Application of phosphine-phosphite ligands in the iridium catalyzed enantioselective hydrogenation of 2-Methylquinoline

Article abstract of DOI:10.3390/molecules15117732

The hydrogenation of 2-methylquinoline with Ir catalysts based on chiral phosphine-phosphites has been investigated. It has been observed that the reaction is very sensitive to the natureof the ligand. Optimization of the catalyst, allowed by the highly modular structure of these phosphine-phosphites, has improved the enantioselectivity of the reaction up to 73% ee. The influence of additives in this reaction has also been investigated. Contrary to the beneficial influence observed in related catalytic systems, iodine has a deleterious effect in the present case. Otherwise, aryl phosphoric acids produce a positive impact on catalyst activity without a decrease on enantioselectivity.

Full text of DOI:10.3390/molecules15117732

Molecules 2010, 15, 7732-7741; doi:10.3390/molecules15117732
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Application of Phosphine-Phosphite Ligands in the Iridium
Catalyzed Enantioselective Hydrogenation of 2-Methylquinoline
Miguel Rubio and Antonio Pizzano *
Instituto de Investigaciones Químicas, Consejo Superior de Investigaciones Científicas and
Universidad de Sevilla, Avda. Américo Vespucio 49, 41092 Sevilla, Spain
* Author to whom correspondence should be addressed; E-Mail: pizzano@iiq.csic.es;
Tel.: +34-954-489-556; Fax: +34-954-460-565.
Received: 6 October 2010; in revised form: 26 October 2010 / Accepted: 28 October 2010 /
Published: 29 October 2010
Abstract: The hydrogenation of 2-methylquinoline with Ir catalysts based on chiral
phosphine-phosphites has been investigated. It has been observed that the reaction is very
sensitive to the nature of the ligand. Optimization of the catalyst, allowed by the highly
modular structure of these phosphine-phosphites, has improved the enantioselectivity of
the reaction up to 73% ee. The influence of additives in this reaction has also been
investigated. Contrary to the beneficial influence observed in related catalytic systems,
iodine has a deleterious effect in the present case. Otherwise, aryl phosphoric acids
produce a positive impact on catalyst activity without a decrease on enantioselectivity.
Keywords: asymmetric hydrogenation; chiral ligands; phosphines; phosphites; iridium;
quinolines
1. Introduction
The use of two coordinating functions of different nature in a chiral ligand constitutes as a very
powerful approach in the field of asymmetric hydrogenation [1]. Thus, excellent catalyst performance
has been achieved in a plethora of reactions by the use of ligands which appropriately combine diverse
C, N, S and P donor groups [2-5].
The catalytic asymmetric hydrogenation of quinolines to produce optically active tetrahydro-
quinolines is a very interesting reaction due to the importance of the resulting products. For instance,
chiral tetrahydroquinolines are ubiquitous products in Nature (Figure 1) which exhibit, in addition, a

Molecules 2010, 15
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wide range of biological properties of interest to the pharmaceutical industry [6-12]. A variety of
catalytic systems, mostly based on Ir complexes and chiral chelating ligands with either equivalent
(C2 symmetric) or non equivalent (C1 symmmetric) coordinating functions, have provided satisfactory
results for this transformation. In this regard, Zhou et al. have described a catalytic system of
[IrCl(cod)]2, MeO-Biphep and I2 that hydrogenates a variety of substituted quinolines with high
enantioselectivities [13]. Likewise, Chan et al. have successfully applied other diphosphines such as
P-phos and Difluorphos in this reaction [14-15]. Interestingly, this transformation can also be
effectively catalyzed by species based on less donor diphosphonites, as shown by Reetz et al. [16].
Moreover, C1 symmetric phosphine-oxazoline, phosphine-sulfoximine or phosphine-phosphoramidite
ligands have also led to efficient catalysts [17-19]. In addition, complexes based on a combination of a
monodentate chiral phosphoramidite and an achiral phosphine, which provide good levels of activity
and enantioselectivity, have been described by Feringa et al. [20]. Despite the excellent results
obtained in these precedents, the knowledge about this reaction is still limited. Then, studies aimed to
understand the influence of important features like ligand basicity, bite angle or the influence of
additives are highly interesting [13-21].
Figure 1. Some naturally occurring chiral tetrahydroquinolines.
OMe
N
O
O
N
N
Me
OMe
Me
Me
Cuspareine
Angustrureine
Galipinine
Among chelating ligands with unequal coordinating groups, we have focused on phosphine-
phosphites (P-OP) and their application in asymmetric catalytic hydrogenation reactions. Interestingly,
the dissimilar electronic properties of their P functionalities provides an efficient differentiation
between coordination positions, which reduces the number of reaction intermediates and allows a
better stereocontrol [22-23]. Moreover, the highly modular structure of the P-OP derivatives developed
in our laboratory (Figure 2), enables a detailed catalyst screening covering the influence of phosphine,
phosphite and backbone fragments. This approach has successfully been applied in the Rh catalyzed
enantioselective hydrogenation of several types of olefins [24-26]. In addition, we have demonstrated
the usefulness of P-OP ligands in the Ir catalyzed hydrogenation of N-aryl imines [27]. As an extension
of the scope of chiral phosphine-phosphites in the hydrogenation of C=N bonds, we describe herein
preliminary results about the application of these ligands in the Ir catalyzed asymmetric hydrogenation
of 2-methylquinoline.
Figure 2. General structure of P-OP ligands.
R
R
R
R
R'
R'
P
P
R = alkyl, aryl
R' = H, But
O
O
O P
O P
O
O
R'
R'

