Enantioselective synthesis of tunable chiral clickphine P,N-ligands and their application in Ir-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/acs.joc.5b00438

A small library of highly tunable chiral Clickphine P,N-ligands has been prepared in an enantioselective fashion by Cu^I-catalyzed asymmetric propargylic amination using a single chiral complex and a subsequent in situ cycloaddition click reaction. The scope of the propargylic amination to yield optically active triazolyl amines is described. The amines are transformed in a one-pot procedure to the corresponding Ir-Clickphine complexes, which serve as catalysts for the asymmetric hydrogenation of di-, tri-, and tetrasubstituted unfunctionalized alkenes. Enantioselectivities of up to 90% ee were obtained in these hydrogenations, which are among the best reported in the case of the tetrasubstituted substrate 2-(4′-methoxyphenyl)-3-methylbut-2-ene (9) (87% ee). This is a demonstration of the effective use of the chiral pool, as from one chiral catalyst a library of chiral Ir complexes has been synthesized that can hydrogenate various alkenes with high selectivity.

Full text of DOI:10.1021/acs.joc.5b00438

Article
pubs.acs.org/joc
Enantioselective Synthesis of Tunable Chiral Clickphine P,N-Ligands
and Their Application in Ir-Catalyzed Asymmetric Hydrogenation
Jeroen Wassenaar,†,∥ Remko J. Detz,† Sandra Y. de Boer,† Martin Lutz,§ Jan H. van Maarseveen,*,‡
Henk Hiemstra,‡ and Joost N. H. Reek*,†
†Supramolecular & Homogeneous Catalysis, van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904,
1098 XH Amsterdam, The Netherlands
‡Biomolecular Synthesis, van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH
Amsterdam, The Netherlands
§Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Padualaan 8,
3584 CH Utrecht, The Netherlands
S
* Supporting Information
ABSTRACT: A small library of highly tunable chiral Clickphine P,N-ligands has been prepared in an enantioselective fashion by
CuI-catalyzed asymmetric propargylic amination using a single chiral complex and a subsequent in situ cycloaddition click
reaction. The scope of the propargylic amination to yield optically active triazolyl amines is described. The amines are
transformed in a one-pot procedure to the corresponding Ir−Clickphine complexes, which serve as catalysts for the asymmetric
hydrogenation of di-, tri-, and tetrasubstituted unfunctionalized alkenes. Enantioselectivities of up to 90% ee were obtained in
these hydrogenations, which are among the best reported in the case of the tetrasubstituted substrate 2-(4′-methoxyphenyl)-3-
methylbut-2-ene (9) (87% ee). This is a demonstration of the effective use of the chiral pool, as from one chiral catalyst a library
of chiral Ir complexes has been synthesized that can hydrogenate various alkenes with high selectivity.
this concept, we studied the chiral synthesis of P,N-ligands for
the iridium-catalyzed asymmetric hydrogenation of alkenes.
Asymmetric hydrogenation of alkenes provides a means to
rapidly access a vast range of chiral compounds relevant to
pharmaceutical and agrochemical use.1,2 Whereas rhodium-
based catalysts are used extensively for functionalized alkenes,
iridium provides the catalysts of choice for unfunctionalized
substrates.4 Recently, however, Ir catalysts have also been found
to be applicable for increasingly functionalized substrates4b such
as phosphorus-containing alkenes,5−7 furans,8 pyridine deriva-
tives,9 imines,10−18 vinyl boronates,19 and α,β-unsaturated
esters.20−22 With this increasing number of potential substrates,
there is a demand for highly tunable chiral iridium catalysts that
are able to convert these substrates with high enantioselectivity.
Since the discovery of the high activity and selectivity of Ir−
PHOX catalysts in the hydrogenation of imines and
unfunctionalized alkenes by Pfaltz and co-workers,10b,23,24
P,N-ligands have been used frequently in Ir-catalyzed hydro-
INTRODUCTION
■
Asymmetric catalysis is increasingly important for the
preparation of chiral compounds for the pharmaceutical,
agrochemical, and fine chemical industries.1 Typically, a metal
complex based on a chiral ligand is used for asymmetric
transformations, and often several chiral ligands need to be
explored before a sufficiently selective complex can be
identified. The preparation of chiral ligands is mostly based
on the use of the available pool of chiral building blocks (i.e.,
sugars, amino acids), which are built in the ligand or used to
prepare the chiral ligand.2 Remarkably, the use of asymmetric
catalysis to prepare chiral ligands for direct use in a certain
asymmetric conversion has hardly been explored. Several
contributions deal with the asymmetric synthesis of chiral
ligands, mainly chiral phosphines, but typically no further
catalysis is performed with the synthesized ligands.3 We
wondered whether it would be possible to use one chiral
complex to prepare a library of bidentate ligands with a chiral
backbone that in turn could be used in the exploration of a
certain desired asymmetric transformation. This would result in
the catalytic expansion of the chiral pool. In order to validate
Received: February 25, 2015
© XXXX American Chemical Society
A
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Scheme 1. Retrosynthesis of Chiral Clickphine P,N-Ligands Using Asymmetric Catalysis
a
Table 1. Preparation of Optically Pure Triazolyl Amines 2
entry
Ar1
Ar2
R′
product
yield (%) (ee (%))
yield (%) recryst.
ee (%) recryst.
1
2
3
4
5
6
Ph
2-OMe-Ph
2-OMe-Ph
Ph
Ph
Ph
Bn
Bn
(S)-2a
(R)-2b
(S)-2c
(R)-2d
(S)-2e
(R)-2f
91 (84)
75 (82)
75 (85)
−
63
23
17
49
68
48
>99
>99
99
4-OMe-Ph
Ph
Ph
2-OMe-Ph
Ph
>99
94
Ph
4-CF3-Ph
Ph
90 (84)
2-naphthyl
2-OMe-Ph
−
98
a
Reaction conditions: 1 (1.0 equiv), ArNH2 (2.0 equiv), DIPEA (4 equiv), CuI (0.05−0.10 equiv), and the ligand (0.06−0.12 equiv) were stirred in
methanol at 0 °C. After full conversion (as determined by TLC), the azide (1.0 equiv) was added. For entries 1, 3, and 5, bis(4S,5R)-diPh-pybox was
used, and for entries 2, 4, and 6, bis(4R,5S)-diPh-pybox was used.
genation and seem to be privileged for this transformation.25
The majority of these ligands rely on chiral oxazolines and
pyridines as the nitrogen atom donors. On the other hand,
chiral triazole-containing P,N-ligands have not been used to
date in Ir-catalyzed hydrogenations or successfully applied in
any other asymmetric transformation.26 The use of achiral
triazole-containing P,N-ligands for highly regioselective allylic
substitution reactions has been demonstrated by us.27,28 We
anticipated the facile preparation of chiral P,N-ligands via CuI-
catalyzed cycloaddition, allowing for easy derivatization and
fine-tuning of the chiral pocket provided by the ligand.
Importantly, asymmetric propargylic amination catalyzed by a
Pybox−CuI complex potentially gives propargylic amines in
enantiomerically pure form,29,30 which is the basis of our chiral
ligand synthesis. In principle, a single chiral catalyst can be used
to generate a library of chiral P,N-ligands, as azide ligation to
these propargylic amines would furnish triazolyl imines 2,
which can be further decorated with a phosphine to give chiral
P,N-ligands 3 (Scheme 1). As CuI is already present in the
reaction mixture after propargylic amination, we envisioned
that addition of the azide to this mixture would result in a one-
pot three-component reaction, giving enantiomerically enriched
triazolyl amines in only one step. This synthetic strategy would
allow the incorporation of four different substituents in only
two reaction steps. Therefore, these ligands would be highly
tunable, allowing the facile construction of ligand libraries to
find suitable catalysts for a range of substrates in Ir-catalyzed
hydrogenation. Furthermore, complexation to iridium would
result in the formation of a six-membered cyclic chelate, which
was found to be a prerequisite for most successful ligands in Ir-
catalyzed asymmetric hydrogenations. We anticipate that the
chiral center, which resides in the backbone of the ligand,
controls the chiral pocket around the metal and thus effects
efficient enantioface discrimination.
situ cycloaddition to furnish chiral triazolyl amines 2, which are
transformed into chiral P,N-ligands 3. The corresponding Ir
complexes are evaluated in the asymmetric hydrogenation of
di-, tri-, and tetrasubstituted largely unfunctionalized alkenes.
