Application of Crabtree/Pfaltz-Type Iridium Complexes for the Catalyzed Asymmetric Hydrogenation of an Agrochemical Building Block

Article abstract of DOI:10.1021/acs.oprd.9b00466

Herein we report improved chemo- A nd enantioselective hydrogenations of 1-(2,2,4-trimethylquinolin-1(2H)-yl)ethan-1-one (1) toward (R)-1-(2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (2) using well-defined novel Crabtree-type iridium complexe

Full text of DOI:10.1021/acs.oprd.9b00466

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Communication
Application of Crabtree/Pfaltz-type iridium complexes for the catalyzed
asymmetric hydrogenation of an agrochemical building block
Jacob Schneekoenig, Weiping Liu, Thomas Leischner, Kathrin
Junge, Christoph Schotes, Christian Beier, and Matthias Beller
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00466 • Publication Date (Web): 20 Feb 2020
Downloaded from pubs.acs.org on February 24, 2020
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Application of Crabtree/Pfaltz-type iridium
complexes for the catalyzed asymmetric
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hydrogenation of an agrochemical building block
Jacob Schneekönig,†, ‡ Weiping Liu, §, ‡ Thomas Leischner, † Dr. Kathrin Junge, † Dr.
Christoph Schotes,ǁ Dr. Christian Beier , ǁ Prof. Dr. Matthias Beller †,*
†: Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Straße
29a, 18059 Rostock, Germany
§: College of Chemistry, Chemical Engineering and Biotechnology, Donghua University,
Shanghai, 201620, China.
ǁ: Bayer AG – CropScience Division - Product Supply – Active Ingredient Manufacturing
Innovation, Building A729, 41539 Dormagen, Germany
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Table of Content (TOC) Graphic
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Abstract: Herein we report improved chemo- and enantioselective hydrogenations of 1-
(2,2,4-trimethylquinolin-1(2H)-yl)ethan-1-one (1) towards (R)-1-(2,2,4-trimethyl-3,4-
dihydroquinolin-1(2H)-yl)ethan-1-one (2) using well-defined novel Crabtree-type iridium
complexes.
Keywords: Asymmetric hydrogenation; Alkene reduction; Catalyst design; Iridium
catalysis, Unactivated olefins; N-heterocycles
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Aminoindanes are important building blocks for the synthesis of aminoindane amides,
which were disclosed to be active compounds for the control of phytopathogenic fungi
(Scheme 1).1 First protocols for the preparation of this class of compounds were reported
in 1985 by the Sumitomo Chemical Company.2 Since then, the majority of commercially
available fungicides of this type were used as racemic mixtures. Since the individual
enantiomers usually have a different performance, an enantioselective synthesis is highly
desirable for efficiency and sustainability. Thus, first attempts to isolate enantiomerically
pure building blocks used crystallization of a diastereomeric salts with D-tartaric acid.3
Scheme 1. Selected example for the synthesis of an aminoindane amide fungicide.4
O
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H
N
H
H2
NH2
N
F
F
F
CF2H
COCl
N
N
F
F
O
HF2C
O
HF2C
Acid rearrangement
N
N
N
N
N
N
H
However, the asymmetric hydrogenation of 1-(2,2,4-trimethylquinolin-1(2H)-yl)ethan-1-
one would represent a much more elegant solution, as it offers advantageous features
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such as excellent atom-economy and quantitative yields as well as high levels of
stereoselectivity. Following this approach, a selective hydrogenation of the non-
functionalized tri-substituted alkene moiety has to be achieved. The selective
hydrogenation of such types of double bonds is still challenging and best results are
typically obtained applying chiral Crabtree/Pfaltz-type iridium complexes.5 Previously, it
was discovered that by replacing the established hexafluorophosphate anion with the
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weakly coordinating BArF anion enabled not only the use of catalyst loadings lower than
1 mol% but also provided a catalytic system less sensitive to moisture.6 Impressive
examples for the asymmetric hydrogenation using these complexes were the
hydrogenation of γ-tocotrienyl acetate,7 and the total synthesis of dimethyl
methoxycalamenene.8 Unfortunately, utilizing 1.25 mol% of the commercially available
complex [Ir(COD)ThrePHOX]BArF for the asymmetric hydrogenation of 1 to 2 resulted
only in 14% conversion and low enantioselectivity (31% ee) (Figure 1).9 Clearly, from an
industrial point of view, neither the activity nor the selectivity is suitable for any application.
