8-Amino-5,6,7,8-tetrahydroquinolines as ligands in iridium(III) catalysts for the reduction of aryl ketones by asymmetric transfer hydrogenation (ATH)

Article abstract of DOI:10.1016/j.tetasy.2014.06.003

Aqua iridium(III) complexes with 8-amino-5,6,7,8-tetrahydroquinolines CAMPY L1 and its derivatives as chiral ligands proved to be very efficient catalysts for the reduction of a wide range of prochiral aryl ketones, revealing a variety of behaviours in te

Full text of DOI:10.1016/j.tetasy.2014.06.003

Tetrahedron: Asymmetry 25 (2014) 1031–1037
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Tetrahedron: Asymmetry
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8-Amino-5,6,7,8-tetrahydroquinolines as ligands in iridium(III)
catalysts for the reduction of aryl ketones by asymmetric transfer
hydrogenation (ATH)
Daniele Zerla a, Giorgio Facchetti a, Marco Fusè a, Michela Pellizzoni a, Carlo Castellano b, Edoardo Cesarotti a,
Raffaella Gandolfi a, Isabella Rimoldi a,
⇑
a Dipartimento di Scienze Farmaceutiche, Sez. Chimica Generale e Organica ‘A. Marchesini’, Università degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
b Dipartimento di Chimica, Università degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 May 2014
Accepted 6 June 2014
Aqua iridium(III) complexes with 8-amino-5,6,7,8-tetrahydroquinolines CAMPY L1 and its derivatives as
chiral ligands proved to be very efficient catalysts for the reduction of a wide range of prochiral aryl ketones,
revealing a variety of behaviours in terms of reaction rate and stereoselectivity. As standard substrates,
differently substituted acetophenones were studied and good enantioselectivity (86% ee) was achieved
in the reduction of 1-(o-tolyl)ethan-1-one 6. Particularly interesting was the ATH reaction in the case of
b-amino keto esters, precursors of b-lactams and azetidinones. The best results were obtained with
[Cp⁄Ir(H2O)(L1)]SO4 affording the corresponding diastereomeric alcohols in an (R,S)-configuration with
an excellent 99% ee in the reduction of 2-(benzamido methyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)
propanoate 12.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
++
2-
SO4
One of the most significant applications of asymmetric transfer
hydrogenation (ATH) is the reduction of different substituted aryl
ketones. Over the last decade, many approaches have been reported
and many types of catalysts were used especially when the metal
was ruthenium(II).1–4 Our research group developed optically active
ruthenium(II) catalysts based on complexes between diphosphines
and a well-known chiral diamine DPEN, or a new chiral diamine
CAMPY, with good results.5,6 Recently, the possibility of using irid-
ium complexes has been demonstrated as a valid alternative to the
use of classical ruthenium systems.7–17 In particular Carreira et al.
reported that chiral aqua iridium(III) complexes bearing DPEN and
its derivatives were very promising catalysts in the reduction of
2-cyanoacetophenones and b-keto esters.18,19 Herein we report
the use of a [Cp⁄Ir(H2O)3]SO4 complex and 8-amino-5,6,7,8-tetrahy-
droquinoline, CAMPY hereafter, as a source of chirality, its derivative
2-methyl-5,6,7,8-tetrahydroquinolin-8-amine Me-CAMPY, and the
corresponding NH-CH3 diamines (Scheme 1).
L1
L2
R = R' = H;
CAMPY
R = CH3; R' = H; Me-CAMPY
NHR'
Ir
L3 R = H; R' = CH3; CAMPY-NHMe
L4 R = R' = CH3;
Me-CAMPY-NHMe
N
H2O
R
Scheme 1. Catalysts used for ATH.
b-Amino keto esters are an important class for the synthesis of
unnatural b-aminoacids which are used in the preparation of
peptide mimetics and azetidinones.20 The most common azetidi-
none precursor, used for the preparation of carbapenems, is ethyl
2-(benzamidomethyl)-3-oxobutanoate in which the methyl group
is in
a
position to the carbonyl moiety.21,22 In recent years the
-position to the carbonyl
influence of different substituents at the
a
group was studied.23,24 With regard to the unique pharmacological
properties attributed to the fluorine in helping absorption of the
drug through the cell wall, selectively fluorinated organic interme-
diates still remain challenging targets for the synthesis of b-lactam
antibiotic precursors.25 Herein we focused our attention on the
stereoselective reduction of different aromatic ketones and
b-amino keto esters bearing either an electron donating or an
electron withdrawing substituent.
The asymmetric reduction of ketones is a synthetically relevant
reaction as the corresponding chiral alcohols are precursors of a
wide range of bioactive compounds.
⇑
Corresponding author. Tel.: +39 02 503 14609; fax: +39 02 503 14615.
E-mail address: isabella.rimoldi@unimi.it (I. Rimoldi).
http://dx.doi.org/10.1016/j.tetasy.2014.06.003
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1032
D. Zerla et al. / Tetrahedron: Asymmetry 25 (2014) 1031–1037
reduction of substrate 1 (entries 9, 11 and 12). For substrate 1,
2. Results and discussion
the best results were obtained with L1 in the presence of HCOOH
as the hydrogen donor (62% ee, entry 1). For substrate 2, the
azeotropic mixture of HCOOH/TEA gave 75% ee with [Cp⁄Ir(H2O)
(L2)]SO4 (entry 18). In the case of substrate 3, data did not show
any appreciable difference in terms of reaction conditions or cata-
The approach used for the synthesis of L3 and L4 is outlined in
Scheme 2. Enantiomerically pure CAMPY L1 and Me-CAMPY L2
were obtained as salts by crystallization of racemic amines with
enantiomerically pure tartaric acids.
Table 1
ATH reaction of 2-cyanoacetophenones
NH2
NHCH3
N
N
OH
O
a, b
[Cp*Ir((R)-L)H2O]SO4
(0.5 mol %)
CN
CN
Ar
Ar
hydrogen donor,
H2O:MeOH = 1:1;
70°C
L2
L4
R'
R'
1
2
Ar = Ph; R'= H
1a Ar = Ph; R'= H
2a Ar = thienyl; R'= H
3a Ar = furyl; R'= H
Ar = thienyl; R'= H
NHCOCH3
NHCH3
3 Ar = furyl; R'= H
4 Ar = Ph; R'= CH2CH3
4a
N
N
Ar = Ph; R'= CH2CH3
c, d, e
Entrya Sub.
