Alternatives to Phosphinooxazoline (t-BuPHOX) Ligands in the Metal-Catalyzed Hydrogenation of Minimally Functionalized Olefins and Cyclic β-Enamides

Article abstract of DOI:10.1002/adsc.201700573

This study presents a new series of readily accessible iridium- and rhodium-phosphite/oxazoline catalytic systems that can efficiently hydrogenate, for the first time, both minimally functionalized olefins and functionalized olefins (62 examples in total) in high enantioselectivities (ees up to >99%) and conversions. The phosphite-oxazoline ligands, which are readily available in only two synthetic steps, are derived from previous privileged 4-alkyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline (PHOX) ligands by replacing the phosphine moiety by a biaryl phosphite group and/or the introduction of a methylene spacer between the oxazoline and the phenyl ring. The modular design of the ligands has given us the opportunity not only to overcome the limitations of the iridium-PHOX catalytic systems in the hydrogenation of minimally functionalized Z-olefins and 1,1-disubstituted olefins, but also to expand their use to unfunctionalized olefins containing other challenging scaffolds (e.g., exocyclic benzofused and triaryl-substituted olefins) and also to olefins with poorly coordinative groups (e.g., α,β-unsaturated lactams, lactones, alkenylboronic esters, etc.) with enantioselectivities typically >95% ee. Moreover, both enantiomers of the hydrogenation product could be obtained by simply changing the configuration of the biaryl phosphite moiety. Remarkably, the new catalytic systems also provided excellent enantioselectivities (up to 99% ee) in the asymmetric hydrogenation of another challenging class of olefins – the functionalized cyclic β-enamides. Again, both enantiomers of the reduced amides could be obtained by changing the metal from Ir to Rh. We also demonstrated that environmentally friendly propylene carbonate can be used with no loss of enantioselectivity. Another advantage of the new ligands over the PHOX ligands is that the best ligands are derived from the affordable (S)-phenylglycinol rather than from the expensive (S)-tert-leucinol. (Figure presented.).

Full text of DOI:10.1002/adsc.201700573

Title: Alternatives to Phosphinooxazoline (tBuPHOX) Ligands in the
Metal-Catalyzed Hydrogenation of Minimally Functionalized
Olefins and Cyclic β-Enamides
Authors: Maria Biosca, Marc Magre, Mercedes Coll, Oscar Pàmies,
and Montserrat Diéguez
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700573
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Alternatives to Phosphinooxazoline (tBuPHOX) Ligands in the
Metal-Catalyzed Hydrogenation of Minimally Functionalized
Olefins and Cyclic β-Enamides
Maria Biosca,a Marc Magre,a Mercè Coll,a Oscar Pàmiesa* and Montserrat Diégueza*
a
Departament de Química Física i Inorgànica, Universitat Rovira i Virgili, Campus Sescelades, C/ Marcel·lí Domingo, 1.
43007 Tarragona, Spain. Fax: +34-977559563; Tel: +34-977558780; email: montserrat.dieguez@urv.cat;
oscar.pamies@urv.cat
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. This study presents a new series of readily groups (e.g., α,β unsaturated lactams, lactones,
accessible iridium- and rhodium-phosphite/oxazoline alkenylboronic esters, ...) with enantioselectivities typically
catalytic systems that can efficiently hydrogenate, for the >95% ee. Moreover, both enantiomers of the hydrogenation
first time, both minimally functionalized olefins and product could be obtained by simply changing the
functionalized olefins (62 examples in total) in high configuration of the biaryl phosphite moiety. Remarkably,
enantioselectivities (ee's up to >99%) and conversions. The the new catalytic systems also provided excellent
phosphite-oxazoline ligands, which are readily available in enantioselectivities (up to 99% ee) in the asymmetric
only two synthetic steps, derive from previous privileged 4- hydrogenation of another challenging class of olefins – the
alkyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline (PHOX) functionalized cyclic β-enamides. Again, both enantiomers
ligands by replacing the phosphine moiety by a biaryl of the reduced amides could be obtained by changing the
phosphite group and/or the introduction of a methylene metal from Ir to Rh. We also demonstrated that
spacer between the oxazoline and the phenyl ring. The environmentally friendly propylene carbonate can be used
modular design of the ligands have given us the opportunity with no loss of enantioselectivity. Another advantage of the
not only to overcome the limitations of the iridium-PHOX new ligands over the PHOX ligands is that the best ligands
catalytic systems in the hydrogenation of minimally are derived from the affordable (S)-phenylglycinol rather
functionalized Z-olefins and 1,1-disusbtituted olefins, but than from the expensive (S)-tert-leucinol.
also to expand their use to unfunctionalized olefins
containing other challenging scaffolds (e.g., exocyclic
benzofused and triaryl substituted olefins) and also to olefins
with poorly coordinative
Keywords: Hydrogenation; unfunctionalized olefins; cyclic
β-enamides; rhodium; iridium
consuming ligand design and synthesis. Phosphine-
oxazoline PHOX ligands are considered privileged
ligands. They have been successfully applied in
asymmetric metal-catalyzed reactions such as
hydrogenation, Heck coupling and allylic substitution
reactions among others.[4] PHOX ligands have also
the advantage that they are prepared from amino
alcohols in just two steps. However, the catalyst that
has provided the best enantiomeric excesses in most
processes is the tert-leucinol-derived PHOX
Introduction
The demand for enantiomerically pure chemicals (i.e.