In order to justify the use of an expensive iridium precursor, a lower catalyst loading and
a higher selectivity have to be achieved.
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BArF
Bn
BArF
Bn
O
O
O
O
Cy2P
[Ir], H2
N
O
N
N
Cy2P
N
Ir
Ir
Ph
2
1
Ir-ThrePHOX
TON = 11.2
This work
9
TON > 9000
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Figure 1. Crabtree/Pfaltz-type iridium complexes for the desired transformation.
Here, we report a state-of-the-art process for this transformation, which allows for the
first time a practical and industrial feasible synthesis of 2 and related building blocks via
asymmetric hydrogenation.
Results and Discussion
A preliminary catalyst screening using commercially available and tailor-made iridium
complexes revealed complex 5a as a benchmark catalyst (Figure 2).10 Notably, this type
of ligand was originally introduced by Pfaltz and co-workers for asymmetric hydrogenation
of olefins and furane derivatives.11
BArF
BArF
R1
O
R22P
O
tBu
2P
N
N
R3
Ir
Ir
5a
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Figure 2. Benchmark catalyst for the hydrogenation of 1.
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Initially, we started to investigate the influence of different substituents of 5a (indicated
by the R groups in Figure 2). Following the protocol by Pfaltz and co-workers, we started
synthesizing chiral pyridyl alcohols using the building blocks (R)-7-((tert-
butyldimethylsilyl)oxy)-2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (3a) and (S)-7-
((tert-butyldimethylsilyl)oxy)-2-chloro-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine (3b)
(Scheme 2).12 Eighteen different pyridyl alcohols were obtained overall in moderate to
good yields (4a-r) from the Suzuki reaction of 3a or 3b with the corresponding boronic
acids, followed by deprotection of the silyl ether.
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Scheme 2. Synthesis of chiral pyridyl alcohols.
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iPr
iPr
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2
CX 32
1) R -B(OH)2 (2 eq.),
(4 mol%),
OH
*
N
N
O Si
*
R2
N
NaOtBu (2.2 eq.), iPrOH, 60 °C, 24 h
N
Cl
iPr
iPr
Pd
2) TBAF, H2O (1 mL), THF, 75 °C, 16 h
Cl
R1
R1
1
4a r
-
3a
3b
: R = H
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yielda (yieldb)
1
: R = Me
CX 32
MeO
OH
OH
N
OH
OH
N
N
N
Me
4a
4b
4c
4d
79% (86%)
75% (82%)
71% (84%)
19% (43%)
tBu
F
MeO
F3C
OH
OH
N
OH
OH
N
N
N
Me
4e
4f
4g
4h
63% (80%)
65% (77%)
77% (82%)
76% (80%)
Me
tBu
OH
OH
N
OH
OH
Me
N
N
N
Me
Me
Me
Me
4i
4j
4k
4l
48% (57%)
46% (n.d.)
82% (85%)
25% (51%)
tBu
Me
MeO
Me
N
Me
OH
OH
OH
OH
tBu
N
N
N
Me
Me
Me
Me
4mc
Me
4nc
Me
4od
4p
51% (69%)
79% (86%)
81% (95%)
68% (82%)
iPr
tBu
iPr
N
Me
N
OH
OH
Me
iPr
Me
4qe
Me
4rc
58% (66%)
70% (85%)
a Isolated yield over two steps. Isolated yield of the Suzuki reaction is given. 3b (2
mmol), boronic acid (2.3 mmol), CX 32 (2 mol%), NaOH, i-PrOH, H2O, 115 °C, 48 h. d 3a
b
c
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(2 mmol), trimethylboroxine (1.5 eq.), (dppf)PdCl2 DCM (5 mol%), K2CO3 (3 eq.),
1,4-dioxane, 120 °C, 20 h. e 3b (1 mmol), (2,4,6-triisopropylphenyl)boronic acid (1.2 eq.),
7
8
Pd(PPh3)4 (15 mol%), K3PO4 (5.0 eq.), H2O (1.0 mL), DME (5.0 mL), 110 °C, 24 h.