L
Hydrogen
donor
Conv.b (%) ee (%)
de (%)
L1-Ac
L3
1
2
3
4
5
6
7
8
1
2
3
4
L1 HCOOH
100
100
62 (S)
47 (S)
53 (S)
57 (S)
56 (S)
48 (S)
40 (S)
45 (S)
24 (S)
44 (S)
60 (S)
51 (S)
HCOONa
HCOOH/TEA 100
L2 HCOOH
HCOONa
HCOOH/TEA 100
L3 HCOOH
HCOONa
HCOOH/TEA
L4 HCOOH
Scheme 2. Synthesis of ligands L3 and L4. Reagents and conditions: (a) K2CO3,
ClCOOEt, THF/H2O, 0 °C to rt; (b) LiAIH4, THF, 0 °C to reflux; (c) NaH, THF, rt to
reflux; (d) CH3I, THF, 0 °C to rt; (e) HCl 6 M, reflux.
100
100
100
98
82
100
47
33
The absolute configuration of Me-CAMPY L2 ligand was assigned
by single-crystal X-ray diffraction studies of the PtCl4((S)-(+)-Me-
CAMPY)ÁH2O salt (Fig. 1). This contains the L2 ligand protonated
on both nitrogen atoms (Fig. 2), a square planar PtCl24À counterion
and one water molecule. PtCl24À and H2O interact with L2 through
intramolecular hydrogen bonds [N1Á Á ÁH3 N-Ow 139(3)°, N1Á Á ÁOw
2.982(6) Å; N2Á Á ÁH2-Ow 167.5(3)°, N2Á Á ÁOw 2.772(7) Å; N1Á Á ÁH1
N-Cl2 165(5)°, N1Á Á ÁCl2 3.184(6) Å] involving the hydrogens bonded
to the two nitrogen atoms. The C1–C6 ring displays an envelope con-
formation with a deviation of the C3 atom from the meanplane
defined by C2, C1, C6, C5 and C4 atoms of 0.310 Å and with the fol-
lowing torsion angles: C4–C5–C6–C1 –2.9° and C2–C1–C6–C5 –4.0°.
9
10
11
12
HCOONa
HCOOH/TEA
13
14
15
16
17
18
19
20
21
22
23
24
L1 HCOOH
HCOONa
HCOOH/TEA 100
L2 HCOOH
HCOONa
HCOOH/TEA 100
L3 HCOOH
HCOONa
HCOOH/TEA 100
L4 HCOOH
HCOONa
100
100
50 (S)
46 (S)
46 (S)
61 (S)
73 (S)
75 (S)
61 (S)
34 (S)
19 (S)
48 (S)
44 (S)
54 (S)
100
100
100
100
100
100
HCOOH/TEA 100
25
26
27
28
29
30
31
32
33
34
35
36
L1 HCOOH
HCOONa
HCOOH/TEA 100
L2 HCOOH
HCOONa
HCOOH/TEA 100
L3 HCOOH
HCOONa
HCOOH/TEA 100
L4 HCOOH
HCOONa
100
100
34 (S)
40 (S)
34 (S)
50 (S)
37 (S)
41 (S)
48 (S)
48 (S)
49 (S)
50 (S)
45 (S)
56 (S)
100
100
100
100
100
100
HCOOH/TEA 100
37
38
39
40
41
42
43
44
45
46
47
48
L1 HCOOH
HCOONa
HCOOH/TEA 100
L2 HCOOH
HCOONa
HCOOH/TEA 100
L3 HCOOH
HCOONa
HCOOH/TEA 100
L4 HCOOH
HCOONa
100
46
94 (R,S); 68 (S,S) 38 syn
89 (R,S); 65 (S,S) 37 syn
84 (R,S); 62 (S,S) 20 syn
90 (R,S); 75 (S,S) 40 syn
93 (R,S); 80 (S,S) 40 syn
68 (R,S); 53 (S,S) 16 syn
88 (R,S); 64 (S,S) 55 syn
84 (R,S); 62 (S,S) 53 syn
30 (R,S); 22 (S,S) 22 syn
74 (R,S); 55 (S,S) 55 syn
84 (R,S); 80 (S,S) 65 syn
16 (R,S); 7 (S,S) 14 syn
100
72
Figure 1. A perspective view of the PtCl4((S)-(+)-Me-CAMPY)ÁH2O salt. Selected
interatomic distances (Å) are: Pt–Cl1 2.302(2), Pt–Cl2 2.299(2), Pt–Cl3 2.304(2),
Pt–Cl4 2.305(2), C1–N1 1.508(6), C1–C2 1.533(7), C2–C3 1.430(10), C3–C4
1.516(11), C4–C5 1.510(7), C5–C6 1.373(6), C1–C6 1.511(6).
68
11
CAMPY and its derivatives were used as ligands for the one-pot
synthesis of iridium(III) complexes after reaction with [Cp⁄Ir(H2-
O)3]SO4, which could be used directly in ATH reactions. Screening
was carried out for the reduction of different types of aryl ketones.
The results obtained for 2-cyanoacetophenone and its heteroaro-
matic analogues are reported in Table 1.
The conversion of substrates 1, 2 and 3 into the corresponding
alcohols was achieved for all of the complexes in only 3 h with
the exception of the complexes with ligands L3 and L4 in the
70
8
HCOOH/TEA 100
a
Reactions were carried out at 70 °C using 0.5 mmol of substrate with 0.5 mol %
of iridium complex in 2 mL of MeOH/water = 1:1 mixture when HCOOH or HCOONa
was used as hydrogen donors, while an HCOOH/TEA azeotropic mixture was used
neat.
Conversion and ee were determined by GC after 3 h for substrate 1 while for
substrates 2 and 3 they were determined by HPLC after 3 h, for substrate 4 after
b
24 h by HPLC (OD-H Chiralcel column).

D. Zerla et al. / Tetrahedron: Asymmetry 25 (2014) 1031–1037
1033
Table 2
ATH reaction of acetophenones
O
OH
[Cp*Ir((R)-L)H2O]SO4
(0.5 mol %)
hydrogen donor,
H2O:MeOH = 1:1;
70°C
R
R
5 R = H
5a R = H
6 R = o-CH3
6a R = o-CH3
7
8
R = p-CF3
7a
8a
R = p-CF3
R = m-OCH3
R = m-OCH3
Entrya
Sub.
L
Hydrogen donor
Conv.b (%)
ee (%)
1
2
3
4
5
6
7
8
5
L1
HCOOH
88
46
49
74
59
48
71
38
8
46 (S)
48 (S)
45 (S)
74 (S)
30 (S)
27 (S)
43 (S)
33 (S)
23 (S)
21 (S)
31 (S)
0
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
L2
L3
L4
Figure 2. A perspective view of the Me-CAMPY L2 dication.
9
10
11
12
37
10
50
lyst used. The presence of an additional racemic stereogenic centre
as in substrate 4 allowed the reaction to reach high stereoselectiv-
ity (90–94% ee) even with moderate diastereoselectivity (40% de)
(entries 37 and 40). The best results were achieved using HCOOH
as the hydrogen donor with complexes in which the diamines car-
ried a primary amino group L1 and L2. When the ATH reductions
were carried out in the presence of HCOONa, the conversion
decreased dramatically (entries 38, 44 and 47).