drugs, agrochemicals, flavors ...) has stimulated the
search for efficient synthetic methodologies.[1]
Among them, transition-metal based asymmetric
catalysis is a reliable, selective, and atom-economic
strategy to access optically pure compounds.[1] The
catalyst’s ability to transfer the chiral information to
the product depends on key reaction parameters that
must be optimized in order to achieve the desired
activity and selectivity.[1] The ligand structure plays a
central role in the catalyst's performance, in which an
electronically and sterically well defined scaffold is
the most important factor.[1,2] In this context,
thousands of chiral ligands have been developed
although only few of them - called privileged ligands
- have a general scope.[2,3] Broad substrate and
reaction scopes are desirable to reduce time
t
(tBuPHOX) ligand. One drawback of BuPHOX (and
of other state-of-the-art oxazoline-based ligands) is
that the high cost of the tert-leucinol as starting
material makes them less appealing for industrial
scale application. Another limitation is that the free
PHOX ligands are prone to oxidation. Although
related phosphine-oxazoline ligands have been
developed to solve these limitations (such as
SimplePHOX, ThrePHOX, NeoPHOX, etc)[5] they
are limited in substrate and reaction scope and/or
1
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
require more reaction steps.[5] The discovery of
efficient ligands prepared in only a few steps from
inexpensive raw materials, easy to handle (i.e., solid,
robust and air stable) and that tolerate a broad range
of substrates has therefore attracted the attention of
many researchers. Our group has expertise in
preparing easy to handle ligand families from readily
available starting materials.[6] We and others have
shown the benefits of having biaryl phosphite
moieties in the ligands for several asymmetric
catalytic transformations.[1,6a-e] Our group has
contributed with an improved generation of
phosphite-N ligand libraries.[6e] In this context, we
found that replacing the phosphine moiety in
phosphine-oxazoline PHOX ligands by a biaryl
phosphite-moiety not only improved activity but also
increased substantially the substrate scope in the Pd-
that P,S ligands can be also successfully applied in
the hydrogenation of both, β-enamides derived from
2-aminotetralines and 3-aminochromanes with ee's up
to 99%.[13] Despite these advances, the potential of
P,X ligands for the hydrogenation of functionalized
olefins has been overlooked. The need for easy-to-
synthesize, easy-to-handle and highly efficient P,X
ligands for the reduction of β-enamides derived from
both, 2-tetralones and 3-chromanones continues.
Another important class of olefins are the so-called
minimally functionalized olefins, that do not have an
adjacent
coordinative
polar
group.[14]
The
hydrogenation of minimally functionalized olefins
has not reached the same level of development as the
hydrogenation of functionalized olefins and its
synthetic utility remains limited. Following the
pioneering work of Pfaltz et al. using
allylic
substitution[7]
and
the
Ir-catalyzed
[Ir(cod)(PHOX)]BArF
catalyst
precursors,[15]
hydroboration[8]. The reason for this exceptional
performance is the flexiblility of the biaryl phosphite
group that allows the chiral pocket of the catalyst to
accommodate itself according to the steric demands
of the substrate.[7b] Moreover, their easy preparation
from alcohols and their higher stability towards air
and other oxidizing agents than other commonly used
research in this field has focussed in Ir-catalysts
modified with chiral heterodonor P/N ligands.[16,17]
However, most of the Ir-catalysts are still very
sensitive to the olefin geometry as well as to the
number and nature of substituents in the olefin. Many
important substrates still provide suboptimal results
with known catalysts. For example, Ir-phosphine-
oxazoline PHOX catalysts have only been able to
phosphines
make
phosphite
ligands
very
attractive.[2,6a-e] These features facilitate preparing
large series of ligands in the quest to maximize
catalytic performance for each particular reaction and
substrate.
successfully hydrogenate
a
limited range of
trisubstituted alkenes with E-geometry.[15,18] Our
group has shown the benefits of using phosphite-
oxazoline ligands for this process, which has become
the state of art for the reduction of these challenging
substrates.[19]
Because of its perfect atom economy, operational
simplicity and effectiveness, the hydrogenation of
prochiral olefins is one of the most reliable
asymmetric catalytic methods for the synthesis of
Combining Verdaguer et al.'s work and our biaryl
phosphite-containing ligands, in this paper we report
the family of phosphite-oxazoline ligands (L1-L7a-g,
Figure 1) for the reduction of both, minimally
functionalized olefins and cyclic -enamides.
Ligands L1-L4 are based on privileged phosphine-
oxazoline PHOX ligands in which the phosphine
moiety was replaced with biaryl phosphite
moieties.[20] Ligands L5-L7 were designed to study
the effect of the size of the chelate ring than has been
found to influence the catalytic performance in the
hydrogenation of several olefins. They differ from
ligands L1-L4 by a methylene spacer between the
oxazoline and the phenyl ring of the ligand
backbone.[21]
optically active compounds.[1,9] Nowadays,
a
remarkable range of ligands are being applied to
transform a broad range of substrates. The best results
are obtained when the substrate has a good
coordinating group close to the C=X bond because its
chelating ability facilitates transferring the chirality
from the catalyst to the product. There are, however,
functionalized
substrates
whose
asymmetric
hydrogenation is still not solved. Among them cyclic
β-enamides have recently attracted the attention
because their reduction products are found in many
pharmaceuticals and biologically active products.[10]
In contrast to α-enamides, most of the catalysts for -
enamides give low enantiomeric excesses and are
based on Rh and Ru-catalysts modified with
diphosphine ligands.[11] A breakthrough in this area
came in 2016, when Verdaguer et al. showed that Ir-
P,N catalysts, which had been mainly used to reduce
unfunctionalized olefins, could also reduce cyclic β-
enamides derived from 2-tetralones with better
enantioselectivities
than
the
Ru/Rh-catalysts
described in the literature (up to 99% ee).[12a] Just
afterwards, our group showed that Ir catalysts
modified with PHOX-based phosphite-oxazoline
ligands L1a-c, L3a-c and L4-L6b (Figure 1) can also
be successfully used to reduce cyclic β-enamides
derived
from
both
2-tetralones
and
3-
chromanones.[12b] More recently, our group also found
Figure 1. Phosphite-oxazoline ligands L1-L7a-g
2
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
Results and Discussion
The VT-NMR in CD2Cl2 (+35 to -85 °C) spectra
showed only one isomer in solution. In all cases, one
singlet in the 31P-{1H} NMR spectra was observed.
See Supporting Information for characterization
details.
