyclic carbenes has resulted in an interesting
new breed of fused bicyclic N-heterocyclic ligand derived from a hybrid oxazolidine-
imidazole motif.6-9 In asymmetric catalysis, owing to its unique feature of having a restricted
rotation along N−C bond housing the chiral substituent, this type of ligands exhibit promising
enantioselectivities over conventional chiral ligands in many reactions namely, Micheal
addition,10 benzoin condensation,11 α−arylation,12 Stetter reaction,13 Coates-Claisen
1
4
15
rearrangement and hydration of α−halo aldehydes. For example, under Ligand Assisted
Catalysis (LAC) conditions for the asymmetric Michael addition reaction of 1,3-
diphenylpropane-1,3-dione and (E)-(2-nitrovinyl)benzene, a fused bicyclic N-heterocyclic
carbene
ligand
namely,
(5aS,10bR)-2-mesityl-4,5a,6,10b-tetrahydroindeno[2,1-
b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborate, having a restricted rotation
around N–C bond, exhibited a higher enantiomeric excess (ee) of 76 %, whereas another
chiral N-heterocyclic carbene ligand namely, (1,3-bis((S)-1-phenylethyl)-1H-imidazol-3-ium
tetrafluoroborate, having a free rotation around the N–C bond, showed no chiral induction
under analogous conditions.16
Despite the promise, the multi-step sequences required for synthesising these fused bicyclic
oxazolidine N−heterocyclic carbene ligands has somewhat constricted a larger applicability
of these ligands, and this has attracted our attention. Specifically, with our interest being in
exploring the catalytic utility of different ring types of the N‒heterocyclic carbene ligands,17-
2
0
spanning from the ubiquitous 5-membered cyclic imidazole21-26 and triazole27-29 based
4
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
3
0
ones to the less common variety like, the acyclic 6-membered N−heterocyclic carbenes, the
bicyclic imidazo[1,2-a]pyridine31, 32 and the tricyclic triazolooxazine derived ones,33 we
became interested in exploring the catalytic exploits of one such less frequently encountered
chiral bicyclic oxazolidine fused N-heterocyclic carbene ligands. Furthermore, as much of
the catalysis reported for these bicyclic oxazolidine fused N−heterocyclic carbene based
8
systems were performed under in-situ Ligand Assisted Catalysis (LAC) conditions, with no
examples known of well-defined transition metal complexes, we decided to employ
structurally characterized molecular complexes for our study in asymmetric catalysis in order
to obtain a better insight on the catalyst mode of action.
To begin with, we chose to study the asymmetric transfer hydrogenation of ketones for its
scope for a larger applicability.34, 35 Though the hydrogenation of ketones to the
corresponding alcohols is achieved by conventional stoichiometric reducing agents like
NaBH
4
, LiAlH and other hydrides, the subsequent economic considerations and the hazards
4
involved in handling post–reaction wastes in scale up processes calls for cleaner
methodologies for this simple reaction. In this scenario, the catalytic hydrogenation of
ketones in both achiral and chiral fashion has gained prominence in recent times.36 It is
interesting to note that, though the transition metal complexes of N–heterocyclic carbenes
have been extensively studied for the transfer hydrogenation of ketones to alcohols,37, 38 the
reports of the related chiral versions are surprisingly few.39-43
Here in this manuscript, we report the design and synthesis of a less explored chiral
oxazolidine fused N-heterocyclic carbene ligand using a multi-step synthetic protocol
avoiding tedious chiral resolution procedure by starting from cheap commercially available
5
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
enantiopure amino acids. We further demonstrate the utility of the rhodium (1−3)h and the
iridium (1−3)i complexes of these ligands in asymmetric transfer hydrogenation of ketones
(Figure 1).
6
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
O
N
N
R
M Cl
R = sec-butyl, M = Rh (1h), Ir (1i)
R = i-butyl, M = Rh (2h), Ir (2i)
R = i-propyl, M = Rh (3h), Ir (3i)
Figure 1. Rhodium(I) (1–3)h and iridium(I) (1−3)i complexes supported over NHC ligands derived from chiral oxazolidine-fused imidazole
scaffolds synthesized from commercially available amino acids.