Generally, acetophenone was used as the standard substrate to
study the catalytic behaviour of catalysts in ATH. We decided to
investigate a range of substituted acetophenones with the aim of
determining the influence of different groups on the aromatic ring
in terms of electronic properties and steric hindrance (substrates 6,
7 and 8). The results are reported in Table 2. In the case of
substituted acetophenones 6, 7 and 8, [Cp⁄Ir(H2O)(L1)]SO4 in the
presence of HCOOH generally gave the best results (entries 13,
25 and 37). In fact when there was a steric hindrance at the
ortho-position with respect to ketone 6, 86% ee was obtained with
L1 (entry 13); instead for acetophenone 5, 74% ee was obtained
using diamine ligand L2 (entry 4).
Generally when the steric hindrance of the substrate was
increased by the introduction of a group at the ortho-position, the
stereoselectivity was increased. In our case, this behaviour sug-
gested that the ideal matching between the ligand and the substrate
was realized in the presence of a methyl group either on the
substrate or on the backbone of the ligand. In the case of substrates
7 and 8, the presence of a meta-methoxy group or a para-trifluoro-
methyl group improved the catalytic performance compared to
acetophenone 5 (66% ee vs 46% ee, entries 1, 25 and 37, Table 2).
These results, in terms of reaction rate, confirmed that the with-
drawing properties of both substituents favoured the keto form over
the enolic one, thus increasing the reaction rate and the stereoselec-
tivity. For all of the substrates, when a secondary amine on the
amino stereogenic centre of the ligands L3 and L4 was present, the
reduction did not proceed well, either in terms of conversion or in
terms of stereoselectivity. The same behaviour was observed under
azeotropic mixture conditions.
13
14
15
16
17
18
19
20
21
22
23
24
6
7
8
L1
L2
L3
L4
HCOOH
73
58
29
17
19
23
37
7
86 (S)
83 (S)
70 (S)
31 (S)
47 (S)
10 (S)
58 (S)
35 (S)
15 (S)
9 (S)
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
10
5
3
51 (S)
0
9
25
26
27
28
29
30
31
32
33
34
35
36
L1
L2
L3
L4
HCOOH
100
77
63
98
96
92
67
13
24
31
32
58
65 (S)
57 (S)
61 (S)
46 (S)
38 (S)
41 (S)
43 (S)
25 (S)
16 (S)
27 (S)
29 (S)
6 (S)
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
37
38
39
40
41
42
43
44
45
46
47
48
L1
L2
L3
L4
HCOOH
89
50
49
81
81
67
44
37
4
66 (S)
62 (S)
61 (S)
34 (S)
30 (S)
45 (S)
43 (S)
32 (S)
13 (S)
47 (S)
45 (S)
18 (S)
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
45
11
78
a
Reactions were carried out at 70 °C using 0.5 mmol of substrate with 0.5 mol%
of iridium complex in 2 mL of MeOH/water = 1:1 mixture when HCOOH or HCOONa
were used as hydrogen donors, while an HCOOH/TEA azeotropic mixture was used
neat.
b
Conversion and ee were determined by GC after 6 h.
As reported in previous work this type of catalyst was also
applied to the reduction of b-ketoesters such as ethyl 3-oxo-3-phe-
to different substituted b-keto esters. In particular we focused
our attention on the reduction of b-lactam precursors. Starting
from substrate 9, we synthesized the corresponding b-amino keto
ester 10 and its substituted p-OMe and p-CF3 derivatives 11 and 12.
The results are reported in Table 3.
The reduction of ethyl 3-oxo-3-phenylpropanoate 9 proceeded
with modest enantiomeric excesses except for complex bearing L1
in the presence of HCOOH with 73% ee (entry 1). The reactions
nylpropanoate
9 utilizing a monosulfonylated diamine as a
ligand.19 First screening with the monotosylated CAMPY deriva-
tives did not lead to appreciable results with lower conversion
and selectivity (data not reported), probably due to the excessive
steric hindrance and the electronic effect of the tosyl group deplet-
ing the primary amine present in our ligands. For this reason, we
decided to apply the non-sulfonylated catalysts, reported herein

1034
D. Zerla et al. / Tetrahedron: Asymmetry 25 (2014) 1031–1037
carried out with [Cp⁄Ir(H2O)(L3)]SO4 and [Cp⁄Ir(H2O)(L4)]SO4, did
not lead to the complete formation of the corresponding alcohols
as expected on the basis of the results with the monotosylated
CAMPY derivatives. Regarding substrates 10, 11 and 12 our expecta-
tions were confirmed. The presence of an electron donor group at
the para-position in the ketone moved the keto–enol equilibrium
towards the enolic form, thus decreasing the conversion of
substrate 11 even if the stereoselectivity remained acceptable.
Conversely, when the aromatic moiety was substituted with an
electron-withdrawing group, at the para-position, complete conver-
sion was observed during the majority of the experiments mirroring
the results obtained in the reduction of 10. For substrates 10 and 12
when the reactions were conducted in the presence of a base (with
HCOONa), a variable amount of by-products was detected, which
Table 3
ATH reaction of b-ketoesters
OH
O
O
O
[Cp*Ir((R)-L)H2O]SO4
(0.5 mol %)
OEt
OEt
hydrogen donor,
H2O:MeOH = 1:1;
70°C
R'
R'
R
R
9a R = H; R' = H
9
R = H; R' = H
10a
11a
12a
R = H; R' = -CH2NHCOPh
10
11
R = H; R' = -CH2NHCOPh
R = p-OCH3; R' = -CH2NHCOPh
R = p-CF3; R' = -CH2NHCOPh
R = p-OCH3; R' = -CH2NHCOPh
12 R = p-CF3; R' = -CH2NHCOPh
Entrya
Sub.
