P-Stereogenic and Non-P-Stereogenic Ir-MaxPHOX in the Asymmetric Hydrogenation of N -Aryl Imines. Isolation and X-ray Analysis of Imine Iridacycles

Article abstract of DOI:10.1021/acs.joc.8b00361

A small library of Ir-MaxPHOX catalysts has been applied to the asymmetric hydrogenation of N-aryl imines. A structure-activity analysis of the three-chiral-center MaxPHOX ligand has been performed. Using complex 1b, the hydrogenation of N-aryl imines too

Full text of DOI:10.1021/acs.joc.8b00361

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P-Stereogenic and Non P-Stereogenic Ir-MaxPHOX
in the Asymmetric Hydrogenation of N-Aryl Imines.
Isolation and X-ray Analysis of Imine-Iridacycles
Ernest Salomo, Pep Rojo, Pol Hernández-Lladó, Antoni Riera, and Xavier Verdaguer
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00361 • Publication Date (Web): 04 Apr 2018
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PꢀStereogenic and Non PꢀStereogenic Irꢀ
MaxPHOX in the Asymmetric Hydrogenation of
NꢀAryl Imines. Isolation and Xꢀray Analysis of
ImineꢀIridacycles.
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†
†
†
†,‡,
Ernest Salomó, Pep Rojo, Pol Hernández-Lladó, 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.
ABSTRACT: A small library of IrꢀMaxPHOX catalysts has been applied to the
asymmetric hydrogenation of Nꢀaryl imines. A structureꢀactivity analysis of the three
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chiral center MaxPHOX ligand has been performed. Using complex 1b, the
hydrogenation of Nꢀaryl imines took place with up to 96% enantiomeric excess at
atmospheric pressure of hydrogen and low temperature. The impact of the
stereochemical information at the phosphorous center is small with respect the
selectivity, but large with respect the catalyst activity. Non Pꢀstereogenic analogs of
MaxPHOX were also synthesized and tested but provided lower selectivity. The
selectivity observed could be explained by taking into account that the actual catalysts
were cyclometalated imine complexes formed in situ. [IrHCl(MaxPHOX)(imine)]
complexes 9 and 10 were synthesized and characterized by Xꢀray crystallography.
These complexes, via chloride abstraction, provided the active catalytic species with the
same levels of selectivity. Finally, the influence of the counter ion on the catalyst
performance was also studied.
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INTRODUCTION
Many active pharmaceutical ingredients and agrochemicals contain chiral amines. In
this regard, there is considerable interest in developing efficient methods that provide
single enantiomers of such compounds, thus avoiding inefficient racemate resolutions.
Metalꢀcatalyzed asymmetric hydrogenation of imines is one of the methods of choice in
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terms of industrial applicability. While ruthenium has provided excellent results in
transferꢀhydrogenation reactions, iridium has shown better performance for the direct
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hydrogenation of imines. In this field, Pfaltz and others have shown that IrꢀP,N
3
catalysts provide an excellent platform for the reduction of Nꢀaryl imines.
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Figure 1: General structure of the MaxPHOX ligands.
We recently developed the MaxPHOX ligand system, which is built from three
fragments—an amino alcohol, an amino acid and a Pꢀstereogenic phosphinous acid
4
(
Figure 1). The IrꢀMaxPHOX complexes have shown outstanding selectivity in the
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hydrogenation of cyclic enamides. One of the key advantages of the MaxPHOX ligand
is the structural diversity arising from its possible configurations and substitution
patterns, which can be adapted to a specific reaction. To demonstrate this versatility,
here we report on the asymmetric hydrogenation of Nꢀaryl imines using the Irꢀ
MaxPHOX catalyst system. To study the influence of the stereogenic center of the
phosphorus atom, nonꢀPꢀstereogenic MaxPHOX ligands were also synthesized and
evaluated in the asymmetric hydrogenation. We spotted a catalyst that hydrogenates Nꢀ
aryl imines with up to 96% enantiomeric excess (ee) at atmospheric pressure of
hydrogen (balloon). The putative imineꢀcyclometalated catalyst derivatives were also
isolated, characterized by Xꢀray analysis and tested in the reaction.
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Figure 2: IrꢀMaxPHOX catalysts used in the present study.
RESULTS AND DISCUSSION
Ligand Synthesis. The iridium catalysts used in the present study are shown in
Figure 2. Twelve Pꢀstereogenic MaxPHOX catalysts were employed. These arise from
the four possible diastereomeric configurations 1, 2, 3 and 4, plus three distinct
oxazoline substitutions, R = Ph, (a), R = iPr (b), and R = tBu (c). The synthesis of these
ligands (1a-c, 2a-c, 3a-c and 4a-c) involved the coupling of amino acid, amino alcohol
and Pꢀstereogenic phosphinous acid fragments and final complexation with an iridium
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precursor. The corresponding nonꢀPꢀstereogenic 5a and 5b ligands with a
dicyclohexylphosphine moiety were also synthesized in a similar fashion, as shown in
Scheme 1. NꢀBoc protected valine was coupled to either Dꢀ or Lꢀvalinol. The
unprotected amino alcohols 6a-b were then coupled to a phosphinyl mesyl mixed
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anhydride derived from dicyclohexylphosphinous acid borane. This reaction is highly
selective for amine nucleophiles and it provided boraneꢀprotected aminophosphines 7a-
b. Reaction with SOCl
2
and treatment with NaHCO
3
gave the protected phosphineꢀ
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oxazoline ligands 8a-b. Finally, borane deprotection with pyrrolidine, treatment with
[Ir(cod)Cl] , and counter ion exchange with NaBAr afforded non Pꢀstereogenic
2
F
catalysts 5a and 5b (Scheme 1).
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Scheme 1: Synthesis of non Pꢀstereogenic IrꢀMaxPHOX catalysts.
BH3
1) iBuOCOCl, Et N
2) D or L-valinol
3
P Cy
iPr
iPr
iPr
BH3
MsO
H
H
3) HCl
Cy
rt, DCM
41-59%
HO
N
N
P
Cy
Cy
*
*
NHBoc
HO
NH2
HO
N
H
O
iPr
O
iPr
O
6
a-b
7a-b
iPr
Ir
BArF
1
) pyrrolidine,
1) SOCl2, DCM
) NaHCO3
BH3
Cy
Cy
iPr
2) [Ir(cod)Cl]2, DCM
O
N
2
HN
P
3
) NaBArF
N
P
Cy
iPr
N
H
*
9
6-99 %
*
52-74 %
Cy
O
R
1
8
a-b
5
a-b
Asymmetric hydrogenation of imines. With the IrꢀMaxPHOX catalysts in hand, we
proceeded to study their performance in the hydrogenation of acetophenone Nꢀphenyl
imine with 1 mol% catalyst loading in DCM at 55 bar of H (Table 1). The best results
2
were obtained for catalysts with configurations 1 and 4, the isopropyl group on the
oxazoline providing the best results. Thus, complex 1b gave the highest enantiomeric
excess (89% ee) and 4b the second best (85% ee) but with the opposite configuration.
Catalysts 1b and 4b would be enantiomers of each other, except that the chirality at
phosphorus is inverted. This result suggests that the stereochemical configuration at
phosphorus had a limited impact on the selectivity. On the other hand, we observed that
the configuration of the chiral center on the backbone of the ligand had a major effect
on the selectivity. Catalysts 2b and 3b, while having the same configuration at the Pꢀ
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center and oxazoline with respect 1a and 4b, provided much lower selectivity. We
called this phenomenon the “tail effect”. We believe this behavior is associated with
conformational changes within the IrꢀP,N sixꢀmembered ring chelate. Finally, non Pꢀ
stereogenic catalysts 5a and 5b were also tested, providing 57% and 81% ee,
respectively. These results demonstrate that although the chiral oxazoline plays the most
important role for our system, the presence of additional stereogenic centers both at the
phosphine and the tail position is beneficial in terms of selectivity.
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Table 1: Hydrogenation of acetophenone Nꢀphenyl imine. Influence of the oxazoline
a
substituent and the relative configuration of the catalysts.