Synthesis of Ir(I)- and Rh(I)-catalyst precursors
The Ir- and Rh-catalyst precursors [Ir(cod)(L1-L7a-
g)]BArF and [Rh(cod)(L1-L7a-g)]BF4 have been
synthesized in only three steps from readily available
starting materials as shown in Scheme 1. First, the
coupling of hydroxyl-cyanides 1 and 2 with the
appropriate amino alcohol yielded the hydroxyl-
oxazolines 3-9 with diverse oxazoline substituents
(Scheme 1, step i).[22] Then, condensation of the
desired in situ formed phosphorochloridites
(ClP(OR)2 (OR)2= a-g) with the corresponding
hydroxyl-oxazoline yielded phosphite-oxazoline
ligands with several biaryl phosphite groups L1-L7a-
g, in high yields as white solids (Scheme 1, step ii).
Advantageously, L1-L7a-g are stable in air, so
manipulation and storage was performed in air. In the
last step of the synthesis, complexation of the ligands
Asymmetric hydrogenation of minimally functionalized olefins
Asymmetric hydrogenation of trisubstituted olefins
The efficiency of ligands L1-L7 in the hydrogenation
of trisubstituted olefins with different geometry was
initially evaluated with E-substrates S1 (model
olefin), S2 and S3; and the Z-substrates S4 and S5
(Table 1). Z-Trisubstituted olefins are usually
hydrogenated less enantioselectively than the related
E-trisubstituted olefins. By selecting the ligand
parameters we could achieve high enantioselectivities
in the reduction of E- and Z-olefins (ee’s up to 97%
and 90%, respectively) thus overcoming one of the
limitations of the parent tBuPHOX phosphine-
oxazoline ligand in the reduction of Z-olefins (ee
to [Ir(μ-Cl)(cod)]2 followed by in situ Cl-/BArF
-
counterion exchange with NaBArF gave access to the
desired cationic Ir-catalyst precursors (Scheme 1, step
iii). These were isolated in pure form as air-stable
red-orange solids in excellent yields after simple
extraction. No further purification was required. For
the Rh-catalyst precursors, in the last step of the
synthesis [Rh(cod)2]BF4 reacted with one equivalent
of the appropriate ligand and the complexes were
isolated in pure form as yellow powders by adding
cold hexane (Scheme 1, step iv).
values up to 42% for S4, entry 24)[15]
.
In general, the enantioselectivities were found to be
highly dependent on the ligand structure and the
substrate type. While the best enantioselectivities for
E-substrates were obtained with L5b and L5c that
contain a methylene spacer between the oxazoline
and the phenyl ring of the ligand backbone (Table 1
entries 16 and 17), for Z-substrates the best
enantioselectivities were obtained with the ligand
without the methylene spacer L3c (Table 1, entry 11).
Moreover, the oxazoline substituents and the
substituent/configuration of the biaryl phosphite
group also affected the enantioselectivity. Reactions
conducted with ligands containing a Ph oxazoline
group proceeded with the highest enantioselectivities
for both substrate types (entries 11 and 17). This is
economically advantageous because the (S)-
phenylglycinol used in the preparation of L5 is the
cheapest of the amino alcohols employed (up to eight
times cheaper than tert-leucinol that is used in L4 and
L7 as well as in other state-of-the-art oxazoline-based
All ligands L1-L7a-g and complexes [M(cod)(L1-
L7a-g)]X (M= Ir; X= BArF and M= Rh; X= BF4)
were characterized by 31P{1H}, 1H and 13C{1H} NMR
spectra and mass spectrometry. All data were in
agreement with assigned structures. The spectra
assignments were supported by the information
obtained from 1H-1H and 1H-13C correlation
measurements. HRMS-ESI spectra showed the
heaviest ions at m/z corresponding to the loss of the
BArF anion from the molecular species for the Ir-
complexes and the loss of BF4 anion for Rh-
1
complexes. The H, 13C, and 31P NMR spectra
showed the expected pattern for these C1-complexes.
Scheme 1. Synthesis of phosphite-oxazoline ligands L1-L7a-g and the corresponding Ir- and Rh-catalyst precursors. (i)
ZnCl2, toluene or chlorobenzene at reflux for 18-72 h (yields 62-79%). (ii) ClP(OR)2 (OR)2= a-g, Py, toluene at rt for 18 h
(yields 40-80%). (iii) [Ir(μ-Cl)(cod)]2, CH2Cl2 at 40ºC for 60 min then H2O, NaBArF at rt for 30 min (yields 91-96%). (iv)
[Rh(cod)2]BF4, CH2Cl2 at rt for 60 min then precipitated with cold hexane (yields 88-93%).
3
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
t
ligands such as the BuPHOX phosphine-oxazoline
ligand). Additionally, whereas for the more
demanding Z-substrates the best enantioselectivity is
obtained with L3c, which contains an S binaphthyl
group c (entry 11), for E-substrates the best
enantioselectivities were obtained with either S or R
binaphthyl groups (b and c; entries 16 and 17). From
these latter results we can conclude that both
enantiomers of the hydrogenated E-substrates can be
obtained in high enantioselectivities by simply
switching the configuration of the biaryl phosphite
group in ligands L5.
hydrogenation of substrates S1−S5 with the ligands
that provided the best enantioselectivities (Table 1,
entries 28-30). We were pleased to see no loss of
enantioselectivity.