L
Hydrogen donor
Conv.b (%)
ee (%)
de (%)
1
2
3
4
5
6
7
8
9
L1
HCOOH
100
100
100
100
100
100
100
17
10
52
24
100
73 (S)
48 (S)
36 (S)
19 (S)
21 (S)
18 (S)
47 (S)
48 (S)
49 (S)
27 (S)
50 (S)
0
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
L2
L3
L4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
10
11
12
L1
L2
L3
L4
HCOOH
100
100c
100
57
73 (S,S); 81 (R,S)
68 (S,S); 80 (R,S)
42 (S,S); 51 (R,S)
75 (S,S); 83 (R,S)
9 (S,S); 18 (R,S)
15 (S,S); 26 (R,S)
78 (S,S); 80 (R,S)
20 (S,S); 42 (R,S)
23 (S,S); 50 (R,S)
57 (S,S); 78 (R,S)
63 (S,S); 75 (R,S)
0 (S,S); 0 (R,S)
13 anti
25 anti
0
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
0
100c
100
100
100c
10
9 anti
34 anti
0
10 anti
0
17 anti
34 anti
34 anti
29
50
100
25
26
27
28
29
30
31
32
33
34
35
36
L1
L2
L3
L4
HCOOH
71
92
40
32
48
79
11
13
13
13
14
72
81 (S,S); 32 (R,S)
89 (S,S); 76 (R,S)
76 (S,S); 63 (R,S)
86 (S,S); 69 (R,S)
88 (S,S); 62 (R,S)
56 (S,S); 44 (R,S)
96 (S,S); 78 (R,S)
94 (S,S); 78 (R,S)
73 (S,S); 53 (R,S)
67 (S,S); 52 (R,S)
36 (S,S); 47 (R,S)
37 anti
32 anti
57 anti
32 anti
20 anti
8 anti
23 anti
16 anti
0 anti
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
4 anti
19 anti
29 anti
0
; 0
37
38
39
40
41
42
43
44
45
46
47
48
L1
L2
L3
L4
HCOOH
100
100c
100
100
100c
100
38
83 (S,S); 99 (R,S)
64 (S,S); 91 (R,S)
70 (S,S); 99 (R,S)
92 (S,S); 99 (R,S)
73 (S,S); 86 (R,S)
86 (S,S); 99 (R,S)
70 (S,S); 98 (R,S)
70 (S,S); 25 (R,S)
46 (S,S); 67 (R,S)
71 (S,S); 97 (R,S)
40 (S,S); 33 (R,S)
69 (S,S); 93 (R,S)
18 anti
0
15 anti
20 anti
0
13 anti
23 anti
25 anti
33 anti
37 anti
59 anti
56 anti
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
HCOOH
HCOONa
HCOOH/TEA
100c
78
100
100c
100
a
Reactions were carried out at 70 °C using 0.5 mmol of substrate with 0.5 mol % of iridium complex in 2 mL of
MeOH/water = 1:1 mixture when HCOOH or HCOONa were used as hydrogen donors, while an HCOOH/TEA azeo-
tropic mixture was used neat.
b
Conversion, ee and de were determined by HPLC (AD Chiralpak column) after 24 h.
Under these conditions N-(3-oxo-3-phenylpropyl)benzamide and its reduction products were observed as in
c
previous work.

D. Zerla et al. / Tetrahedron: Asymmetry 25 (2014) 1031–1037
1035
were attributable to spontaneous decarboxylation after hydrolysis
of the ethyl ester function as observed in the literature.26
ture and complete crystallization was obtained at À18 °C. Yield
273 mg of (R)-(À)-Me CAMPY/(R,R)-(+)-
L-tartrate (0.87 mmol, 58%
For both substrates, the best catalytic performances were
achieved in favour of the (R,S)-diastereomer with an ee of up to
99% for 12 (entries 37, 39, 40 and 42). On the contrary, the (S,S)-dia-
stereomer was predominant for the reduction of substrate 11. The
preferential formation of the couple of diastereomers with an anti-
configuration for this type of catalysts is noteworthy. In our previous
work, only the syn-diastereomers were formed by using classical
transition metal catalysts in which the source of chirality was an
atropoisomeric diphosphine. Finally in all of the reductions of these
substrates, an increase in the diastereomeric excess was obtained
along with a decrease in stereoselectivity on the prochiral centre.
yield); 1H NMR (CDCl3, 300 MHz, 25 °C): d = 1.64–1.77 (m, 2H),
2.04–2.14 (m, 2H), 2.46 (s, 3H), 2.60–2.77 (m, 2H), 3.93 (t,
J = 6.3 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H)
ppm; 13C NMR (CDCl3, 75 MHz, 25 °C): d = 20.06, 24.00, 28.63,
31.89, 50.91, 121.64, 128.60, 137.77, 155.77, 157.75 ppm. FTIR
m
= 3493, 3456, 3320, 2973, 2916, 1725, 1627, 1602, 1485, 1305,
1264, 1135, 1107, 1077, 1067, 680 cmÀ1 Elemental analysis of
14H0N2O6 calcd C 53.84 H 6.45 N 8.97; found C 53.85 H 6.66 N
C
8.82; MS (ESI) of
C10H14N2 (m/z): calcd 162.1, found 163.1
[M+1]+. The enantiomeric excess of Me-CAMPY was evaluated
using the corresponding acetylated derivatives by chiral GC analy-
sis (conditions: 140 °C 10 min, 2 °C/min to 165 °C).
3. Conclusions
Crystal structure of PtCl4((S)-(+)-Me-CAMPY)ÁH2O: C10H18Cl4N2
OPt, M = 519.15, monoclinic, a = 12.6157(5), b = 8.2091(3), c = 15.
4482(6) Å, b = 90.4678(5), U = 1599.8(1) Å3, T = 294(2) K, space
In conclusion a series of efficient iridium catalysts based on
CAMPY derivatives has been studied in the reduction of different
types of aryl ketones. A wide variety of behaviours was seen by
changing the reaction conditions. In particular the presence of
HCOOH as a hydrogen donor played an important role with regard
to the stereoselectivity of the catalysts. In the case of ligands L3
and L4, by changing the primary amino group into a secondary
one, the catalytic performance was reduced. Finally ATH reactions
on b-lactam precursors led to very high ee. Further investigations
are currently underway with the aim of increasing the de without
losing the excellent stereoselectivity obtained.
group C2 (No. 5), Z = 4,
l = (Mo-Ka
) 9.427 mmÀ1. 8475 reflections
(4809 unique; Rint = 0.019) were collected at room temperature in
the range 5.28° < 2h < 62.92°, employing a 0.25 Â 0.20 Â 0.15 mm
crystal mounted on a Bruker APEX II CCD diffractometer and using
graphite-monochromatized Mo-Ka radiation (k = 0.71073 Å). Data-
sets were corrected for Lorentz polarization effects and for absorp-
tion (SADABS).29 The structure was resolved by direct methods
(SIR-97)30 and was completed by iterative cycles of full-matrix least
squares refinement on Fo2 and
D
F synthesis using the SHELXL-9731
F maps,
program (WinGX suite).32 Hydrogen atoms located on the
D
were allowed to ride on the carbon atoms for the phenanthroline
ligand and on N2, whereas the position of those bonded to the N1
atom and to the water molecule were refined without constraint.
The presence of the anomalous X-ray scatterer platinum atom
allowed us to unambiguously determine the absolute configuration,
the Flack parameter was 0.017(8) which confirmed that the absolute
structure given by the structure refinement was correct. Final R1
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in CDCl3 or D2O on Bruker
DRX Avance 300 MHz equipped with a non-reverse probe. Chemical
shifts (in ppm) are referenced to residual solvent proton/carbon
peak. FTIR spectra were collected by using a Perkin Elmer (MA,
USA) FTIR Spectrometer ‘Spectrum One’ in the spectroscopic region
between 4000 and 450 cmÀ1 and analysed by transmittance tech-
niques with 32 scansions and 4 cmÀ1 resolution. Polarimetry analy-
ses were carried out on Perkin Elmer 343 Plus equipped with Na/Hal
lamp. MS analyses were performed by using a Thermo Finnigan (MA,
USA) LCQ Advantage system MS spectrometer with an electronspray
ionization source and an ‘Ion Trap’ mass analyser. The MS spectra
were obtained by direct infusionof a sample solutionin MeOHunder
ESI positive ionization. Catalytic reactions were monitored by gas
chromatography analysis using a chiral stationary phase column
(MEGA DMT b, 25 m, internal diameter 0.25 mm) or by HPLC analy-
sis with Merck-Hitachi L-7100 equipped with Detector UV6000LP
and a chiral column (OD-H Chiralcel or AD Chiralpak).