7
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
O
OH
OH
H
O
N
NH2
OH
HN
H
O
N
O
n-BuCOOCl
H
TsCl
O
N
H
R
HN
Et N
R
3
R
O
(
1-3)a
b
(1-3)c
(1-3)d
P2O
5
R = sec-butyl (1), i-butyl (2), i-propyl (3)
1
O
O
O
O
8
Ag O
2
7
{
(COD)MCl}2
2
CH3I
3
N
N
N
N
N
N
I
N
N6
-
4
R
5
R
R
R
M Cl
Ag
I
(
1-3)g
(1-3)f
(1-3)e
M = Rh (1-3)h
M = Ir (1-3)i
Scheme 1. Synthetic protocol for the chiral oxazolidine-fused imidazole derived N-heterocyclic carbene complexes of rhodium(I) (1−3)h and
iridium(I) (1−3)i.
8
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
Results and discussion
A new class of chiral oxazolidine fused N–heterocyclic carbene ligand namely, {(3S)-
-R-6-methyl-7-phenyl-2,3-dihydroimidazo[5,1-b]oxazol-5-ylidene} (R = sec-butyl,
3
i-butyl, i-propyl), having a restricted rotation along the C–N bond containing the
chiral centre, has been synthesized using a multi-step sequence (Scheme 1). The
strategy successfully avoids tedious chiral resolution steps by making use of cheap
and commercially available optically pure amino acids. In particular, the chiral
oxazolidine fused imidazoles (1–3)e were constructed in four steps, starting from the
reaction of amino alcohols (1–3)a with (R)-2-formamido-2-phenylacetic acid (b) in
presence of n-butyl chloroformate and N-methyl morpholine as a base at –30 °C
producing an amide intermediate (1–3)c in 20–49 % yield. The intramolecular
cyclization of the amide intermediate (1–3)c in presence of p-toluene sulphonyl
chloride (TsCl) at room temperature resulted in the formation of the formyl oxazole
derivatives (1–3)d in 35–66 % yield. A second intramolecular cyclization leading to
the chiral bicyclic oxazolidine fused imidazole compounds (1–3)e was affected by the
dehydration of formyl oxazole (1–3)d in presence of anhydrous P
2
5
O in 46–66 %
yield.
The alkylation of the oxazolidine fused imidazoles (1–3)e with methyl iodide gave the
corresponding chiral bicyclic oxazolidine fused N–heterocyclic carbene precursors
(1–3)f in 51–96 % yield. The formation of (1–3)f was evident by the appearance of a
1
characteristic downfield NCHN peak at ca 9.74 – 9.89 ppm in the H NMR spectrum.
The treatment of chiral bicyclic oxazolidine fused imidazolium iodide salts (1–3)f
with Ag
2
O at room temperature yielded the corresponding silver complexes (1–3)g in
9
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
8
5–90 %. The formation of silver complexes (1–3)g was characterized by the
1
disappearance of the NCHN peak of the reactant (1–3)f in H NMR spectrum along
with the appearance of the downfield shifted silver bound NCN (Ag–Ccarbene
)
13
1
resonance at ca. 169.4 – 170.8 ppm in the C{ H} NMR spectrum. The rhodium
complexes (1–3)h were subsequently prepared by a transmetallation reaction from the
silver complexes (1–3)g by the treatment with {(COD)RhCl} at room temperature in
2
1
8
5–97 % yield. The H NMR spectrum of (1−3)h revealed the presence of two
isomers in a ca. 60 : 40 ratio at room temperature as observed from the N-CH
3
resonance at ca 4.03 – 4.05 ppm for the major isomer and at ca. 4.00 – 4.01 ppm for
the minor isomer. The existence of these isomers in solution arise due to the rotation
around the M−Ccarbene bond in these complexes (Scheme 2), which was further
confirmed by variable temperature 1H NMR experiment performed for a
representative complex 1h, where the coalescence of N-CH
3
resonance observed at
1
3
1
6
0°C (Supporting Information figures S300 and S301). The C{ H} NMR spectrum
showed the expected Rh−Ccarbene coupling manifesting as a doublet at 176.3 ppm (JRh-
= 48 Hz) for 1h, 171.7 ppm (JRh-C = 50 Hz) for 2h and at 171.9 ppm (JRh-C = 50 Hz)
for 3h.