RESULTS AND DISCUSSION
■
Propargylic Amination with in Situ Cycloaddition. The
first step in the synthesis was the preparation of the propargylic
amine by application of the enantioselective copper-catalyzed
propargylic amination conditions to racemic propargylic acetate
1. Subsequent triazole formation by the CuI-catalyzed azide−
alkyne cycloaddition would afford the desired triazolyl amines
2. Interestingly, most of the reagents required for this “click”
reaction were already present in the propargylic amination:
copper(I), base, and the acetylene. Since methanol would not
disturb the reaction, the addition of the azide should be
sufficient for a one-pot procedure. After full consumption of the
propargylic acetate, azide addition indeed provided triazole 2 in
high yield with retention of the stereochemistry. The absolute
configuration of the products can be controlled by using either
enantiomer of the diPh-pybox ligand (2,6-bis((4R,5S)-4,5-
diphenyl-4,5-dihydrooxazol-2-yl)pyridine). The products ob-
tained after the reaction were highly crystalline, allowing further
enantioenrichment by recrystallization. The first attempt was
directly promising: a single recrystallization step gave the single
enantiomer in good yield (Table 1, entry 1).
With other compounds we were also able to isolate
enantiopure triazolyl amines, although several recrystallization
cycles were required for sufficient enantioenrichment, which
lowered the yields (entries 2 and 3). Although no single
enantiomer was obtained, the 4-trifluoromethylphenyl-substi-
tuted triazole 2e illustrates the ease of ligand variation via this
method. In the case of 2d and 2f, the products crystallized in
high ee from the reaction mixture, and in only one
recrystallization step, optically pure product was obtained in
moderate yield (entries 4 and 6). The availability of both
Here we report a detailed study of the scope and limitations
of the asymmetric CuI-catalyzed propargylic amination with in
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Figure 1. Displacement ellipsoid plot (50% probability level) of triazolyl amine (R)-2d. The absolute configuration could not be determined
crystallographically by anomalous scattering but was assigned according to the enantiopure synthesis. Selected bond lengths (Å) and angles (deg):
C1−N4 1.448(3), C1−C2 1.507(3), C2−N1 1.360(3), O1···H4N 2.22(3), N1···H4N 2.35(3); N4−C1−C2 107.6(2), C1−C2−N1 121.5(2), N4−H4N···O1
108(2), N4−H4N···N1 110(2).
Table 2. One-Pot Synthesis of Ir−Clickphine Complexes 4
a
entry
complex
R
R′
Ar
yield (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
Ph
Ph
Ph
Ph
iPr
iPr
iPr
iPr
Ph
Ph
Bn
Ph
Ph
Ph
Bn
Ph
Ph
53
67
61
70
52
60
60
60
p-MeO-C6H4
Ph
2-naphthyl
Ph
p-MeO-C6H4
Ph
4g
4h
2-naphthyl
a
Overall yields from triazolyl amine.
enantiomers of the ligand enables the preparation of both (R)-
and (S)-triazolyl amines.
with enantiopure propargylic amines obtained by kinetic
enzymatic resolution of racemic propargylamines.
The three-dimensional structure of triazolyl amines 2 was
unambiguously confirmed by X-ray crystal structure determi-
nation of (R)-2d (Figure 1). Unfortunately, the configuration
of the chiral center at C1 could not be reliably determined
because of twinning of the crystal and the absence of a strong
anomalous scatterer. The structure features two intramolecular
S(5) hydrogen bonds with the NH group as donor and with the
triazole-N1 and the OMe group as acceptors. These interactions
are likely to increase the NH proton’s pKa value, as
deprotonation proved difficult. A strong base such as n-
butyllithium is necessary to remove this proton (vide infra).
The preparation of this type of triazolyl amines 2 is not the
first reported. In 2007, similar compounds were synthesized by
the group of Botta as potential antimicrobial agents.31,32 The
copper-catalyzed azide−alkyne cycloaddition was performed
One-Pot Synthesis of Ir−Clickphine Complexes. P−N
bond formation is typically achieved by condensation of the
amine with a phosphorus chloride in the presence of a weak
base such as triethylamine. Application of these conditions to
triazolyl amines 2 did not result in any reactivity toward the
desired product, which is rationalized by the stabilizing
hydrogen-bonding interactions of the NH proton with the
triazole and OMe moieties. However, prior deprotonation of
the amine with n-butyllithium followed by condensation with a
phosphorus chloride gave the desired P,N-ligands 3 in almost
quantitative conversion (Table 2). Unfortunately, these
compounds proved to be highly moisture-sensitive, as they
are prone to hydrolysis resulting in P−N bond cleavage,
complicating chromatographic isolation. We demonstrated
previously that isolation is feasible but with significant loss of
C
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material due to decomposition.29 Therefore, we decided to skip
isolation of the ligands 3 and immediately perform complex-
ation with Ir and counteranion exchange to give Ir−BArF
complexes 4. These complexes are insensitive toward air and
moisture and can even be purified by flash chromatography
with dichloromethane.31 This results in the rapid one-pot
synthesis of Ir complexes 4 from triazolyl amines 2 in good
overall yield (50−70%), allowing the construction of a small
library of chiral Ir−Clickphine complexes 4a−h (Table 2).
Asymmetric Hydrogenation. The potential of Ir−
Clickphine complexes as catalysts for asymmetric hydro-
genation was evaluated in the asymmetric hydrogenation of
di-, tri-, and tetrasubstituted largely unfunctionalized alkenes 5,
7, and 9. When standard conditions for the hydrogenation of
unfunctionalized alkenes (50 bar H2) were used in the
hydrogenation of the terminal aryl,alkyl-disubstituted substrate
5, a moderate ee of 47% was obtained with complex 4a (Table
3, entry 1). It was observed previously that lowering the
Encouraged by the results obtained in the hydrogenation of
disubstituted alkene 5, we applied our Ir−Clickphine catalysts
in the hydrogenation of trisubstituted α-methylstilbene (7)
(Table 4). Higher pressures (50 bar H2) and longer reaction
Table 4. Hydrogenation of α-Methylstilbene (7) by Ir−
a
Clickphine Complexes 4a−h
b
c
entry
complex
conv. (%)
ee (%)
d
1
4a
4a
4b
4c
4d
4e
4f
>99
>99
>99
>99
>99
>99
>99
>99
>99
86
90
86
87
83
71
72
59
51
2
3
4
5
6
7
8
9
Table 3. Hydrogenation of α-Ethylstyrene (5) by Ir−
a
Clickphine Complexes 4a−h
4g
4h
a
Reaction conditions: 2.0 mol % 4, [4] = 1 mM, 50 bar H2, CH2Cl2, rt.
Conversion determined by GC after 20 h. Enantiomeric excess
b
c
determined by chiral HPLC (Chiralcel OJ-H). In all cases the R
d
enantiomer was obtained as the major product. 1.0 mol % 4a.
b
c
entry
complex
conv. (%)
ee (%)
d
1
4a
4a
4b
4c
4d
4e
4f
>99
>99
>99
>99
>99
>99
>99
>99
>99
47
75
73
71
69
44
41
39
40
2
3
4
5
6
7
8
9
times were necessary for the reaction to go to completion
compared with those for the disubstituted substrate.
Quantitative conversion and an ee of 86% were obtained
after 20 h with 1 mol % complex 4a (entry 1). A higher catalyst
loading of 2 mol % improved the ee to 90% and was therefore
used for all further hydrogenations of 7 (entry 2). Variation of
the substitution pattern on the backbone of the ligand (Ar and
R′) led only to slight differences in the enantioselectivity (86−
90% ee; entries 3−5) while maintaining quantitative con-
version. Similarly as for disubstituted alkene 5, complexes 4e−h
based on diisopropyl-functionalized phosphines gave lower
enantioselectivity (51−72% ee; entries 6−9). α-Methylstilbene
(7) is frequently used as a benchmark substrate for hydro-
genation of unfunctionalized alkenes.3 The enantioselectivity
obtained with Ir−Clickphine complex 4a (90% ee) is good
compared with many known examples but not excellent, as over
99% ee has been reported for this substrate.