Molecules 2010, 15
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2. Results and Discussion
In a first stage, we have carried out a set of reactions to search for appropriate conditions for the
catalytic hydrogenation of 2-methylquinoline (Eq 1). Thus, under 40 bar of hydrogen pressure and at
room temperature, the catalyst generated from [Ir(Cl)(COD)]2 and ligand (S)-1a (Figure 3), produced
only a moderate conversion and a low enantioselectivity (entry 1, Table 1). Interestingly, the presence
of a more donating phosphine group in (S)-1b led to an important increase in catalyst activity, with a
slight improvement on enantioselectivity (entry 2). Moreover, a cationic catalyst precursor based on
(S)-1b generated a poorer catalyst (entry 3). Interestingly, the neutral catalysts produced an increased
conversion at a lower pressure but again with low selectivities (entries 4, 5). From this preliminary
screening, conditions of the latter reactions were chosen to analyze the influence of ligand structure on
enantioselectivity (Table 2).
Figure 3. P-OP ligands used in the present study.
H2
(1)
N
[Ir(Cl)(COD)]2 + P-OP
N
H
R
R
R
Ph
R
Ph
But
O
But
O
P
P
P
O
O P
O
O P
O P
O
O
But
But
R = Ph [(S)-1a], Pri [(S)-1b]
R = Pri [(R)-2b)], But [(R)-2c],
2-MeC6H4 [(R)-2d],
(S)-3a
1-naphthyl [(R)-2e]
R
Ph
Ph
Ph
Ph
R
But
P
P
P
O
O
O
O P
O
O
O P
O
O P
But
R = Ph [(S)-6a], Pri [(S)-6b]
(S)-4a
(R)-5a
A comparison of the catalyst performance along the series of ligands allows one to extract some
interesting observations. Most remarkably, the use of less hindered phosphite groups has a positive
effect on the reaction. Thus, catalyst prepared with ligand (R)-2b produced an important increase on
enantioselectivity over (S)-1b, from 16 to 62% ee, while maintaining a good conversion (entries 2, 3).
Further examination of different phosphine groups did not allow us to improve the values achieved by
(R)-2b (entries 4-6). As an alternative, we considered ligands based on ethane bridged examples, as
this backbone has a positive effect in the hydrogenation of N-aryl imines [27]. Contrary to our
expectations, the enantioselectivities with these ligands were rather low (entries 7-9). In an attempt to