Remarkably, we could also achieve high
enantioselectivity in the hydrogenation of the
challenging exocyclic benzofused five-membered
olefin S6 with Ir/L1g (Table 2, entry 1). Chiral
benzofused five-membered alkanes are key structural
elements in several natural and bioactive
molecules.[24] It should be noted that the
hydrogenation of this type of olefins is not achieved
t
We also studied these reactions at a low catalyst
loading (0.25 mol%) with ligands L3c and L5b-c,
which had provided the best results so far. The high
enantioselectivities were retained (Table 1, entries
25-26). We also tested 1,2-propylene carbonate (PC)
as a solvent. PC has emerged as an environmentally
friendly alternative to standard organic solvents
because of its high boiling point, low toxicity, and
"green" synthesis.[23] Using PC we repeated the
using the parent phosphine-oxazoline Bu-PHOX
ligand (conversions below 5%)[16z] and that only Ir/In-
BiphPHOX has been recently reported to successfully
reduce this type of substrate.[16z]
High enantioselectivities (up to 97%, Table 2, entries
2-3) were also obtained in the reduction of substrates
S7-S8 with the Ir/L5b system. Triaryl-substituted
substrates have been scarcely studied,[16p,17c,19e]
Table 1. Ir-catalyzed hydrogenation of E- and Z-subtrates S1-S5 using ligands L1-L7a-g[a]
Entry
1
2
3
4
5
6
7
8
% ee[b]
72 (R)
78 (R)
61 (R)
25 (R)
55 (R)
29 (R)
58 (R)
9 (R)
% ee[b]
72 (R)
68 (R)
58 (R)
21 (R)
59 (R)
31 (R)
54 (R)
11 (R)
6 (R)
% ee[b]
78 (R)
74 (R)
63 (R)
24 (R)
56 (R)
34 (R)
61 (R)
7 (R)
% ee[b]
86 (S)
30 (S)
85 (S)
15 (S)
72 (S)
0
90 (S)
47 (S)
60 (S)
78 (R)
91 (S)
88 (S)
17 (S)
84 (S)
5 (S)
17 (R)
3 (S)
56 (S)
3 (R)
45 (S)
56 (S)
24 (S)
51 (S)
42 (S)
91 (S)
16 (R)
3 (S)
% ee[b]
51 (S)
7 (R)
81 (S)
14 (R)
83 (S)
4 (R)
87 (S)
41 (S)
64 (S)
81 (R)
89 (S)
71 (S)
3 (R)
L
L1a
L1b
L1c
L1d
L1e
L1f
L1g
L2a
L3a
L3b
L3c
L4a
L4b
L4c
L5a
L5b
L5c
L6a
L6b
L6c
L7a
L7b
L7c
tBuPHOX
L3c
L5b
L5c
L3c
L5b
L5c
9
0
4 (R)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24[c]
25[e]
26[e]
27[e]
28[f]
29[f]
30[f]
40 (R)
15 (S)
72 (R)
19 (R)
44 (R)
15 (R)
94 (R)
95 (S)
81 (R)
92 (R)
65 (S)
76 (R)
23 (R)
0
61 (R)
14 (S)
94 (R)
95 (S)
13 (S)
93 (R)
95 (S)
35 (R)
22 (S)
73 (R)
17 (R)
46 (R)
11 (R)
94 (R)
96 (S)
78 (R)
91 (R)
69 (S)
71 (R)
24 (R)
4 (S)
43 (R)
19 (S)
74 (R)
21 (R)
45 (R)
14 (R)
96 (R)
97 (S)
84 (R)
93 (R)
68 (S)
72 (R)
28 (R)
8 (S)
97 (R)
19 (S)
96 (R)
97 (S)
21 (S)
96 (R)
96 (S)
75 (S)
6 (R)
48 (R)
51 (R)
31 (R)
40 (S)
31 (R)
87 (S)
69 (S)
28 (R)
[d]
[d]
-
-
21 (S)
94 (R)
96 (S)
20 (S)
94 (R)
95 (S)
88 (S)
48 (R)
51 (R)
89 (S)
46 (R)
54 (R)
91 (S)
14 (R)
6 (S)
[a] Reactions carried out at room temperature by using 0.5 mmol of substrate and 1 mol% of Ir-catalyst precursor at 50 bar
of H2 using dichloromethane (2 mL) as solvent. Otherwise noted, full conversions were achieved after 2 h.[b] Enantiomeric
[c]
[d]
[e]
excesses measured by chiral GC or HPLC. Data from ref. [15]. Data not reported. Reactions carried out at 0.25
mol% of Ir-catalyst precursor at 50 bar of H2. Full conversions were achieved after 6 h. Reactions carried out using PC
[f]
as solvent and 1 mol% of Ir-catalyst precursor at 100 bar of H2. Full conversions were achieved after 12 h.
4
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
Table 2. Selected results for the hydrogenation of trisubstituted olefins S6-S36 using [Ir(cod)(L1-L7a-g)]BArF catalyst
precursors.[a]
[a]
[b]
1
Reaction conditions: 2 mol % catalyst precursor, CH2Cl2 as solvent, 50 bar H2, 4 h.
Conversion measured by H-
NMR after 2 h. [c] Enantiomeric excesses measured by chiral GC or HPLC. [d] Reactions carried out during 24 h.
5
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
although their hydrogenation is a sustainable and
straightforward method to achieve diarylmethine
chiral centers.[25]
alkenylboronic esters will open up
a
new
straightforward and sustainable route for preparing
enantiomerically pure organoboron compounds.
Chiral organoboron compounds are interesting
because the boronate group can undergo
stereospecific transformations to form C-N, C-O and
C-C bonds. On the other hand, the effective
hydrogenation of enol phosphinates opens up an
We then moved towards the reduction of key
trisubstituted substrates with poorly coordinative
groups. Their hydrogenation is of interest because
they can be further functionalized and become key
intermediates for more complex chiral molecules.