9
For the majority of the boronic acids [1,3-bis(2,6-di-isopropylphenyl)-4,5-
dihydroimidazol-2-ylidene]chloro][3-phenylallyl]palladium(II) (CX 32) was found to be a
suitable pre-catalyst for the coupling step. However, for highly bulky boronic acids higher
temperatures and longer reaction times (4m, 4n and 4r) or even other palladium
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precursors ((dppf)PdCl2 DCM, 4o or Pd(PPh3)4, 4q) were necessary in order to obtain
decent product yields. Next, using these pyridyl alcohols, 22 different bench-stable iridium
pre-catalysts were synthesized via the corresponding phosphonites (Scheme 3).
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Scheme 3. Synthesis of iridium precatalysts.
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BArF
R1
[Ir(COD)2]BArF,
THF, 3 h, 50 °C
1) n-BuLi, THF, -78 °C to
O
R22P
OH
O PR2
2
r.t., 15 min
R3
N
N
R3
N
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9
2) R22PCl, THF, -78 °C to
50 °C, 16 h
R3
Ir
R1
R1
5a-r
4a-r
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1st generation
2nd generation
BArF
H
BArF
Me
BArF
BArF
Me
H
O
O
O
O
R2
R2
2P
2P
tBu
2P
tBu
2P
N
N
N
N
Ir
Ir
Ir
Ir
Ph
Ph
Ph
R3
: 71% R2 = Cy
: 54% R2 = Cy
3
5f
5a
5b
5c
5d
5e
: 44% R = Ph
: 39% R3 = p-MeO-Ph
: 39% R2 = iPr
: 75% R2 = Cyclopentyl
2
5g
5h
: 39% R = Et
3rd generation
: 78% R3 = napth-1-yl
: 64% R3 = p-tBu-Ph
5n
5o
5p
5q
5r
3
5i
5j
: 74% R = p-tBu-Ph
BArF
BArF
Me
3
: 85% R3 = 3,5-dimethyl-Ph
H
: 48% R = p-F3C-Ph
O
O
: 70% R3 = p-F-Ph
3
5k
5l
: 82% R = 2,6-dimethyl-Ph
: 40% R3 = 2,4,6-trimethyl-Ph
Cy
Cy
2P
2P
N
3
N
: 36% R = anthracen-9-yl
R3
: 73% R3 = Me
R3
Ir
Ir
3
5m
5s
: 78% R = anthracen-9-yl
: 42% R3 = 3,5-di-tBu-4-MeO-Ph
5t
:14% R3 = 2,4,6-tri-iPr-Ph
5u
5v
: 73% R3 = 2,6-di-Me-4-tBu-Ph
Then, we investigated the effect of the different pre-catalysts in the benchmark
hydrogenation of 1 (60 bar H2, 85 °C, 6-40 h, HFIP, 0.1-0.01 mol% Ir). In order to get a
fast insight into the catalytic behavior of the pre-catalysts and to avoid single
hydrogenation reactions, all experiments were performed in a six-fold parallel manner
(see SI). To our delight, in this “1st generation” screening a positive influence on the
reaction outcome was obtained by replacing the proton in four position (R1) of the pyridine
moiety with a methyl group (5a vs. 5b, Table 1, entries 2, 3). This observation was also
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confirmed by later examples (5d vs. 5f and 5l vs. 5s, Table 1, entries 6, 8, 15, 22). Next,
a set of complexes were synthesized in order to elucidate the influence of R2 groups on
the phosphorus atom (Scheme 3, “2nd generation”). Since aryl-substituted phosphinites
showed poor activity, we focused on alkyl phosphonites. Gratifyingly, when replacing the
tert-butyl groups on the phosphorus atom with cyclohexyl groups, an increased activity
and high enantioselectivity was observed (5b vs. 5f, Table 1, entries 4, 8) at low catalyst
loading (0.05 mol%). This result is in contrast to previous work by Pfaltz and co-workers,
using similar type of ligands for the hydrogenation of (E)-2-(4-methoxyphenyl)-2-butene.
Here, usually the tert-butyl substituted complexes gave significantly higher
enantioselectivities compared to the cyclohexyl-substituted ones.11a Inspired by the work
of Woodmansee et al.,11b we synthesized further complexes with less sterically
demanding alkyl groups on the phosphorus atom.13 However, the resulting complexes
were less active and also less selective compared to 5f (5e, 5g and 5h, Table 1, entries
7, 9, 10).