C
Scheme 2. Conformational exchange in complexes (1−3)h and (1−3)i.
1
0
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European Journal of Inorganic Chemistry
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The iridium complexes (1–3)i were analogously obtained from the silver complexes
1–3)g by the transmetallation reaction with {(COD)IrCl} in 45–96 % yield at room
temperature. Both the H NMR and C{ H} NMR spectra of iridium complexes
1−3)i were similar to that of the rhodium complexes (1−3)h in terms of the
observation of two isomers in solution.
(
2
1
13
1
(
1
1
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
Figure 2. ORTEP of 1h with thermal ellipsoids are shown at the 50 % probability
level. Selected bond lengths (Å) and angles (°): Rh(1)−C(1) 2.0209(18), Rh(1)−Cl(1)
.3823(5), Rh(1)−C(16) 2.100(2), Rh(1)−C(23) 2.1004(19), Rh(1)−C(20) 2.185(2),
2
Rh(1)−C(19) 2.2102(18), C(1)−Rh(1)−Cl(1) 89.91(5), C(1)−Rh(1)−C(16) 89.49(7),
C(1)−Rh(1)−C(23) 92.15(8), C(1)−Rh(1)−C(19) 162.16(8), C(1)−Rh(1)−C(20)
1
61.38(8).
1
2
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European Journal of Inorganic Chemistry
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Figure 3. ORTEP of 1i with thermal ellipsoids are shown at the 50 % probability
level. Selected bond lengths (Å) and angles (°): Ir(1)−C(1) 2.018(5), Ir(1)−Cl(1)
.3670(13), Ir(1)−C(17) 2.096(5), Ir(1)−C(16) 2.096(5), Ir(1)−C(20) 2.154(5),
2
Ir(1)−C(21) 2.193(5), C(1)−Ir(1)−Cl(1) 90.68(14), C(1)−Ir(1)−C(16) 89.3(2),
C(1)−Ir(1)−C(17) 92.4(2), C(1)−Ir(1) −C(20) 160.6(2), C(1)−Ir(1)−C(21) 161.89(19).
1
3
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
Figure 4. ORTEP of 2h with thermal ellipsoids are shown at the 50 % probability
level. Selected bond lengths (Å) and angles (°): Rh(1)−C(1) 2.023(4), Rh(1)−Cl(1)
.376(10), Rh(1)−C(24) 2.091(4), Rh(1)−C(17) 2.104(4), Rh(1)−C(20) 2.187(4),
2
Rh(1)−C(21) 2.200(4), C(1)−Rh(1)−Cl(1) 88.90(10), C(1)−Rh(1)−C(24) 91.55(15),
C(1)−Rh(1)−C(17) 92.63(15), C(1)−Rh(1)−C(20) 159.25(14), C(1)−Rh(1)−C(21)
1
64.32(15).
1
4
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European Journal of Inorganic Chemistry
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Figure 5. ORTEP of 2i with thermal ellipsoids are shown at the 50 % probability
level. Selected bond lengths (Å) and angles (°): Ir(1)−C(1) 2.026(3), Ir(1)−Cl(1)
.3619(9), Ir(1)−C(17) 2.092(3), Ir(1)−C(20) 2.175(3), Ir(1)−C(21) 2.167(3),
2
Ir(1)−C(24) 2.097(4), C(1)−Ir(1)−Cl(1) 89.52(9), C(1)−Ir(1)−C(17) 92.22(13),
C(1)−Ir(1)−C(24) 91.95(13), C(1)−Ir(1)−C(20) 163.97(14), C(1)−Ir(1)−C(21)
1
58.83(13).