Next, we turned to the more challenging tetrasubstituted
alkene 9, which is known to be notoriously unreactive with
iridium catalysts.3 Initial attempts in the hydrogenation of 9
using a 1 mol % loading of Ir−Clickphine complex 4a and 50
bar H2 gave only 5% conversion after 20 h but a promising
enantioselectivity of 57% ee (Table 5, entry 1). Increasing the
catalyst loading to 2 mol % resulted in 51% conversion and
78% ee (entry 2). Under these conditions, all of the Ir−
Clickphine complexes were evaluated in the hydrogenation of
substrate 9. For the diphenylphosphine-based complexes, we
found a positive influence of the size of the Ar substituent on
the conversion and ee (entries 2−5). The p-methoxyphenyl-
substitueted complex 4b gave 82% ee at 84% conversion, and
the 2-naphthyl derivative afforded 87% ee at 98% conversion. A
benzyl substituent on the triazole (R′) resulted in a slightly
lower selectivity of 72% ee at 68% conversion. In analogy to the
results obtained with substrates 5 and 7, the diisopropylphos-
4g
4h
a
Reaction conditions: 1.0 mol % 4, [4] = 1 mM, 1 bar H2, CH2Cl2, rt.
Conversion determined by GC after 2 h. Enantiomeric excess
b
c
determined by chiral GC (Supelco β-DEX 225). In all cases the R
enantiomer was obtained as the major product. Reaction performed
at 50 bar.
d
dihydrogen pressure for this class of substrates can be beneficial
for the enantioselectivity.33 Indeed, when the hydrogenation
was conducted at ambient pressure, a good ee of 75% was
obtained with complex 4a (entry 2). Evaluation of the whole
library revealed quantitative conversions and ee’s of 69−75%
for Clickphine complexes 4a−d containing a diphenylphos-
phine donor group. However, the use of diisopropylphosphine-
functionalized complexes 4e−h resulted in reduced enantiose-
lectivity (39−44% ee; entries 6−9). The lack of aromatic
phosphine substituents may preclude necessary π-stacking
interactions required to induce good ee.
The enantioselectivity (up to 75% ee) provided by Ir−
Clickphine complexes for terminal disubstituted alkenes is
lower than that provided by iridium catalysts based on
ThrePHOX (up to 94% ee),33 phosphinite−oxazole (up to
97% ee),34 and phosphite−oxazoline ligands (up to 99%
ee)35,36 but shows the ability of these complexes to induce
significant enantioface discrimination for unfunctionalized
alkenes. It should be noted that despite the recent successful
examples cited above, many other iridium-based catalysts are
completely unselective or unreactive for this substrate.3,17
D
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suited for these substrates than the diisopropylphosphine-
containing derivatives 4e−h (R = Pr). A likely explanation is
Table 5. Hydrogenation of 2-(4′-Methoxyphenyl)-3-
methylbut-2-ene (9) by Ir−Clickphine Complexes 4a−h
a
i
the lack of π-stacking interactions with the substrate during the
enantioface selection in the latter case. The effects of the other
substituents (Ar1, Ar2, R′) on the enantioselectivity are more
subtle and vary for the different substrates, which demonstrates
the potential of fine-tuning of the catalyst by variation of these
substituents. Most importantly, we report the modular
synthesis of chiral Clickphine ligands by generating a small
library using an enantioselective propargylic amination step
based on one chiral Cu catalyst. The diversity in chirality
generated is important because it shows that different efficient
iridium catalysts can be made for various challenging
unfunctionalized alkenes. We now aim to expand the substrate
scope toward other substrates such as phosphinates, furans, and
imines with a larger and more diverse library of Clickphine
ligands.
b
c
entry
complex
conv. (%)
ee (%)
d
1
4a
4a
4b
4c
4d
4e
4f
5
51
84
68
98
98
99
98
84
57
78
82
72
87
56
60
43
49
2
2
3
4
5
6
7
8
4g
4h
a
Reaction conditions: 2.0 mol % 4, [4] = 1 mM, 50 bar H2, CH2Cl2, rt.
Conversion determined by GC after 20 h. Enantiomeric excess
b
c
EXPERIMENTAL SECTION
■
determined by chiral GC (Supelco β-DEX 225). In all cases the (−)
General Experimental Procedures. All of the reactions were
carried out under an atmosphere of argon using standard Schlenk
techniques. THF, pentane, hexane, and diethyl ether were distilled
from sodium benzophenone ketyl; CH2Cl2, isopropanol, and methanol
were distilled from CaH2; and toluene was distilled from sodium under
nitrogen. Except for the compounds given below, all of the reagents
were purchased from commercial suppliers and used without further
purification. The following compounds were synthesized according to
published procedures: DiPh-pybox40 and substrates 541 and 9.42 High-
resolution mass spectra were recorded on a four-sector mass
spectrometer; for FAB-MS, 3-nitrobenzyl alcohol was used as the
matrix.
d
enantiomer was obtained as the major product. 1.0 mol % 4a.
phine-based complexes 4e−h give lower ee’s but good
conversion (43−60% ee, 84−99% conversion; entries 6−9).
There are only few reports of efficient iridium catalysts for
the hydrogenation of tetrasubstituted alkenes. Co and Kim37
reported 88% ee at 22% conversion after 24 h for the
hydrogenation of 9 with an iminophosphoranylferrocene
ligand. Pfaltz and co-workers have published several efficient
catalysts for this substrate that give up to 92% ee and full
conversion at 50 bar.23,38,39 In the light of these precedents, the
performance of Ir−Clickphine catalyst 4d can be considered
among the best reported to date for this substrate.
General Procedure A: Cu-Catalyzed Propargylic Amination
with in Situ Cycloaddition. Copper iodide (0.05 equiv) and 2,6-
bis((4R,5S)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine (DiPh-
pybox) (0.055 equiv) were suspended in methanol. The mixture was
stirred for 20 min before addition of a solution of the propargylic
acetate (1 equiv) in methanol. At the indicated temperature (between
−20 and 0 °C), a solution of nucleophile (2 equiv) and DIPEA (4
equiv) in methanol was added. The suspension was stirred until TLC
analysis indicated complete conversion of the propargylic acetate.
When the reaction was finished, a solution of azide (1 equiv) in
methanol was added to the mixture. After full consumption of the
acetylene, filtration or evaporation gave the crude product. Silica gel
chromatography (typically a small percentage of MeOH in CH2Cl2)
gave the pure product.
CONCLUSION
■
We report here for the first time a catalytic strategy to generate
libraries of chiral ligands using one chiral parent complex. The
strategy is based on CuI-catalyzed enantioselective propargylic
amination, in situ copper-catalyzed cycloaddition, and sub-
sequent condensation with the phosphorus precursor to yield
chiral Clickphine P,N-ligands. The scope of the reaction was
investigated, and it was found that the protocol allows for
substantial variation of the substituents, giving good yields
(17−63%) and excellent ee’s after crystallization (94−99% ee)
for triazolyl amines 2a−f. Limitations arise only if the
enantioselective step does not proceed with sufficient selectivity
and the product cannot be further enantiomerically purified by
recrystallization. The triazolyl amines were transformed into the
corresponding P,N-ligands 3a−h after deprotonation with n-
BuLi and reaction with the corresponding phosphorus chloride,
and these ligands were reacted immediately to form Ir−
Clickphine complexes. This resulted in a one-pot synthesis of a
library of Ir−Clickphine complexes 4a−h in good overall yields
(52−67%). Iridium complexes 4a−h are active catalysts for the
asymmetric hydrogenation of di-, tri-, and tetrasubstituted
unfunctionalized alkenes, providing enantioselectivities of up to
90% ee. The catalysts are especially suited for notoriously
unreactive tetrasubstituted substrates. Up to 87% ee was
obtained in the hydrogenation of 9, which is among the highest
selectivities reported for this substrate. Furthermore, the
catalyst screening results indicate that complexes based on a
diphenylphosphine donor group (4a−d, R = Ph) are better
(S)-2-Methoxy-N-(phenyl(1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-
aniline (2a). General procedure A was followed with the enantiomer
of the ligand. 1-Phenylprop-2-ynyl acetate (1a) (35 mg, 0.20 mmol)
was added to the catalyst suspension, which was cooled to 0 °C before
the mixture of o-anisidine (45 μL, 0.4 mmol) and DIPEA was added.