Molecules 2010, 15
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increase the practical utility of the present system we have also analyzed the performance of BINOL
based ligands (S)-6a [28] and (S)-6b. These compounds are structurally similar to 2, but considerably
easier to synthesize, as the required chlorophosphite can be prepared in one step from commercially
available BINOL [29]. New (S)-6b was readily prepared by condensation between 2-hydroxyphenyl-
diisopropyl phosphine and BINOL chlorophosphite (see Experimental).
Table 1. Catalytic asymmetric hydrogenation of 2-methylquinoline with P-OP ligands.1
Entry
Cat. Precursor
P/atm
40
%Conv
% ee
7
Conf
1
2
3
4
5
½ [Ir(Cl)(COD)]2 + (S)-1a
½ [Ir(Cl)(COD)]2 + (S)-1b
[Ir(COD)(1b)]BF4
48
84
9
S
S
40
27
6
40
n.d.
-
½ [Ir(Cl)(COD)]2 + (S)-1a
½ [Ir(Cl)(COD)]2 + (S)-1b
20
72
96
0
20
16
S
1
Reactions were carried out at room temperature in toluene at a S/C = 100 and 0.6 M substrate
concentration. Catalyst precursor was generated from [Ir(Cl)(COD)]2 and P-OP ligand at a
1
Ir:P-OP =1:1.1 ratio unless otherwise stated. Conversion was determined by H-NMR and
enantiomeric excess (ee) by chiral HPLC. Configuration was determined by comparison of optical
rotation to the literature value.
Table 2. Catalytic asymmetric hydrogenation of 2-methylquinoline with P-OP ligands.1
Entry
1
Ligand
(S)-1a
(S)-1b
(R)-2b
(R)-2c
(R)-2d
(R)-2e
(S)-3a
(S)-4a
(R)-5a
(S)-6a
(S)-6b
(S)-6b
(S)-6b
P/atm
20
%Conv
72
% ee
0
Conf
-
2
20
96
16
62
56
46
20
9
S
S
S
S
S
S
-
3
20
88
42
52
6
20
7
20
30
20
34
7
20
98
8
20
100
6
0
92
10
11
12
13
20
10
45
65
73
63
S
R
R
R
R
20
28
20
82
40
63
10
40
1
Reactions were carried out at room temperature in toluene at a S/C = 100 and 0.6 M substrate
concentration unless otherwise stated. Catalyst precursor was generated from [Ir(Cl)(COD)]2 and
1
P-OP ligand at a Ir:P-OP =1:1.1 ratio. Conversion was determined by H-NMR and enantiomeric
excess (ee) by chiral HPLC. Configuration was determined by comparison of optical rotation to the
literature value. 2 0.2 M substrate concentration.
Most remarkably, (S)-6b led to similar results as those obtained with (R)-2b. On the other hand,
(S)-6a produced a moderate enantioselectivity, but lower than the iPr derivative. As shown by ligands 1,
a more electron donating ligand leads to a more active catalyst. Finally, examination of catalyst based
on (S)-6b at different pressures exhibited an increase in enantioselectivity up to a 73% ee at 40 atm,
but a lower value at 10 atm (entries 12, 13). Interestingly, product configuration depends on the nature

Molecules 2010, 15
7736
of the phosphite fragment. Thus, the S product is favoured by ligands with a tert-butyl-substituted S
phosphite group. On the contrary, ligands with an unsubstituted S phosphite fragment (e.g., (S)-6a) and
(S)-6b), give predominantly the R amine.
As mentioned, the present hydrogenation is very sensitive to the presence of additives. In particular,
excellent results have been reported in the literature by the use of iodine as cocatalyst [13-17]. Based
on these precedents we prepared a set of reactions using different ligands in the presence of I2 (Table 3).
As observed before, the cocatalyst produces an important increase in reactivity, leading to reaction
completion in all cases. Noteworthily, the presence of iodine produces a reversal of product
configuration in reactions performed with ligands 1. However, the enantioselectivities were
deceptively low in all cases. Presumably, coordination of π-acidic phosphite fragment in the Ir(III)
species generated by iodine addition [30], should not be favoured, which may erode the chiral
induction exerted by the P-OP ligand.
Table 3. Hydrogenation of 2-methylquinoline in presence of iodine.1
Entry
Ligand
(S)-1a
(S)-1a
(S)-1b
(S)-3a
(S)-4a
(S)-6b
(S)-6b
P/atm
40
%Conv
100
% ee
30
16
7
Conf
1
2
3
4
5
6
7
R
R
R
-
20
100
20
100
20
100
0
20
100
11
0
R
-
40
100
20
100
5
R
1
Reactions were carried out at room temperature in toluene at a S/C = 100 and 0.6 M substrate
concentration. Catalyst precursor was generated from [Ir(Cl)(COD)]2, P-OP ligand and I2 at
a Ir:P-OP:I2 =1:1.1:10 ratio. Conversion was determined by 1H NMR and enantiomeric excess (ee) by
chiral HPLC. Configuration was determined by comparison of optical rotation to the literature value.
In order to improve the performance of catalyst based on (S)-6b, we have next studied the influence
of other additives mentioned in the literature (Table 4). Several salts were tested first, although they
did not provide a beneficial effect over the reference system (entries 1-5). On the contrary, an
interesting effect is provided by phosphoric acids [31-33]. Thus, diphenylphosphoric acid produced a
more active catalyst, although less enantioselective (entry 6). From this result and the reported
asymmetric reduction of quinolines catalyzed by binaphthol based phosphoric acids [34], we have
tested the two enantiomers of 1,1’-binaphthyl-2,2’-diylphosphoric acid (BINOL-PO2H, entries 7, 8).
Interestingly, these acids also have a beneficial effect on catalyst reactivity and maintain the
enantioselectivity. However, they did not show any influence of the configuration of the acid on
enantioselectivity. Probably, more elaborated binaphthyl fragments, including aromatic groups in
3,3’ positions, are needed to provide a synergistic effect to improve the catalytic system [35].