1
5
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
Figure 6. ORTEP of 3h with thermal ellipsoids are shown at the 50 % probability
level. Selected bond lengths (Å) and angles (°): Rh(1)−C(1) 2.019(3), Rh(1)−Cl(1)
.3810(9), Rh(1)−C(16) 2.104(3), Rh(1)−C(17) 2.103(3), Rh(1)−C(20) 2.187(3),
2
Rh(1)−C(21) 2.206(3), C(1)−Rh(1)−Cl(1) 87.97(8), C(1)−Rh(1)−C(16) 90.63(12),
C(1)−Rh(1)−C(17) 93.75(11), C(1)−Rh(1)−C(20) 160.17(11), C(1)−Rh(1)−C(21)
1
63.16(11).
1
6
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
Figure 7. ORTEP of 3i with thermal ellipsoids are shown at the 50 % probability
level. Selected bond lengths (Å) and angles (°): Ir(1)−C(1) 2.029(5), Ir(1)−Cl(1)
.3695(11), Ir(1)−C(12) 2.173(5), Ir(1)−C(15) 2.081(4), Ir(1)−C(16) 2.097(5),
2
Ir(1)−C(19) 2.179(5), C(1)−Ir(1)−Cl(1) 88.66(12), C(1)−Ir(1)−C(15) 94.07(19),
C(1)−Ir(1)−C(16) 91.1(2), C(1)−Ir(1)−C(12) 160.3(3), C(1)−Ir(1)−C(19) 162.0(2).
1
7
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European Journal of Inorganic Chemistry
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Table 1. X-ray crystallographic data for the rhodium complexes (1−3)h
Compound
Lattice
1h
2h
3h
Orthorhombic
ORhCl
Orthorhombic
Orthorhombic
Formula
Formula weight
Space group
a/Å
C
24
H
32
N
2
ORhCl
C
24
H
32
N
2
ORhCl
C
23
H
30
N
2
502.88
P2 P2
502.88
P2 P2
488.85
P2 P2
1
1
P2
1
1
1
P2
1
1
1
P2
1
8.2908(11)
12.5399(16)
21.613(3)
90.00
8.2533(15)
13.907(3)
19.371(4)
90.00
8.4079(19)
12.317(3)
20.926(5)
90.00
b/Å
c/Å

/°
/°
/°

90.00
90.00
90.00

90.00
90.00
90.00
V/Å3
2247.0(5)
4
2223.4(8)
4
2167.1(9)
4
Z
Temperature (K)
Radiation (,Å)
ρ (calcd.), g cm-3
θ max, deg.
No. of data
No. of parameters
100(2)
0.71075
1.486
100(2)
0.71070
1.502
100 (2)
0.71070
1.498
29.18
29.11
29.50
26214
262
14202
262
28174
257
R
1
0.0217
0.0523
1.026
0.0377
0.0740
0.878
0.0351
0.0678
1.053
wR
2
GOF
Crystal habit
Crystal size mm3
Block
Block
Block
0.30  0.29  0.11 0.45  0.23  0.08 0.25  0.22  0.12
Absorption coefficient (μ) 0.896
0.906
0.927
No. of independent
6
0
057
5813
6262
reflections
No. of restraints
Rint
36
0
0.0311
0.0919
1017714
none
0.0534
990173
None
CCDC number
1047074
Extinction coefficient (μ) none
1
8
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
Table 2. X-ray crystallographic data for the iridium complexes (1−3)i
Compound
Lattice
1i
2i
3i
Orthorhombic
OIrCl
Orthorhombic
Orthorhombic
Formula
Formula weight
Space group
a/Å
C
24
H
32
N
2
OIrCl
C
24
H
32
N
2
OIrCl
C
23
H
30
N
2
592.17
P2 P2
592.17
P2 P2
578.14
P2 P2
1
1
P2
1
1
1
P2
1
1
1
P2
1
8.285(2))
12.558(3)
21.674(6)
90.00
8.2948(13)
13.914(2)
19.407(3)
90.00
8.4206(13)
12.3709(18)
20.986(3)
90.00
b/Å
c/Å

/°
/°
/°

90.00
90.00
90.00

90.00
90.00
90.00
V/Å3
2255.0(10)
4
2239.8(6)
4
2186.1(6)
4
Z
Temperature (K)
Radiation (,Å)
ρ (calcd.), g cm-3
θ max, deg.
