Extending the Substrate Scope in the Hydrogenation of Unfunctionalized Tetrasubstituted Olefins with Ir-P Stereogenic Aminophosphine-Oxazoline Catalysts

Article abstract of DOI:10.1021/acs.orglett.8b04084

Air-stable and readily available Ir-catalyst precursors modified with MaxPHOX-type ligands have been successfully applied in the challenging asymmetric hydrogenation of tetrasubstituted olefins under mild reaction conditions. Gratifyingly, these catalyst precursors are able to efficiently hydrogenate not only a range of indene derivatives (ee's up to 96%) but also 1,2-dihydronapthalene derivatives and acyclic olefins (ee's up to 99%), which both constitute the most challenging substrates for this transformation.

Full text of DOI:10.1021/acs.orglett.8b04084

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Extending the Substrate Scope in the Hydrogenation of
Unfunctionalized Tetrasubstituted Olefins with Ir‑P Stereogenic
Aminophosphine−Oxazoline Catalysts
†
‡
†
‡,§
Xavier Verdaguer,*,‡,§
́
́
Maria Biosca, Ernest Salomo, Pol de la Cruz-Sanchez, Antoni Riera,
,†
,†
̀
́
Oscar Pamies,* and Montserrat Dieguez*
†
̀
Departament de Química Física i Inorganica, Universitat Rovira i Virgili, C/Marcel·lí Domingo, 1, 43007 Tarragona, Spain
‡Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), C/Baldiri
Reixac, 10, 08028 Barcelona, Spain
§
̀
̀
́
̀
̀
Departament Química Inorganica i Organica, Seccio Organica, Universitat de Barcelona, C/Martí i Franques, 1, 08028 Barcelona,
Spain
S
* Supporting Information
ABSTRACT: Air-stable and readily available Ir-catalyst precursors
modified with MaxPHOX-type ligands have been successfully applied
in the challenging asymmetric hydrogenation of tetrasubstituted
olefins under mild reaction conditions. Gratifyingly, these catalyst
precursors are able to efficiently hydrogenate not only a range of
indene derivatives (ee’s up to 96%) but also 1,2-dihydronapthalene
derivatives and acyclic olefins (ee’s up to 99%), which both
constitute the most challenging substrates for this transformation.
symmetric hydrogenation (AH) is one of the most
common, reliable, and environmentally friendly industrial
A
processes for the preparation of chiral compounds, such as
drugs and crop-protecting chemicals.1 Its strategic relevance
has spurred research in both academia and industry over the
last decades. Nowadays, an important number of Rh, Ru, and
Ir catalysts exist for the AH of a broad range of substrates.2
However, for some substrates such as tetrasubstituted olefins,
attaining high activity and enantioselectivity is still a challenge.
Their reduction would open up opportunities to simulta-
neously generate two vicinal tertiary stereocenters, which are
present in many natural and high-valued products.3 Achieving
high enantiocontrol is even more difficult if the olefin lacks a
coordinative group that can assist in the transfer of the chiral
information from the catalyst to the product.2 The AH of
tetrasubstituted unfunctionalized olefins is therefore under-
developed compared to the AH of olefins that contain a
coordinative functional group.3 To date, high catalytic
performance has been reported in very few publications and
with a limited substrate scope. In addition, for each type of
olefin a different ligand family was required. In 1999
Buchwald’s group reported the first successful AH of
tetrasubstituted unfunctionalized olefins.4 A series of indenes
were hydrogenated using the zirconozene catalyst 1 (Figure 1)
with moderate-to-high enantioselectivities (ee’s in the range
52−99%).5 They found that enantioselectivity was negatively
Figure 1. Representative catalysts for the AH of unfunctionalized
tetrasubstituted olefins.
affected by substituents other than a methyl in the benzylic
position of the substrate. In addition to the low substrate
scope, the high catalyst loading (8 mol %), the high H2
pressure (typically >110 bar) required, and the low stability of
Received: December 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04084
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the catalyst hampered its broad use. Later, Pfaltz and then
others demonstrated that the stability and the harsh reaction
condition issues of the Zr catalyst can be overcome by using
Ir/P-N catalysts. The use of these stable Ir catalysts allowed
the AH of tetrasubstituted olefins to be therefore carried out
under mild reaction conditions and low catalyst loading
(typically 1−2 mol %).2g Nevertheless, high enantioselectivities
were not achieved until it was found that the optimum ligand
structures for tri- and tetrasubstituted olefins differed strongly.