Commercially reagent grade solvents were dried according to
standard procedures and freshly distilled under nitrogen before
use. Unless otherwise stated, materials were obtained from
commercial sources and used without further purification; enantio-
merically pure (R)-(À)- and (S)-(+)-8-amino-5,6,7,8-tetrahydro-
quinolines (CAMPY) were obtained as reported in the literature;6
rac-2-methyl-5,6,7,8-tetrahydroquinolin-8-amines (Me-CAMPY)
were synthesized according to literature procedures.27,28
[wR2] values are 0.0199 [0.0584] on I > 2r(I) [all data].
CCDC-989123 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
4.2.2. (R)-N-Methyl-5,6,7,8-tetrahydroquinolin-8-amine ((R)-NH
Me-CAMPY) L3
(R)-N-Acetyl-5,6,7,8-tetrahydroquinolin-8-amine
(141 mg,
0.74 mmol) and NaH (24 mg, 1 mmol) in anhydrous THF (5 mL)
were refluxed for 1 h, cooled to 0 °C and CH3I (142 mg, 1 mmol)
was added dropwise. The reaction mixture was stirred at room tem-
perature and monitored by TLC (CH2Cl2/MeOH 9:1). The solution
was quenched with water and the aqueous layers were extracted
with diethyl ether (3 Â 10 mL). The combined organic layers were
dried over Na2SO4. The crude product was purified by Kugelrohr
distillation to give N-methyl-N-(5,6,7,8-tetrahydroquinolin-8-
yl)acetamide (GC: iso 140 °C 10 min, 1 °C/min to 160 °C). The corre-
sponding N-acetyl derivate was hydrolysed by refluxing in HCl 6 M
(3 mL). The solution was cooled to room temperature, quenched
with Na2CO3, extracted with CH2Cl2 and dried over Na2SO4. The
crude oil was dissolved in hexane (10 mL) and filtered on a Celite
pad to give the product as a pale yellow oil (100 mg, 0.62 mmol,
82% yield). 1H NMR (CDCl3, 300 MHz, 25 °C): d = 1.69–1.81 (m,
2H), 1.93–2.01 (m, 1H), 2.10–2.18 (m, 1H), 2.53 (s, 3H), 2.50–2.78
(m, 3H), 3.67 (t, J = 5.2 Hz, 1H), 7.05 (dd, J = 7.7, 4.7 Hz, 1H), 7.39
(d, J = 7.6 Hz, 1H), 8.40 (d, J = 4.6 Hz, 1H) ppm; 13C NMR (CDCl3,
75 MHz, 25 °C): d = 19.55, 27.82, 28.85, 34.26, 59.56, 121.86,
4.2. Synthesis of the ligands
4.2.1. (R)-2-Methyl-5,6,7,8-tetrahydroquinolin-8-amine ((R)-Me-
CAMPY) L2
Rac-Me-CAMPY (486 mg, 3 mmol) was dissolved in EtOH
132.46, 136.89, 146.86, 157,23 ppm. FTIR
m = 3333.9, 3049.6,
(30 mL), then
a solution of (R,R)-L-(+)-tartaric acid (225 mg,
2926.7, 2855.2, 2784.1, 1648.1, 1575.3, 1444.5, 1428.1, 1238.7,
1104.1, 782.2 cmÀ1. MS (ESI) of C10H14N2 (m/z): calcd 162.1, found
1.5 mmol) in EtOH (20 mL) was added. The suspension was heated
until the disappearance of the solid salt, cooled to room tempera-
163.2 [M+1]+. [
a
]
D
20 = À20.8 (c 0.5, CH2Cl2).

1036
D. Zerla et al. / Tetrahedron: Asymmetry 25 (2014) 1031–1037
4.2.3. (R)-(À)-N-2-Dimethyl-5,6,7,8-tetrahydroquinolin-8-amine
((R)-NHMe-Me-CAMPY) L4
4.4. Synthesis of the substrates
To a solution of (R)-Me-CAMPY L2 (121 mg, 0.75 mmol) in THF
(5 mL), aqueous K2CO3 (1.5 mL, 1 M) and ethyl chloroformate
(0.11 mL, 1.1 mmol) were added at 0 °C. The solution was warmed
to room temperature and stirred for 2.5 h. The organic phase was
dried and the solvent was removed in vacuo. The crude oil
obtained was dissolved in anhydrous THF (5 mL) and added drop-
wise into a suspension of LiAlH4 (46 mg, 1.2 mmol) in anhydrous
THF (5 mL) at 0 °C, stirred at room temperature for 1 h and refluxed
for 2 h. The reaction mixture was quenched by adding THF, aque-
ous KOH and extracted with diethyl ether (3 Â 10 mL). The crude
product was purified by Kugelrohr distillation to obtain a pale yel-
low oil (99 mg, 0.56 mmol; 56% yield). 1H NMR (CDCl3, 300 MHz,
25 °C): d = 1.56–1.74 (m, 1H), 1.81–1.95 (m, 2H), 2.08 (s, 3H),
2.52 (s, 3H), 2.55–2.68 (m, 1H), 2.77 (t, J = 6.5 Hz, 2H), 4.76 (dd,
J = 9.6, 4.9 Hz, 1H), 6.70 (br, 1H), 7.00 (d, J = 7.9 Hz, 1H), 7.33 (d,
J = 7.9 Hz, 1H) ppm; 13C NMR (CDCl3, 75 MHz, 25 °C): d = 20.29,
24.13, 24.35, 28.14, 29.56, 51.64, 122.49, 130.15, 137.96, 154.62,
4.4.1. Enzymatic synthesis of rac-2-benzoylbutanenitrile 4
Commercial Baker’s yeast (50 g/L) was suspended in a phos-
phate buffer (200 mL, 0.1 M, pH 7) containing 50 g/L of glucose
and 5 g/L of the substrate 1 was added. The biotransformation sys-
tem was shaken with a mechanical stirrer at 28 °C. When total con-
version was achieved, the cells were separated by centrifugation.