After 5 h of stirring, phenyl azide (24 μL, 0.22 mmol) was added at
room temperature. The mixture was stirred for an additional 22 h. The
residue obtained after filtration contained the product and some
ligand. Silica gel chromatography (EtOAc/PE 1:1) afforded product
2a as a white solid (65 mg, 91% yield, 84% ee). Recrystallization from
EtOAc gave white crystals (45 mg, 63% yield, >99.5% ee). [α]2D0 +2 (c
0.5, CHCl3). HPLC conditions: Chiralcel AD (4.6 mm × 250 mm),
1
85:15 heptane/HOi-Pr, 1.0 mL/min, λ = 254 nm. H NMR (400
MHz; CDCl3): δ (ppm) = 7.73 (d, J = 0.3 Hz, 1H), 7.68 (d, J = 7.3
Hz, 2H), 7.56−7.31 (m, 8H), 6.83−6.70 (m, 3H), 6.53 (d, J = 7.7 Hz,
1H), 5.82 (d, J = 3.7 Hz, 1H), 5.27 (d, J = 3.6 Hz, 1H), 3.88 (s, 1H).
13C{1H} NMR (101 MHz; CDCl3): δ (ppm) = 151.4, 147.1, 141.7,
137.1, 137.0, 129.7, 129.0, 128.8, 127.9, 127.2, 121.1, 120.5, 120.0,
117.5, 111.4, 109.4, 55.6, 55.5. FTIR (film, cm−1): 3428 (m), 3143
(w), 3064 (m), 2835 (w), 1600 (s), 1509 (s), 1458 (s), 1424 (m),
1343 (m), 1224 (s), 1128 (m), 1039 (m), 910 (m). Anal. Calcd for
C22H20N4O: C, 74.14; H, 5.66; N, 15.72. Found: C, 74.07; H, 5.71; N,
E
DOI: 10.1021/acs.joc.5b00438
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The Journal of Organic Chemistry
Article
15.64. HRMS (FAB+) m/z: [M + H]+ calcd for C22H21N4O 357.1715;
found 357.1716.
(S)-N-(Phenyl(1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-
methyl)aniline (2e). General procedure A was followed with the
enantiomer of the ligand. The starting material was 1-phenylprop-2-
ynyl acetate (174 mg, 1.0 mmol), and the total amount of MeOH was
10 mL. As the nucleophile, aniline (182 μL, 2.0 mmol) was used. After
6 h of stirring at 0 °C, 1-azido-4-(trifluoromethyl)benzene (187 mg,
1.0 mmol) was added, and the mixture was stirred for 22 h before the
solvent was evaporated. Silica gel column chromatography (EtOAc/PE
(1:4) with 10−20% CH2Cl2 to prevent crystallization) gave 2e in good
yield (353 mg, 90% yield, 84% ee). Recrystallization from EtOAc/c-
hexane for one night gave the enantioenriched product (266 mg, 68%
yield, 94% ee). [α]2D0 +10 (c 1.0, CHCl3); mp (single enantiomer) 162
°C. HPLC conditions: Chiralcel AD (4.6 mm × 250 mm), 80:20
heptane/HOi-Pr, 1.0 mL/min, λ = 254 nm, 29.4 min (minor isomer),
(R)-2-Methoxy-N-((4-methoxyphenyl)(1-phenyl-1H-1,2,3-triazol-
4-yl)methyl)aniline (2b). General procedure A was followed. The
starting material was 1-(4-methoxyphenyl)prop-2-ynyl acetate (612
mg, 3.0 mmol), and the total amount of MeOH was 25 mL. As the
nucleophile, o-anisidine (680 μL, 6.0 mmol) was used. After 7 h,
slowly warming from −18 to 0 °C, phenyl azide (357 mg, 3.0 mmol)
was added, and the mixture was stirred for 17 h before the filtration
was performed. Silica gel column chromatography (gradient: 0.5 to
2.0% MeOH in CH2Cl2) gave 2b in good yield (863 mg, 75% yield,
82% ee). Two recrystallization steps from EtOAc gave the enantiopure
product (270 mg, 23% yield, >99.5% ee). [α]2D0 −26 (c 0.5, CHCl3);
mp (single enantiomer) 160−162 °C. HPLC conditions: Chiralcel AD
(4.6 mm × 250 mm), 80:20 heptane/HOi-Pr, 1.0 mL/min, λ = 254
1
34.6 min (major isomer). H NMR (400 MHz; CDCl3): δ (ppm) =
1
7.84 (d, J = 8.7 Hz, 2H), 7.77−7.75 (m, 3H), 7.52 (d, J = 8.7 Hz, 2H)
7.41−7.30 (m, 3H), 7.17−7.13 (m, 2H), 6.74 (t, J = 7.3 Hz, 1H), 6.65
(d, J = 7.9 Hz, 2H), 5.80 (d, J = 2.8 Hz, 1H), 4.77 (br s, 1H). 13C{1H}
NMR (101 MHz; CDCl3): δ (ppm) = 151.7, 146.9, 141.3, 139.4,
nm, 20 min (major isomer), 48 min (minor isomer). H NMR (400
MHz; CDCl3): δ (ppm) = 7.72−7.67 (m, 3H), 7.50−7.46 (m, 2H),
7.43−7.40 (m, 3H), 6.92−6.89 (m, 2H), 6.81−6.69 (m, 3H), 6.53−
6.50 (m, 1H), 5.73 (s, 1H), 5.2 (br s, 1H), 3.87 (s, 3H), 3.80 (s, 3H).
13C{1H} NMR (101 MHz; CDCl3): δ (ppm) = 159.2 (Cq), 151.7
(Cq), 147.1 (Cq), 137.1 (Cq), 137.0 (Cq), 133.7 (Cq), 129.7, 128.7,
128.4, 121.1, 120.5, 120.0, 117.4, 114.4, 111.4, 109.4, 55.5, 55.3, 55.0.
HRMS (FAB+) m/z: [M + H]+ calcd for C23H23N4O2 387.1821;
found 387.1817.
130.8 (q, J = 33.2 Hz), 129.3, 129.2, 128.2, 127.3, 127.2 (q, JCF
=
CF
3.7 Hz), 123.6 (q, JCF = 272.3 Hz), 120.5, 119.9, 118.5, 113.9, 55.8.
HRMS (FAB+) m/z: [M + H]+ calcd for C22H18F3N4 395.1484, found
395.1485.
(R)-2-Methoxy-N-(2-naphthyl(1-phenyl-1H-1,2,3-triazol-4-yl)-
methyl)aniline (2f). General procedure A was followed. The starting
material was 1-(2-naphthyl)prop-2-ynyl acetate (300 mg, 1.3 mmol),
and the total amount of MeOH was 20 mL. As the nucleophile, o-
anisidine (302 μL, 2.7 mmol) was used. After 16 h, slowly warming
from −18 to 0 °C, phenyl azide (160 mg, 1.3 mmol) was added, and
the mixture was stirred for 17 h before the filtration was performed.
The crude product was washed with cold MeOH and recrystallized
from EtOAc to give enantiomerically pure white crystals (260 mg, 48%
yield, 98% ee). [α]2D0 −23 (c 1.0, CHCl3); mp (single enantiomer)
187−191 °C. HPLC conditions: Chiralcel AD (4.6 mm × 250 mm),
(S)-N-((1-Benzyl-1H-1,2,3-triazol-4-yl)(phenyl)methyl)aniline (2c).
General procedure A was followed with the enantiomer of the ligand.
The starting material was 1-phenylprop-2-ynyl acetate (348 mg, 2.0
mmol), and the total amount of MeOH was 25 mL. As the
nucleophile, aniline (365 μL, 4.0 mmol) was used. After 6 h, slowly
warming from −18 to 10 °C, benzyl azide (251 μL, 2.0 mmol) was
added, and the mixture was stirred for 17 h before the solvent was
evaporated. Silica gel column chromatography (gradient: 0.8% MeOH
in CH2Cl2) gave 2c in good yield (512 mg, 75% yield, 85% ee).