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Table 1. Hydrogenation results of 1.a,b
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O
O
O
[Ir], H2 (60 bar),
N
85 °C
N
N
or
6
7
HFIP (4 mL)
8
1
2 (R)
2 (S)
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Loading
Entry
Complex
Time [h]
Conv. [%]
TON
ee [%]
[mol%]
1
2
5a
5a
5b
5b
5c
5d
5e
5f
16
6
0.1
0.1
99.2
81.5
94.5
86.8
91.2
88.2
30
992
815
98.0 (R)
97.5 (R)
97.5 (R)
97.6 (R)
97.0 (R)
97.6 (S)
90.0 (S)
97.3 (R)
96.0 (R)
95.8 (R)
96.8 (S)
3
6
0.1
945
4
16.5
6
0.05
0.1
1736
912
5
6
16.5
16
0.05
0.1
1764
300
7
8
16.5
6
0.05
0.1
94.4
76.0
87.9
98.4
1888
760
9
5g
5h
5i
10
11
16.5
16.5
0.05
0.05
1758
1968
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5i
5j
16
16.5
16.5
16.5
16
0.025
0.05
67.2
34.6
64.7
98.9
79.5
92.4
91.6
42.2
81.7
98.0
94.1
2688
692
97.3 (S)
83.2 (S)
92.4 (S)
95.8 (S)
97.5 (S)
96.9 (R)
97.3 (R)
94.5 (R)
97.9 (R)
98.1 (R)
97.5 (R)
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5k
5l
0.05
1294
1978
3180
1848
3664
1688
3268
3920
3764
0.05
5l
0.025
0.05
5n
5o
5p
5q
5r
5s
16.5
16
0.025
0.025
0.025
0.025
0.025
16
16
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16
23
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27c
5m
5t
16
16
16
16
40
0.025
0.025
0.025
0.025
0.01
7.2
288
2400
2960
390
70.8 (S)
92.1 (R)
98.0 (R)
97.3 (R)
98.0 (R)
60.0
74.0
97.5
93.9
5u
5v
5r
9390
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28d
5r
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0.01
93.4
9340
97.6 (R)
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a In general, only the lowest tested catalyst loadings for each complex are presented.
b Standard reaction conditions: 1 (3 mmol), [Ir], HFIP (4 mL), H2 (60 bar), 85 °C. c 12 mmol
scale, 16 mL HFIP. d 25 mmol scale, 33 mL HFIP.
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From the evaluation of complexes 5i-v in the benchmark reaction (Scheme 3, “3rd
generation”), some interesting trends were found: Electron-withdrawing groups, such as
fluoro or trifluoromethyl, in the para position of the phenyl moiety lowered the activity as
well as the selectivity dramatically (5j and 5k vs. 5d, Table 1, entries 6, 13, 14).
Interestingly, previous work by Zhou’s group did not show a similar trend in activity.14
Replacing the phenyl group in position two of 5d with an anthracenyl group led to a more
active catalyst (5l), which gave nearly full conversion working with 0.05 mol% catalyst
loading and still good conversion of 79.5% when 0.025 mol% was used. The naphthyl-
substituted analogue (5n), however, was slightly less active than its phenyl-substituted
counter-part (5f, Table 1, entries 8, 17). As expected, 5s was more active than 5l, giving
a very good conversion of 94.1% at 0.025 mol% catalyst loading (Table 1, entry 22). While
the methoxy-substituted complex 5c was less active than 5b (Table 1, entries 3, 5), the
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p-tert-butyl-substituted derivative 5o was more active compared to 5f , providing the
product in 91.4% yield (Table 1, entry 18). Encouraged by the results achieved with 5o,
we synthesized the complexes 5p-r using the corresponding commercially available
boronic acids. While 5p and 5q had a lower performance than 5o (Table 1, entries 19,
20), 5r gave 98% conversion at 0.025 mol% catalyst loading (Table 1, entry 21). Further
increasing the steric demand of the ligand either led to a catalytically less active system
(5u, Table 1, entry 25) or to an equally active catalytic system (5v, Table 1, entry 25). The
motive in complex 5t, which was used before by Pfaltz’ group,11b gave only poor results
for the desired reaction. As 5r gave higher yield and selectivity compared to 5v, we
continued working with this complex. Notably, using only 0.01 mol% of 5r was sufficient
to give 93.9% of the product with an ee of 98% (R). This reaction could furthermore
successfully be scaled-up to 25 mmol, yielding 93.4% of 2 with an excellent ee of 97.6%.
