Iridium complexes with P-stereogenic phosphino imidazole ligands: Synthesis, structure and catalysis

Article abstract of DOI:10.1016/j.tet.2019.04.032

The synthesis of optically and diastereomerically pure P-stereogenic phosphine-imidazole ligands is reported. The new ligands contain either a benzoimidazole or a 4-phenylimidazole as a N-donor fragment. The ligands have been coordinated to iridium and th

Full text of DOI:10.1016/j.tet.2019.04.032

Accepted Manuscript
Iridium complexes with P-Stereogenic phosphino imidazole ligands: Synthesis,
structure and catalysis
Rubén Álvarez-Yebra, Pep Rojo, Antoni Riera, Xavier Verdaguer
PII:
S0040-4020(19)30444-2
https://doi.org/10.1016/j.tet.2019.04.032
TET 30277
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 February 2019
Revised Date: 10 April 2019
Accepted Date: 12 April 2019
Please cite this article as: Álvarez-Yebra Rubé, Rojo P, Riera A, Verdaguer X, Iridium complexes with
P-Stereogenic phosphino imidazole ligands: Synthesis, structure and catalysis, Tetrahedron (2019), doi:
https://doi.org/10.1016/j.tet.2019.04.032.
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TOC Graphic
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Iridium Complexes with P-Stereogenic
Phosphino Imidazole Ligands: Synthesis,
Structure and Catalysis.
Rubén Álvarez-Yebra,† Pep Rojo,† Antoni Riera,†,‡,* Xavier Verdaguer†,‡,*
†
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science
and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain.
‡
Dept. Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de
Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain.
Email: xavier.verdaguer@irbbarcelona.org, antoni.riera@irbbarcelona.org
Keywords: P,N-Ligands, P-Stereogenic phosphines, Iridium, Asymmetric
Hydrogenation.
Dedicated to Steve Buchwald for his inspiring contributions to the field of
organometallic catalysis.
ABSTRACT: The synthesis of optically and diastereomerically pure P-stereogenic
phosphine-imidazole ligands is reported. The new ligands contain either a
benzoimidazole or a 4-phenylimidazole as a N-donor fragment. The ligands have been
coordinated to iridium and the structure of the corresponding cationic COD complexes
has been determined by X-ray analysis. The combination of the chiral phosphorus atom
and the imidazole substituents generate a strong chiral environment around the metal
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center. Preliminary hydrogenation reactions with a model cyclic β-enamide are also
reported.
INTRODUCTION
The use of P-stereogenic ligands (P*) is as old as organometallic asymmetric
catalysis.1 Although at some point this family of ligands fell from favor, in the last
decades a number of research groups have developed new type of P*-ligands which
may be recognized among the most effective ligands in the chemist toolbox.2-4 Since
2010, our group has developed different P-stereogenic synthons that can be
conveniently used to assemble P-P, P-O and P-N ligands.5-7 Among these synthons, we
have recently reported the synthesis of optically pure tert-butylmethylphosphinous acid
borane 1, which we used in the synthesis of P-stereogenic phosphino-oxazoline
MaxPHOX family of ligands. MaxPHOX ligands have provided excellent results in the
Ir-catalyzed asymmetric isomerization and hydrogenation reactions.8-12 P,N-Iridium
complexes with imidazole as heterocyclic N-donor group have been reported in the
literature, however, to our knowledge none of these contain a P-stereogenic
phosphine.13,14 In this work we report on the synthesis, coordination and X-ray
structures of phosphine-imidazole ligands derived from phosphinous acid 1 and valine.
Preliminary asymmetric hydrogenation reactions of a model cyclic β-enamide are also
reported.
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Figure 1: General structure of the ligands.
RESULTS AND DISCUSSION
Ligand Synthesis. Phosphino imidazole ligands have been synthetized according to
the retrosynthetic analysis shown in Scheme 1. Condensation of valine with ortho-
phenylenendiamine and 2-bromoacetophenone should provide the corresponding chiral
protected benzo- and 4-phenylimidazole amines. N-Alkylation and Boc deprotection
would provide the corresponding primary amines. These will be coupled with either
enantiomer of the optically pure tert-butylmethylphosphinous acid borane in a SN2
reaction at the stereogenic P-center (SN2@P) to afford the desired ligands.
Scheme 1: Retrosynthetic plan for the synthesis of phosphino imidazole ligands.
The synthesis of free (R)-2-methyl-1-(1-methylbenzoimidazol-2-yl)propan-1-amine 4
was conducted as shown in Scheme 2. Condensation of N-Boc valine with ortho-
phenylenendiamine was carried out through a two-step procedure as described in the
literature.15 Isobutyl chlorocarbonate-mediated amide coupling and cyclization with
AcOH at 65 ºC provided the desired N-Boc protected benzoimidazole 2 in 54% yield.
Next, N-methylation of the benzoimidazole heterocycle was carried selectively with
MeI and NaOH pellets in acetonitrile. This cleanly afforded 3 in 90% yield. Finally,
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Boc deprotection was performed in MeOH/HCl(aq) which afforded the desired
benzoimidazole amine 4 in excellent yield and purity.
Scheme 2: Synthesis of benzoimidazole amine 4.