Recrystallization from EtOAc (two portions, 406 mg, 89% ee) and
stirring in CH2Cl2/c-hexane (3:1) and, after filtration, again in
CH2Cl2/c-hexane (1:1) gave the almost enantiopure product (115 mg,
17% yield, 99% ee). [α]2D0 −1 (c 0.25, CHCl3); mp (single enantiomer)
175−178 °C. HPLC conditions: Chiralcel AD (4.6 mm × 250 mm),
80:20 heptane/HOi-Pr, 0.8 mL/min, λ = 254 nm, 28 min (minor
1
80:20 heptane/HOi-Pr, 1.0 mL/min, λ = 254 nm. H NMR (400
MHz; CDCl3): δ (ppm) = 8.02 (s, 1H), 7.87 (m, 3H), 7.75−7.62 (m,
4H), 7.58−7.46 (m, 4H), 7.43 (d, J = 7.3 Hz, 1H), 6.83 (dd, J = 7.5,
1.8 Hz, 1H), 6.80−6.66 (m, 2H), 6.56 (dd, J = 7.3, 1.8 Hz, 1H), 5.96
(d, J = 3.7 Hz, 1H), 5.36 (d, J = 3.6 Hz, 1H), 3.92 (s, 3H). 13C{1H}
NMR (126 MHz; CDCl3): δ (ppm) = 133.6 (Cq), 133.3 (Cq), 129.8,
129.0, 128.8, 128.2, 127.8, 126.40, 126.25, 126.17, 125.3, 121.2, 120.7,
55.6. HRMS (FAB+) m/z: [M + H]+ calcd for C26H23N4O 407.1872,
found 407.1878.
General Procedure B: Synthesis of Phosphinotriazole
Ligands 3. To a solution of triazolyl amine (R)-2 (1 equiv) in
THF (50 mM) at −78 °C was added n-BuLi (2.5 M in hexanes, 1.05
equiv), and the resulting yellow solution was stirred for 15 min. The
corresponding phosphorus chloride (1.05 equiv, Ph2PCl for 3a−d and
iPr2PCl for 3e−f) was added, and the solution was stirred for 1 h while
1
isomer), 31 min (major isomer). H NMR (400 MHz; CDCl3): δ
(ppm) = 7.44 (d, J = 8.5 Hz, 2H), 7.37−7.19 (m, 8H), 7.16 (s, 1H),
7.13−7.09 (m, 2H), 6.70 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 7.7 Hz, 2H),
5.69 (d, J = 4.0 Hz, 1H), 5.49 (A of AB, d, J = 15.0 Hz, 1H), 5.42 (B of
AB, d, J = 15.0 Hz, 1H), 4.80 (d, J = 3.6 Hz, 1H). 13C{1H} NMR (101
MHz; CDCl3): δ (ppm) = 150.8 (Cq), 147.1 (Cq), 141.8 (Cq), 134.7
(Cq), 129.2 (4C), 129.0, 128.8, 128.0, 127.8, 127.1, 121.7, 118.1,
113.9, 55.7, 54.3. HRMS (FAB+) m/z: [M + H]+ calcd for C22H21N4
341.1766, found 341.1765.
(R)-2-Methoxy-N-((1-benzyl-1H-1,2,3-triazol-4-yl)(phenyl)-
methyl)aniline (2d). General procedure A was followed. The starting
material was 1-phenylprop-2-ynyl acetate (1.0 g, 5.7 mmol), and the
total amount of MeOH was 50 mL. As the nucleophile, o-anisidine
(1.3 mL, 11.5 mmol) was used. After 16 h, slowly warming from −18
to 10 °C, benzyl azide (717 μL, 5.7 mmol) was added, and the mixture
was stirred for 17 h. The resulting suspension was concentrated to a
volume of ca. 15 mL and cooled to 0 °C. Filtration of the suspension
gave an off-white solid, which was recrystallized from EtOAc to yield a
white crystalline solid (1.05 g, 49% yield, >99.5% ee). [α]2D0 +5 (c 1.0,
CHCl3); mp (single enantiomer) 155 °C. HPLC conditions: Chiralcel
AD (4.6 mm × 250 mm), 80:20 heptane/HOi-Pr, 1.0 mL/min, λ =
being allowed to warm to rt. Formation of the phosphinotriazole was
checked by unlocked 31P NMR spectroscopy, which showed
resonances at 56−60 and 135−138 ppm for 3a−d and 3e−f,
respectively. Evaporation of the solvent in vacuo yielded a white
foam, which was directly used without further purification for
complexation with iridium.
General Procedure C: Synthesis of Iridium Complexes 4. The
corresponding phosphinotriazole (1 equiv) and [IrCl(cod)]2 (0.5
equiv) were stirred in dichloromethane at rt for 1.5 h. NaBArF (1.25
equiv) and H2O (10 mL) were added, and the heterogeneous mixture
was stirred vigorously for 10 min. The aqueous phase was removed
and extracted with dichloromethane (2 × 10 mL). The combined
organic phases were washed with H2O (10 mL), dried over MgSO4,
and filtered, and the solvent was removed in vacuo. Purification by
flash SiO2 chromatography (CH2Cl2) gave the product as a brown or
red solid.
1
254 nm, 17 min (major isomer), 32 min (minor isomer). H NMR
(400 MHz, CDCl3) δ (ppm) = 7.45 (d, J = 7.5 Hz, 2H), 7.39−7.34
(m, 5H), 7.31 (d, J = 7.6 Hz, 1H), 7.26−7.17 (m, 3H), 6.79 (dd, J =
7.6, 1.7 Hz, 1H), 6.71 (m, 2H), 6.45 (dd, J = 7.6, 1.7 Hz, 1H), 5.71 (d,
J = 4.1 Hz, 1H), 5.52 (A of AB, d, J = 15.0 Hz, 1H), 5.46 (B of AB, d, J
= 15.0 Hz, 1H), 5.19 (d, J = 4.2 Hz, 1H), 3.86 (s, 3H). 13C{ 1H} NMR
(126 MHz; CDCl3): δ (ppm) = 134.7 (Cq), 129.2, 128.95, 128.80,
128.1, 127.8, 127.3, 121.1, 55.5. HRMS (FAB+) m/z: [M + H]+ calcd
for C23H23N4O 371.1872, found 371.1871.
Complex 4a. According to general procedure C, ligand (R)-3a (144
mg, 0.26 mmol), [IrCl(cod)]2 (87 mg, 0.13 mmol), NaBArF (292 mg,
0.33 mmol), and 15 mL of CH2Cl2 were used to give the complex as
an orange-red solid (233 mg, 53% yield). [α]2D0 +51 (c 0.5, CHCl3). 1H
NMR (400 MHz; CDCl3): δ (ppm) = 8.07 (s, 1H), 7.88 (br s, 2H),
F
DOI: 10.1021/acs.joc.5b00438
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The Journal of Organic Chemistry
Article
7.78−7.70 (br m, 10H), 7.57−7.49 (br m), 7.46−7.38 (m, 2H), 7.38−
7.30 (m, 2H), 7.29−7.22 (m, 2H), 7.22−7.15 (m, 2H), 7.14 (t, J = 7.6
Hz, 1H), 6.95−6.78 (m, 3H), 6.71 (br t, J = 7.3 Hz, 1H), 6.45 (d, J =
8.1 Hz, 1H), 6.24 (br s, 1H), 5.78 (br d, JHP = 22.3 Hz, 1H), 5.18 (br s,
1H), 3.27 (br s, 1H), 2.75 (s, 3H), 2.60−2.47 (m, 1H), 2.47−2.36 (m,
2H), 2.36−2.23 (m, 2H), 2.22−1.98 (m, 3H), 1.93−1.76 (m, 1H).