No. of data
No. of parameters
100(2)
0.71070
1.744
29.21
12620
265
150(2)
0.71075
1.756
150(2)
0.71070
1.757
25.00
25.00
16440
265
8606
256
R
1
0.0314
0.0525
0.877
Block
0.0141
0.0368
0.717
0.0215
0.858
wR
2
GOF
0.858
Crystal habit
Block
Block
Crystal size mm3
0.39  0.16  0.04 0.20  0.20  0.20 0.30  0.27  0.11
Absorption coefficient (μ)
6.057
6.098
3913
0
6.245
3794
0
No. of independent reflections5632
No. of restraints
Rint
0
0.0489
1039096
none
0.0247
1021593
none
0.0312
1438249
None
CCDC number
Extinction coefficient (μ)
1
9
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European Journal of Inorganic Chemistry
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All of the rhodium (1–3)h and the iridium (1–3)i complexes, as structurally characterized by
the X-ray single crystal diffraction studies (Figures 2-7 and Tables 1 and 2), were found to be
monomeric in nature with the metal center adopting a tetrahedral geometry being surrounded
4
by N–heterocyclic carbene, chloride and a η –bound 1, 5–cyclooctadiene (COD) ligands. Of
particular interest is the M−Ccarbene bond distances in the rhodium (1−3)h and the iridium
(1−3)i complexes. The Rh−Ccarbene bond distances of 2.020(18) Å (1h), 2.023(4) Å (2h) and
2
.019(4) Å (3h) is slightly shorter than the sum of the covalent radii of the individual atoms
[
d/(Rh−C) = 2.182 Å]44 but are comparable to the structurally characterized examples
namely, (1-i-propyl,3-phenyl-benzimidazol-2-ylidene)Rh(COD)Cl [d/Rh−Ccarbene = 2.015(9)
Å]45 and (1,3-dicyclohexyl-1,3-dihydro-2H-imidazol-2-ylidene)Rh(COD)F [d/Rh−Ccarbene
.022(3) Å].46
=
2
Similarly, the Ir−Ccarbene bond distances of 2.018(5) Å (1i), 2.026(3) Å (2i) and 2.029(5) Å
(3i) are shorter to the sum of the individual covalent radii of the iridium and carbon atoms
4
4
[
d/(Ir−C) = 2.172 Å] and are comparable with other structurally characterized examples
like, (1,3-di-i-propylbenzimidazol-2-ylidene)Ir(COD)Cl [d/Ir−Ccarbene = 2.020(4) Å]47 and
1,3-di-i-propyl-1,3-dihydro-2H-imidazol-2-ylidene)Ir(COD)F [d/Ir−Ccarbene = 2.014(3) Å].46
(
2
0
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
O
OH
(
1-3)h / (1-3)i
t-BuOK, i-PrOH
(
4)
Equation 1. Asymmetric transfer hydrogenation of acetophenone with chiral oxazolidine-fused imidazole derived N-heterocyclic carbene
complexes of rhodium(I) (1−3)h and iridium(I) (1−3)i.
2
1
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European Journal of Inorganic Chemistry
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Table 3. Base variation study of the asymmetric transfer hydrogenation of acetophenone
with the representative rhodium(I) (1h) and iridium(I) (1i) complexes.
S.No.
base
(
1h)
(1i)
eeb
yielda
%)
eeb
yielda
(%)
TON
TON
(
(%)
(%)
1
2
3
4
5
K
2
CO
3
64
56
54
72
73
17
15
21
13
16
127
111
109
145
146
60
61
40
64
85
25
20
14
22
14
120
121
80
NaOH
KOH
CS
2
CO
3
129
170
t-BuOK
Reaction conditions: Acetophenone (1.97 mmol), base (78.8 µmol), 1h or 1i (9.85 µmol, 0.5
mol %) in 8 mL of i-PrOH at 75 °C for 3 hours. a. yields are after isolation of the product. b.
enantiomeric excess (ee) was determined by chiral HPLC with chiralpak-RJ chiral column.