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Conclusion
In conclusion, we synthesized and tested 22 different chiral iridium complexes for the
hydrogenation of 1 to 2, which is of general interest for the preparation of novel
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agrochemicals. In the presence of the optimal iridium catalyst 5r this transformation
proceeds with high efficiency (TON >9300) and (enantio)selectivity (ee values up to 98%),
so that industrially viable catalyst loadings can be achieved.
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Experimental Procedures
General experimental procedure: The Ir-complex (catalyst loading given) and the
substrate (3 mmol) were placed in an 8-mL autoclave vial containing a PTFE-coated
stirring bar. The autoclave vial was closed using a screw cap with septum, placed in a
fitted metal plate, connected to a Schlenk line and subsequently flushed with argon (10
min). HFIP (4 mL) was added via the septum to the vial. The vial was placed in an argon
containing autoclave and the autoclave was flushed with argon (10 min). The autoclave
was pressurized with hydrogen gas (10 bar) and subsequently depressurized to
atmospheric pressure three times. After this the autoclave was pressurized to 60 bar
hydrogen pressure and was placed in a suitable alumina block. After heating to 85 °C
(~4°C/min; 15 min) the reaction was kept at this temperature for the given time. The
autoclave was placed in an ice bath to allow fast cooling to room temperature. After
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depressurizing, the vial was taken out of the autoclave and the reactions outcome was
determined by GC-FID analysis (diluted with EtOH) and the enantiomeric excess by
HPLC analysis.
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General experimental procedure for up-scaling experiment (12 mmol): Complex 5r
(0.01 mol%) and the substrate (12 mmol) were placed in an 25-mL autoclave containing
a PTFE-coated stirring bar and dissolved in hexafluoroisopropanol (16 mL). The
autoclave was closed, flushed with Ar for 10 minutes and subsequently pressurized with
hydrogen gas (10 bar) and depressurized to atmospheric pressure (three times). After
this the autoclave was pressurized to 60 bar hydrogen pressure and was placed in a
suitable alumina block. After heating to 85 °C (~4°C/min; 15 min) the reaction was kept at
this temperature for the given time. The autoclave was placed in an ice bath to allow fast
cooling to room temperature. After depressurizing, the reactions outcome was determined
by GC-FID analysis (diluted with EtOH) and the enantiomeric excess by HPLC analysis.
General experimental procedure for up-scaling experiment (25 mmol): Complex 5r
(0.01 mol%) and the substrate (25 mmol) were placed in an 50-mL autoclave containing
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a PTFE-coated stirring bar and dissolved in hexafluoroisopropanol (33 mL). The
autoclave was closed, flushed with Ar for 10 minutes and subsequently pressurized with
hydrogen gas (10 bar) and depressurized to atmospheric pressure (three times). After
this the autoclave was pressurized to 60 bar hydrogen pressure and was placed in a
suitable alumina block. After heating to 85 °C (~4°C/min; 15 min) the reaction was kept at
this temperature for the given time. The autoclave was placed in an ice bath to allow fast
cooling to room temperature. After depressurizing, the reactions outcome was determined
by GC-FID analysis (diluted with EtOH) and the enantiomeric excess by HPLC analysis.
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ASSOCIATED CONTENT
Supporting Information
Synthetic procedures, NMR data TBS protected pyridyl alcohols, NMR data of
deprotected pyridyl alcohols, NMR data of synthesized Ir-complexes, HR-MS data
synthesized Ir-complexes, results of deuterium experiments, experimental procedures for
catalytic tests.
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Author Contributions
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‡These authors contributed equally.
Funding Sources
This work is supported by Bayer AG, the State of Mecklenburg-Vorpommern and the
BMBF, Germany.
ACKNOWLEDGMENT
We thank the analytical team of LIKAT for their kind support. We especially thank Dr. Wolfgang
Baumann for NMR measurements and detailed interpretation of analytical data.
ABBREVIATIONS
HFIP = 1,1,1,3,3,3-hexafluoro-propan-2-ol
BArF = Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
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REFERENCES
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(1) (a) Venturini, I.; Vazzola, M. S.; Pellacini, F.; Filippini, L. Aminoindanes Amides
Having a High Fungicidal Activity and Their Phytosanitary Compositions. Patent
WO2012/084812A1, 2012. (b) Swart, G. M.; Oostendorp, M. Fungicidal Compositions.