13C{1H} NMR (101 MHz; CDCl3): δ (ppm) = 162.0 (q, JCB = 49.9
Hz, 4C, Cq), 156.3 (Cq), 148.6 (d, JCP = 5.4 Hz, Cq), 135.6 (Cq),
135.3, 135.1 (br, 8C), 134.1 (Cq), 132.4, 132.3, 132.0, 131.8 (Cq),
2.12−2.09 (m, 1H), 2.06−2.01 (m, 1H), 1.86−1.83 (m, 1H), 1.77 (m,
1H). 13C{1H} NMR (126 MHz; CDCl3): δ (ppm) = 161.9 (q, JCB
=
49.8 Hz, Cq), 156.2 (Cq), 148.6 (Cq), 135.4 (Cq), 134.9, 133.4 (Cq),
133.0 (Cq), 132.2 (br), 132.0 (d, JCP = 2.1 Hz), 131.6, 131.5 (Cq),
131.3 (d, JCP = 1.9 Hz), 131.2 (Cq), 130.7, 130.6 (Cq), 130.0 (Cq),
129.8, 129.6, 129.0 (qq, JCF = 31.5 Hz, JCB = 2.8 Hz, Cq), 128.3, 128.2
(d, JCP = 1.5 Hz), 128.02, 127.98, 127.94 (Cq), 127.89, 127.7 (d, JCP
=
6.1 Hz), 127.2 (br), 126.2, 125.8 (Cq), 123.6 (Cq), 121.8, 121.4 (Cq),
121.2, 120.7, 117.6 (septuplet, JCF = 4.0 Hz), 112.3, 97.4 (d, JCP = 10.0
Hz), 91.8 (br), 69.3, 65.7, 65.1 (d, JCP = 13.9 Hz), 54.4, 32.7, 32.1,
29.8, 29.5. 31P{1H} NMR (202 MHz; CDCl3): δ (ppm) = 57.79 (s).
HRMS (FAB+) m/z: [M − BArF]+ calcd for C46H43IrN4OP 891.2933,
found 891.26931.
131.5, 131.4, 131.2 (Cq), 131.0 (Cq), 130.8, 130.4 (Cq), 129.8 (d, JCP
=
2.6 Hz), 129.5, 129.2 (qq, JCF = 31.5 Hz, JCB = 2.7 Hz, Cq), 128.4,
128.3 (d, JCP = 11.0 Hz), 128.0 (d, JCP = 11.3 Hz), 124.8 (q, JCF = 273
Hz, Cq), 121.8, 121.2, 120.8, 117.6 (q, JCB = 3.5 Hz, 4C), 112.3, 97.3
(d, JCP = 10.5 Hz), 92.7 (br), 69.1 (br), 65.5 (br), 65.5 (d, JCP = 13.6
Hz), 54.5, 33.2, 31.9, 30.0, 29.2. 31P{1H} NMR (162 MHz; CDCl3): δ
(ppm) = 55.9 (s). HRMS (FAB+) m/z: [M − BArF]+ calcd for
C42H41IrN4OP 841.2647, found 841.2651.
Complex 4e. According to general procedure C, ligand (R)-3e (103
mg, 0.22 mmol), [IrCl(cod)]2 (73 mg, 0.11 mmol), NaBArF (248 mg,
0.28 mmol), and 10 mL of CH2Cl2 were used to give the complex as a
brown solid (186 mg, 52% yield). [α]2D0 −6 (c 1.0, CHCl3); decomp.
1
90−95 °C. H NMR (500 MHz; CDCl3): δ (ppm) = 8.13 (s, 1H),
Complex 4b. According to general procedure C, ligand (R)-3b (128
mg, 0.22 mmol), [IrCl(cod)]2 (74 mg, 0.11 mmol), NaBArF (244 mg,
0.28 mmol), and 15 mL of CH2Cl2 were used to give the complex as a
red solid (254 mg, 67% yield). [α]2D0 +13 (c 1.0, CHCl3); decomp.
7.70 (m, 10H), 7.61−7.52 (m, 6H), 7.49 (d, J = 16.1 Hz, 4H), 7.32−
7.28 (m, 2H), 6.98−6.95 (m, 2H), 6.86 (q, J = 7.7 Hz, 1H), 6.76 (d, J
= 7.1 Hz, 1H), 5.93 (br s, 1H), 5.14 (d, JHP = 20.1 Hz, 1H), 5.03 (br s,
1H), 4.68 (br s, 1H), 4.57 (br s, 1H), 3.81 (s, 3H), 3.55−3.49 (m,
1H), 3.23−3.18 (m, 1H), 2.90−2.71 (m, 4H), 2.64−2.61 (m, 1H),
2.38−2.35 (m, 1H), 2.13−2.01 (m, 4H), 1.86−1.75 (m, 1H), 1.11 (dd,
J = 19.4, 6.7 Hz, 3H), 0.72−0.67 (dd, J = 17.1, 6.6 Hz, 3H), 0.51−0.42
(m, 3H). 13C{1H} NMR (126 MHz; CDCl3): δ (ppm) = 161.8 (q, JCB
1
100−105 °C. H NMR (500 MHz; CDCl3): δ (ppm) = 8.02 (s, 1H),
7.78 (br s, 2H), 7.70 (s, 10H), 7.55−7.53 (m, 3H), 7.49 (s, 5H), 7.42−
7.34 (m, 5H), 7.28 (d, J = 6.3 Hz, 2H), 7.17 (br s, 2H), 7.11 (t, J = 7.3
Hz, 1H), 7.04 (d, J = 8.3 Hz, 2H), 6.92−6.90 (m, 3H), 6.70−6.69 (m,
1H), 6.42 (d, J = 8.3 Hz, 1H), 6.21 (br s, 1H), 5.72 (br s, 1H), 5.13 (br
s, 1H), 3.89 (s, 3H), 3.26 (br s, 1H), 2.72 (s, 3H), 2.42−2.37 (m, 2H),
2.31−2.28 (m, 2H), 2.15−2.05 (m, 4H), 1.84 (br s, 1H). 13C{1H}
NMR (126 MHz; CDCl3): δ (ppm) = 161.9 (q, JCB = 49.9 Hz, Cq),
160.6 (Cq), 135.45 (Cq), 134.9, 132.0, 131.5, 131.3, 130.7, 129.7, 129.0
(qq, JCF = 31.5 Hz, JCB = 2.7 Hz, Cq), 128.3 (d, JCP = 10.5 Hz), 127.9
(Cq), 125.8 (Cq), 123.6 (Cq), 121.4 (Cq), 121.1, 120.7, 117.6
= 49.9 Hz, Cq), 140.2 (Cq), 138.0, 136.0 (Cq), 134.9, 131.1 (d, JCP
6.7 Hz), 130.8, 130.7, 130.5 (d, JCP = 5.0 Hz), 130.4, 129.0 (qq, JCF
=
=
31.5 Hz, JCB = 2.8 Hz, Cq), 128.4 (d, JCP = 7.6 Hz), 127.9 (Cq), 126.7,
125.8 (Cq), 125.0, 123.6 (Cq), 121.4 (Cq), 120.7 (d, JCP = 8.3 Hz),
120.5, 117.6 (septuplet, JCF = 4.0 Hz), 101.5 (d, JCP = 9.9 Hz), 94.5,
91.8 (d, JCP = 13.9 Hz), 91.3, 85.0 (d, JCP = 23.9 Hz), 54.6, 34.3, 30.3
(d, JCP = 38.8 Hz), 27.9, 27.4, 22.5, 18.7, 16.7 (d, JCP = 37.2 Hz), 14.2.
31P{1H} NMR (202 MHz; CDCl3): δ (ppm) = 58.37 (s). HRMS
(FAB+) m/z: [M − BArF]+ calcd for C36H45IrN4OP 773.3088, found
773.3082.
(septuplet, JCF = 4.0 Hz), 114.6, 112.1 (br), 97.1 (br), 64.7 (d, JCP
=
13.7 Hz), 55.7, 54.4, 29.9, 29.3. 31P{1H} NMR (202 MHz; CDCl3): δ
(ppm) = 56.5 (s). HRMS (FAB+) m/z: [M − BArF]+ calcd for
C43H43IrN4O2P 871.2882, found 871.2879.