Phenylimidazole amine was synthesized as indicated in Scheme 3. Compound 5 was
synthesized as described in the literature in a two-step process.16 Reaction of the
phenacylbromide with N-Boc valine in Et3N/EtOAc afforded the phenacyl ester which
was cyclized with NH4OAc in refluxing toluene to yield N-Boc protected
phenylimidazole 5 in 63% overall yield. N-methylation of 5 with MeI/NaOH at 0 ºC
1
provided a 1:10 mixture of regioisomers 6a/6b as determined by H NMR. After
separation of the isomers by flash chromatography, NOESY experiments showed a
cross-peak between the imidazole hydrogen and the N-CH3 group in the major isomer
6a, while for 6b a cross peak was observed for Ph-Hortho and the N-CH3 group (Figure
2). This means that the alkylation takes place preferably at the less hindered nitrogen on
the azole ring. Finally, from pure 6a, MeOH/HClaq deprotection of the Boc group
afforded the desired phenylimidazole amine 7 in 68 % yield.
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Scheme 3: Synthesis of 1-methyl-4-phenylimidazole amine 7.
Figure 2: NOESY experiments on 6a and 6b isomers. nOe % was calculated with
respect the CH(NHBoc)/CH3(iPr) nOe signal.
With the pure imidazole amines 4 and 7 in hand we proceeded to couple them with
the chiral phosphorus synthon. As we have recently reported,17 pure tert-
butylmethylphosphinous acid borane 1 has limited stability, while the corresponding
dialkylammonium salts are shelf-stable crystalline solids that can be stored indefinitely.
Moreover, they can be directly used in coupling reactions with primary amines. Thus,
activation at -20 ºC of either enantiomer of 1·DA (diisopropylammonium salt) with the
methansulfonic anhydride provides the corresponding mixed anhydride which
undergoes reaction with amines with inversion of configuration (Scheme 4). Reaction
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with benzoimidazole amine 4 provided diastereomers (SP)-8 and (RP)-8, which only
differ from the configuration at the phosphorus center, with 96 and 76% yield
respectively. In the same manner, reaction with phenyl imidazole 7 provided
diastereomer (SP)-9 (99%) and (RP)-9 (57%). In all four cases the compounds were
isolated as diastereomerically pure substances as judged by 1H NMR analysis.
Scheme 4: Amine coupling with the P-stereogenic phosphinous acid salt.
Iridium complexes: Synthesis, structure and catalysis. Ligands 8 and 9 were
coordinated to iridium in a one pot 3-step procedure, as shown in Scheme 5. Borane
deprotection was carried out in neat pyrrolidine (90 ºC) under nitrogen atmosphere, the
pyrrolidine was removed under vacuum and [Ir(COD)Cl]2 in CH2Cl2 was added.
Finally, addition of NaBArF produced the counteranion exchange. The cationic
complexes were easily purified by flash chromatography in hexanes/DCM. Higher
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yields were observed for complexes Ir-(SP)-8 and Ir-(SP)-9 with trans configuration of
tBu/iPr groups, which may respond to a major chelate stability.
Scheme 5: Synthesis of P-stereogenic phosphino imidazole iridium catalysts.
To figure out how these ligands accommodate around the iridium metal center we
sought to determine the solid-state structure of such complexes. Upon layering hexanes
on top of a DCM solution of the pure samples, we could obtain single crystals suitable
for X-ray analysis for complexes Ir-(SP)-8, Ir-(SP)-9 and Ir-(RP)-9.18 Compound Ir-
(RP)-8 precipitated as an oil. The corresponding Ortep drawings are depicted in Figure
3. All three structures share a boat conformation of the 6-membered ligand-metal
chelate. The isopropyl group is in axial position for all 3 structures, thus avoiding steric
strain with the N-methyl group on the imidazole heterocycle. Because of this, the -CH-
proton of the iPr group is in close proximity to the Ir centre (2.64-2.80 Å). For Ir-(SP)-8
and Ir-(SP)-9 with SP,S configuration,19 the tBu group is axial, in what it seems its
preferred disposition, away from the cyclooctadiene ligand. In Ir-(RP)-9 the tBu group
is in equatorial position and to some extent clashes with the cyclooctadiene ligand
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producing a noticeable distortion. X-ray structure of Ir-(SP)-9 and Ir-(RP)-9 confirmed
that N-methylation had taken place at the less hindered nitrogen atom of the imidazole.
Finally, we should also highlight that both benzoimidazole and phenylimidazole P*,N
ligands produce an effective chiral environment around the metal centre. For the
phenylimidazole derivatives, the phenyl group lies right above the metal producing
slightly higher steric encumbrance.
Figure 3: X-ray structures for complexes Ir-(SP)-8, Ir-(SP)-9 and Ir-(RP)-9. Ortep
drawing displays ellipsoids at 50% probability. BArF counter ions have been omitted for
the sake of clarity.
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Finally, we tested the complexes Ir-8 and Ir-9 in the asymmetric hydrogenation of N-
acetyl-3,4-dihydronaphthalen-2-amine. Cyclic β-enamides are challenging substrates to
reduce and the resulting chiral amines have biological and therapeutical interest since
they are precursors of drugs like rotigotine, a treatment for Parkinson’s disease.20
Hydrogenation of such substrates has been reported recently by our group with
excellent conversions and ee using Ir-MaxPHOX family of catalysts.9
In the present case the reaction conditions we employed were: 1 mol % catalyst
loading, 3 bars of H2 overnight at room temperature in DCM. With this set of
conditions, the conversions were low for all four catalysts (Table 1, entries 1-4). To
attain higher conversions, we increased the pressure to 50 bars of hydrogen (Table 1,
entries 4-8). Indeed, higher conversions and selectivities were observed, the best result
being with Ir-(RP)-8 which reported almost complete conversion and 89% enantiomeric
excess (Table 1, entry 6). The activity of the present catalytic system is somewhat
reduced with respect to the MaxPHOX family of catalysts which contain an oxazoline
as a N-donor group. Such a decrease on activity could be caused by structural/steric
differences between the two N-donor moieties. Also, electronic factors could be
invoked. N-Alkyl imidazoles are more electron rich that oxazolines. It is know that
phoshino imidazole ligands are among the most electron-rich P,N systems.14 In this
regard, it has been shown that for amidine P,N type ligands, closely related to the
present system, N-acyl amidines are more active and selective that N-alkyl ones.21 This
suggests that the electron rich nature of N-methyl imidazole unit could be responsible
for the low efficiency of the present catalytic system.