P-stereogenic
R
1
(S
P
RS)
2 (S
P
SS)
3 (S
P
RR)
P
4 (S SR)
b
R
S
ee (%)
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0% ee
12% ee
43% ee
47% ee
Ph
1a
2a
3a
4a
0-25
8
7
9% ee
37% ee
65% ee
85% ee
iPr
tBu
25-50
50-75
1b
2b
3b
4b
9% ee
53% ee
53% ee
77% ee
1c
2c
3c
4c
75-100
Non P-stereogenic
7% ee
5
81% ee
iPr
5a
5b
a) All reactions were left to run overnight and went to 100% conversion as shown by
H NMR spectroscopy. b) Enantiomeric excess was determined by chiral HPLC.
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With the best catalyst in hand (1b), we then studied the influence of hydrogen
pressure, solvent and temperature on the reaction outcome (Table 2). Selectivity was
relatively insensitive to the reaction pressure. In this regard, a reduction in the pressure
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from 55 bar to 3 bar produced only a slight increase in enantiomeric excess (from 89 to
90% ee, Table 2, entries 1 and 2). The pressure was even reduced to the atmospheric
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pressure of H (balloon), giving the same results with respect to conversion and
selectivity (Table 2, entry 3). Switching the reaction solvent from DCM to more
coordinating solvents like EtOAc or MeOH caused a dramatic drop in selectivity (Table
1
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2, entries 4 and 5). A reduction in reaction temperature enhanced selectivity. Thus at 0
ºC and atmospheric H pressure, the imine was reduced with 94% ee and lowering the
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temperature to –20 ºC afforded the reduced amine with 96% ee (Table 2, entries 7 and
8). At this point, catalyst 4b that only differs from the configuration at the Pꢀcenter and
which provided the second best selectivity (85% ee) in the initial catalysts screening at
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5 bar, was also tested at atmospheric H pressure (Table 2, entry 9). We observed that
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4b was considerably less active; since, after 72h, only 8% conversion was achieved.
This demonstrates that while the chirality on phosphorous has a small influence on the
selectivity it has a great impact on the catalyst activity.
Table 2: Optimization of reaction conditions. Influence of H pressure, solvent and
2
a
temperature.
b
c
Entry
Cat
1b
1b
1b
1b
1b
1b
H
2
(bar)
Solvent
DCM
Temp (ºC)
Conv (%)
100
ee (%)
1
2
3
4
5
6
55
3
rt
rt
rt
rt
rt
rt
89
DCM
100
90
balloon
DCM
100
90
3
3
3
EtOAc
MeOH
Toluene
100
66
100
45
100
85
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1b
1b
4b
balloon
balloon
balloon
DCM
DCM
DCM
0
–20
rt
100
100
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94
96
nd
d
a) All reactions were left to run overnight unless otherwise noted. b) Conversion was
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determined by H NMR spectroscopy. c) Enantiomeric excess was determined by chiral
HPLC. d) Reaction time 72h.
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Once the reaction parameters had been optimized, we proceeded to assess the scope
of the hydrogenation with catalyst 1b with various aryl imines. Reduction of pꢀ and mꢀ
methoxyacetophenone Nꢀphenyl imine proceeded with 95% and 92% ee, respectively
(Table 3, entries 2 and 3). However, oꢀmethoxyacetophenone Nꢀphenyl imine was
hydrogenated with only 28% ee (Table 3, entry 4). This decrease in selectivity is most
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likely due to a less favorable E/Z ratio of the starting imine. NꢀPhenyl imines derived
from pꢀchloroacetophenone and methyl 2ꢀnaphthyl ketone were both reduced, with 94%
ee (Table 3, entries 5 and 6). Imine derived from ethyl phenyl ketone was also reduced,
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showing a lower enantiomeric excess (74%, Table 3, entry 7). Finally, acetophenone
imines derived from other anilines, such as pꢀanisidine, pꢀtoluidine and 2,3ꢀ
dimethylaniline, were again reduced with excellent selectivity and with 90ꢀ95% ee.
a
Table 3: Hydrogenation of aryl amines with catalyst 1b.
Entry
Imine
Conv. (%)
ee (%)
1
100
96
2
100
95
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100
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c
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1
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N
Ph
a) Unless specified all reactions were conducted overnight with 1 mol% catalyst
loading in DCM at –20°C with atmospheric H pressure (balloon). b) Reaction carried
out with 2 mol% of catalyst loading at 3 bar of H
temperature.
2
2
. c) Reaction conducted at room
Effect of the counter ion on the reaction rate, catalyst intermediates and
mechanistic considerations. Since catalyst 1b showed activity and selectivity that
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paralleled the best P,NꢀIr systems reported for the hydrogenation of Nꢀphenyl ketimines,
we studied the rate of the reaction and how the counter ion influences the performance
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of the catalyst. The hydrogenation of acetophenone Nꢀphenyl imine using 1 mol% of
1
b-BAr
analysis, as shown in Figure 4. Catalyst 1b-BAr
conversion was observed after 50 min using only atmospheric H pressure. The use of a
F
and 1b-BF
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at atmospheric pressure of hydrogen was monitored by GC
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F
proved extremely active, and 100%
2
smaller counter ion, such as BF , resulted in a slower reaction and full conversion was
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only achieved after 150 min (2.5 h). Furthermore, the use of BF
significant deleterious effect on selectivity since the product amine was obtained with
only 41% ee (90% ee using BAr , Figure 3).
4
as counter ion had a
F
Figure 3: Conversion vs. reaction time graph for the hydrogenation of acetophenone Nꢀ
phenyl imine using catalysts 1b with BAr and BF counter ions. Reactions were run at
F
4
room temperature, 1 mol% catalyst loading, and atmospheric pressure of hydrogen in
DCM.
120
100
8
6
4
2
0
0
0
0
0
0
50
100
150
200
250
300
min.
BARF (90% ee)
BF4 (41% ee)
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9
Pfaltz and coworkers have recently shown that an imine iridacycle is the actual
9
catalyst when using IrꢀP,N complexes. These cyclometallated Ir (III) species form
spontaneously upon reaction between the iridium complex and the starting imine under
hydrogen pressure. With this in mind, and to further increase knowledge of the true
catalytic system, we questioned whether these intermediates are also involved in our Irꢀ
MaxPHOX system. Complexes 1b and 3b were reacted under hydrogen atmosphere
with acetophenone Nꢀphenyl imine in THF (Scheme 2). Treatment of the reaction
mixture with LiCl afforded the corresponding cyclometallated iridium hydride neutral
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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0
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7
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9
0
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9
0
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0
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4
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8
9
0
1
2
3
4
5
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7
8
9
0
9
complexes 9 and 10. These complexes were isolated as a pale yellow solids by
1
31
filtration on silica gel. H and P NMR analysis confirmed compounds 9 and 10 as
diastereomerically pure compounds. A single resonance for the IrꢀH was observed at –
1
9.76 ppm (d, J = 26 Hz) and –19.62 ppm (d, J = 23 Hz) for 9 and 10, respectively. It
P
P
should be noted that heteroleptic octahedral complexes such as 9 and 10 can, in
principle, provide various diastereomers. It is therefore remarkable that in this case a
single stereoisomer was generated.
Scheme 2: Synthesis of iridacylcles 9 and 10.
1
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5
5
5
5
6
To further characterize these species, compounds 9 and 10 were crystalized from
hexane/DCM mixtures to obtain single crystals for Xꢀray analysis. The resulting solid
state structures are shown in Figure 4. As expected, the iridium (III) displays octahedral
coordination. The phosphinoꢀoxazoline ligand and the cyclometallated imine ligand are
perpendicular to each other, with the oxazoline nitrogen atom trans with respect the
phenyl ring. The chiral center of the oxazoline fragment seems to control the
coordination of the imine nitrogen. In both complexes, the C=NꢀPh group is positioned
away from the isopropyl substituent of the oxazoline ring. Finally, the hydride and
chloride ligands are cis to each other and trans to the imine nitrogen and phosphine
ligands respectively.