The results are shown in Table 2 (for a complete
series of results, see Table SI-1 in the Supporting
Information). We found that, again, the parameters of
the ligands must be optimized for each substrate if
enantioselectivities are to be high. We first
hydrogenated a large series α,β-unsaturated esters S9-
S15 (Table 2, entries 4-10), with different electronic
properties in the phenyl ring (S9-S11) and with
different steric properties of the alkyl substituents
(S9, S12-S14). The hydrogenation of these substrates
provides a simple entry point to chiral carboxylic
ester derivatives, which are found in relevant
products.[26] For all of them enantioselectivities (ee’s
up to 99%) were excellent and comparable to the best
reported to date. It should be highlighted the 93% ee
obtained for the more demanding Z-isomer S15 (entry
10). The effect of the ligand parameters on
enantioselectivity is different than for previous S1-S8
substrates. The best enantioselectivities were
obtained with ligand L3a, which maintains the
economic benefits of a Ph oxazoline substituent but
with the added advantage that an achiral inexpensive
3,3’,5,5’-tetra-tert-butyl-[1,1’-biphenyl]-2,2’-diyl
phosphite moiety (a) can be used. With the Ir/L5c
catalytic system we were also able to hydrogenate
α,β-unsaturated enones S16-S21 with results (ee's up
to 98%; Table 2, entries 11-16) comparable to the
best enantioselectivities previously reported.[27,28]
Interestingly, Ir/L5c provided similar high
enantioselectivities irrespective of the nature of the
alkyl substituent and the electronic nature of the
substrate phenyl ring. Being able to hydrogenate such
a wide range of α,β-unsaturated enones is highly
significant since the obtained ketones are found in
many relevant products. Despite their importance,
they have been less studied and less successfully
hydrogenated than other trisubstituted olefins with
poorly coordinative polar groups.[27] Other difficult
substrates such as α,β-unsaturated δ- and γ-lactones
S22-S23 (entries 17 and 18), acyclic amide S24
(entry 19) and δ-lactams S25-S27 (entries 20-22)
were also successfully reduced with the Ir/L5c
system (ee’s up to >99%). Chiral amides with
stereogenic centres in the α-position and δ- and γ-
lactones/lactams are common in a variety of natural
products as well as useful building blocks in synthetic
chemistry (i.e. amide group can be easily transformed
into other useful compounds such as amines). Despite
their relevance, very few successful examples of Ir-
catalysts can be found in the literature and they have
a limited substrate scope.[29]
appealing
route
for
obtaining
chiral
organophosphinates, which can be easily transformed
into high value compounds such as alcohols and
phosphines. Despite the importance of hydrogenating
alkenylboronic esters and enol phosphinates, only a
few reports have been published and show a limited
success.[30] In this context, it was noteworthy that by
modifying the ligand parameters we could reach high
enantioselectivities for alkenylboronic esters S28-S31
(Table 2, entries 23-26) and enol phosphinates S32-
S36 (Table 2, entries 27-31). In the reduction of
alkenylboronic esters, the highest enantioselectivities
(up to 99%) were achieved using [Ir(cod)(L5c)]BArF,
while
for
enol
phosphinates
the
best
enantioselectivities (ee’s up to 96%) were obtained
with [Ir(cod)(L5b)]BArF.
In summary, the simple substitution of the
phosphine by a phosphite group and/or the
introduction of a methylene spacer between the
oxazoline and the phenyl ring of the ligand backbone
t
in phosphine-oxazoline BuPHOX ligand extended
the range of trisubstituted olefins that could be
successfully hydrogenated with enantioselectivities
that were among the best reported so far.[14h] In
addition, the ligands that provided the best
enantioselectivities contained the Ph substituent in
t
the oxazoline moiety instead of the pricy Bu
substituent.
Asymmetric hydrogenation of disubstituted olefins
To further study the potential of the L1-L7a-g
ligands, we screened them in the Ir-catalyzed
hydrogenation of 1,1-disubstituted substrates.
Enantioselectivity is more difficult to control in these
substrates than in trisubstituted olefins. Most catalysts
fail either to control the face-selective coordination of
the less hindered disubstituted substrate or to
suppress the isomerization of the olefin that leads to
the formation of the more stable E-trisubstituted
substrates, which in turn form the opposite
enantiomer when hydrogenated.[14e]
As a model substrate we chose the 3,3-dimethyl-2-
phenyl-1-butene S37. The results are summarized in
Table SI-2 in the Supporting Information. The best
enantioselectivity (ee's up to 98%), comparable to the
best one reported in the literature, was obtained with
L3a (Figure 2). This ligand has the economic benefits
of both a Ph oxazoline substituent and an achiral
biaryl phosphite moiety a. The introduction of a
methylene spacer between the oxazoline and the
phenyl ring of the ligand backbone did not improve
the enantioselectivity.
Alkenylboronic esters and enol phosphinates are
two other relevant sets of substrates that are receiving
much attention. The asymmetric reduction of
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700573
Advanced Synthesis & Catalysis
We next studied the asymmetric hydrogenation of
of the corresponding deuterated product from S48
showing species with more than two deuterium
atoms. In line with this, the Ir/L6b system shows less
deuterium atoms incorporated at the allylic position
than the Ir/L1b. This indicates that Ir/L6b controls
better the isomerization than Ir/L1b, which agrees
with the higher enantioselectivity observed with
Ir/L6b. Although in olefins prone to isomerization
(S45-S48) this competing reaction was not
completely suppressed, the introduction of a biaryl
phosphite group together with the combination of the
right ligand parameters minimized this side reaction
to achieve ee's comparable to the best ones reported.
Besides, by introducing the biaryl phosphite moiety,
the face coordination mode was successfully
controlled thus facilitating the reduction of a broad
range of 1,1-disubstituted substrates.
other terminal disubstituted olefins (Figure 2; for a
complete series of results, see Table SI-3 in the
Supporting Information). We noted that Ir/L3a easily
tolerates variations in the electronic and steric
properties of the substituents in the aryl moiety of the
substrate. A broad range of terminal olefins (S38-
S44) were reduced in high enantioselectivities
comparable to S37. For S43 and S44 with ortho
substituents, longer reaction times were required to
achieve full conversions.
Among the results, it is worth mentioning that the
hydrogenation
of
α-alkylstyrenes
bearing
decreasingly sterically demanding alkyl substituents
(S45-S48) proceeded with somewhat lower
enantioselectivities (from 83% to 91%). Nevertheless,
we found that enantioselectivities for these substrates
could be maximized by choosing the ligand
parameters. A plausible explanation for the lower
enantioselectivity can be either that hydrogenation
competes with isomerization or that face selectivity
problems occur. To clarify this aspect, we run
deuterium labeling experiments (Scheme 2) in which
we hydrogenated S1 and S48 with deuterium with
Ir/L1b and Ir/L6b catalyst precursors.
Scheme 2. Deuterium labeling experiments of substrates
S1 and S48 using Ir/L1b and Ir/L6b catalyst precursors.
The percentage of incorporation of deuterium atoms is
shown in brackets. The results of the indirect addition of
deuterium due to the isomerization process are shown in
red.