Molecules 2010, 15
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Table 4. Influence of diverse additives in the hydrogenation of 2-methylquinoline with
ligand (S)-6b.1
Entry
Additive
none
P/atm
20
%Conv
82
% ee
65
Conf
R
1
2
3
4
5
6
7
piperidine·HCl
Bu4NI
20
19
66
R
20
63
62
R
KCl
20
80
36
R
NaBF4
20
69
49
R
(PhO)2PO2H
(R)-BINOL-PO2H
(S)-BINOL-PO2H
20
92
49
R
20
89
70
R
8
20
92
67
R
1
Reactions were carried out at room temperature in toluene at a S/C = 100 and 0.6 M substrate
concentration. Catalyst precursor was generated from [Ir(Cl)(COD)]2, ligand 6b and additive at a
Ir:6b:additive =1:1.1:10 ratio. Conversion was determined by 1H-NMR and enantiomeric excess (ee)
by chiral HPLC. Configuration was determined by comparison of optical rotation to the literature value.
3. Experimental
3.1. General
All reactions and manipulations were performed under nitrogen or argon, either in a Braun
Labmaster 100 glovebox or using standard Schlenk-type techniques. All solvents were distilled under
nitrogen using the following dessicants: Sodium-benzophenone-ketyl for benzene, diethylether (Et2O)
and tetrahydrofuran (THF); sodium for petroleum ether and toluene; CaH2 for dichloromethane
(CH2Cl2) and NaOMe for methanol (MeOH). NMR spectra were obtained on Bruker DPX-300, DRX-400
or DRX-500 spectrometers. 31P{1H} NMR shifts were referenced to external 85% H3PO4, while
1
13C{1H} and H shifts were referenced to the residual signals of deuterated solvents. All data are
reported in ppm downfield from Me4Si. HPLC analyses were performed by using a Waters 2690
System. HRMS data were obtained using a Jeol JMS-SX 102A mass spectrometer. Optical rotations
were measured on a Perkin-Elmer Model 341 polarimeter.
(S)-2-(Diisopropylphosphino)phenyl-1,1’-binaphthyl-2,2’-diyl phosphite [(S)-6b]. A solution of
(S)-2,2’-bisnaphtoxyphosphorus chloride (0.35 g, 1.0 mmol) in toluene (10 mL) was added dropwise to
(2-hydroxyphenyl)diisopropyl phosphine (0.21 g, 1.0 mmol) and NEt3 (0.15 mL, 1.1 mmol) dissolved
in toluene (10 mL). The resulting suspension was stirred for 24 h, the mixture filtered and volatiles
removed. The solid obtained was dissolved in toluene and passed through a short pad of neutral
1
alumina. Solution was evaporated yielding a white solid (0.25 g, 50%). [α]D = +222 (c 0.5, THF). H-
20
NMR (CDCl3, 500 MHz): δ 0.93 (m, 6H, 2 CH3, iPr), 1.08 (dd, JHP = 14 Hz, JHH = 7 Hz, 3H, CH3, iPr),
i
i
1.12 (dd, JHP = 14 Hz, JHH = 7 Hz, 3H, CH3, Pr), 2.18 (m, 2H, 2 CH, Pr), 7.12-7.22 (m, 2H, 2 H
arom), 7.25-7.35 (m, 3H, 3 H arom), 7.37-7.50 (m, 5H, 5 H arom), 7.57 (d, JHH = 8.3 Hz, 1H, H arom),
7.60 (d, JHH = 8 Hz, 1H, H arom), 7.87-7.95 (m, 3H, 3 H arom), 8.00 (d, JHH = 8.6 Hz, 1H, H arom).
31P{1H} NMR (CDCl3, 202.4 MHz): δ -2.3 (br, P-C), 143.1 (d, P-O, JPP = 30 Hz); 13C{1H} NMR
i
i
(CDCl3, 125.8 MHz): δ 19.5 (d, JCP = 10 Hz, Me, Pr), 19.6 (d, JCP = 10 Hz, Me, Pr), 20.0 (Me, iPr),
20.2 (Me, iPr), 23.2 (d, JCP = 13 Hz, CH, iPr), 23.3 (d, JCP = 13 Hz, CH, iPr), 120.1 (d, JCP = 11 Hz, CH