0
1
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4: Xꢀray structures of iridacycles 9 and 10. Ortep diagram shows ellipsoids at
50% probability. Only the hydrogen atom attached to iridium has been drawn.
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9
0
To verify whether the isolated imine iridacycles can be used as precatalysts,
compound 9 was tested in the hydrogenation of imines. Thus, 1 mol% of 9 was treated
F
with 2 equivalents of NaBAr in order to produce the active catalyst by counter ion
exchange (Scheme 3). The use of this mixture as catalyst afforded the reduced product
with 60% conversion and 91% ee. Despite the lower conversion observed, that can be
justified by an inefficient chloride abstraction reaction, this result strongly suggests that
the cationic cyclometallated complex arising from chloride abstraction of 9 is an active
species in the catalytic cycle.
Scheme 3: The use of iridacycle 9 as precatalyst in the hydrogenation of imines.
iPr
O
HN
Me
H
P
N
iPr
+ NaBArF (2 mol%)
tBu
1 mol%)
Ir
(
Cl
N
Ph
9
Ph
Ph
N
HN
H2 (ballon), rt, DCM
6
9
0% conv.
1% ee
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6
For several years, the mechanism of imine reduction by iridium catalysts has been the
10
subject of debate. During the preparation of this manuscript, Wiest and coworkers
11
published a theoretical DFT mechanistic study of this process. The authors took into
account the findings of Pfaltz and considered cyclometalated iridium(III)ꢀhydride
species as the intermediates in the catalytic cycle. The study concluded that the
hydrogenation with the cyclometalated precursors proceeds through an outer sphere
mechanism, as depicted in a simplified manner in Scheme 4. According to this proposal,
the active species in the catalytic cycle would be the cationic hydrideꢀdihydrogen
complex I, which, upon proton transfer, activates the amine to form the neutral
dihydride complex II. The stereodetermining step is the hydride transfer trans to
phosphorus to the activated imine to yield complex III.
0
1
2
3
4
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7
8
9
0
1
2
3
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9
0
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4: Outer sphere mechanism for the iridiumꢀcatalyzed hydrogenation of imines.
Our results are in agreement with this proposal. In this system, the imine ligand and
the oxazoline isopropyl substituent are the fragments that surround the hydride
transferred to the protonated imine in the stereodetermining step (Figure 5). Analyzing
the selectivity observed with the four stereoisomers of MaxPHOX ligands (1b, 2b, 3b
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and 4b, Table 1), we can conclude that the chirality on phosphorus and the tail position
is highly relevant. The intriguing question now is that since phosphine and the tail
moiety are placed far away from the reacting center, why does the chirality on these
fragments have such an impact on selectivity?
1
1
1
1
1
1
1
1
1
1
2
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2
2
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0
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5
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7
8
9
0
Two concurrent effects could explain this behavior. First, small conformational
differences on the reacting site may provide a selectivity bias. Observing the pseudoꢀ
enantiomeric reacting sites (Figure 5) in complex 9, the Nꢀphenyl of the cyclometalated
imine is tilted upwards, while for 10, the Nꢀphenyl ring is almost perpendicular to the Irꢀ
imine metallacycle. These conformational differences of the Nꢀphenyl group are
ultimately governed by the configuration of the phosphine and tail positions and should
12
lead to a difference in selectivity between 9 and 10.
Figure 5: Reacting sites for complexes 9 and 10 as extracted from the corresponding Xꢀ
ray structures. The phosphine and ligand backbone have been deleted for clarity. View
along the ClꢀIr bond axis (green dot). The green dot also corresponds to the hydride
transferred in the stereodetermining step.
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5
6
A second effect would be the relative stability of complexes IVa/IVb with a vacant
coordination site (Scheme 5). It is easy to envisage that the coordination of H to either
2
complex IVa or IVb would provide a different selectivity outcome. Therefore, the
stereochemical stability of the transient iridium complexes appears to be essential to
guarantee high selectivity during hydrogenation. This notion is in agreement with the
fact that in our case 9 and 10 have the stereochemistry of IVa, while Pfaltz and coꢀ
0
1
2
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4
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8
9
0
1
2
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7
8
9
0
1
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
workers, reported the Xꢀray crystal structure of an [IrH(THF)(PHOX)(imine)]
complex, where the cyclometalated phenyl group is trans to phosphine and which, upon
removal of the solvent molecule, provides a complex with the same stereochemistry at
9
the metal as IVb. We believe that the chirality on phosphorous and the tail positions in
the MaxPHOX ligand system are important for stabilizing the arrangement of the
ligands around the metal center in the true catalytic species.
Scheme 5: Equilibrium between complexes IVa and IVb with a vacant coordination
site.
CONCLUSIONS
From a small family of Pꢀstereogenic IrꢀMaxPHOX precatalysts, we pinpointed
complex 1b, which shows activity and selectivity that matches the best IrꢀP,N systems
in the hydrogenation of acyclic imines. Catalyst 1b hydrogenated Nꢀaryl imines with up
to 96% ee at atmospheric pressure of hydrogen and low temperature. Catalyst 4b that
only differs from the configuration at the Pꢀcenter was significantly less active,
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demonstrating that the chirality on phosphorous has a great impact on the catalyst
activity. NonꢀPꢀstereogenic analogs of IrꢀMaxPHOX were also synthesized and
provided lower selectivity. The nature of the counter ion greatly influences the reaction
4
outcome; smaller counter ions (e.g. BF ) provided slower reactions and reduced
1
1
1
1
1
1
1
1
1
1
2
2
2
2
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0
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1
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9
0
enantiomeric excess. The active catalyst species are cationic iridium complexes that
have an imine molecule from the substrate incorporated via cyclometalation.
Cyclometalated [IrHCl(MaxPHOX)(imine)] complexes 9 and 10 were isolated and
characterized by Xꢀray crystallography. Chloride abstraction with NaBAr
F
on 9
provided a functional catalytic system with the same level of selectivity as that obtained
with catalyst 1b. While the chirality of phosphorus and the tail position are away from
the reacting center, they are nonꢀinnocent with respect the performance of the catalyst.
We propose that these moieties modify the reacting site by inducing small
conformational differences on the Nꢀphenyl ring of the cyclometalated imine and by
stabilizing the relative arrangement of the imine and phosphineꢀoxazoline ligands
around the iridium center.
EXPERIMENTAL SECTION
General methods. All reactions were carried out in dried solvents under nitrogen
2 2 2
atmosphere. Et O and CH Cl 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 TLCꢀaluminum sheets with silica gel. Flash
chromatography was performed by using an automated chromatographic system with
hexane/ethyl acetate or hexane/dichloromethane gradients as eluent unless otherwise
stated. NMR spectra were recorded at 23°C on a 400 MHz, 500 MHz or 600 MHz
1
13
apparatus. H NMR and C NMR spectra were referenced either to relative internal
31
TMS or to residual solvent peaks. P NMR spectra were referenced to phosphoric acid.
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9
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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5
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5
6
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 FTꢀIR apparatus. HRMS were
recorded in a LTQꢀFT spectrometer using the Nanoelectrospray technique. Catalysts 1,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
2
, 3 and 4 were prepared as described previously.
6
Dicyclohexyl phosphinous acid borane. In a N purged round bottom flask 2g of
2
chlorodicyclohexylphosphine (8.59 mmol, 1 eq) were weighed. Anhydrous THF (8 mL)
was added and the reaction was cooled to 0 ºC. Then, 815 µL (8.59 mmol, 1 eq) of
3 2
BH .SMe were added dropwise. The reaction was left stirring 1 hour at room
temperature. Then it was cooled again to 0 ºC and 2g (51.5 mmol, 6 eq) of NaOH
solved in 32 mL of H O/THF (1/2) were slowly added. The solution was left stirring
2
overnight at room temperature. Using a diluted solution of aqueous HCl, the reaction
was quenched and brought to neutral pH. It was then extracted thrice with Et
2
O. The
organic layers were dried over MgSO and concentrated on a rotary evaporator under
4
2
reduced pressure. Purification by column chromatography (SiO , hexanes:EtOAc)
1
yielded 1.67 g (85%) of the desired product as a white solid. H NMR (400 MHz,
CDCl ) δ; 2.68 (br s, 1H), 1.92 – 1.68 (m, 12H), 1.56 – 1.40 (m, 2H), 1.40 – 1.20 (m,
3
8H), 0.97 – 0.01 (m, 3H, P–BH
3
) ppm.