Finally, due to the relevance of olefins with poorly
coordinative groups, we wanted to see if the excellent
catalytic performance in the reduction of the
trisubstituted enol phosphinates and alkenylboronic
esters was maintained for the even more challenging
terminal analogues. We were able to obtain high-to-
excellent enantioselectivities (ee's up to 99%) in the
reduction of substrates S49-S54 (Figure 2). The
results are among the best in the literature for each
substrate, even in the reduction of highly appealing
substrates such as pinacolatoboron-containing
substrates S49-S53[32] and enol phosphinate S54[33]
for which only very few catalytic systems have
provided high enantioselectivities. The successful
reduction of aryl-substituted boronic esters S49-S52
is a relevant finding that overcomes the results
reported in the literature in the hydrogenation of this
type of substrates and nicely complements the current
state of the art. It is also noteworthy that although
S53 is prone to isomerization, it was hydrogenated
with excellent enantioselectivity. Similarly, the
hydrogenation of the allylic acetate S55[34] also
proceeded with high activity and enantioselectivity
with catalyst Ir-L3a. Derivatives of the
hydrogenation product of S55 are used as
Figure 2. Selected results for the hydrogenation of
disubstituted olefins S37-S55 using [Ir(cod)(L1-L7a-
g)]BArF catalyst precursors. Reaction conditions: 1 mol %
catalyst precursor, CH2Cl2 as solvent, 1 bar H2, 4 h.
[b] Reaction carried out for 12 h.
In contrast to S1, the reduction of S48 led to the
addition of deuterium not only at the double bond (as
expected) but also at the allylic position. This agrees
with the existence of a competing isomerization
pathway. [31] This was supported by the mass spectra
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700573
Advanced Synthesis & Catalysis
components of fragrance mixtures (i.e., Pamplefleur)
and also as intermediates for the synthesis of natural
products and drugs (i.e., modulators of dopamine D3
receptors).[35]
Our preliminary results (at 50 bar of H2 at room
temperature using 1 mol% of the corresponding
[Ir(cod)(L)]BArF catalyst precursors) showed that
ligands with a methylene spacer between the
oxazoline and the phenyl ring provided higher
enantioselectivities than ligands without this
methylene moiety. We also found that a chiral R-
To summarize, the results for the asymmetric
hydrogenation of disubstituted olefins are among the
best reported for this type of challenging substrates
and overcome one of the limitations of the parent
binaphthyl moiety
b
was needed for high
t
phosphine-oxazoline BuPHOX ligand, which was
enantioselectivities.[12b]
unable to reduce the 1,1-disubstituted substrate class
with high enantioselectivities.
Therefore, and in order to further improve
enantioselectivities, in this work we expanded our
previous study to other phosphite containing-PHOX
based ligands with a methylene spacer. Thus, we
Asymmetric hydrogenation of cyclic -enamides
t
tested the new ligands containing a Bu oxazoline
We finally turned our attention to the asymmetric
moiety (ligands L7) and those incorporating other R-
configured biaryl phosphite moieties (ligands L5-
L7c,d,f). For comparison we also tested the new
ligands L1-L4d,f that contain the R-biaryl phosphite
moieties d and f but not the methylene spacer. See
Table 3 for selected results (for a complete series of
results, see Table SI-4 in the Supporting Information).
Neither these new chiral biaryl phosphite groups nor
reduction
of
challenging
-enamides.
2-
Aminotetralines and 3-aminochromanes are key
structural units in many therapeutic agents and
biologically active natural products (Figure 3).[10]
The asymmetric hydrogenation of β-enamides will
open up a direct, atom-efficient, path to synthesize
these compounds. So far, only few successful
examples can be found in the literature and they are
limited in substrate scope. In contrast to the α-
enamides, most of the catalysts for -enamides
provide low enantiomeric excesses and are based on
Rh and Ru-catalysts.[11] Among the most successful
reports, Ratovelomanana et al. published the
t
the Bu oxazoline moiety improved the previous
t
enantioselectivities. Indeed the presence of the Bu
oxazoline group lowered both activity and
enantioselectivity. The use of the new ligands with
other R-biaryl phosphite moieties (d, f) provide the
same enantioselectivities than the best ones obtained
with ligands L5-L6b. Therefore, ligands L5b and
L6b,d,f provided the reduced product in full
conversion and 98% of ee (Table 3).
synthesis
of
3-aminochromanes
with
enantioselectivities up to 96% using Ru-diphosphine
catalysts.[11f] A more recent report showed similar
high enantioselectivities in the reduction of enamides
derived from 2-tetralones (ee's up to 96%) and
enamides derived from 3-chromanones (ee's in the
range 94-98%), using a Rh-diphosphine catalysts.[11k]
They needed, however, to use WingPhos, a P-
stereogenic diphosphine ligand synthesized in nine
steps.
More recently, our group also found for the first
time that with P-thioether ligands both enantiomers of
the hydrogenated can been obtained by switching
from Ir to Rh.[13] Therefore, in this paper we also
extended the use of ligands L1-L7 in the Rh-
catalyzed hydrogenation of -enamides. For
comparison, we firstly evaluated ligands L1-L7 in the
Rh-catalyzed hydrogenation of the model N-(3,4-
dihydronaphthalen-2-yl)acetamide S56 substrate. The
selected results are shown in Table 3 (for complete
series of results see Table SI-4 in the Supporting
Information). We used the same optimal reaction
conditions found in our previous study with Rh-P,S
catalytic systems in the reduction of cyclic -
enamides. The reactions were therefore performed in
dichloromethane using 1 mol% of the catalyst loading
under 30 bar of H2. The catalysts were prepared in
situ by adding the appropriate ligand to the
[Rh(cod)2]BF4 catalyst precursor. Again the
methylene spacer between the oxazoline and the
phenyl ring affected positively the enantioselectivity
Figure 3. Examples of chiral 2-aminotetralines and 3-
aminochromanes with pharmaceutical applications
t
while the presence of a Bu oxazoline group affected
negatively. The effect of the methylene spacer is
more significant in Rh-catalysts than in Ir-catalysts.