2
2
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European Journal of Inorganic Chemistry
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Table 4. Asymmetric transfer hydrogenation of acetophenone with various chiral oxazolidine-
fused imidazole derived N-heterocyclic carbene complexes of rhodium(I) (1−3)h and
iridium(I) (1−3)i.
O
OH
(
1-3)h / (1-3)i (0.5 mol %)
t-BuOK, i-PrOH
(4)
Rh-NHC
complex
yielda
(%)
eeb
(%)
Ir-NHC
complex
yielda eeb
S.No.
TON
146
TON
170
(%)
(%)
8
5
14
1
73
73
65
16
(1h)
(2h)
(3h)
(1i)
2
3
2
146
130
76
95
6
152
190
(2i)
14
18
(3i)
Reaction conditions: Acetophenone (1.97 mmol), t-BuOK (78.8 µmol), (1−3)h or (1−3)i (9.85
µmol, 0.5 mol %) in 8 mL of i-PrOH at 75 °C for 3 hours. a. yields are after isolation of the
product. b. enantiomeric excess (ee) was determined by chiral HPLC with chiralpak-RJ chiral
column.
2
3
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European Journal of Inorganic Chemistry
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Table 5. Time dependence study of the asymmetric transfer hydrogenation of acetophenone
with chiral oxazolidine-fused imidazole derived N-heterocyclic carbene complexes of
rhodium(I) (1h) and iridium(I) (3i) complexes.
O
OH
(1h / 3i) (0.5 mol %)
t-BuOK, i-PrOH
(
4)
time
S.No.
(min)
(1h)
(3i)
yielda
%)
eeb
yielda
(%)
eeb
TON
TON
(
(%)
(%)
1
2
3
4
5
60
32
47
74
79
80
18
15
16
16
13
65
94
75
77
95
85
87
21
19
18
20
21
150
154
190
170
175
120
180
360
720
148
159
161
Reaction conditions: Acetophenone (1.97 mmol), t-BuOK (78.8 µmol), 1h or 3i (9.85 µmol,
.5 mol %) in 8 mL of i-PrOH at 75 °C at various time intervals. a. yields are after isolation
0
of the product. b. enantiomeric excess (ee) was determined by chiral HPLC with chiralpak-
RJ chiral column.
2
4
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1
0.1002/ejic.201700303
European Journal of Inorganic Chemistry
Table 6. Asymmetric transfer hydrogenation of ketones with chiral oxazolidine-fused imidazole derived N-heterocyclic carbene complexes of rhodium(I) (1h) and iridium(I) (3i) complexes.
S.No.
substrate
Product
(1h)
(3i)
a
eeb
a
eeb
yield (%)
TON
146
yield (%)
TON
190
1
2
3
73
64
55
16
95
84
72
18
21
16
(
4)
5)
11
25
128
110
168
144
(
(6)
4
62
19
123
45
13
89
(
7)
8)
5
6
70
51
13
20
139
101
66
62
24
15
131
123
(
(9)
7
8
9
58
32
50
22
5
116
63
73
76
80
15
5
146
151
159
(
10)
11)
(
19
99
21
(
12)
13)
1
0
35
20
70
18
16
36
(
1
1
1
1
1
2
3
4
21
64
47
52
4
5
42
128
93
38
72
54
60
20
3
76
(14)
(15)
(16)
(17)
144
107
116
11
18
41
9
102
1
5
0
0
0
0
0
0
(18)
Reaction conditions: Ketone (1.97 mmol), t-BuOK (78.8 µmol), 1h or 3i (9.85 µmol, 0.5 mol %) in 8 mL of i-PrOH at 75 °C for 3 hours. a. yields are after isolation of the product. b. enantiomeric
excess (ee) was determined by chiral HPLC with chiralpak-RJ, chiralpak-OH and Chiralpak IA column.