General procedure for the synthesis of aminophosphines (7a-b). A solution of
dicyclohexylphosphinous acid borane (1 eq) and methansulfonic anhydride (1.2 eq) in
CH Cl (0.2M) was cooled to 0 ºC. To this solution, anhydrous NEt (2.5 eq) was slowly
2
2
3
added, and the mixture was stirred 1 h at 0 ºC. The corresponding amine (1.5 eq) was
then added and the solution was stirred overnight at room temperature. Water was added
and the mixture was allowed to warm to room temperature. The organic layer was
2 2
separated and the aqueous phase was extracted twice with CH Cl . The combined
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extracts were washed with brine and concentrated under reduced pressure. Purification
by flash chromatography (SiO , hexanes:EtOAc) yielded the corresponding products as
2
white solids.
(S)-2-((dicyclohexylphosphanyl)amino)-N-((S)-1-hydroxy-3-methylbutan-2-yl)-3-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
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2
3
4
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7
8
9
0
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2
3
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7
8
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0
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6
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8
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8
9
0
1
2
3
4
5
6
7
8
9
0
methylbutanamide borane (7a). White solid. Yield: 41% (150 mg). Mp: 200–201 ºC.
ꢀ1 1
[
α] : –5.6 (c 0.53, CHCl ). IR (KBr) ʋ : 3297, 2918, 2386, 2343 and 1648 cm . H
D 3 max
NMR (400 MHz, CDCl ) δ; 5.9 (br d, J = 7 Hz, 1H), 3.75 – 3.60 (m, 3H), 3.52 (td, J =
3
10, 6 Hz, 1H), 2.77 (br s, 1H), 2.23 (dd, J = 10, 4 Hz, 1H), 1.95 – 1.60 (m, 14H), 1.43 –
1.15 (m, 10H), 0.99 (d, J = 4 Hz, 3H), 0.98 – 0.96 (m, 6H), 0.96 (d, J = 4 Hz, 3H), 0.78
13
–
ꢀ0.07 (m, P–BH
3 3
).ppm. C NMR (101 MHz, CDCl ) δ; 174.3 (C), 63.9 (CH), 62.3
(
CH), 57.7 (CH), 35.2 (d, J = 32 Hz, CH), 34.9 (d, J = 41 Hz, CH), 33.7 (d, J = 5 Hz,
P
P
P
CH), 28.8 (CH), 26.8 – 25.2 (m, 10 x CH ), 19.4 (CH ), 19.0 (CH ), 18.9 (CH ), 18.7
2
3
3
3
31
(CH
3
) ppm. P NMR (202 MHz, CDCl
3
) δ; 73.3 – 71.1 (m, P–BH
3
) ppm. HRMS
+
(nanoESIꢀOrbi) m/z: [M + H] Calcd for C22
H
46
O
2
N
2
BP 413.3463; Found 413.3458.
(S)-2-((dicyclohexylphosphanyl)amino)-N-((R)-1-hydroxy-3-methylbutan-2-yl)-3-
methylbutanamide borane (7b). White solid. Yield: 59% (214 mg). Mp: 122–123 ºC.
ꢀ1
1
[
α] : +25.0 (c 0.58, CHCl ). IR (KBr) ʋ : 3318, 2935, 2854, 2368 and 1652 cm . H
D 3 max
NMR (400 MHz, CDCl
3
) δ; 5.86 (br s, 1H), 3.72 – 3.65 (m, 3H), 3.41 (td, J = 10, 7 Hz,
1H), 2.78 (br s, 1H), 2.16 (br d, J = 8 Hz, 1H), 1.97 – 1.60 (m, 14H), 1.44 – 1.14 (m,
13
10H), 1.00 (d, J = 7 Hz, 3H), 0.99 – 0.93 (m, 9H), 0.72 – 0.08 (m, BH
3
) ppm. C NMR
(101 MHz, CDCl ) δ; 174.5 (C), 63.7 (CH ), 62.9 (d, J = 2 Hz, CH), 57.6 (CH), 35.1 (d,
3
2
J = 43 Hz, CH), 34.9 (d, J = 36 Hz, CH), 33.4 (d, J = 6 Hz, CH), 28.8 (CH), 26.8 –
P
P
31
2
5.2 (m, 10 x CH
MHz, CDCl
Calcd for C22
2
), 19.6 (CH), 19.4 (CH), 19.0 (CH), 18.9 (CH) ppm. P NMR (202
+
3
3
) δ; 74.5 – 69.7 (m, P–BH ) ppm. HRMS (nanoESIꢀOrbi) m/z: [M + H]
H
46
O
2
N
2
BP 413.3463; Found 413.3461.
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General procedure for the synthesis of phosphino-oxazolines (8a-b). The
corresponding aminophosphane (1 eq) was dissolved in CH Cl (0.08 M) and SOCl
2
2
2
(
2.4 eq) was added drop wise at 0 ºC. The solution was stirred 4 h at room temperature.
The solution was then cooled down to 0 ºC and NaHCO saturated aqueous solution was
3
0
1
2
3
4
5
6
7
8
9
0
1
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9
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2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
added slowly until pH 8ꢀ9. The mixture was left stirring for 15 min at room
temperature. The two phases were separated and the aqueous phase was extracted twice
with CH Cl . The combined organic layers were washed with brine. The organic layer
2
2
4
was dried over MgSO and concentrated on a rotary evaporator under reduced pressure.
Purification by column chromatography (SiO
products as white solids.
2
, hexanes:EtOAc) yielded the desired
1
,1-dicyclohexyl-N-((S)-1-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-2-
methylpropyl)phosphanamine borane (8a). White Solid. Yield: 96% (120 mg). Mp:
22–123 ºC. [α] : –29.3 (c 0.53, CHCl ). IR (KBr) ʋmax: 3318, 2922, 2845, 2390, 2330
and 1666 cm . H NMR (400 MHz, CDCl ) δ; 4.27 (t, 1H), 4.01 (t, J = 8 Hz, 1H), 3.94
– 3.76 (m, 2H), 2.26 (br d, J = 10 Hz, 1H), 1.99 – 1.59 (m, 14H), 1.47 – 1.16 (m, 10H),
1
D
3
ꢀ1 1
3
13
1
.01 (d, J = 7 Hz, 3H), 0.94 – 0.88 (m, 9H), 0.70 – 0.10 (m, 3H, BH ) ppm. C NMR
3
(
101 MHz, CDCl ) δ; 168.1 (C), 71.9 (CH), 70.9 (CH ), 56.1 (d, J = 2 Hz, CH), 35.8 (d,
3
2
J
P
= 34 Hz, CH), 34.3 (d, J
P
= 44 Hz, CH), 34.0 (d, J = 4 Hz, CH), 33.0 (CH), 26.9 –
3
1
2
5.2 (m, 10 x CH), 19.2 (CH
MHz, CDCl ) δ 73.0 – 71.2 (m, PꢀBH
Calcd for C H ON BP 395.3357; Found 395.3350.