Table 1: Asymmetric hydrogenation of N-acetyl-3,4-dihydronaphthalen-2-amine.
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H
Entry
Catalyst
Ir-(SP)-8
Ir-(RP)-8
Ir-(SP)-9
Ir-(RP)-9
Ir-(SP)-8
Ir-(RP)-8
Ir-(SP)-9
Ir-(RP)-9
Conv. (%)a
ee (%)b
n.d.c
n.d.c
57
2
3 bar
5
1
2
3
4
5
6
7
8
3 bar
3 bar
12
35
10
35
98
59
72
3 bar
n.d.c
86
50 bar
50 bar
50 bar
50 bar
89
59
72
a) Conversion was determined by 1H NMR analysis of the reaction
crude. b) Enantiomeric excess determined by chiral HPLC. c) n.d.
= not determined.
CONCLUSIONS
A synthetic route to prepare optically and diastereomerically pure P-stereogenic
phosphino imidazole ligands has been optimized. Up to 4 ligands have been prepared in
good yields. The ligands contain either a benzoimidazole or a 4-phenylimidazole N-
donor fragment. These ligands have been coordinated to iridium to afford the
corresponding cationic COD complexes. The solid-state structures of Ir-8S, Ir-9S and
Ir-9R have been determined by X-ray analysis. The combination of the chiral
phosphorus atom and the imidazole substituents generate a strong chiral environment
around the metal center; however, the catalytic activity of the imidazole ligands is low
in comparison with the oxazoline analogs. We hypothesize that the reduced activity is
due the electron rich nature of the imidazole moiety.
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EXPERIMENTAL SECTION
General methods. All reactions were carried out in dried solvents under nitrogen
atmosphere. Et2O and CH2Cl2 were dried in a purification system. Other commercially
available reagents and solvents were used with no further purification. Thin layer
chromatography was carried out using TLC-aluminum sheets with silica gel. Flash
chromatography was performed by using an automated chromatographic system with
hexane/ethyl acetate or hexane/dichloromethane gradients as eluents, unless otherwise
stated. NMR spectra were recorded at 23°C on a 400 MHz, 500 MHz or 600 MHz
1
apparatus. H NMR and 13C NMR spectra were referenced either to relative internal
TMS or to residual solvent peaks. 31P NMR spectra were referenced to phosphoric acid.
Optical rotations were measured at room temperature (25°C) and concentration is
expressed in g/100 mL. Melting points were determined using a Büchi apparatus and
were not corrected. IR spectra were recorded in a FT-IR apparatus. HRMS were
recorded in a LTQ-FT spectrometer using the Nanoelectrospray technique. Boc
protected amines 2 and 5 were prepared according to described procedures.15,16
(R)-N-Boc-2-methyl-1-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-amine, (3). 15
N-Boc protected imidazole amine 2 (3.50 g, 12 mmol), NaOH (pellets) (1,10 g, 28
mmol) in acetonitrile (30 mL) was stirred at room temperature. Iodomethane (0.75 ml,
12 mmol) was added and the solution was stirred overnight at room temperature. Upon
completion of the reaction as monitored by TLC, the solvent was removed under
reduced pressure. The crude was partitioned with H2O/CH2Cl2 and the aqueous phase
was extracted three times with CH2Cl2. The organic phase was washed with water and
dried over anhydrous MgSO4 and the solvent was removed under vacuum to afford 3 as
white solid (2.95 g, 80%).
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1H NMR (400 MHz, CDCl3) δ 7.76 – 7.71 (m, 1H), 7.38 – 7.26 (m, 4H), 7.25 (d, J = 2
Hz, 0H), 5.43 (d, J = 10 Hz, 1H), 4.80 (dd, J = 10, 8 Hz, 1H), 3.83 (s, 3H), 2.30 (dq, J =
14, 7 Hz, 1H), 1.41 (s, 9H), 1.06 (d, J = 7 Hz, 3H), 0.92 (d, J = 7 Hz, 3H) ppm.
(R)-2-methyl-1-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-amine, (4).15
Methyl imidazole amine 3 (1.95 g, 6.4 mmol), MeOH (32 ml) and HCl 3M (32 ml)
were stirred overnight at room temperature. Then, the MeOH was removed under
reduced pressure and the aqueous layer was extracted twice with EtOAc. The combined
organic layers were dried over anhydrous MgSO4 and the solvent evaporated under
vacuum. This afforded 4 as a white solid (1.15 g, 88%).
IR (KBr) ʋmax: 3366, 3053, 2959, 2869, 1614, 1467 cm-1. 1H NMR (400 MHz, CDCl3) δ
7.77 – 7.71 (m, 1H), 7.35 – 7.31 (m, 1H), 7.29 – 7.23 (m, 2H), 3.91 (d, J = 7 Hz, 1H),
3.79 (s, 3H), 2.17 (h, J = 7 Hz, 1H), 1.05 (d, J = 7 Hz, 3H), 0.95 (d, J = 7 Hz, 3H) ppm.
13C NMR (101 MHz, CDCl3) δ 157.6 (C), 142.2 (C), 135.77 (C), 122.2 (CH), 121.9
(CH), 119.4 (CH), 109.1 (CH), 54.8 (CH), 34.3 (CH), 30.0 (CH3), 20.0 (CH3), 18.1
(CH3) ppm. HRMS (ESI): calc for [M+H]+: 204.1495, found 204.1493.