Both the aqueous phases and the cell mixture were extracted with
diethyl ether (3 Â 50 mL), dried over Na2SO4 and the solvent was
removed in vacuo. The crude product was purified by flash chro-
matography (CH2Cl2/hexane/ethyl acetate = 4:1:1) to give 860 mg
of 4 (86% yield). 1H NMR (CDCl3, 300 MHz, 25 °C): d = 1.16 (t,
J = 7.7 Hz, 3 H), 2.02–2.15 (m, 2H), 4.30 (dd, J = 6.2, 4.3 Hz, 1H),
7.49–7.56 (m, 2H), 7.65 (d, J = 7.6 Hz, 1H) 7.95 (d, J = 6.7 Hz, 2H)
ppm; 13C NMR (CDCl3, 75 MHz, 25 °C): d = 11.71, 23.77, 41.69,
117.41, 128.92–134.63, 170.91, 190.97 ppm. FTIR
m = 3467, 2975,
2936, 2249, 1694, 1597, 1449, 1265, 1233, 1208, 1000, 696 cmÀ1
.
MS (ESI) of C11H11NO (m/z): calcd 173.2, found 196.1 [M+Na+].
155.75 ppm. FTIR
m
= 3330, 2940, 2860, 2785, 1707, 1596, 1574,
Compound 4a: 1H NMR (CDCl3, 300 MHz, 25 °C): d = 1.09 (t,
J = 7.7 Hz, 3H, anti), d = 1.17 (t, J = 7.6 Hz, 3H, syn), 1.51–1.69 (m,
2H), 2.76–2.83 (m, 2H, anti), 2.87–2.95 (m, 2H, syn), 4.79 (d,
J = 6.2 Hz, 1H, anti), 4.83 (d, J = 6.6 Hz, 1H, syn), 7.33–7.56 (m, 5H)
ppm; 13C NMR (CDCl3, 75 MHz, 25 °C): d = 9.84 (syn), 10.38 (anti),
24.86 (anti), 25.87 (syn), 76.86 (syn), 77.46 (anti), 127.04, 128.05
(anti), 128.22 (syn), 128.55 (anti), 128.69 (syn), 140.61 (anti)
1471, 1444, 1258, 1147, 1119, 1105, 1035, 850, 813, 783 cmÀ1
.
MS (ESI) of C11H16N2 (m/z): calcd 176.1, found 177.2 [M+1]+.
[a
]
D
20 = À52.5 (c 1, CH2Cl2).
4.3. General procedure for the synthesis of [Cp⁄Ir(H2O)(L)]SO4
141.42 (syn) ppm. FTIR
m = 3390, 2964, 1494, 1453, 160, 1103,
The complexes were prepared according to
procedure.18
a literature
1038, 702 cmÀ1. MS (ESI) of C11H11NO (m/z): calcd 175.1, found
198.3 [M+Na+]. Yield was evaluated by 1H NMR analysis. HPLC
data: OD-H Chiralcel, eluent: hexane: 2-propanol = 95:5,
flow = 0.8 mL/min, k = 216 nm. rt: (R, S) = 25.6 min, (S, S) = 26.5
min, (S, R) = 34.6 min, (R, R) = 36.0 min.
4.3.1. [Cp⁄Ir(H2O)(L1)]SO4
1H NMR (D2O, 300 MHz, 25 °C): d = 1.63 (m, 2H), 1.72 (s, 15H),
2.04–2.06 (m, 1H), 2.45–2.48 (m, 1H), 2.85–2.99 (m, 2 H), 4.02–
4.13 (m, 1H), 7.58 (dd, J = 5.9 Hz,1 H), 7.80 (d, J = 7.9 Hz,1 H),
8.70 (d, J = 5.5 Hz, 1H) ppm; 13C NMR (D2O, 75 MHz, 25 °C):
d = 10.24, 20.11, 29.39, 37.57, 51.79, 122.34, 132.17, 137.28,
147.39, 155.12 ppm. MS (ESI) of C17H27IrN2 [MÀSO4ÀH2OÀH] (m/
z): calcd 475.7, found 475.4.
4.4.2. Ethyl-2-(benzamidomethyl)-3-oxo-phenylpropanoate 10
The substrate was prepared according to a literature proce-
dure.26 1H NMR (CDCl3, 300 MHz, 25 °C): d = 1.18 (t, J = 6.9 Hz,
3H), 3.93–3.97 (m, 2H), 4.09–4.16 (m, 2H), 4.19 (q, J = 6.9 Hz,
2H), 4.87 (dd, J = 5.5, 3.7 Hz, 1H), 6.73 (br, 1H), 7.42–7.62 (m,
2H), 7.71 (dd, J = 8.0, 1.5 Hz, 4H), 8.10 (dd, J = 5.1, 2.2 Hz, 4H)
ppm; 13C NMR (CDCl3, 75 MHz, 25 °C): d = 14.1, 39.2, 53.7, 62.03,
127.1–135.9, 167.9 (isomer), 169.2 (isomer), 194.8 ppm. FTIR
4.3.2. [Cp⁄Ir(H2O)(L2)]SO4
1H NMR (D2O, 300 MHz, 25 °C): d = 1.52 (s, 15H), 1.62–1.66 (m,
2H), 1.74–1.85 (m, 2H), 2.28–2.32 (m, 2H), 2.70 (s, 3H), 4.58–4.66
(m, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H) ppm; 13C
NMR (D2O, 75 MHz, 25 °C): d = 8.76, 20.12, 26.61, 26.83, 31.74,
62.37, 87.85, 126.62, 133.89, 141.28, 157.86, 158.02 ppm. MS (ESI)
of C20H29IrN2 [MÀSO4ÀH2OÀH] (m/z): calcd 489.7, found 489.6.
m
= 3334, 1961, 1734, 1679, 1637, 1534, 1311, 1250, 1211, 1198,
1078, 694 cmÀ1. MS (ESI) of C19H19NO4 (m/z): calcd 325.1, found
348.5 [M+Na+].
Compound 10a: 1H NMR (CDCl3, 300 MHz, 25 °C): d = 1.01 (t,
J = 7.0 Hz, 3H), 2.93–3.01 (m, 1H, syn), 3.15–3.24 (m, 1H, anti),
3.61–3.69 (m, 2H), 3.98 (q, J = 7.0 Hz, 2H), 4.12–4.19 (m, 2H),
4.95 (d, J = 7.3 Hz, 1H, anti), 4.96 (d, J = 7.3 Hz, 1H, syn), 6.72 (br,
1H), 7.29–7.53 (m, 4H), 7.77 (dd, J = 8.0, 1.5 Hz, 4H) ppm; 13C
NMR (CDCl3, 75 MHz, 25 °C): d = 14.0, 37.9 (syn), 38.0 (anti), 53.0,
4.3.3. [Cp⁄Ir(H2O)(L3)]SO4
1H NMR (D2O, 300 MHz, 25 °C): d = 1.54 (s, 15H), 1.66–1.69 (m,
2H), 1.75–1.78 (m, 2H), 2.54–2.69 (m, 2H), 3.10 (d, J = 6.1 Hz, 3H),
3.93–4.2 (m, 1H), 7.38 (dd, J = 7.7 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H),
8.51 (d, J = 5.5 Hz, 1H) ppm; 13C NMR (D2O, 75 MHz, 25 °C):
d = 8.46, 14.07, 22.35, 23.38, 28.79, 54.09, 116.39, 126.99, 131.42,
141.39, 151.76 ppm. MS (ESI) of C20H29IrN2 [MÀSO4ÀH2OÀH] (m/
z): calcd 489.7, found 489.5.