As previously observed with Ir-catalysts, the results
also indicated that the ligand backbone is not able to
control the tropoisomerism of the biphenyl phosphite
moiety (a). Therefore the chiral R-biaryl phosphite
moieties are needed to maximize enantioselectivities
and activities. However, in contrast to Ir-catalysts, the
presence of the corresponding chiral S-biaryl
In 2016, two reports showed that Ir-P,N catalysts,
that have been mainly used to reduce
unfunctionalized olefins, are also able to reduce
cyclic β-enamides.[12] In this respect, we identified
that Ir-catalysts modified with the simple PHOX-
based phosphite-oxazoline L1a-c, L3a-c and L4-L6b
can be successfully used to reduce cyclic β-enamides
derived from 2-tetralones and 3-chromanones.[12b]
8
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
phosphite moiety also provided quite good
substrate (0.5 mmol), CH2Cl2 (2 mL), 10 bar H2, 5 °C, 50 h.
For comparative purposes the results achieved with related
Ir-L6d catalytic system (1 mol%) using 50 bar of H2 are
also included.
enantioselectivities.
In
summary,
the
best
enantioselectivities of up to 94% ee were therefore
obtained with ligands L5b and L6b,d,f.
Advantageously, we also found that both enantiomers
of the hydrogenated products could be reached with
the same ligand by simple exchanging Ir to Rh (Table
3).
A range of substituted cyclic enamides derived
from -tetralones (S57-S61), that contemplate all
possible variations in the substitution pattern of the
3,4-dihydronaphthalene core were hydrogenated with
high enantioselectivities comparable to the best one
reported (ee's up to 96%). Also, the replacement of
the metal gave access again to both enantiomers of
the reduced products with high enantioselectivities.
Finally, we were pleased to find that we could also
effectively hydrogenate the enamide derived from 3-
chromanone, S62, in high enantioselectivities and
yields (ee's up to 91%).
In summary, by simply choosing the metal center,
we have been able to obtain both reduced
enantiomers for a broad range of cyclic -enamides
in enantioselectivities comparable to the best one
reported under mild reaction conditions. Again the
ligand that contains the phenyl substituent at the
oxazoline instead of the pricy t-Bu has provided
excellent enantioselectivities.
Table 3. Selected results for the reversal of
enantioselectivity observed in the Ir- and Rh-catalyzed
hydrogenation of S56 [a]
[Ir(cod)(L)]BArF
[Rh(cod)2]BF4/L
Entry
11
13
%Conv[b]
100
%ee[c]
98 (S)[d]
98 (S)[d]
98 (S)
%Conv[b] %ee[c]
L
100
100
100
100
94 (R)
94 (R)
93 (R)
94 (R)
L5b
L6b
L6d
L6f
100
100
14
15
100
98 (S)
[a]
Reactions carried out using 0.5 mmol of substrate, 1
mol% of catalyst precursor using dichloromethane (2 mL)
as solvent and at room temperature and 50 bar of H2 for Ir-
[b]
catalysts or at 5 °C and 30 bar of H2 for Rh-catalysts.
Conversion measured by 1H-NMR after 20 h for Ir-
catalysts and 36 h for Rh-catalysts. Enantiomeric excess
Finally, we went one step further and evaluated
this novel set of catalysts in the M-catalyzed (M= Rh
and Ir) hydrogenation of cyclic -enamides S56-S58
[c]
determined by HPLC. [d] Data from ref [12b].
using
1,2-propylene
carbonate.
The
enantioselectivities in both enantiomers of the
hydrogenated products remained as high as those
achieved with dichloromethane (Scheme 3).
We then evaluated the effect of several reaction
parameters on catalytic performance (see Table SI-5
in the Supporting Information). We were pleased to
find
that
full
conversions
and
high
enantioselectivities can be maintained by lowering
the pressure of H2 to 10 bar. We also found that the
catalytic performance is unaffected when using either
the in situ formed or the preformed catalyst precursor
[Rh(cod)(L)]BF4. In the optimal reaction conditions
we then evaluated the substrate scope with other
cyclic β-enamides. Figure 4 shows the results using
Rh/L6d catalyst as example (for a complete series of
results, see Table SI-3 in the Supporting Information).
For comparison, Figure 4 also collects the results
with the corresponding Ir-catalyst.
Scheme 3. Asymmetric hydrogenation of cyclic β-
enamides S56-S58 using 1,2-propylene carbonate (PC).
Reactions carried out using 0.5 mmol of substrate, 1 mol%
of catalyst precursor using PC (2 mL) as solvent.
Conclusions
We have identified readily accessible Ir- and Rh-
phosphite/oxazoline PHOX-based catalytic systems
that can hydrogenate, for the first time, both a broad
range of minimally functionalized and functionalized
olefins (62 examples in total) in high
enantioselectivities (ee's up to >99%) and
conversions . Starting from privileged PHOX ligands,
the phosphine moiety was replaced by a biaryl
phosphite group and, in some cases, a methylene
Figure 4. Asymmetric Rh-catalyzed hydrogenation of
cyclic β-enamides S57-S62 using [Rh(cod)(L6d)]BF4.
Reactions conditions: catalyst precursor (1 mol%),
9
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
To a solution of in situ generated phosphochloridite (1.1
mmol) in dry toluene (6 mL), pyridine (0.16 mL, 2.0
mmol) was added. Then, this solution was placed in a -78
ºC bath. After 2 min at that temperature, a solution of the
alcohol-oxazoline (1.0 mmol) and pyridine (0.16 mL, 2.0
mmol) in toluene (6 mL) was added dropwise at -78 °C.
The mixture was left to warm to room temperature and
stirred overnight at this temperature. The precipitate
formed was filtered under argon and the solvent was
evaporated under vacuum. The residue was purified by
flash chromatography (under argon, using neutral alumina
spacer was introduced between the oxazoline and the
phenyl ring. With these simple modifications, the
phosphite-based ligands not only had a more modular
design than the source phosphine-oxazoline PHOX,
but also were air-stable solids with no increase in the
number of synthetic steps. With a careful selection of
the ligand components, the new ligands were superior
to the privileged phosphine-oxazoline PHOX ligands
in the metal catalyzed hydrogenation of challenging
olefins, with enantioselectivities comparable to the
best one reported. Therefore, these ligands improved
the enantioselectivities achieved for challenging
minimally functionalized Z-olefins and 1,1-
disubstituted olefins, and expanded their use to
olefins containing other challenging scaffolds (e.g.,
exocyclic benzofused and triaryl substituted olefins),
olefins with poorly coordinative groups (e.g., α,β
unsaturated lactams, lactones, alkenylboronic
esters, ...) and cyclic β-enamides that have a fully
coordinative group. Interestingly, in the Ir-
hydrogenation of minimally functionalized olefins,
the sense of enantioselectivity was mainly controlled
by the configuration of the biaryl phosphite moiety so
both enantiomers of the hydrogenated product can be
obtained with the same ligand scaffold. In the
and dry toluene (1% NEt ) as eluent system) to afford the
3
corresponding phosphite-oxazoline as white solids (see
Supporting Information for characterization details).