(R)-N-Boc-2-methyl-1-(1-methyl-4-phenyl-1H-imidazol-2-yl)propan-1-amine, (6a).
N-Boc protected imidazole amine 516 (2.50 g, 8 mmol), NaOH (pellets) (0.63 g, 16
mmol) in acetonitrile (50 mL) was stirred at 0 ºC. Iodomethane (0.49 ml, 12 mmol) was
added and the solution was let to warm stirring overnight to room temperature. Upon
completion of the reaction as monitored by TLC, the solvent was removed under
reduced pressure. The crude was partitioned with H2O/CH2Cl2 and the aqueous phase
was extracted three times with CH2Cl2. The CH2Cl2 phase was washed with water and
dried over anhydrous MgSO4, and the solvent was removed under vacuum to afford a
6a/6b as an oil. Flash column chromatography (SiO2, hexane/EtOAc) allowed
separation of both isomers to yield 1.93 g (74%) of 6a and 0.19 g (7%) of 6b.
1
6a: [α]D: –91.8 (c 1.00, CHCl3). IR (KBr) ʋmax: 3302, 2972, 1705, 1496, 1170 cm-1. H
NMR (400 MHz, CDCl3) δ 7.76 – 7.68 (m, 2H), 7.34 (dd, J = 8, 7 Hz, 2H), 7.27 – 7.16
(m, 1H), 7.01 (d, J = 2 Hz, 1H), 5.52 (d, J = 9 Hz, 1H), 4.56 (dd, J = 9 and 8 Hz, 1H),
3.64 (s, 3H), 2.25 (dp, J = 8, 7 Hz, 1H), 1.43 (s, 9H), 1.04 (d, J = 7 Hz, 3H), 0.90 (d, J =
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7 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 155.71 (C), 155.4 (C), 136.3 (C), 135.1
(C), 129.0 (CH), 128.0 (CH), 126.8 (CH), 123.0 (CH), 119.6 (CH), 110.4 (CH), 79.8
(C), 52.5 (CH), 47.3 (CH), 33.1 (CH3), 28.4 (3xCH3), 19.8 (CH3), 18.5 (CH3) ppm.
HRMS (ESI): Calc for [M+H]+: 330.2176, found 330.2180.
6b: [α]D: –66.0 (c 1.02, CHCl3). IR (KBr) ʋmax: 3295, 2973, 2931, 1682, 1508, 1169 cm-
1. 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.40 (m, 2H), 7.40 – 7.34 (m, 3H), 7.26 (s, 1H),
7.03 (s, 1H), 5.38 (d, J = 10 Hz, 1H), 4.64 (dd, J = 10 and 8 Hz, 1H), 3.62 (s, 3H), 2.33
– 2.19 (m, 1H), 1.44 (d, J = 4 Hz, 9H), 1.05 (d, J = 7 Hz, 3H), 0.93 (d, J = 7 Hz, 3H)
ppm. 13C NMR (101 MHz, CDCl3) δ 155.9 (C), 133.6 (C), 130.2 (CH), 129.0 (CH),
128.8 (CH), 128.1 (CH), 126.3 (CH), 79.6 (C), 52.6 (CH), 33.6 (CH), 31.5 (CH3), 28.5
(3xCH3), 19.7 (CH3), 18.6 (CH3) ppm. HRMS (ESI): Calc for [M+H]+: 330.2176, found
330.2180.
(R)-2-methyl-1-(1-methyl-4-phenyl-1H-imidazol-2-yl)propan-1-amine, (7).
Methyl imidazole amine 6a (1.54 g, 4.7 mmol), MeOH (25 ml) and HCl 3M (25 ml)
were stirred overnight at room temperature. Then, MeOH was removed under reduced
pressure and the aqueous layer was extracted twice with EtOAc. The combined organic
layers were dried over anhydrous MgSO4 and the solvent evaporated under reduced
pressure. The resulting crude was disaggregated with Et2O and filtered to afford 7 as a
white solid (0.73 g, 68%).
1
[α]D: –27.0 (c 1.04, CHCl3). IR (KBr) ʋmax: 3418, 3133, 2965, 2876, 1607 cm-1. H
NMR (400 MHz, CDCl3) δ 7.77 – 7.69 (m, 2H), 7.39 – 7.30 (m, 2H), 7.20 (ddt, J = 8, 7
and 1 Hz, 1H), 7.04 (s, 1H), 3.70 (d, J = 7 Hz, 1H), 3.66 (s, 3H), 2.16 – 2.01 (m, 1H),
13
1.05 (d, J = 7 Hz, 3H), 0.89 (d, J = 7 Hz, 3H) ppm. C NMR (101 MHz, CDCl3) δ
151.3 (C), 140.1 (C), 134.6 (C), 128.6 (CH), 126.6 (CH), 125.0 (CH), 116.5 (CH), 54.7
(CH), 34.7 (CH), 33.0 (CH3), 20.0 (CH3), 18.7 (CH3) ppm. HRMS (ESI): calc for
[M+H]+: 230.1652 found 230.1649.
General method for P-stereogenic phosphine coupling.
A solution of tert-butylmethylphosphinous acid borane diisopropyl ammonium salt (1
eq) and methansulfonic anhydride 97% (1.2 eq) in CH2Cl2 (0.2 M) was cooled down to
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–20 ºC. To this solution, anhydrous NEt3 (2.5 eq) was slowly added, and the mixture
was stirred 1.5 h at –20 ºC. A solution of the corresponding amine (2 eq) in CH2Cl2 (0.2
M) was then added dropwise and the solution was stirred overnight at –20 ºC. Water
was added to quench the reaction and the mixture was allowed to warm to room
temperature. The organic layer was separated and the aqueous phase was extracted
twice with CH2Cl2. The combined organic extracts were washed with NaOH (1M), HCl
(1M) and water. Finally, the solution was dried over anhydrous MgSO4 and the volatiles
were removed under vacuum.