This led to specific Ir-catalyst design for the AH of
tetrasubstituted olefins (e.g., 2 and 3, Figure 1 and some of
them reported recently).6 In this context, Pfaltz’s group found
that Ir-catalysts 2 (Figure 1), which contained ligands that
form a 5-membered chelate ring, could hydrogenate a wider
range of indenes, with ee’s in the range 94−96%, than the Zr-
catalyst 1.6a Therefore, catalyst 2 performance proved to be
less dependent on the substituents in the benzylic position of
the substrate than 1. Nevertheless, ee’s diminished specially for
1,2-dihydronaphthalenes (ee’s up to 77%), and for non cyclic
olefins high enantioselectivity was only achieved for one
substrate (ee’s between 89 and 97%). Busacca’s group found
that the Ir-catalyst 3 could also hydrogenate two cyclic
substrates with ee’s up to 96% at low catalyst loading. Two
inconveniences were that low temperature (0 °C) was required
and that the 1,8-disubstituted naphthalene core of the ligand
was difficult to prepare.6b
Figure 2. Ir(I)-aminophosphine-oxazoline precatalysts 5−8a−c.
Initially, we explored the AH of 2,3-dimethyl-1H-indene S1
with Ir-precatalysts 5−8 (Table 1). S1 was chosen as the
Table 1. Asymmetric Hydrogenation of 2,3-Dimethyl-1H-
indene S1 Using Ir-Catalyst Precursors 5−8a−c
a
b
entry
Ir complex
PH2 (bar)
% conv (% yield)
% ee
c
1
2
3
4
5
6
7
5a
5b
5c
6b
7b
8b
5b
5b
50
50
50
50
50
50
75
10
100 (−)
83 (R,R)
93 (R,R)
90 (R,R)
63 (R,R)
82 (S,S)
74 (S,S)
92 (R,R)
95 (R,R)
In 2017, Zhang’s group reported an Rh-catalyst 4 (Figure 1),
containing a P-stereogenic diphosphine ligand synthesized in
nine steps7 that provided 85−95% ee’s in the AH of indenes.8
In contrast to Ir catalysts, their Rh catalyst required high
catalyst loading (10 mol %), 60 °C, and longer reaction times
(4 days).
100 (96)
c
100 (−)
100 (95)
100 (96)
100 (95)
c
100 (−)
Despite the relevance of the above-mentioned advances, the
substrate scope for the AH of tetrasubstituted olefins still
remains limited. Research for a stable, easy to synthesize,
catalytic system for the AH of different types of cyclic and
acyclic unfunctionalized tetrasubstituted olefins under mild
reaction conditions is still needed. In this respect, we thought
that the combination in a catalyst system of the advantageous
reaction conditions of Pfaltz’s Ir/phosphine-N catalysts and
Zhang’s P-stereogenic concept could be expected to lead to
improved stereocontrol in the AH of unfunctionalized
tetrasubstituted olefins under mild reaction conditions. This
development was however delayed by the difficulty of
synthesizing bulky P-sterogenic phosphines in optically pure
form. Fortunately, Riera and Verdaguer’s group recently
presented a novel, straightforward synthetic route that solved
this problem and allowed the synthesis of a library of P-
stereogenic aminophosphine-oxazoline (MaxPHOX) ligands in
which both enantiomeric series are equally available.9
We therefore report here the AH of unfunctionalized
tetrasubstituted olefins using stable Ir complexes 5−8a−c
(Figure 2), containing MaxPHOX ligands. Compounds 5−
8a−c were easily prepared in four steps from readily available
materials,9b and their advantageous properties also derive from
the bulky P stereogenic center and their high modular
approach. Precatalysts 5−8a−c represent the four diastereo-
meric possibilities of varying the configuration of substituents
at the oxazoline and at the alkyl backbone chain, while
maintaining the configuration of the P-stereogenic center
(precursors 5−8). We also studied the effect of increasing the
steric bulk of the oxazoline substituent (from a to c).
d
8
100 (96)
a
1
Conversions were measured by H NMR spectroscopy after 24 h.
b
c
Enantiomeric excesses determined by chiral GC. Isolated yield not
d
calculated. Reaction performed using 2 mol % of catalysts.