61.1, 72.6, 126.4–132.0, 164.31, 173.5 ppm. FTIR
m = 3364, 1948,
1724, 1649, 1607, 1535, 1301, 1246, 1111, 828 cmÀ1. MS (ESI) of
C
19H21NO4 (m/z): calcd 327.1, found 350.4 [M+Na+]. (2R,3R)
[a
]
20 = +33.2 (c 0.15, CHCl3); (2S,3S) [
a
]
D
20 = À11.0 (c 0.18, CHCl3);
D
(2R,3S) [
a
]
D
20 = À11.3 (c 0.12, CHCl3); Yield was evaluated by 1H
NMR analysis. HPLC data: AD Chiralpak, eluent hexane/2-propa-
nol = 90:10, flow = 0.6 mL/min, k = 230 nm. rt: (R, R) = 35.1 min,
(S, S) = 37.1 min, (S, R) = 49.8 min, (R, S) = 68.8 min.
4.3.4. [Cp⁄Ir(H2O)(L4)]SO4
1H NMR (D2O, 300 MHz, 25 °C): d = 1.68 (s, 15H), 1.94–1.97 (m,
2H), 2.48–2.50 (m, 2H), 2.62–2.65 (m, 2H), 2.70 (s, 3H), 3.14 (d,
J = 5.9 Hz, 3H), 3.99–4.04 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.60 (d,
J = 8.1 Hz, 1H) ppm; 13C NMR (D2O, 75 MHz, 25 °C): d = 8.81,
19.78, 26.58, 38.77, 69.15, 88.43, 126.87, 134.00, 141.43, 156.67,
158.30 ppm. MS (ESI) of C21H31IrN2 [MÀSO4ÀH2OÀH] (m/z): calcd
503.7, found 503.4.
4.4.3. Ethyl 2-(benzamidomethyl)-3-(4-methoxyphenyl)-3-oxo-
propanoate 11
The substrate was prepared according to the literature by start-
ing from ethyl 3-(4-methoxyphenyl)-3-oxopropanoate.26 1H NMR
(CDCl3, 300 MHz, 25 °C) d = 1.22 (t, J = 7.3 Hz, 3H); 3.78 (s, 3H);
3.86–4.93 (m, 1H); 4.01–4.13 (m, 1H); 4.15 (q, J = 5.9 Hz, 2H);
4.88 (dd, J = 5.9, 3.8 Hz, 1H); 6.88 (d, J = 8.8 Hz, 2H); 7.37–7.67

D. Zerla et al. / Tetrahedron: Asymmetry 25 (2014) 1031–1037
1037
(m, 3H) 7.74 (d, J = 8.4 Hz, 2H); 8.09 (d, J = 8.8 Hz, 2H) ppm. 13C
NMR (CDCl3, 75 MHz, 25 °C): d = 13.92, 39.14, 53.23, 55.77, 62.19,
114.04, 127.17, 128.24, 128.78, 131.61, 134.25, 164.03, 167.96,
time (3 h for 2-cyanoacetophenones, 6 h for acetophenones and
24 h for b-ketoesters). The reaction mixture was quenched with
brine (4 mL) and extracted with ethyl acetate (2 Â 5 mL). The com-
bined organic layers were dried over Na2SO4 and concentrated in
vacuo.
186.91, 192.70 ppm. FTIR
1533, 1261, 1205, 1184, 1016, 838, 714 cmÀ1
20H21NO5 (m/z): calcd 355.1, found 378.2 [M+Na+].
Compound 11a: 1H NMR (CDCl3, 300 MHz, 25 °C): d = 0.96 (t,
m
= 3401, 2979, 1731, 1665, 1602, 1574,
.
MS (ESI) of
C
4.5.2. Method B
J = 7.3 Hz, 3H, syn), 1.21 (t, J = 6.9 Hz, 3H, anti); 2.94–3.02 (m, 1H,
syn); 3.10–3.24 (m, 1H, anti); 3.54–3.68 (m, 2H); 3.73 (s, 3H);
3.99 (q, J = 7.0 Hz, 2H, syn); 4.16 (q, J = 7.3 Hz, 2H, anti); 4.88 (dd,
J = 6.8, 3.9 Hz, 1H, syn); 4.95 (dd, J = 6.9, 3.9 Hz, 1H, anti); 6.55–
6.68 (br, NH); 6.88 (d, 2H); 7.43 (d, J = 2.7 Hz, 2H); 7.47–7.59 (m,
3H); 7.79 (d, J = 2.5 Hz, 2H) ppm. 13C NMR (CDCl3, 75 MHz,
The ATH procedure when the HCOOH/TEA azeotropic mixture
(5:2) was used as the hydrogen donor. To a solution of the sub-
strate (0.5 mmol) in 2 mL of HCOOH/TEA azeotropic mixture
(5:2), [Cp⁄Ir(H2O)(L)]SO4 (0.0025 mmol) was added. The reaction
mixture was stirred at 70 °C for a fixed time (3 h for 2-cyanoace-
tophenones, 6 h for acetophenones and 24 h for b-ketoesters).
The reaction mixture was quenched with 5% NaHCO3 solution
(4 mL) and extracted with ethyl acetate (2 Â 5 mL). The combined
organic layers were dried over Na2SO4 and concentrated in vacuo.
25 °C):
d = 14.36, 39.55, 53.67, 56.23, 62.14, 71.63, 114.61,
128.03, 128.73, 129.25, 132.32, 134.60, 164.75, 168.03,
170.00 ppm. FTIR
m = 3371, 2940, 1724, 1635, 1544, 1513, 1308,
1245, 1114, 836 cmÀ1. MS (ESI) of C20H23NO5 (m/z): calcd 357.2,
found 380.3 [M+Na+]. Yield was evaluated by 1H NMR analysis.
HPLC data: AD Chiralpak, eluent: hexane/2-propanol = 80:20, flow
= 1.0 mL/min, k = 230 nm. rt: (S, S) = 9.7 min, (R, R) = 10.7 min,
(S, R) = 14.9 min, (R, S) = 21.7 min.