3
), 18.5 (CH
3
), 18.2 (CH
3
), 18.1 (CH
3
) ppm. PꢀNMR (202
+
3
3
) ppm. HRMS (nanoESIꢀOrbi) m/z: [M + H]
2
2
44
2
1
,1-dicyclohexyl-N-((S)-1-((R)-4-isopropyl-4,5-dihydrooxazol-2-yl)-2-
methylpropyl)phosphanamine borane (8b). White Solid. Yield: 99% (66 mg). Mp:
23.5–124.5 ºC. [α] : +16.0 (c 0.31, CHCl ). IR (KBr) ʋmax: 3328, 2916, 2398, 2362
and 1667 cm . H NMR (400 MHz, CDCl ) δ; 4.28 (dd, J = 9, 8 Hz, 1H), 3.97 – 3.73
1
D
3
ꢀ1 1
3
2
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(
m, 3H), 2.14 (dd, J = 10, 3 Hz, 1H), 1.97 – 1.59 (m, 14H), 1.47 – 1.17 (m, 10H), 0.98
(d, J = 7 Hz, 3H), 0.96 – 0.91 (m, 6H), 0.89 (d, J = 7 Hz, 3H), 0.72 – 0.05 (m, 3H, BH3)
13
ppm. C NMR (101 MHz, CDCl
d, J = 33 Hz, CH), 34.3 (d, J
x CH ), 19.2 (CH ), 18.4 (CH
3 2
) δ; 168.2 (C), 71.9 (CH), 70.4 (CH ), 55.9 (CH), 35.7
(
P
P
= 44 Hz, CH), 33.8 (CH), 32.5 (CH), 27.0 – 25.1 (m, 10
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
31
2
3
3
), 18.3 (CH
3
), 18.1(CH
3
).ppm. P NMR (202 MHz,
+
CDCl ) δ; δ 73.6 – 72.0 (m, PꢀBH ) ppm. HRMS (nanoESIꢀOrbi) m/z: [M + H] Calcd
3
3
for C H ON BP 395.3357; Found 395.3349.
22 44
2
F
General procedure for the preparation of [Ir(P,N)(COD)]BAr complexes (5a-b).
The corresponding borane protected ligand (1 eq) was dissolved in freshly distilled
pyrrolidine (0.06 M) and stirred for 16 h at 90 ºC. Afterwards, pyrrolidine was removed
in vacuo. When no pyrrolidine remained, the crude was further dried under vacuum for
3
0 min at 50 ºC (the crude was under N during all the procedure). A solution of
2
[
Ir(COD)(Cl)]
2
(0.5 eq) in CH
2
Cl
2
(0.06 M) was added to the free ligand via cannula.
(1 eq) was
The resulting mixture was stirred for 40 min at room temperature. NaBAr
F
then added and the solution was stirred 1 h more at room temperature. The resulting
crude was filtered through a small plug of silica gel, (first washed with Et O) under N ,
2
2
eluting with hexanes:CH Cl (50ꢀ100%). The orange fraction was collected and
2
2
concentrated to yield the corresponding iridium complexes as deep orange solids.
Ir(8a)(COD)]BAr (5a). Orange solid. Yield: 74% (145 mg). Mp: 167–168 ºC. [α]
+46.9 (c 0.60, CHCl
[
F
D
:
ꢀ1 1
3
). IR (KBr) ʋmax: 2929, 2855, 1628, 1276 and 1129 cm . H NMR
1
(400 MHz, CDCl ) δ; H NMR (400 MHz, Chloroformꢀd) δ 7.75 – 7.68 (m, 8H), 7.53
3
(br s, 4H), 4.84 – 4.75 (m, 1H), 4.55 – 4.47 (m, 2H), 4.26 (t, J = 10 Hz, 1H), 4.12 – 4.04
(m, 1H), 3.95 – 3.86 (m, 1H), 3.54 – 3.47 (m, 1H), 3.47 – 3.36 (m, 2H), 2.42 – 2.34 (m,
2
3
H), 2.26 – 2.18 (m, 2H), 2.16 – 1.52 (m, 17H), 1.42 – 1.15 (m, 12H), 1.09 (d, J = 7 Hz,
13
H), 1.02 (d, J = 7 Hz, 3H), 0.88 (d, J = 7 Hz, 3H), 0.82 (d, J = 7 Hz, 3H) ppm. C
2
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2
2
2
2
2
2
2
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3
3
3
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6
NMR (101 MHz, CDCl ) δ; 175.0 (C), 161.7 (q, J = 50 Hz, 4 x C), 134.8 (8 x CH),
3
B
129.5 – 128.3 (m, 8 x C), 124.5 (q, J = 273 Hz, 8 x CF ), 117.40 (hept, J = 4 Hz, 4 x
F
3
F
CH), 92.70 (d, J
P
= 11 Hz, CH), 89.0 (d, J
P
= 13 Hz, CH), 69.9 (CH), 69.2 (CH), 62.6
= 33 Hz,
), 20.6 (CH ), 19.9
(CH), 59.9 (CH), 59.7 (CH), 41.1 (d, J
P
= 32 Hz, CH), 38.2 (CH), 37.1 (d, J
), 29.6 – 25.6 (m, 12 x CH
P
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH), 36.0 (CH
2
), 31.9 (CH), 31.9 (CH
2
2
3
3
1
(
CH ), 18.6 (CH ), 15.1 (CH ) ppm. P NMR (202 MHz, CDCl ) δ; 60.7 (s) ppm.
3 3 3 3
+
HRMS (nanoESIꢀOrbi) m/z: [M] Calcd for C H ON IrP 681.3519; Found 681.3502.
30 53
2
‒
HRMS (nanoESIꢀOrbi) m/z: [M] Calcd for C32
[Ir(8b)(COD)]BAr (5b). Orange solid. Yield: 52% (102 mg). [α]
CHCl ). IR (KBr) ʋmax: 2940, 2856, 1622, 1351 and 1271 cm . H NMR (400 MHz,
CDCl ) δ; 7.74 – 7.67 (m, 8H), 7.53 (br s, 4H), 4.80 – 4.73 (m, 1H), 4.61 (p, J = 7 Hz,
H
12BF24 863.0654; Found 863.0634.
F
D
: –41.2 (c 0.49,
ꢀ1 1
3
3
1
H), 4.54 (dd, J = 10, 4 Hz, 1H), 4.28 (t, J = 10 Hz, 1H), 4.05 – 3.99 (m, 1H), 3.90 (dt, J
10, 3 Hz, 1H), 3.82 – 3.76 (m, 1H), 3.39 – 3.31 (m, 1H), 2.52 – 1.16 (m, 33H), 1.11
(d, J = 7 Hz, 3H), 0.93 (d, J = 7 Hz, 3H), 0.92 (d, J = 7 Hz, 3H), 0.74 (d, J = 7 Hz, 3H)
=
13
ppm. C NMR (101 MHz, CDCl
3 B
) δ; 175.0 (C), 161.7 (q, J = 50 Hz, 4 x C), 134.8 (8 x
CH), 129.5 – 128.3 (m, 8 x C), 124.5 (q, J = 273 Hz, 8 x CF ), 117.40 (hept, J = 4 Hz,
F
3
F
4
x CH), 93.8 (d, J = 12 Hz, CH), 92.0 (CH), 70.3 (CH ), 68.4 (CH), 61.7 (CH), 60.1
P
2
(
CH), 58.7 (CH), 39.7 (d, J
P
= 37 Hz, CH), 37.6 (d, J
and 1 x CH), 20.1 (CH
) ppm. P NMR (202 MHz, CDCl
P
= 29 Hz, CH), 35.3 (CH
2
3
), 31.8
), 14.2
(CH), 30.9 – 25.5 (m, 13 x CH
2
3 3
), 18.9 (CH ), 16.2 (CH
31
(CH
3
3
) δ; 59.7 (s) ppm. HRMS (nanoESIꢀOrbi) m/z:
+
[M] Calcd for C H ON IrP 681.3519; Found 681.3501. HRMS (nanoESIꢀOrbi) m/z:
30
53
2
‒
[
M] Calcd for C H BF 863.0654; Found 863.0654.