(S)-1-tert-butyl-1-methyl-N-((S)-2-methyl-1-(1-methyl-1H-benzo[d]imidazol-2-
yl)propyl)phosphanamine borane complex, (Ir-(SP)-8).
Following the general procedure, benzoimidazole amine 4 (360 mg, 1.8 mmol), Ms2O
(185 mg, 1.1 mmol), phosphinite salt (R)-1·DA (208 mg, 0.9 mmol) and NEt3 (0.3 ml,
2.2 mmol) were employed. White solid; 273 mg (96%).
1
[α]D: –18.3 (c 1.00, CHCl3). IR (KBr) ʋmax: 3317, 3032, 2963, 2378, 1467 cm-1. H
NMR (400 MHz, CDCl3) δ 7.74 – 7.65 (m, 1H), 7.40 – 7.31 (m, 1H), 7.31 – 7.20 (m,
2H), 4.44 (dt, J = 11 and 8 Hz, 1H), 3.83 (s, 3H), 2.79 (dd, J = 12 and 6Hz, 1H), 2.06
(h, J = 7 Hz, 1H), 1.18 (d, JP = 14 Hz, 9H), 1.08 (d, J = 7 Hz, 3H), 1.02 (d, JP = 9 Hz,
3H), 0.91 (d, J = 7 Hz, 3H), 0.81 – -0.03 (m, 3H, BH3) ppm. 13C NMR (101 MHz,
CDCl3) δ 157.4 (C), 142.0 (C), 135.3 (C), 122.3 (CH), 122.1 (CH), 118.9 (CH), 109.6
(CH), 55.1 (CH), 35.7 (d, JP = 8 Hz, CH), 30.6 (C), 30.1 (CH3), 24.4 (d, JP = 3 Hz,
31
3xCH3), 19.4 (CH3), 18.6 (CH3), 10.4 (d, JP = 32 Hz, CH3) ppm. P NMR (202 MHz,
CDCl3) δ 71.5 (q, J = 51 Hz) ppm. HRMS (ESI): calc for [M+H]+: 318.2265, found
318.2265.
(R)-1-tert-butyl-1-methyl-N-((S)-2-methyl-1-(1-methyl-1H-benzo[d]imidazol-2-
yl)propyl)phosphanamine borane complex, (Ir-(RP)-8).
Following the general procedure, benzoimidazole amine 4 (403 mg, 2 mmol), Ms2O
(213 mg, 1.2 mmol), phosphinite salt (S)-1·DA (233 mg, 1 mmol) and NEt3 (0.3 ml, 2.5
mmol). Oil; 240 mg (76%).
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1
[α]D: –42.9 (c 1.06, CHCl3). IR (KBr) ʋmax: 3345, 2963, 2870, 2377, 1467 cm-1. H
NMR (400 MHz, CDCl3) δ 7.84 – 7.74 (m, 1H), 7.48 – 7.33 (m, 3H), 4.51 (q, J = 10
Hz, 1H), 3.91 (s, 3H), 3.63 (d, J = 11 Hz, 1H), 2.33 (dp, J = 8 and 7 Hz, 1H), 1.39 (d, J
= 9 Hz, 3H), 1.30 (d, J = 7 Hz, 3H), 1.13 (d, J = 7 Hz, 3H), 0.89 (d, J = 14 Hz, 9H),
13
0.78 (d, J = 7 Hz, 3H) 0.65 – 0.00 (m, 3H, BH3) ppm. C NMR (101 MHz, CDCl3) δ
157.2 (C), 137.5 (C), 133.4 (C), 124.1 (CH), 123.9 (CH), 117.7 (CH), 110.3 (CH), 55.6
(d, JP = 4 Hz, CH), 35.8 (d, JP = 8 Hz, CH), 31.1 (C), 30.7 (CH3), 24.3 (d, JP = 3 Hz,
31
3xCH3), 19.3 (CH3), 19.2 (CH3), 11.4 (d, JP = 43 Hz, CH3) ppm. P NMR (202 MHz,
CDCl3) δ 74.4 (q, J = 56 Hz) ppm. HRMS (ESI): calc for [M+H]+: 320.2421, found
320.2422.
(S)-1-tert-butyl-1-methyl-N-((S)-2-methyl-1-(1-methyl-4-phenyl-1H-imidazol-2-
yl)propyl)phosphanamine borane complex, (Ir-(SP)-9).
Following the general procedure; phenylimidazole amine 7 (402 mg, 1.8 mmol), Ms2O
(186 mg, 1.1 mmol), phosphinite salt (R)-1·DA (205 mg, 0.9 mmol) and NEt3 (0.3 ml,
2.2 mmol). White solid; 300 mg (99%).