Complex 4c. According to general procedure C, ligand (R)-3c (162
mg, 0.29 mmol), [IrCl(cod)]2 (97 mg, 0.15 mmol), NaBArF (319 mg,
0.36 mmol), and 15 mL of CH2Cl2 were used to give the complex as
an orange solid (303 mg, 61% yield). [α]2D0 +19 (c 1.0, CHCl3);
decomp. 85−90 °C. 1H NMR (500 MHz; CDCl3): δ (ppm) = 7.83 (s,
10H), 7.59 (s, 4H), 7.57 (s, 1H), 7.55 (d, J = 6.9 Hz, 3H), 7.43−7.40
(m, 4H), 7.39 (br s, 1H), 7.35 (m, 4H), 7.29 (td, J = 7.7, 2.6 Hz, 2H),
7.21 (t, J = 6.7 Hz, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.91 (br s, 3H), 6.71
(t, J = 7.5 Hz, 1H), 6.40 (d, J = 8.2 Hz, 1H), 6.23 (br s, 1H), 5.75 (A
of AB, d, J = 14.5 Hz, 1H), 5.62 (br m, 1H, CH), 5.49 (B of AB, d, J =
14.5 Hz, 1H), 5.13 (br s, 1H), 3.25 (br s, 1H), 2.50 (br s, 1H), 2.44 (s,
3H), 2.42−2.32 (m, 4H), 2.19−2.18 (m, 1H), 2.06 (m, 2H), 1.84−
1.82 (m, 1H). 13C{1H} NMR (126 MHz; CDCl3): δ (ppm) = 161.9
Complex 4f. According to general procedure C, ligand (R)-3f (100
mg, 0.20 mmol), [IrCl(cod)]2 (67 mg, 0.10 mmol), NaBArF (222 mg,
0.25 mmol), and 10 mL of CH2Cl2 were used to give the complex as a
brown solid (200 mg, 60% yield). [α]2D0 +9 (c 1.0, CHCl3); decomp.
1
90−94 °C. H NMR (500 MHz; CDCl3): δ (ppm) = 8.10 (s, 1H),
7.70 (s, 8H), 7.60−7.52 (m, 4H), 7.51 (s, 4H), 7.28 (d, J = 8.7 Hz,
1H), 7.12 (br s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.92−6.85 (m, 3H),
6.79 (d, J = 8.5 Hz, 1H), 6.75−6.67 (m, 1H), 6.49 (d, J = 8.2 Hz, 1H),
5.87 (br s, 1H), 5.11 (d, JHP = 19.7 Hz, 1H), 5.02 (br s, 1H), 4.67 (br
s, 1H), 4.57 (br s, 1H), 3.82−3.66 (m, 8H), 3.57−3.53 (m, 1H), 3.24−
3.19 (m, 1H), 2.90−2.62 (m, 4H), 2.12−2.01 (m, 3H), 1.79−1.78 (m,
1H), 1.12 (dd, J = 18.8, 6.7 Hz, 3H), 0.89−0.84 (m, 1H), 0.77 (dd, J =
17.3, 6.5 Hz, 3H), 0.50−0.42 (m, 3H). 13C{1H} NMR (126 MHz;
CDCl3): δ (ppm) = 161.8 (q, JCB = 50.0 Hz, Cq), 158.9 (Cq), 136.0
(Cq), 134.9, 133.4 (Cq), 131.1, 130.8, 130.5 (d, JCP = 5.3 Hz), 129.0
(qq, JCF = 31.5 Hz, JCB = 2.8 Hz, Cq), 127.9 (Cq), 127.2, 125.8 (Cq),
125.0, 123.6 (Cq), 121.4 (Cq), 120.5, 117.6 (septuplet, JCF = 4.0 Hz),
112.6, 108.4, 101.4, 94.5, 91.7 (d, JCP = 13.7 Hz), 91.3, 55.3, 54.6 (2C
missing, probably of the cod ligand). 31P{1H} NMR (202 MHz;
CDCl3): δ (ppm) = 58.18 (s). HRMS (FAB+) m/z: [M − BArF]+
calcd for C37H47IrN4O2P 803.3194, found 803.3194.
(q, JCB = 50.0 Hz, Cq), 156.1 (Cq), 135.0, 132.2 (Cq), 131.9 (d, JCP
=
2.5 Hz), 131.7 (Cq), 131.3 (d, JCP = 1.6 Hz), 131.2 (Cq), 130.3, 129.9,
129.6 (d, JCP = 2.7 Hz), 129.3, 129.0 (qq, JCF = 31.4 Hz, JCB = 2.8 Hz,
Cq), 128.4, 128.3, 128.2, 128.0 (Cq), 127.8 (d, JCP = 12.0 Hz), 125.8
(Cq), 123.6 (Cq), 121.5 (Cq), 121.0, 117.6 (septuplet, JCF = 4.0 Hz),
112.0, 97.1 (d, JCP = 10.3 Hz), 68.5 (br), 65.2 (br), 65.0 (d, JCP = 13.5
Hz), 56.3, 53.9, 33.3, 31.6, 30.2, 29.1. 31P{1H} NMR (202 MHz;
CDCl3): δ (ppm) = 57.10 (s). HRMS (FAB+) m/z: [M − BArF]+
calcd for C43H43IrN4OP 855.2933, found 855.2924.
Complex 4g. According to general procedure C, ligand (R)-3g (143
mg, 0.29 mmol), [IrCl(cod)]2 (97 mg, 0.15 mmol), NaBArF (319 mg,
0.36 mmol), and 15 mL of CH2Cl2 were used to give the complex as a
brown solid (286 mg, 60% yield). [α]2D0 −5 (c 1.0, CHCl3); decomp.
Complex 4d. According to general procedure C, ligand (R)-3d (83
mg, 0.14 mmol), [IrCl(cod)]2 (47 mg, 0.07 mmol), NaBArF (160 mg,
0.18 mmol), and 10 mL of CH2Cl2 were used to give the complex as
an orange solid (173 mg, 70% yield). [α]2D0 +6 (c 1.0, CHCl3);
1
80−84 °C. H NMR (500 MHz; CDCl3): δ (ppm) = 7.71 (m, 10H),
1
decomp. 98−106 °C. H NMR (500 MHz; CDCl3): δ (ppm) = 8.10
7.57 (s, 1H), 7.52−7.51 (m, 5H), 7.43 (t, J = 3.0 Hz, 2H), 7.36−7.35
(m, 2H), 7.21 (t, J = 8.0 Hz, 1H), 6.95−6.90 (m, 2H), 6.85 (d, J = 7.9
Hz, 2H), 6.81 (t, J = 7.7 Hz, 1H), 6.70−6.68 (m, 1H), 5.87−5.85 (m,
1H), 5.80 (A of AB, d, J = 14.4 Hz, 1H), 5.47 (B of AB, d, J = 14.4 Hz,
1H), 5.00 (br s, 1H), 4.95 (d, JHP = 20.2 Hz, 1H), 4.61 (m, 1H), 4.49−
4.45 (m, 1H), 3.36 (s, 3H), 3.15−3.13 (m, 1H), 2.85−2.70 (m, 4H),
2.58−2.55 (m, 1H), 2.07−1.99 (m, 2H), 1.74−1.72 (m, 1H), 1.08 (dd,
J = 19.1, 6.6 Hz, 3H), 0.89−0.86 (m, 1H), 0.65 (dd, J = 17.1, 6.5 Hz,
(s, 1H), 8.09−8.07 (m, 2H), 7.99 (d, J = 8.3 Hz, 1H), 7.94 (s, 1H),
7.84 (d, J = 7.9 Hz, 1H), 7.75−7.71 (m, 11H), 7.64 (t, J = 7.2 Hz, 1H),
7.60 (t, J = 6.8 Hz, 1H), 7.55 (m, 3H), 7.49 (s, 4H), 7.42 (d, J = 7.5
Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.36−7.30 (m, 2H), 7.21−7.15 (m,
4H), 6.99−6.94 (m, 3H), 6.75 (t, J = 7.5 Hz, 1H), 6.48 (d, J = 8.1 Hz,
1H), 6.31 (br s, 1H), 5.92 (d, JHP = 23.1 Hz, 1H), 5.21 (br s, 1H), 3.21
(br s, 1H), 2.74 (s, 3H), 2.47−2.35 (m, 3H), 2.28−2.22 (m, 2H),
G
DOI: 10.1021/acs.joc.5b00438
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3H), 0.34 (ddd, J = 21.4, 14.6, 6.9 Hz, 6H). 13C{1H} NMR (126 MHz;
CDCl3): δ (ppm) = 161.9 (q, JCB = 49.9 Hz, Cq), 155.5 (Cq), 140.2
(Cq), 137.9, 134.9, 133.4 (Cq), 132.9 (Cq), 130.2, 129.9, 129.8 (d, JCP
= 1.6 Hz), 129.0 (qq, JCF = 31.5 Hz, JCB = 2.8 Hz, Cq), 128.7, 128.5,
128.34, 128.30, 128.2, 128.1, 128.0 (Cq), 126.6, 125.8 (Cq), 124.9,
123.6 (Cq), 122.9 (d, JCP = 4.6 Hz), 121.5 (Cq), 121.4, 117.6
(septuplet, JCF = 4.0 Hz), 112.4, 101.0 (d, JCP = 10.3 Hz), 94.4, 91.4
(d, JCP = 14.1 Hz), 91.0, 84.7 (d, JCP = 15.0 Hz), 69.5 (d, J = 9.5 Hz),
56.4, 54.0, 38.0, 31.7, 30.2 (d, JCP = 38.8 Hz), 27.7, 27.5 (d, JCP = 34.6
Hz), 27.3, 18.6, 16.8 (d, JCP = 7.6 Hz), 16.5 (d, JCP = 3.8 Hz), 15.7.