32 12 24
[
Ir(P*,N)(COD)]BF
propyl)ꢀ4,5ꢀdihydrooxazolꢀ2ꢀyl)ꢀ2ꢀmethylpropyl)ꢀ1ꢀmethylphosphanamine
0.148 mmol, 1 eq) was dissolved in freshly distilled pyrrolidine (0.06 M) and stirred
4
(1b-BF
4
). 45 mg of (R)ꢀ1ꢀtertꢀbutylꢀNꢀ((R)ꢀ1ꢀ((S)ꢀ4ꢀ(isoꢀ
borane
(
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for 16 h at 90 ºC. Afterwards pyrrolidine was removed in vacuo. When no pyrrolidine
remained, the crude was further dried under vacuum for 30 min at 50 ºC (the crude was
under N
CH Cl (2 mL) were added to the free ligand. The resulting mixture was stirred for 40
min at room temperature. Then, 17 mg of NaBF (0.148 mmol, 1 eq) were added and
the solution was left stirring overnight at room temperature. Purification by flash
chromatography (SiO , DCM:MeOH) yielded 63 mg (63%) of product as an orange/red
2 2
during all the procedure). 50 mg of [Ir(COD)(Cl)] (0.074 mmol, 0.5 eq) in
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
2
solid. Mp: 200–202 ºC. [α]
D
: –18.5 (c 0.40, CHCl
1620 and 1213 cm . H NMR (400 MHz, CDCl ) δ; 5.11 – 5.02 (m, 1H), 4.91 – 4.84
m, 1H), 4.69 (t, J = 10 Hz, 1H), 4.56 (dd, J = 10, 4 Hz, 1H), 4.19 – 4.13 (m, 1H), 4.02
dt, J = 10, 4 Hz, 1H), 3.63 – 3.57 (m, 1H), 3.57 – 3.46 (m, 1H), 2.63 – 2.53 (m, 1H),
.53 – 2.42 (m, 1H), 2.39 – 2.17 (m, 3H), 2.16 – 2.06 (m, 2H), 1.84 – 1.65 (m, 4H), 1.42
d, J = 8 Hz, 3H), 1.22 (d, J = 15 Hz, 9H), 1.10 (d, J = 7 Hz, 3H), 1.01 (d, J = 7 Hz,
3H), 0.98 (d, J = 7 Hz, 3H), 0.79 (d, J = 7 Hz, 3H) ppm. C NMR (101 MHz, CDCl
δ; 175.7 (C), 95.1 (d, J = 13 Hz, CH), 92.8 (d, J = 11 Hz, CH), 70.8 (CH ), 68.5 (CH),
4.0 (CH), 57.9 (CH), 56.1 (CH), 36.3 (d, J = 42 Hz, C), 34.3 (CH ), 31.8 (CH), 31.3
3
). IR (KBr) ʋmax: 3346, 2956, 2874,
ꢀ1 1
3
(
(
2
(
P
P
1
3
3
)
P
P
2
6
P
2
(
CH ), 29.8 (CH ), 28.9 (d, J = 9 Hz, CH), 28.0 (CH ), 26.9 (d, J = 4 Hz, 3 x CH ),
2
2
P
2
3
31
1
9.8 (CH
3
), 19.3 (CH
3
), 17.1 (CH
3
), 15.1 (CH
3
), 8.7 (d, J
P
= 27 Hz, CH
3
) ppm.
P
+
NMR (202 MHz, CDCl
3
) δ; 61.9 (s) ppm. HRMS (nanoESIꢀOrbi) m/z: [M] Calcd for
‒
23 2
C H43ON
IrP 587.2737; Found 587.2721. HRMS (nanoESIꢀOrbi) m/z: [M] Calcd for
BF 87.0035; Found 87.0034.
4
General procedure for the synthesis of imines. The corresponding ketone (1 eq)
was dissolved in a dry, N
the corresponding amine (3 eq) was added. The mixture was cooled to 0 ºC. Then neat
TiCl (0.5 eq) was carefully added dropwise via syringe. The reaction was left stirring
2 2
purged round bottom flask in anhydrous Et O (0.5 M). Then
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5
5
5
5
5
5
5
5
6
®
overnight at room temperature. The solution was then filtered through Celite with extra
Et O. The solvent was then removed under reduced pressure to obtain the crude as an
2
oil. The crudes were purified by either crystallization or Kugelrohr distillation.
3a
1
Acetophenone N-phenyl imine. Yield: 73% (10.9 g). H NMR (400 MHz, CDCl
δ; 8.02 – 7.91 (m, 2H), 7.55 – 7.40 (m, 3H), 7.41 – 7.30 (m, 2H), 7.13 – 7.04 (m, 1H),
.84 – 6.76 (m, 2H), 2.23 (s, 3H) ppm.
-Methoxyacetophenone N-phenyl imine. Yield: 63% (9.5 g). H NMR (400
MHz, CDCl ) δ; 8.04 – 7.92 (m, 2H), 7.39 – 7.31 (m, 2H), 7.10 – 7.04 (m, 1H), 6.98 –
6.93 (m, 2H), 6.82 – 6.76 (m, 3H), 3.87 (s, 3H), 2.20 (s, 3H) ppm.
3
)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
3
a
1
4
3
1
3
1
3
-Methoxyacetophenone N-phenyl imine. Yield: 38% (5.7 g). H NMR (400
MHz, CDCl ) δ; 7.61 – 7.54 (m, 1H), 7.53 – 7.48 (m, 1H), 7.39 – 7.31 (m, 3H), 7.11 –
3
7
.06 (m, 1H), 7.04 – 7.00 (m, 1H), 6.81 – 6.77 (m, 2H), 3.88 (s, 3H), 2.22 (s, 3H) ppm.
1
2
-Methoxyacetophenone N-phenyl imine. Yield: 33% (5.4 g). H NMR (400 MHz,
CDCl
(m, 1H), 6.87 – 6.84 (m, 2H), 6.78 – 6.73 (m, 1H), 6.68 – 6.64 (m, 1H), 3.88 (s, 3H),
.19 (s, 3H) ppm.
Acetophenone N-(4-methoxyphenyl) imine. Yield: 55% (5.3 g). H NMR (400
MHz, CDCl ) δ; 8.03 – 7.89 (m, 2H), 7.50 – 7.39 (m, 3H), 6.93 – 6.87 (m, 2H), 6.80 –
.72 (m, 2H), 3.82 (s, 3H), 2.25 (s, 3H) ppm.
1-(Naphthalen-2-yl)-N-phenylethan-1-imine. Yield: 62% (5.4 g). H NMR (400
MHz, CDCl ) δ; 8.37 – 8.33 (m, 1H), 8.24 – 8.21 (m, 1H), 7.95 – 7.85 (m, 3H), 7.57 –
3
) δ; 7.61 – 7.57 (m, 1H), 7.41 – 7.32 (m, 3H), 7.04 – 7.00 (m, 1H), 6.97 – 6.93
2
3a
1
3
6
14
1
3
7
3
.49 (m, 2H), 7.40 – 7.34 (m, 2H), 7.13 – 7.08 (m, 1H), 6.87 – 6.82 (m, 2H), 2.36 (s,
H) ppm.
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a
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N,1-Diphenylpropan-1-imine. Yield: 47% (3.7 g). H NMR (400 MHz, CDCl ) δ;
3
7.95 – 7.90 (m, 2H), 7.48 – 7.42 (m, 3H), 7.37 – 7.31 (m, 2H), 7.07 (tt, J = 8, 1 Hz, 1H),
6
.81 – 6.77 (m, 2H), 2.66 (q, J = 8 Hz, 2H), 1.08 (t, J = 8 Hz, 3H) ppm.
3a
1
4
-Chloroacetophenone N-phenyl imine. Yield: 51% (9.0 g). H NMR (400 MHz,
CDCl ) δ; 7.94 – 7.88 (m, 2H), 7.43 – 7.38 (m, 2H), 7.38 – 7.32 (m, 2H), 7.12 – 7.06
m, 1H), 6.81 – 6.76 (m, 2H), 3.08 (q, J = 7 Hz, 1H), 2.21 (s, 3H), 1.40 (t, J = 7 Hz, 1H)
ppm.