model substrate since it could be compared with the results of
previous catalysts 1−4. For the initial reaction conditions, we
tested 5−8 in the optimal mild reaction conditions from the
previous study with Ir catalysts 2.6a The reactions were
therefore carried out at room temperature using 1 mol % of the
catalyst under 50 bar of H2 in dichloromethane. The reactions
proceeded smoothly to provide the cis-diastereoisomer only. It
was observed that both the diastereomeric backbone of the
ligand and the oxazoline substituent (entries 1−6) had a
remarkable effect on the enantioselectivity. Catalyst precursor
5b provided the highest enantioselectivity of the series (entry
2, ee up to 93%). Interestingly, lowering the hydrogen
pressure, the enantioselectivity increased (see entries 2, 7,
and 8).10 Enantioselectivities up to 95% ee were achieved at
only 10 bar of H2 while maintaining the full conversion (entry
8) under mild reaction conditions. This result is comparable to
the best one reported in the literature.
We further studied the performance of 5b in the reduction
of other indenes (S2−S8) and of the demanding 3,4-dimehtyl-
1,2-dihydronapthalene S9 (Table 2).
Substrates S2−S8 include several substituents at both
benzylic (S2−S4) and vinylic position (S7−S8) and several
substituents at the 6-position of the indene (S5−S6). We
found that precatalyst 5b tolerated well variations of the alkyl
B
DOI: 10.1021/acs.orglett.8b04084
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Letter
Table 2. Asymmetric Hydrogenation of Several Indenes S2−
S8 and 1,2-Dihydronapthalene S9
Table 3. Asymmetric Hydrogenation of (3-Methylbut-2-en-
2-yl)Benzene S10 Using Ir-Catalyst Precursors 5−8a−c
a
b
entry
Ir complex
PH2 (bar)
% conv (% yield)
% ee
c
1
2
3
4
5
6
7
5b
6b
7b
8b
6c
6a
enant-6b
enant-6b
enant-6b
75
75
75
75
75
75
50
10
2
85 (−)
33 (S)
85 (S)
44 (R)
25 (R)
44 (R)
75 (R)
90 (R)
93 (R)
98 (R)
100 (96)
100 (94)
100 (97)
c
85 (−)
c
100 (−)
c
100 (−)
d
c
8
de
,
100 (−)
9
100 (95)
a
1
Conversions were measured by H NMR spectroscopy after 24 h.
b
c
Enantiomeric excesses determined by chiral GC. Isolated yield not
d
calculated. Reaction performed using 2 mol % of catalysts.
e
Conversion measured after 36 h.
Again, there is a positive effect on enantioselectivity when the
hydrogen pressure is lowered (entries 2 and 7−9).
Enantioselectivities increased up to 98% ee when the reduction
was done at only 2 bar of H2 (entry 9).
Under the mild optimal conditions found we further
extended our work to the AH of other acyclic tetrasubstituted
olefins S11−S18 (Figure 3). Advantageously, we found that
a
1
Conversions were measured by H NMR spectroscopy after 24 h.
b
c
Enantiomeric excesses determined by chiral GC. Reaction
d
performed using 75 bar of H2. Isolated yield not calculated.
substituent at both the benzylic (Table 1, entry 8, and Table 2,
entries 1−2) and vinylic positions (Table 2, entries 6 and 7).
The only exception was substrate S4 with a phenyl substituent
at the benzylic position that led to somewhat lower
enantioselectivity (entry 3). The results also indicated that
conversion and yields were comparable for substrates S5 and
S6 (entries 4−5) that contain a different substituent at the 6
position of the indene, although enantioselectivity was slightly
better for the methoxy-substituted indene S6 (entry 5). We
should highlight the high enantioselectivity in the hydro-
genation of 3,4-dimethyl-1,2-dihydronapthalene S9 (entry 8),
which is one of the most challenging substrates because the
catalyst must avoid the dehydrogenation reaction toward the
naphthalene derivative. This result improves the previous
result by Pfaltz6a and is comparable to Busacca’s result,6b but
with our catalyst we do not need to work at low temperature.
Encouraged by the previous results, we then turned our
attention to the AH of the most challenging class of
tetrasubstituted olefinsthe acyclic ones. We first tested Ir
precatalysts 5−8a−c in the AH of (3-methylbut-2-en-2-
yl)benzene S10 as a model substrate (Table 3). The results
indicated again that the diastereomeric ligand backbone and
the oxazoline substituent had a significant influence (entries
1−6). However, in contrast to what was observed for cyclic
olefins, catalyst precursor 6b provided the highest enantiose-
lectivity of the series (entry 2). This result clearly shows the
importance of using a modular scaffold to build a catalyst.