General procedure for the preparation of catalyst precursors
[Ir(cod)(L1-L7a-g)]BAr .
F
The corresponding ligand (0.037 mmol) was dissolved in
CH2Cl2 (2 mL) and [Ir(µ-Cl)(cod)]2 (12.5 mg, 0.0185
mmol) was added. The reaction mixture was refluxed at 50
ºC for 1 hour. After 5 min at room temperature, NaBArF
(38.6 mg, 0.041 mmol) and water (2 mL) were added and
the reaction mixture was stirred vigorously for 30 min at
room temperature. The phases were separated and the
aqueous phase was extracted twice with CH2Cl2. The
combined organic phases were dried with MgSO4, filtered
through a plug of celite and the solvent was evaporated to
give the product as red-orange solids (see Supporting
Information for characterization details).
hydrogenation of
cyclic β-enamides, both
General procedure for the preparation of catalyst precursors
enantiomers of the corresponding 2-aminotetralines
and 3-aminochromanes could also be obtained with
the same ligand by simply changing the metal from Ir
to Rh. Another advantage of the new ligands over the
PHOX ligands is that the best ligands are derived
from affordable (S)-phenylglycinol rather than from
expensive (S)-tert-leucinol. This latter fact together
with the small number of synthetic steps (only 2) to
obtain the ligands, the modularity and air-stability,
and the evidence that the new Ir- and Rh-catalyst
precursors maintain their enantioselectivities with
environmentally friendly propylene carbonate as
solvent makes them very appealing for industrial
applications.
[Rh(cod)(L1-L7a-g)]BF .
4
The corresponding ligand (0.05 mmol) was dissolved in
CH2Cl2 (2 mL) and [Rh(cod)2]BF4 (20.3 mg, 0.05 mmol)
was added. The reaction mixture was stirred at room
temperature for 1 hour. Then the solvent was partially
evaporated and the desired complex was precipitated by
adding cold hexane (3 mL). The precipitate was filtered off,
washed twice with cold hexane (2 mL) and dried to afford
the product as a yellow solid (see Supporting Information
for characterization details).
Typical procedure for the Ir-catalyzed hydrogenation of
minimally functionalized olefins S1-S55.
The alkene (0.5 mmol) and Ir complex (0.25-2 mol %)
were dissolved in the corresponding solvent CH2Cl2 or PC
(2 mL) and placed in a high-pressure autoclave. The
autoclave was purged 4 times with hydrogen. Then, it was
pressurized at the desired pressure. After the desired
reaction time, the autoclave was depressurized and the
solvent evaporated off. The residue was dissolved in Et2O
(1.5 ml) and filtered through a short plug of celite. The
enantiomeric excess was determined by chiral GC or chiral
Experimental Section
General considerations
All reactions were carried out using standard Schlenk
techniques under an atmosphere of argon. Solvents were
purified and dried by standard procedures. All reagents
1
HPLC and conversions were determined by H NMR. The
enantiomeric excesses of hydrogenated products from S1-
S55 were determined using the conditions previously
described (see Supporting Information for details).
1
were used as received. H, 13C{1H} and 31P{1H} NMR
spectra were recorded using a Varian Mercury-400 MHz
spectrometer. Chemical shifts are relative to that of SiMe4
(1H and 13C{1H}) as an internal standard or H3PO4 (31P) as
Typical procedure for the metal-catalyzed hydrogenation of
cyclic β-enamides S56-S62.
1
an external standard. H and 13C assignments were made
on the basis of 1H-1H gCOSY and 1H-13C gHSQC
experiments. Phosphorochloridites were easily prepared in
one step from the corresponding biaryl alcohols.[36]
Compounds 2,[22b] 3-6,[22a] 7-8;[12b] ligands L1-L4a,[7a]
L1b-L1c,[12b] L1f-g,[7b] and L3-L6b;[12 b] and complexes
[Ir(cod)(L)]BArF (L= L1a-c, L3a-c and L4-L6b)[12 b] were
prepared as previously described.
The enamide (0.25 mmol) and the corresponding catalyst
precursor [M(cod)(L)]X (M= Rh, X= BF4 or M= Ir, X=
BArF; 1 mol%) were dissolved in in the corresponding
solvent CH2Cl2 or PC (1 mL) and placed in a high-pressure
autoclave, which was purged four times with hydrogen. It
was then pressurized at the desired pressure. After the
desired reaction time, the autoclave was depressurized and
the solvent evaporated off. The residue was dissolved in
Et2O (1.5 ml) and filtered through a short celite plug.
Conversions were determined by 1H NMR. The
enantiomeric excesses of hydrogenated products were
Typical procedure for the preparation of phosphite-oxazoline
ligands
10
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
determined using the conditions previously described (see
Supporting Information for details).
Acknowledgements
Financial support from the Spanish Ministry of Economy and
Competitiveness (CTQ2016-74878-P) and European Regional
Development Fund (AEI/FEDER, UE), the Catalan Government
(2014SGR670), and the ICREA Foundation (ICREA Academia
awards to M.D) is gratefully acknowledged.
11
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
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behavior has been observed previously and it is
13
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
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14
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10.1002/adsc.201700573
Advanced Synthesis & Catalysis
FULL PAPER
Alternatives to Phosphinooxazoline (tBuPHOX)
Ligands in the Metal-Catalyzed Hydrogenation of
Minimally Functionalized Olefins and Cyclic β-
Enamides
Adv. Synth. Catal. Year, Volume, Page – Page
Maria Biosca, Marc Magre, Mercè Coll, Oscar
Pàmies* and Montserrat Diéguez*
15
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