Mp = 117 – 119 ºC. [α]D: –73.4 (c 1.09, CHCl3). IR (KBr) ʋmax: 2962, 2870, 2378, 1607
1
cm-1. H NMR (400 MHz, CDCl3) δ 7.74 – 7.65 (m, 2H), 7.40 – 7.32 (m, 2H), 7.24 –
7.19 (m, 1H), 7.03 (s, 1H), 4.12 (dt, J = 11 and 8 Hz, 1H), 3.70 (s, 3H), 1.99 (h, J = 7
Hz, 1H), 1.18 (d, JP = 14 Hz, 9H), 1.06 (d, J = 7 Hz, 3H), 1.03 (d, JP = 9 Hz, 3H), 0.88
(d, J = 7 Hz, 3H), 0.80 – -0.05 (m, 3H, BH3) ppm. 13C NMR (101 MHz, CDCl3) δ 150.9
(C), 140.0 (C), 128.5 (2xCH), 126.5 (CH), 124.8 (2xCH), 115.9 (CH), 54.9 (CH), 35.9
(d, JP = 9 Hz, CH), 33.0 (CH3), 30.5 (C), 24.4 (d, JP = 2 Hz, CH3), 19.4 (CH3), 18.9
31
(CH3), 10.3 (d, JP = 31 Hz, CH3) ppm. P NMR (202 MHz, CDCl3) δ 71.4 – 69.9 (m)
ppm. HRMS (ESI): calc for [M+H]+: 346.2578, found 346.2584.
(R)-1-tert-butyl-1-methyl-N-((S)-2-methyl-1-(1-methyl-4-phenyl-1H-imidazol-2-
yl)propyl)phosphanamine borane complex, (Ir-(RP)-9).
Following the general procedure; phenylimidazole amine 7 (399 mg, 1.8 mmol), Ms2O
(186 mg, 1.1 mmol), phosphinite salt (S)-1·DA (206 mg, 0.9 mmol) and NEt3 (0.3 ml,
2.2 mmol). White solid; 172 mg (57%).
15

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Mp = 185 – 187 ºC. [α]D: –122.0 (c 1.02, CHCl3). IR (KBr) ʋmax: 3333, 2957, 2872,
2370, 2347, 1463 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.68 (m, 2H), 7.39 – 7.32
(m, 2H), 7.25 – 7.19 (m, 1H), 6.99 (s, 1H), 4.19 (td, J = 10 and 8 Hz, 1H), 3.68 (s, 3H),
2.79 (d, JP = 11 Hz, 1H, NH), 2.02 (m, 1H), 1.35 (d, JP = 9 Hz, 3H), 1.06 (d, J = 7 Hz,
3H), 0.90 (d, JP = 14 Hz, 9H), 0.82 (d, J = 7 Hz, 3H), 0.53 (m, 3H, BH3) ppm. 13C NMR
(101 MHz, CDCl3) δ 151.4 (C), 140.2 (C), 134.4 (C), 128.5 (2xCH), 126.6 (CH), 124.8
(2xCH), 115.4 (CH), 55.0 (d, JP = 3 Hz, CH), 36.1 (d, JP = 6 Hz, CH), 33.0 (CH3), 30.5
(C), 24.3 (d, JP = 3 Hz, CH3), 19.2 (CH3), 19.0 (CH3), 11.1 (d, JP = 45 Hz, CH3) ppm.
31P NMR (202 MHz, CDCl3) δ 73.0 (q, J = 57 Hz) ppm. HRMS (ESI): calc for [M+H]+:
346.2580, found 346.2582.
General procedure for the synthesis of Ir-[P,N] catalysts.
The corresponding borane protected ligand (1 eq) was dissolved in dry distilled
pyrrolidine under nitrogen (0.06 M) and stirred overnight at 90 ºC. Pyrrolidine was then
removed in high vacuum. The crude was further dried under vacuum for 30 min at 50
ºC. A solution of [Ir(COD)(Cl)]2 (0.5 eq) in CH2Cl2 (0.06 M) was added to the free
ligand via cannula. The resulting mixture was stirred for 40 min at room temperature.
NaBArF (1 eq) was then added and the solution was stirred 1 h at room temperature.
The resulting crude was filtered through a small plug of silica gel under N2 and washed
with dry Et2O, eluting with hexanes/CH2Cl2 (50-100%). The orange coloured fraction
was collected and concentrated to yield the corresponding Ir complexes as orange
solids.
[Ir(COD)(SP-8)][BArF].
Following the general procedure; ligand (SP)-8 (45 mg, 0.14 mmol), pyrrolidine (2.5
ml), [Ir(COD)(Cl)]2 (47 mg, 0.07mmol), NaBArF (125 mg, 0.14 mmol) were employed.
Orange solid; 180 mg (87 %).
Mp = 187 – 188 ºC. [α]D: +34.9 (c 1.02, CHCl3). IR (KBr) ʋmax: 3417, 2958, 2918,
1
2843, 1606, 1454, 1351, 1270, 1124 cm-1. H NMR (400 MHz, CDCl3) δ 7.81 – 7.75
–
–
(m, 1H), 7.71 (m, 8H, BArF ), 7.52 (s, 4H, BArF ), 7.46 – 7.37 (m, 3H), 5.37 (p, J = 8
Hz, 1H, COD), 4.72 (d, J = 5 Hz, 1H, COD), 4.03 (d, J = 6 Hz, 1H, COD), 3.92 (ddd, J
= 23, 11 and 7 Hz, 1H), 3.80 (s, 3H), 3.61 (m, 1H), 3.48 – 3.41 (m, 1H, COD), 2.64 (m,
16

ACCEPTED MANUSCRIPT
2H, COD), 2.36 (d, JP = 15 Hz, 1H, COD), 2.30 (d, JP = 6 Hz, 1H, NH), 2.24 – 2.06 (m,
3H, COD), 1.41 (d, JP = 8 Hz, 3H), 1.20 (d, J = 6 Hz, 3H), 0.83 (d, J = 7 Hz, 3H), 0.76
13
(d, JP = 15 Hz, 9H) ppm. C NMR (101 MHz, CDCl3) δ 161.7 (q, JB = 50 Hz, BArF,
4xC) 155.4 (C), 138.8 (C), 136.0 (BArF, 8xCH), 134.0 (C), 129.2 (m, BArF, C), 128.9
(m, BArF, CF3), 126.1 (CH), 125.2 (CH), 117.9 (BArF, 4xCH), 117.7 (CH), 115.7 (CH),
96.0 (COD, CH), 91.4 (COD, CH), 61.5 (COD, CH), 61.1 (COD, CH), 59.2 (d, JP = 4
Hz, CH), 39.8 (d, JP = 4 Hz, CH), 37.2 (d, JP = 4 Hz, COD, CH2), 36.4 (d, JP = 37 Hz,
C), 32.8 (d, JP = 2 Hz, COD, CH2), 31.0 (CH3), 28.7 (COD, CH2), 25.8 (3xCH3), 25.7
(COD, CH2) 20.0 (CH3), 18.6 (CH3), 8.8 (d, JP = 35 Hz, CH3) ppm. 31P NMR (202
MHz, CDCl3) δ 56.2 (s) ppm. HRMS (ESI): calc for [M+H]+: 606.2584, found
606.2588; calc for [M–H]–: 863.0643, found 863.0636.