31P{1H} NMR (202 MHz; CDCl3): δ (ppm) = 57.90 (s). HRMS
(FAB+) m/z: [M − BArF]+ calcd for C37H47IrN4OP 787.3245, found
787.3232.
g/cm3, μ = 0.08 mm−1. X-ray intensities were measured on a
diffractometer with a rotating anode (graphite monochromator, λ =
0.71073 Å) at a temperature of 150(2) K. The crystal appeared to be
twinned with a twofold rotation about hkl = (101) as the twin
̅
operation. This twin relationship was taken into account during the
integration with Eval1543 and absorption correction with the
TWINABS44 software (0.62−0.75 correction range). 16104 Reflec-
tions were obtained up to a resolution of ((sin θ)/λ)max = 0.61 Å−1.
Because of the absence of strong anomalous scatterers, the absolute
structure could not be determined reliably, and it was decided to
merge the Friedel pairs, resulting in 1994 unique reflections (Rint
=
0.052), of which 1785 were observed [I > 2σ(I)]. The structure was
solved with direct methods using SIR-97.45 Least-squares refinement
was performed with SHELXL-9746 on F2 for all reflections using an
HKLF5 reflection file.47 The absolute configuration was assigned
according to the enantiopure synthesis. Non-hydrogen atoms were
refined with anisotropic displacement parameters. Hydrogen atoms
were introduced in calculated positions. The N−H hydrogen atom was
refined freely with isotropic displacement parameters; all other
hydrogen atoms were refined as rigid groups. 259 parameters were
refined with 1 restraint. R1/wR2 [I > 2σ(I)]: 0.0354/0.0784. R1/wR2
[all reflns]: 0.0429/0.0821. S = 1.048. Twin fraction = 0.124(3).
Δρmin/max = −0.16/0.13 e/Å3. Drawings, structure calculations, and
checking for higher symmetry were performed with the PLATON
software.48
Complex 4h. According to general procedure C, ligand (R)-3h (72
mg, 0.14 mmol), [IrCl(cod)]2 (47 mg, 0.07 mmol), NaBArF (160 mg,
0.18 mmol), and 8 mL of CH2Cl2 were used to give the complex as a
brown solid (140 mg, 60% yield). [α]2D0 −8 (c 1.0, CHCl3); decomp.
1
97−100 °C. H NMR (500 MHz; CDCl3): δ (ppm) = 8.18 (s, 1H),
8.00 (s, 1H), 7.80−7.67 (m, 10H), 7.66−7.52 (m, 4H), 7.50−7.45 (m,
6H), 7.44−7.37 (m, 3H), 7.31−7.28 (m, 2H), 7.00 (d, J = 8.8 Hz,
2H), 6.86 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 7.8
Hz, 1H), 6.13−6.08 (m, 1H), 5.34 (d, JHP = 19.9 Hz, 1H), 5.08−5.05
(m, 1H), 4.73−4.70 (m, 1H), 4.64−4.57 (m, 1H), 3.84 (s, 3H), 3.31−
3.18 (m, 2H), 2.92−2.76 (m, 4H), 2.22−1.94 (m, 3H), 1.88−1.73 (m,
1H), 1.14 (dd, J = 19.5, 6.7 Hz, 3H), 0.69 (dd, J = 17.2, 6.6 Hz, 3H),
0.52 (dd, J = 16.5, 7.0 Hz, 3H), 0.46 (dd, J = 13.2, 7.1 Hz, 3H).
13C{1H} NMR (126 MHz; CDCl3): δ (ppm) = 161.8 (q, JCB = 49.8
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectral data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
Hz, Cq), 156.0 (Cq), 137.8 (Cq), 137.5, 136.9, 134.9, 133.9 (Cq), 133.3
(Cq), 132.2 (Cq), 131.11 (d, JCP = 9.7 Hz), 130.8, 130.5 (d, JCP = 5.1
Hz), 129.0 (qq, JCF = 31.5 Hz, JCB = 2.8 Hz, Cq), 128.3 (d, JCP = 4.0
Hz), 128.2, 127.9 (Cq), 127.3, 126.8, 126.4, 125.8 (Cq), 125.7, 124.4,
124.1, 123.6 (Cq), 122.9, 121.5, 121.4 (Cq), 120.72, 120.66, 120.56,
117.6 (septuplet, JCF = 4.0 Hz), 112.8, 112.6 (d, JCP = 26.8 Hz), 94.3,
91.4, 87.7, 85.0 (d, JCP = 24.0 Hz), 54.7, 35.6, 35.3, 29.9, 27.4, 19.1,
16.6, 15.9. 31P{1H} NMR (202 MHz; CDCl3): δ (ppm) = 59.04 (s).
HRMS (FAB+) m/z: [M − BArF]+ calcd for C40H47IrN4OP 823.3245,
found 823.3253.
General Procedure for Hydrogenation Experiments at High
Pressure. The hydrogenation experiments were carried out in a
Chemspeed Technologies Accelerator SLT workstation under inert
conditions. For a typical screening experiment, stock solutions of
complexes (R)-4a−h and the substrates were prepared and
subsequently mixed by the automated liquid handler. This procedure
resulted in catalyst and substrate concentrations of 1.0 and 50−100
mM, respectively, in the reactor. The hydrogenations were carried out
at a dihydrogen pressure of 50 bar at room temperature for 20 h.
Product samples were prepared directly after completion of the
program and analyzed by chiral GC or HPLC.
Hydrogenation of Alkene 5. 2-Phenylbutane. The ee was
determined by chiral GC analysis (Supelco β-DEX 225, isothermal
at 55 °C): tR = 35.9 min (R), tR = 36.5 min (S).
Hydrogenation of Alkene 7. 1,2-Diphenylpropane. The ee was
determined by chiral HPLC analysis (Chiralcel OJ-H, 0.8 mL min−1, n-
hexane/iPrOH 99.5:0.5 v/v): tR = 8.9 min (R), tR = 11.9 min (S).
Hydrogenation of Alkene 9. 2-(4-Methoxyphenyl)-3-methylbu-
tane. The ee was determined by chiral GC analysis (Supelco β-DEX
225, 50 °C, 1 °C min−1, 130 °C): tR = 66.4 min (major), tR = 67.1 min
(minor), tR = 72.6 min (substrate).
S
AUTHOR INFORMATION
Corresponding Authors
*E-mail: j.n.h.reek@uva.nl.
*E-mail: j.h.vanmaarseveen@uva.nl.
■
Present Address
∥J.W.: Total Research & Technology Feluy, Zone Industrielle
Feluy C, 7181 Seneffe, Belgium.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
NRSC-C and NWO-CW are gratefully acknowledged for
financial support. We thank J. W. H. Peeters for measuring
high-resolution mass spectra.
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