2
5
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European Journal of Inorganic Chemistry
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The utility of chiral oxazolidine fused imidazole derived N‒heterocyclic carbene ligand in the
transfer hydrogenation reaction was explored with its rhodium (1−3)h and iridium (1−3)i
complexes (Equation 1). Initial optimization study involving the variation of bases was
attempted on the transfer hydrogenation of acetophenone in i−PrOH for the representative
rhodium (1h) and iridium (1i) complexes, and which showed t-BuOK to be the most effective
of all bases tried (Table 3, entry 5). Subsequently, the catalyst variation study performed for
the rhodium (1‒3)h and iridium (1‒3)i complexes using t-BuOK as a base, showed the
rhodium (1h) and the iridium (3i) complexes to be superior in performance displaying a
maximum chiral induction of 16 % (ee) in case of rhodium complex (1h) (Table 4, entry 1)
and of 18 % (ee) in case of the iridium complex (3i) for the transfer hydrogenation of
acetophenone substrate (Table 4, entry 3).
Furthermore, the time dependent study was carried out for the two rhodium (1h) and the
iridium (3i) complexes, and after careful analysis of the catalysis data (Table 5), the three
hours of the reaction time was so chosen for the subsequent catalysis runs. The homogenous
nature of the catalysis was evident form the transfer hydrogenation of acetophenone reaction
performed in the presence and absence of Hg (Supporting Information Table S1) that showed
comparable conversions in case of both of the rhodium (1h) [73 % with 16 % ee without Hg
(Table 4) and 69 % with 22 % ee with Hg (Table S1)] and the iridium (3i) [95 % with 18 %
ee without Hg (Table 4) and 75 % with 27 % ee with Hg (Table S1)] complexes, thereby
upholding the homogenous nature of the catalysis. The influence of chiral oxazolidine fused
imidazole based N‒heterocyclic carbene ligand was very much evident from the fact that no
conversion to product was observed in the case of the blank experiment as well as in the
control experiment performed with {(COD)MCl}
Information Table S1).
2
(M = Rh, Ir) precursors (Supporting
2
6
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European Journal of Inorganic Chemistry
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The substrate scope study was undertaken for a wide variety of acetophenone substrates
bearing electron rich and electron deficient groups (Table 6). It is interesting to note that the
iridium (3i) complex performed better than the rhodium (1h) complex both in terms of yield
and enantioselectivity for the halogenated acetophenone (Table 6; entries 3, 7 and 9) and the
alkylated acetophenone substrates (Table 6; entries 2, 5 and 6). Moderate to low yields (18–
7
6 %) were obtained for the 4−methylthio acetophenone and 4-nitro acetophenone substrates
both in case of the rhodium (1h) and iridium (3i) complexes. Furthermore, sterically
demanding substrate like 2-methyl acetophenone, isobutyrophenone, 2,2 dimethyl
propiophenone were reduced in good yields (47–82 %).
The generally low
enantioselectivites observed for the rhodium (1h) and the iridium (3i) complexes, for the
catalysis runs performed at 75 °C, may be attributed to a rapid exchange between the two
1
isomers under the catalysis conditions as seen in the variable temperature H NMR
experiment for a representative rhodium complex (1h).
Important is the comparison of the catalytic activities of the rhodium (1h) and the iridium (3i)
complexes with the reported ones for the asymmetric transfer hydrogenation of
acetophenone. In this regard it is worth noting that although, a lot of reports exist on the
achiral version of the transfer hydrogenation reaction of ketones,48-51 only a handful of
examples have been reported for the chiral version of this reaction.40, 42, 52, 53 We are aware of
only two reports of iridium based N-heterocyclic carbene complexes exhibiting superior
activity as compared to the iridium complex (3i). For example, for the transfer
hydrogenation of acetophenone, the {[(R)-(2-bis(4-(trifluoromethyl)phenyl methyl)5-(2,4,6-
tricyclohexylphenyl)6,7-dihydro,2H-pyrolo[1,2,-c]imidazol-5-ylidene)]Ir(COD)}Cl complex
3
9
exhibited 78 % yield and 73 % ee at 0.05 mol % catalyst loading and the {[(3-((1R,2R)-
((E)-(3,5,di-t-butyl)2-hydroxybenzylidene)amino)cyclohexyl)1-i-propyl-4-phenyl-1-
2
7
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European Journal of Inorganic Chemistry
10.1002/ejic.201700303
imidazol-3-ylidene)]Ir(COD)}BAr
4
(Ar=3,5-(CF
3
)
2
C
6
H
3
) complex exhibited 98 % yield and
4
3
4
3 % ee at 0.5 mol % catalyst loading while the iridium (3i) complex exhibited 95 %
conversion with 18 % ee at 0.5 mol % catalyst loading for the same acetophenone substrate.