Acetophenone N-(3,5-dimethylphenyl) imine. Yield: 57% (7.1 g). H NMR (400
MHz, CDCl ) δ; 7.98 – 7.94 (m, 2H), 7.48 – 7.40 (m, 3H), 6.72 (tp, J = 1, 1 Hz, 1H),
.44 – 6.40 (m, 2H), 2.32 – 2.30 (m, 6H), 2.23 (s, 3H) ppm.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
(
1
5
1
3
6
16
1
Acetophenone N-(p-tolyl) imine. Yield: 40% (7.2 g). H NMR (400 MHz, CDCl )
3
δ; 8.01 – 7.92 (m, 2H), 7.48 – 7.41 (m, 3H), 7.18 – 7.14 (m, 2H), 6.73 – 6.67 (m, 2H),
2
.35 (s, 3H), 2.24 (s, 3H) ppm.
2
General Procedure for the hydrogenation at high H pressure. The corresponding
imine (1 eq) and the corresponding catalyst (0.01 eq) were placed along with stirring bar
in a glass tube inside a stainless steel high pressure reactor. The reactor was entered into
a glove box and deoxygenated anhydrous solvent was added (0.17 M). The reactor was
closed, removed from the glove box and connected to a hydrogen manifold. While
stirring, the reactor was purged with vacuumꢀhydrogen cycles and then it was charged at
the designated pressure. The hydrogen manifold was unplugged and the mixture was
left to stir overnight at room temperature. The reactor was depressurized and the
1
reaction was concentrated under vacuum. The conversion was determined by H NMR.
Catalyst was removed by filtration of the crude reaction through a short silica pad with
CH
2 2
Cl and concentrated under vacuum. At this point, yield and enantiomeric excess
were determined.
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General Procedure for the hydrogenation at atmospheric H pressure. The
2
corresponding imine (1 eq) and the corresponding catalyst (0.01 eq) were placed in a
round bottom flask. The flask was purged with N
was added (0.17 M). The reaction was then set at the desired temperature. While
stirring, a H filled balloon was connected. Using another needle as a gas exit the round
2
and deoxygenated anhydrous solvent
0
1
2
3
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5
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9
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4
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7
8
9
0
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2
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4
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6
7
8
9
0
2
bottom flask was purged with H until the solution went from orange to yellow (usually
2
less than 3ꢀ4 minutes). The gas exit was removed and the reaction was left stirring
overnight. The next day the reaction was concentrated under vacuum. The conversion
1
was determined by H NMR. Catalyst was removed by filtration of the crude reaction
2 2
through a short silica pad with CH Cl and concentrated under vacuum. At this point,
yield and enantiomeric excess were determined.
3a
1
N-(1-phenylethyl)aniline. Yield: 97% (66 mg). H NMR (400 MHz, CDCl ) δ; 7.41
3
–
7.25 (m, 4H), 7.28 – 7.18 (m, 1H), 7.18 – 7.03 (m, 2H), 6.68 – 6.59 (m, 1H), 6.55 –
6.46 (m, 2H), 4.48 (q, J = 7 Hz, 1H), 4.02 (br s, 1H), 1.51 (dd, J = 7, 1 Hz, 3H) ppm.
HPLC: CHIRALCEL ODꢀH. Heptane/iꢀPrOH 90:10, 1 mL/min, λ = 220 nm. t (+)=
5.4 min, t (–)= 17.0 min. (ee = 96%).
R
1
R
3a
1
N-(1-(4-methoxyphenyl)ethyl)aniline. Yield: 96% (76 mg). H NMR (400 MHz,
CDCl ) δ; 7.30 – 7.26 (m, 2H), 7.11 – 7.06 (m, 2H), 6.87 – 6.84 (m, 2H), 6.53 – 6.47
m, 2H), 4.44 (q, J = 6.7 Hz, 1H), 3.78 (s, 3H), 1.49 (d, J = 6.7 Hz, 3H) ppm. HPLC:
3
(
Chiralpak IA. Heptane/iꢀPrOH 96:4, 0.5 mL/min, λ = 210 nm. t
17.6 min. (ee = 95%).
R
R
(+)= 16.1 min, t (–)=
13
1
N-(1-(3-methoxyphenyl)ethyl)aniline. Yield: 98% (77 mg). H NMR (400 MHz,
CDCl
3
) δ; 7.26 – 7.21 (m, 1H), 7.11 – 7.05 (m, 2H), 6.98 – 6.94 (m, 1H), 6.94 – 6.91
(
m, 1H), 6.76 (ddd, J = 8, 3, 1 Hz, 1H), 6.64 (tt, J = 7, 1 Hz, 1H), 6.54 – 6.48 (m, 2H),
4
.45 (q, J = 7 Hz, 1H), 4.01 (s, 1H), 3.78 (s, 3H), 1.51 (d, J = 7 Hz, 3H) ppm. HPLC:
2
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CHIRALCEL OJ. Heptane/EtOH 50:50ꢀ0.2% DEA, 0.5 mL/min, λ = 210 nm. t (+)=
R
18.1 min, t (–)= 20.8 min. (ee = 92%).
R
17
1
N-(1-(2-methoxyphenyl)ethyl)aniline. Yield: 96% (75 mg). H NMR (400 MHz,
CDCl ) δ; 7.27 – 7.20 (m, 1H), 7.15 – 7.08 (m, 1H), 7.03 – 6.96 (m, 2H), 6.83 – 6.77
m, 2H), 6.54 (tt, J = 7, 1 Hz, 1H), 6.46 – 6.37 (m, 2H), 4.77 (q, J = 7 Hz, 1H), 3.82 (s,
3
1
1
1
1
1
1
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3
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5
5
5
5
5
6
0
1
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9
0
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7
8
9
0
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
3H), 1.40 (d, J = 7 Hz, 3H) ppm. HPLC: CHIRALCEL OJ. Heptane/EtOH 70:30ꢀ0.2%
DEA, 0.5 mL/min, λ = 210nm. t (+)= 14.5 min, t (–)= 19.1 min. (ee = 28%).
R
R
3a
1
4-methoxy-N-(1-phenylethyl)aniline. Yield: 98% (77 mg). H NMR (400 MHz,
CDCl ) δ; 7.39 – 7.28 (m, 4H), 7.24 – 7.19 (m, 1H), 6.74 – 6.61 (m, 2H), 6.47 (d, J = 9
3
Hz, 2H), 4.41 (q, J = 7 Hz, 1H), 3.69 (s, 3H), 1.50 (d, J = 7 Hz, 3H) ppm. HPLC:
Chiralpak IC Heptane/iꢀPrOH 96:4, 0.5 mL/min, λ = 210 nm. t (+)= 17.3 min, t (–)=
R
R
1
8.4 min. (ee = 93%).
N-(1-(naphthalen-2-yl)ethyl)aniline. Yield: 96% (82 mg). H NMR (400 MHz,
CDCl ) δ; 7.84 – 7.77 (m, 4H), 7.50 (dd, J = 8, 2 Hz, 1H), 7.48 – 7.39 (m, 2H), 7.13 –
7.03 (m, 2H), 6.66 – 6.59 (m, 1H), 6.59 – 6.53 (m, 2H), 4.64 (q, J = 7 Hz, 1H), 4.18 –
1
8
1
3
4
.04 (m, 1H), 1.59 (d, J = 7 Hz, 3H) ppm. HPLC: CHIRALCEL OJ. Heptane/EtOH
0:50, 0.8 mL/min, λ = 210 nm. t (+)= 14.4 min, t (–)= 17.2 min. (ee = 94%).
5
R
R
3
a
1
N-(1-phenylpropyl)aniline. Yield: 99% (72 mg). H NMR (400 MHz, CDCl
3
) δ;
7.39 – 7.27 (m, 4H), 7.27 – 7.18 (m, 1H), 7.11 – 7.04 (m, 2H), 6.62 (tt, J = 7, 1 Hz, 1H),
6.56 – 6.43 (m, 2H), 4.22 (t, J = 7 Hz, 1H), 4.04 (br s, 1H), 1.90 – 1.72 (m, 2H), 0.95 (t,
J = 7 Hz, 3H) ppm. HPLC: CHIRALCEL ODꢀH. Heptane/iꢀPrOH 95:5, 0.5 mL/min, λ
=
210 nm. t (+)= 11.9 min, t (–)= 14.8 min. (ee = 74%).