Molecules 2010, 15
7738
arom), 121.9 (2 CH arom), 122.9 (Cq arom), 123.8 (CH arom), 124.4 (d, JCP = 5 Hz, Cq arom), 124.9
(CH arom), 125.1 (CH arom), 126.1 (CH arom), 126.3 (CH arom), 127.0 (CH arom), 127.1 (CH
arom), 127.6 (d, JCP = 23 Hz, Cq arom), 128.2 (CH arom), 128.3 (CH arom), 129.7 (CH arom), 130.1
(CH arom), 130.3 (CH arom), 131.2 (Cq arom), 131.6 (Cq arom), 132.6 (Cq arom), 132.9 (Cq arom),
135.0 (d, JCP = 7 Hz, CH arom), 147.2 (Cq arom), 148.0 (d, JCP = 4 Hz, Cq arom), 155.7 (dd, JCP = 14, 6 Hz,
Cq arom); HRMS (FAB): m/z 525, 1766, [M+H]+ (exact mass calculated for C32H31O3P2: 525.1748).
3.2. General Hydrogenation Procedure
In a glovebox, to a 2 mL glass vial was added 2-methylquinoline (0.3 mmol), the appropriate
phosphine-phosphite ligand (3.15 µmol), [IrCl(COD)]2 (1.5 µmol) and the additive (30 µmol) in
toluene (0.5 mL). Vials were placed in a model HEL CAT18 pressure reactor that holds up to eighteen
reactions. The reactor was purged three times with H2 and finally pressurized. After 24 h, the reactor
1
was slowly depressurized, solutions were evaporated and conversions were determined by H-NMR.
The resulting mixtures were dissolved in a 95:5 n-hexane/isopropanol mixture and filtered through a
short pad of silica to remove the catalyst. Enantiomeric excesses of 2-methyl-1,2,3,4-
tetrahydroquinoline were analyzed by chiral HPLC (Chiracel OJ-H, flow 0.5 mL/min, n-
hexane:isopropanol 95:5).
4. Conclusions
We have reported a preliminary study about the Ir catalyzed hydrogenation of 2-methylquinoline with
phosphine-phosphite ligands 1-6. The screening indicates an important influence of the ligand structure
and has led to a convenient catalytic additive-free system which achieves a good conversion and an
enantioselectivity of up to 73% ee. Complementary studies on the influence of additives indicates a
deletorious effect of iodine. On the contrary, phosphoric acids have a positive influence on catalyst
reactivity, without affecting enantioselectivity in the case of binaphthyl phosphoric acids. Studies to deep
into these observations for the improvement of this catalytic system are currently under investigation.
Acknowledgements
We gratefully acknowledge MICINN (CTQ2009-11867 and CONSOLIDER-INGENIO, CSD2007-
00006, FEDER support) and Junta de Andalucía (2008/ FQM-3830). M. R. also thanks CSIC for a
JAE postdoctoral contract.
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Sample Availability: Samples of the compounds are available from the authors.

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