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4.4.4. Ethyl 2-(benzamidomethyl)-3-oxo-3-(4-(trifluoromethyl)-
phenyl)propanoate 12
The substrate was prepared according to the literature by start-
ing from ethyl 2-(benzamidomethyl)-4,4,4-trifluoro-3-oxobutano-
ate.26 1H NMR (CDCl3, 300 MHz, 25 °C): d = 1.17 (t, J = 7.0 Hz,
3H); 3.87–4.15 (m, 1H); 4.16–4.22 (q, J = 5.9 Hz, 2H); 4.91 (dd, J
= 5.9, 3.7 Hz, 1H); 6.92–6.98 (br, NH), 7.35–7.54 (m, 3H), 7.71–
7.77 (m, 4H); 8.20 (d, J = 8.0 Hz, 2H) ppm. 13C NMR (CDCl3,
75 MHz, 25 °C): d = 14.17, 39.15, 53.50, 62.01, 115.52, 120.94,
126.06, 126.37, 127.13, 128.80, 129.41, 131.94, 134.09, 134.91,
9. Li, C.; Zhang, L.; Du, Y.; Zheng, X.-L.; Fu, H.-Y.; Chen, H.; Li, R.-X. Catal. Commun.
2012, 28, 5–8.
10. Wu, X.; Vinci, D.; Ikariya, T.; Xiao, J. Chem. Commun. 2005, 4447–4449.
11. Wu, X.; Liu, J.; Li, X.; Zanotti-Gerosa, A.; Hancock, F.; Vinci, D.; Ruan, J.; Xiao, J.
Angew. Chem., Int. Ed. 2006, 45, 6718–6722.
135.59, 136.33, 138.70, 167.87, 168.81, 193.79 ppm. FTIR
m
12. Sun, X.; Li, W.; Zhou, L.; Zhang, X. Chem. Eur. J. 2009, 15, 7302–7305.
13. de Koning, P. D.; Jackson, M.; Lennon, I. C. Org. Process Res. Dev. 2006, 10, 1054–
1058.
14. Šterk, D.; Stephan, M.; Mohar, B. Org. Lett. 2006, 8, 5935–5938.
15. Lundgren, R. J.; Rankin, M. A.; McDonald, R.; Schatte, G.; Stradiotto, M. Angew.
Chem., Int. Ed. 2007, 46, 4732–4735.
16. Ahlford, K.; Zaitsev, A. B.; Ekström, J.; Adolfsson, H. Synlett 2007, 2541–2544.
17. Talwar, D.; Salguero, N. P.; Robertson, C. M.; Xiao, J. Chem. Eur. J. 2014, 20, 245–
252.
18. Vázquez-Villa, H.; Reber, S.; Ariger, M. A.; Carreira, E. M. Angew. Chem., Int. Ed.
2011, 50, 8979–8981.
19. Ariger, M. A.; Carreira, E. M. Org. Lett. 2012, 14, 4522–4524.
20. Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Tetrahedron: Asymmetry 2008, 19,
2816–2828.
21. Zhu, D.; Yang, Y.; Hua, L. J. Org. Chem. 2006, 71, 4202–4205.
22. Yang, Y.; Zhu, D.; Piegat, T. J.; Hua, L. Tetrahedron: Asymmetry 2007, 18, 1799–
1803.
= 3258, 2986, 1740, 1730, 1633, 1542, 1325, 1293, 1192, 1166,
1129, 1112, 1067, 1014, 710, 696 cmÀ1. MS (ESI) of C20H18F3NO4
(m/z): calcd 393.1, found 416.1 [M+Na+].
Compound 12a: 1H NMR (CDCl3, 300 MHz, 25 °C): d = 0.87 (t, J
= 7.0 Hz, 3H, syn); 0.99 (t, J = 7.3 Hz, 3H, anti); 2.94–2.99 (m, 1H,
syn); 3.17–3.27 (m, 1H, anti); 3.55–3.87 (m, 1H); 3.96 (q, J
= 7.0 Hz, 2H, syn); 4.14 (q, J = 7.3 Hz, 2H, anti); 4.17–4.27 (m, 1H),
4.94 (d, J = 8.1 Hz, 1H, syn); 5.09 (d, J = 5.1 Hz, 1H, anti); 6.77–
6.79 (br, NH, anti), 6.93–6.96 (br, NH, syn), 7.36–7.68 (m, 7H);
7.70 (d, J = 6.9 Hz, 2H, anti); 7.73 (d, J = 5.4 Hz, 2H, syn) ppm. 13C
NMR (CDCl3, 75 MHz, 25 °C): d = 13.97, 37.82, 53.18, 61.39,
71.93, 121.47, 125.41, 126.96, 127.25, 127.44, 128.64, 129.98,
130.63, 131.32, 131.89, 133.64, 145.28, 168.87, 173.09 ppm. FTIR
23. Meng, Q.; Sun, Y.; Ratovelomanana-Vidal, V.; Genêt, J. P.; Zhang, Z. J. Org. Chem.
2008, 73, 3842–3847.
24. Plantan, I.; Stephan, M.; Urleb, U.; Mohar, B. Tetrahedron Lett. 2009, 50, 2676–
2677.
25. Zhu, D.; Malik, H. T.; Huo, L. Tetrahedron: Asymmetry 2006, 17, 3010–3014.
26. Rimoldi, I.; Cesarotti, E.; Zerla, D.; Molinari, F.; Albanese, D.; Castellano, C.;
Gandolfi, R. Tetrahedron: Asymmetry 2011, 22, 597–602.
27. Petit, M.; Tran, C.; Roger, T.; Gallavardin, T.; Dhimane, H.; Palma-Cerda, F.;
Blanchard-Desce, M.; Acher, F. C.; Ogden, D.; Dalko, P. I. Org. Lett. 2012, 14,
6366–6369.
m
= 3368, 2980, 2937, 1728, 1644, 1536, 1514, 1304, 1248, 1112,
1033, 834 cmÀ1. MS (ESI) of C20H20F3NO4 (m/z): calcd 395.1 found
418.2 [M+Na+]. Yield was evaluated by 1H NMR analysis. HPLC
data: AD Chiralpak, eluent: hexane/2-propanol = 90:10, flow
= 0.8 mL/min, k = 230 nm. rt: (S, S) = 17.3 min, (R, R) = 18.3 min,
(R, S) = 29.9 min, (S, R) = 31.8 min.
4.5. General procedure for the asymmetric transfer hydrogen-
ation (ATH)
28. Skupinska, K. A.; McEachern, E. J.; Skerlj, R. T.; Bridger, G. J. J. Org. Chem. 2002,
67, 7890–7893.
29. SADABS Area-Detector Absorption Correction Program, B. A. I. M., WI, USA.
2000.
30. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.;
Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystallogr.
1999, 32, 115–119.
4.5.1. Method A
The ATH procedure when formic acid or sodium formate was
used as the hydrogen donor. To a solution of the substrate
(0.5 mmol) in a 1:1 mixture methanol and water (2 mL), [Cp⁄Ir(H2-
O)(L)]SO4 (0.0025 mmol) and hydrogen donor (2.5 mmol, 5 equiv)
were added. The reaction mixture was stirred at 70 °C for a fixed
31. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122.
32. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838.