With regard to the utility of rhodium N−heterocyclic carbene complexes in asymmetric
transfer hydrogenation reaction, we are aware of only one report of the transfer
hydrogenation of ketones with a rhodium based N−heterocyclic carbene catalyst, and which
showed only 40 % conversion with minimal chiral induction of 4 % in case of the transfer
hydrogenation of acetophenone substrate at 0.1 mol % of catalyst loading.52 In this backdrop
the rhodium (1h) complex exhibiting 73 % yield and 16 % ee at 0.5 mol % catalyst loading
for the same transfer hydrogenation of acetophenone is significant and it points towards
possible entry of chiral oxazolidine fused N−heterocyclic carbene based rhodium complexes
for the catalysis of this reaction.
Conclusions
In summary, a new class of chiral oxazolidine fused N−heterocyclic carbene ligand has been
synthesized using a multi-step protocol starting from commercially available chiral amino
acids without requiring any enantiomeric separation step. The utility of this class of ligand in
the form of its rhodium (1−3)h and the iridium (1−3)i complexes have been demonstrated in
asymmetric transfer hydrogenation reactions of ketones. The study paves way for exploring
further applications of chiral oxazolidine fused N−heterocyclic carbenes as ligand platforms
in homogenous catalysis.
2
8
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European Journal of Inorganic Chemistry
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Experimental section
General procedures
All manipulations were carried out using standard Schlenk techniques. RhCl
IrCl •3H O, D-phenyl glycine, L-Valine, L-Leucine, L-Isoleucine were purchased from
Sigma Aldrich. {(COD)RhCl}
3
•3H O,
2
3
2
54
,55 (2R)-2-amino-3-methylpentan-1-ol (1a),56
2
, {(COD)IrCl}
2
5
6
56
(
R)-2-amino-4-methylpentan-1-ol (2a), (R)-2-amino-3-methylbutan-1-ol (3a) and (R)-2-
5
7
1
formamido-2-phenylacetic acid (1b) were synthesised by literature procedures. H NMR,
1
3
1
1
C{ H} NMR, spectrum were recorded on Bruker 300 MHz spectrometer. H NMR peaks
are labeled as singlet (s), doublet (d), triplet (t), broad (br), triplet of triplet (tt), doublet of
doublet (dd), multiplet (m) and septet (sept). Infrared spectra were recorded on a Perkin
Elmer Spectrum One FT-IR spectrometer. Mass spectrometry measurements were done on a
Micromass Q-Tof spectrometer and Bruker maxis impact spectrometer. Elemental Analysis
was carried out on ThermoFinnigan FLASH EA 1112 SERIES (CHNS) Elemental Analyzer.
The enantiomeric excess were determined by HPLC with a Chiralpak-1A, Chiralpak-1C,
Chiralpak-OH and Chiralpak-RJ chiral column on a Shimadzu LC-2010. The X-ray
diffraction data for compounds (1−3)h, (1−3)i were collected on Rigaku Hg 724+
diffractometer. The structures were solved using direct method and standard difference map
techniques, and refined by full-matrix least-squares procedures on F2.58, 59 CCDC-1047074
(for 1h), CCDC-1039096 (for 1i), CCDC-1017714 (for 2h), CCDC-1021593 (for 2i), CCDC-
9
90173 (for 3h) and CCDC-1438249 (for 3i) contain the supplementary crystallographic data
related to this article. These data can be obtained free of charge from the Cambridge
Crystallographic Data center via www.ccdc.cam.ac.uk/data_request/cif.
Synthesis
of
(2S)-2-formamido-N-((2S)-1-hydroxy-3-methylpentan-2-yl)-2-
phenylacetamide (1c)
2
9
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