Patent WO2015/049168A1, 2015. (c) Kiguchi, S. Synergistic Fungicidal Composition For
Controlling Plant Diseases. Patent WO2017/155088A1 (d) Montagne, C.; Hildebrand, S.;
Es-Sayed, M.; Görtz, A.; Wachendorff-Neumann, U. Active Compound Combinations.
Patent WO2018/108977A1, 2018.
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(2) Nishida, S.; Ohsumi, T.; Tsushima, K.; Matsuo, N.; Maeda, K.; Inoue, S.;
Bourgognon, J.-M. Pyrazolecarboxamide Derivatives, Process For Their Preparation,
And Bactericides Containing Them As Effective Ingredients. Patent WO1986/002641A1,
1986.
(3) Matsunaga, T.; Hiraguri, N.; Takahashi, T.; Inui, T.; Tanimoto, M.; Nakayama, T.
Method For Producing (R)-1,1,3-Trimethyl-4-aminoindane. Patent WO2015/118793A1,
2015.
(4) Analogue reaction scheme to the one presented in Bellandi, P.; Zanardi, G.; Datar,
R. V.; Devarajan, C.; Murali, S.; Swamy, N. Process For The Preparation Of 4-
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Aminoindane Derivates And Related Aminoindane Amides. Patent WO2017/178868A1,
2017.
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(5) For excellent reviews about the developments of Crabtree-type iridium complexes
for the hydrogenation of alkenes see (a) Woodmansee, D. H.; Pfaltz, A. Asymmetric
hydrogenation of alkenes lacking coordinating groups. Chem. Commun. 2011, 47, 7912-
7916. (b) Verendel, J. J.; Pàmies, O.; Diéguez, M.; Andersson, P. G. Asymmetric
Hydrogenation of Olefins Using Chiral Crabtree-type Catalysts: Scope and Limitations.
Chem. Rev. 2014, 114, 2130-2169. (c) Margarita, C.; Andersson, P. G. Evolution and
Prospects of the Asymmetric Hydrogenation of Unfunctionalized Olefins. J. Am. Chem.
Soc. 2017, 139, 1346-1356.
(6) (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Enantioselective Hydrogenation of Olefins
with Iridium – Phosphanodihydrooxazole Catalysts. Angew. Chem. Int. Ed. 1998, 37,
2897-2899. (b) Smidt, S. P.; Zimmermann, N.; Studer, M.; Pfaltz, A. Enantioselective
Hydrogenation of Alkenes with Iridium-PHOX Catalysts: A Kinetic Study of Anion Effects.
Chem. Eur. J. 2004, 10, 4685-4693.
(7) Bell, S.; Wüstenberg, B.; Kaiser, S.; Menges, F.; Netscher, T.; Pfaltz, A.
Asymmetric Hydrogenation of Unfunctionalized, Purely Alkyl-Substituted Olefins. Science
2006, 311, 642-644.
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(8) Schrems, M. G.; Pfaltz, A. NeoPHOX—an easily accessible P,N-ligand for iridium-
catalyzed asymmetric hydrogenation: preparation, scope and application in the synthesis
of demethyl methoxycalamenene. Chem. Commun. 2009, 6210-6212.
(9) Takashi T.; Ujita, S.; Method For Manufacturing Optically Active Compound. Patent
WO2015/141564A1, 2015.
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(10) This screening has been performed as part of cooperation between Solvias AG
and Bayer AG.
(11) (a) Kaiser, S.; Smidt, S. P.; Pfaltz, A. Iridium Catalysts with Bicyclic Pyridine–
Phosphinite Ligands: Asymmetric Hydrogenation of Olefins and Furan Derivatives
Angew. Chem. Int. Ed. 2006, 45, 5194-5197. (b) Woodmansee, D. H.; Müller, M.-A.;
Neuburger, M.; Pfaltz, A. Chiral pyridyl phosphinites with large aryl substituents as
efficient ligands for the asymmetric iridium-catalyzed hydrogenation of difficult substrates.
Chem. Sci. 2010, 1, 72-78.
(12) 3a and 3b were provided by Bayer AG.
(13) Tolman, C. A. Steric Effects of Phosphorus Ligands in Organometallic Chemistry
and Homogeneous Catalysis. Chem. Rev. 1977, 77, 313-348.
(14) Liu, Q.-B.; Yu, C.-B.; Zhou, Y.-G. Synthesis of tunable phosphinite–pyridine ligands
and
their applications in asymmetric hydrogenation Tetrahedron Lett. 2006, 47, 4733-4736.
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