[Ir(COD)(RP-8)][BArF]
Following the general procedure; ligand (RP)-8 (50 mg, 0.16 mmol), pyrrolidine (2.5
ml), [Ir(COD)(Cl)]2 (53 mg, 0.07mmol), NaBArF (139 mg, 0.14 mmol) were employed.
Orange solid; 80 mg (35 %).
Mp =152 – 155 ºC. [α]D: +66.0 (c 1.01, CHCl3). IR (KBr) ʋmax: 3417, 2950, 2914,
1
2851, 1601, 1484, 1353, 1271, 1116 cm-1. H NMR (400 MHz, CDCl3) δ 7.91 – 7.85
–
–
(m, 1H), 7.70 (p, J = 2 Hz, 8H, BArF ), 7.51 (s, 4H, BArF ), 7.48 – 7.42 (m, 2H), 7.42 –
7.36 (m, 1H), 4.98 (s, 1H, COD), 4.80 (s, 2H, COD), 4.01 (d, J = 7 Hz, 1H, COD), 3.90
– 3.77 (m, 1H, COD), 3.74 (s, 3H), 3.30 (br. s, 1H, COD), 2.59 (br. s, 1H, COD), 2.45
(br. s, 1H, COD), 2.19 (br. s, 4H), 2.08 (br. s, 1H, NH), 1.55 (br. s, 2H), 1.31 (d, JP = 6
Hz, 3H), 1.13 (d, JP = 16 Hz, 9H), 0.91 (d, J = 7 Hz, 3H), 0.78 (d, J = 7 Hz, 3H) ppm.
13C NMR (101 MHz, CDCl3) δ 161.6 (q, JB = 50 Hz, BArF, 4xC), 138.4 (C), 135.9
(BArF, 8xCH), (m, BArF, C), 128.9 (m, BArF, CF3), 126.0 (CH), 125.2 (CH), 118.5
(BArF, 4xCH), 117.6 (CH), 111.8 (CH), 110.2 (C), 94.3 (COD, CH), 85.6 (COD, CH),
65.7 (COD, CH), 58.0 (CH), 56.6 (COD, CH), 38.0 (CH), 37.5 (COD, 2xCH2), 34.8
(C), 33.5 (COD, CH2), 31.0 (CH3), 29.5 (COD, CH2), 25.8 (3xCH3), 25.3 (COD, CH2)
20.8 (CH3), 19.0 (CH3), 14.2 (CH3) ppm. 31P NMR (202 MHz, CDCl3) δ 60.6 (s), ppm.
HRMS (ESI): calc for [M+H]+: 606.2584, found 606.2580; calc for [M–H]–: 863.0643,
found 863.0672.
17

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[Ir(COD)(SP-9)][BArF].
Following the general procedure; ligand (SP)-9 (50 mg, 0.15 mmol), pyrrolidine (2.5
ml), [Ir(COD)(Cl)]2 (45 mg, 0.07mmol), NaBArF (128 mg, 0.14 mmol) were employed.
Orange solid; 173 mg (82 %).
Mp = 201 – 203 ºC. [α]D: +46.6 (c 1.02, CHCl3). IR (KBr) ʋmax: 3417, 2954, 2923,
1
2851, 1614, 1459, 1353, 1271, 1127 cm-1. H NMR (400 MHz, CDCl3) δ 7.87 (s, 2H),
7.73 – 7.69 (m, 8H), 7.53 (s, 4H), 7.48 – 7.43 (m, 3H), 7.00 (s, 1H), 4.62 (br. s, 1H,
COD), 4.17 (m, 1H, COD), 3.75 (ddd, JP = 23, J = 11 and 7 Hz, 1H), 3.64 (s, 3H), 3.59
(m, 1H+1H COD), 3.34 (m, 1H, COD), 2.45 (m, 2H, COD), 2.27 – 2.17 (m, 2H, COD),
2.13 – 1.99 (m, 2H, COD), 1.46 (m, 2H, COD), 1.42 (d, JP = 8 Hz, 3H), 1.16 (d, J = 6
13
Hz, 3H), 0.92 (d, JP = 15 Hz, 9H), 0.77 (d, J = 7 Hz, 3H) ppm. C NMR (101 MHz,
CDCl3) δ 161.8 (q, JB = 50 Hz, BArF, 4xC), 149.8 (C), 140.9 (C), 134.9 (BArF, 8xCH),
129.7 (2xCH), 129.2 (m, BArF, C), 128.9 (CH), 128.9 (m, BArF, CF3), 127.9 (2xCH),
120.6 (C), 120.1 (CH), 117.6 (d, J = 4 Hz, BArF, 4xCH) 110.2 (C), 96.3 (d, J = 11 Hz,
COD, CH), 92.1 (d, J = 13 Hz, COD, CH), 61.7 (COD, CH), 61.3 (COD, CH), 58.8 (d,
J = 4 Hz, CH), 39.5 (CH), 37.4 (d, J = 4 Hz, COD, CH2), 34.4 (CH3), 33.3 (COD, CH2),
29.9 (C), 28.3 (COD, CH2), 25.4 (d, J = 5 Hz, 3x CH3), 20.0 (CH3), 18.6 (CH3), 9.7 (d,
31
J = 35 Hz, CH3) ppm. P NMR (202 MHz, CDCl3) δ 54.7 (s) ppm. HRMS (ESI): calc
for [M+H]+: 632.2740, found 632.2725; calc for [M–H]–: 863.0643, found 863.0640.