R R
3a
1
N-(1-(4-chlorophenyl)ethyl)aniline. Yield: 98% (78 mg). H NMR (400 MHz,
CDCl ) δ; 7.25 – 7.18 (m, 4H), 7.05 – 6.97 (m, 2H), 6.62 – 6.54 (m, 1H), 6.43 – 6.35
m, 2H), 4.38 (q, J = 7 Hz, 1H), 1.42 (d, J = 7 Hz, 3H) ppm. HPLC: CHIRALCEL ODꢀ
3
(
2
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H. Heptane/iꢀPrOH 95:5, 1 mL/min, λ = 210 nm. t (+)= 10.4 min, t (–)= 14.8 min. (ee
R
R
= 94%).
,5-dimethyl-N-(1-phenylethyl)aniline. Yield: 99% (77 mg). H NMR (400 MHz,
CDCl ) δ; 7.38 – 7.28 (m, 3H), 7.24 – 7.19 (m, 1H), 6.32 – 6.27 (m, 1H), 6.18 – 6.10
m, 2H), 4.47 (q, J = 7 Hz, 1H), 3.90 (br s, 1H), 2.16 (s, 6H), 1.49 (d, J = 7 Hz, 3H)
ppm. HPLC: CHIRALCEL ODꢀH. Heptane/iꢀPrOH 95:5, 0.5 mL/min, λ = 254 nm.
t (+)= 10.7 min, t (–)= 12.4 min. (ee = 90%).
19
1
3
3
0
1
2
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9
0
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0
1
2
3
4
5
6
7
8
9
0
(
R
R
20
1
4-methyl-N-(1-phenylethyl)aniline. Yield: 96% (70 mg). H NMR (400 MHz,
CDCl ) δ; 7.38 – 7.28 (m, 4H), 7.24 – 7.19 (m, 1H), 6.94 – 6.84 (m, 2H), 6.47 – 6.39
m, 2H), 4.45 (q, J = 7 Hz, 1H), 2.18 (s, 3H), 1.50 (d, J = 7 Hz, 3H) ppm. HPLC:
CHIRALCEL OJ. Heptane/iꢀPrOH 50:50, 1 mL/min, λ = 210 nm. t (+)= 12.2 min, t (–
3
(
R
R
)
= 15.4 min. (ee = 95%).
General Procedure for synthesis of imine iridacycles. In a round bottom flask 100
mg of complex ent-1b or ent-3b (0.069 mmol, 1 eq) and 27 mg of acetophenone Nꢀ
phenyl imine (0.138 mmol, 2 eq) were placed. The flask was then purged with N and
2
THF (2 mL) was added. The solution was purged with a balloon of H until the orange
2
color changed to yellow. The reaction mixture was stirred at room temperature during 4
hours. The solvent was removed with a N
EtOAc (2 mL) were added. The reaction was left to stir overnight. The solvent was
again removed with a N flow. The crude was suspended in pentane/TBME (1:1) and
2 2
flow and LiCl (100 mg), SiO (100 mg) and
2
eluted through SiO . Only the yellow colored band was collected affording the desired
2
products. The complexes were crystalized with hexanes/DCM to obtain single crystals
for Xꢀray analysis.
1
[
IrHCl(P*,N)(imine)] (9). Yellow solid. Yield: 60% (29 mg). H NMR (400 MHz,
2 2
CD Cl ) δ; 7.80 – 7.68 (m, 2H), 7.57 – 7.50 (m, 1H), 7.40 – 7.30 (m, 2H), 7.17 (tt, J =
2
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, 1 Hz, 1H), 6.96 – 6.91 (m, 3H), 5.02 – 4.96 (m, 1H), 4.30 (dd, J = 9, 5 Hz, 1H), 3.98
(dd, J = 10, 9 Hz, 1H), 3.01 – 2.93 (m, 1H), 2.74 – 2.65 (m, 1H), 2.41 (s, 3H), 1.86 (dd,
J = 9, 1 Hz, 3H), 1.84 – 1.78 (m, 1H), 1.12 (br d, J = 10 Hz, 1H), 0.86 (d, J = 7 Hz, 3H),
P
0.81 (d, J = 7 Hz, 3H), 0.78 (d, J = 7 Hz, 3H), 0.64 (d, J = 7 Hz, 3H), 0.57 (d, J = 14
1
1
1
1
1
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2
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2
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2
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5
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5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
13
Hz, 9H), ꢀ19.76 (d, JP(cis) = 26 Hz, 1H) ppm. C NMR (101 MHz, CD
2
Cl
2
) δ; 180.0 (C),
1
68.5 (C), 155.6 – 154.2 (m, C), 149.5 (C), 148.4 (C), 143.2 (d, J = 1 Hz, CH), 130.6
CH), 129.2 (CH), 128.4 – 127.7 (m, 2 x CH), 125.5 (CH), 123.6 (CH), 121.9 (CH),
119.8 (CH), 68.8 (CH ), 67.5 (CH), 57.5 (d, J = 2 Hz, CH), 37.4 (d, J = 37 Hz, C), 28.1
(d, J = 8 Hz, CH), 27.8 (CH), 25.8 (d, J = 4 Hz, 3 x CH ), 22.3 – 21.3 (m, CH ), 20.1
CH ), 18.2 (CH ), 17.6 (CH ), 16.8 (CH ), 13.4 (CH
(
2
P
3
3
3
1
(
3
3
3
3
3
) ppm. P NMR (202 MHz,
+
CDCl ) δ; 36.3 (d, J = 20 Hz) ppm. HRMS (nanoESIꢀOrbi) m/z: [M – Cl] Calcd for
3
H
C H IrN OP 674.2846; Found 674.2834.
29
44
3
1
[
IrHCl(P*,N)(imine)] (10). Yellow solid. Yield: 56% (27 mg). H NMR (400 MHz,
CD Cl ) δ; 7.85 – 7.56 (m, 2H), 7.51 – 7.48 (m, 1H), 7.41 – 7.26 (m, 2H), 7.15 (tt, J =
8, 1 Hz, 1H), 7.01 – 6.74 (m, 3H), 4.93 (dtd, J = 9, 3, 1 Hz, 1H), 4.20 (dd, J = 9, 3 Hz,
2
2
1
H), 3.73 – 3.68 (m, 1H), 3.65 (dd, J = 9, 9 Hz, 1H), 2.89 (hd, J = 7, 3 Hz, 1H), 2.35 (s,
H), 2.07 – 1.95 (m, 1H), 1.55 – 1.49 (m, 1H), 1.07 (d, J = 15 Hz, 9H), 0.90 (d, J = 9
3
P
P
Hz, 3H), 0.86 (d, J = 7 Hz, 3H), 0.77 (d, J = 7 Hz, 3H), 0.63 (d, J = 7 Hz, 3H), 0.43 (d,
1
3
2 2
J = 7 Hz, 3H), ꢀ19.62 (d, JP(CIS) = 23 Hz, 1H) ppm. C NMR (101 MHz, CD Cl ) δ;
180.3 (C), 162.1 (C), 154.3 (C), 149.6 (C), 148.3 (C), 143.4 (2 x CH), 130.4 (CH),
128.7 (2 x CH), 128.6 (CH), 125.3 (CH), 119.6 (2 x CH), 70.3 (CH), 67.5 (CH ), 57.8
2
(CH), 36.2 (d, J = 43 Hz, C), 30.6 (d, J = 6 Hz, CH), 28.6 (CH), 26.4 (3 x CH ), 19.4
P 3
(CH
3
), 18.3 (CH
3
), 17.4 (CH
3
), 16.2 (CH
) δ; 43.93 (d, J
OP 674.2846; Found 674.2835.
3
), 13.6 (CH
3 P 3
), 9.1 (d, J = 42 Hz, CH ) ppm.
31
P NMR (202 MHz, CDCl
3
H
= 19 Hz) ppm. HRMS (nanoESIꢀOrbi) m/z:
+
[
M – Cl] Calcd for C29
H44IrN
3
2
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