[Ir(COD)(RP-9)][BArF]
Following the general procedure; ligand (RP)-9 (50 mg, 0.15 mmol), pyrrolidine (2.5
ml), [Ir(COD)(Cl)]2 (45 mg, 0.07mmol), NaBArF (128 mg, 0.14 mmol) were employed.
Orange solid; 118 mg (54 %).
Mp = 173 – 175 ºC. [α]D: +52.8 (c 1.03, CHCl3). IR (KBr) ʋmax: 3412, 2959, 2918,
1
2843, 1606, 1476, 1353, 1274, 1119 cm-1. H NMR (400 MHz, CDCl3) δ 7.93 – 7.87
(m, 2H), 7.73 – 7.67 (m, 10H), 7.52 (s, 4H), 7.50 – 7.44 (m, 3H), 7.01 (s, 1H), 5.02 (d, J
= 8 Hz, 1H, COD), 4.63 (d, J = 6 Hz, 1H, COD), 3.90 (d, J = 8 Hz, 1H, COD), 3.73 –
3.60 (m, 1H), 3.59 (s, 3H), 3.42 (p, J = 8 Hz, 1H), 3.32 (m, 1H, COD), 2.43 – 2.30 (m,
1H), 2.18 (dd, J = 15 and 8 Hz, 1H), 2.13 – 2.00 (m, 4H), 1.54 (s, 2H), 1.27 (d, JP = 6
Hz, 3H), 1.25 (d, J = 8 Hz, 3H), 1.16 (d, J = 15 Hz, 9H), 0.76 (d, J = 7 Hz, 3H) ppm.
13C NMR (101 MHz, CDCl3) δ 161.7 (q, JB = 50 Hz, BArF, 4xC), 150.0 (C), 141.3 (C),
18

ACCEPTED MANUSCRIPT
134.9 (BArF, 8xCH), 129.2 (2xCH), 129.2 (m, BArF, C), 128.9 (m, BArF, CF3), 126.0
(C), 127.3 (2xCH), 123.3 (C), 120.2 (CH), 117.6 (BArF, 4xCH), 94.1 (d, J = 10 Hz,
COD, CH), 87.7 (d, J = 15 Hz, CH), 65.1 (COD, CH), 56.0 (COD, CH), 37.6 (CH),
37.3 (COD, CH2), 37.3 (COD, CH2), 34.5 (CH3), 33.6 (COD, CH2), 29.9 (COD, CH2),
20.0 (COD, CH2), 26.0 (d, J = 4 Hz, 3x CH3), 20.9 (CH3), 19.0 (CH3), 15.7 (CH3) ppm.
31P NMR (202 MHz, CDCl3) δ 58.2 (s) ppm. HRMS (ESI): Calc for [M+H]+: 632.2740,
found 632.2750; calc for [M–H]–: 863.0643, found 863.0687.
Hydrogenation reactions.
N-acetyl-3,4-dihydronaphthalen-2-amine (1 eq) and the corresponding catalyst (0.01 eq)
were weighted in a test tube and then placed in a stainless steel high pressure reactor.
The corresponding solvent was added and the reactor was closed and connected to a
hydrogen manifold. While stirring, the reactor was purged with vacuum-nitrogen cycles
and then vacuum-hydrogen cycles. Finally it was charged at the corresponding
hydrogen pressure. The hydrogen manifold was unplugged and the mixture was left to
stir overnight at room temperature. The reactor was depressurized. The mixture crude
1
was dried, and at this point the conversion was determined by H NMR analysis.
Determination of the optical purity was carried out by chiral HPLC upon solving the
sample in heptane/isopropyl alcohol (1:1) and filtration.
1H NMR (400 MHz, CHCl3) δ 7.19 – 7.01 (m, 3H), 4.37 – 4.24 (m, 1H), 3.18 – 3.08 (m,
1H), 2.98 – 2.79 (m, 2H), 2.69 – 2.59 (m, 1H), 2.05 (m, 1H), 1.98 (s, 3H), 1.79 (m, 1H)
ppm. HPLC: CHIRALCEL OJ. Heptane/i-PrOH 70:30-0.2% NEt3, 0.5 mL/min, λ = 254
nm. t(S) (–)= 8.1 min, t(R) (+)= 9.4 min.
Acknowledgement
We thank MINECO (CTQ2017-87840-P) and IRB Barcelona for financial support. We
gratefully acknowledge institutional funding from the Severo Ochoa Award (MINECO)
and from the CERCA program (Generalitat de Catalunya). P. R. thanks AGAUR for a
fellowship.
19

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Supplementary Data. Crystallographic data in CIF format file for Ir-(SP)-8, Ir-(SP)-9
and Ir-(RP)-9. NMR spectra for new compounds.
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