Figure 3. Asymmetric hydrogenation of several acyclic tetrasub-
stituted olefins S11−S18 (hydrogenated products 19−26). Reactions
carried out using 2 mol % of enant-6b at 2 bar of hydrogen at 23 °C
for 36 h.
enantioselectivity was neither affected by different electronic
and steric decorations of the phenyl group of the substrate
(S10−S14) nor by the nature of the alkyl chain (S12, S15, and
S16), nor by the use of heteroaromatic olefins (S17 and S18).
Improving previously reported results,6a,c a broad range of
substituted acyclic tetrasubstituted olefins were therefore
hydrogenated in excellent enantioselectivities (ee’s ranging
from 96% to 99%; Figure 3).
We finally studied the AH of acyclic tetrasubstituted olefins
with relevant poorly coordinative groups. Due to the
importance of chiral fluorine molecules, in particular those
with two vicinal stereogenic centers,11 we focused on the AH
of acyclic vinyl fluorides as a direct and atom-efficient method
for their preparation. We therefore studied the AH of several
vinyl fluorides containing an ester group (S19−S23, Figure 4;
see Supporting Information for reaction condition optimiza-
C
DOI: 10.1021/acs.orglett.8b04084
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
products; and enantiomeric excess determination and
characterization details of hydrogenated products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xavier.verdaguer@irbbarcelona.org.
*E-mail: oscar.pamies@urv.cat.
*E-mail: montserrat.dieguez@urv.cat.
ORCID
Antoni Riera: 0000-0001-7142-7675
Xavier Verdaguer: 0000-0002-9229-969X
Figure 4. Asymmetric hydrogenation of several acyclic tetrasub-
stituted vinyl fluorides S19−S23 (hydrogenated products 27−30).
Reactions carried out using 2 mol % of 6a at 2 bar of hydrogen using
CH2Cl2 as solvent at 23 °C for 24 h.
́
Montserrat Dieguez: 0000-0002-8450-0656
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
tion).6d The challenge of these substrates is that the catalyst
must not only control the face selectivity but also avoid the
side defluorination reaction. Advantageously, the reaction
proceeded smoothly without defluorination in high diastereo-
and enantioselectivities, regardless of the nature of the olefin
substituents (aryl or alkyl) and the olefin geometry under mild
reaction conditions. Interestingly, the use of olefins with
different geometries gives access to both diastereoisomers of
the hydrogenated products in high enantioselectivities. Thus,
while substrate S19, with E-geometry, provides the R,R-
diastereoisomer, the Z-analogue S20 gives access to the R,S-
diastereoisomer. These results are comparable to the best ones
reported in the literature.6d
This paper reports a new approach in catalyst design for the
successful hydrogenation of challenging unfunctionalized
tetrasubstituted olefins. We therefore present the first
application of an Ir/P-stereogenic P−N catalyst library, with
a simple, modular architecture, in the AH of a broad range of
different types of unfunctionalized tetrasubstituted olefins.
These catalysts combine the advantageous reaction conditions
of Ir/P,N catalysts with the advantages of having a bulky P-
stereogenic center. These air-stable catalysts can also be easily
prepared in a few steps from readily available sources.
Improving previous results, the same family of catalysts is
able to efficiently reduce indenes and the challenging 1,2-
dihydronapthalene derivatives (ee’s up to 96%) and also a
broad range of acyclic olefins with unprecedented enantiose-
lectivities (ee’s up to 99%) under mild reaction conditions.
Moreover, the excellent catalytic performance is maintained for
a range of aryl and alkyl vinyl fluorides (dr’s > 99% and ee’s up
to 98%), where two vicinal stereogenic centers are created.
These results pave the way for further development of new
generations of modular and readily available Ir/P-stereogenic
aminophosphine-oxazoline catalyst libraries for the AH of
unfunctionalized tetrasubstituted olefins, including the chal-
lenging acyclic ones.
■
We gratefully acknowledge financial support from the Spanish
Ministry of Economy and Competitiveness (CTQ2016-74878-
P and CTQ2017-87840-P), IRB Barcelona, European Regional
Development Fund (AEI/FEDER, UE), the Catalan Govern-
ment (2017SGR1472), and the ICREA Foundation (ICREA
Academia award to M.D). IRB Barcelona is the recipient of a
Severo Ochoa Award of Excellence from MINECO. E.S.
thanks MINECO for a fellowship.
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■
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̂
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ASSOCIATED CONTENT
* Supporting Information
■
(3) Kraft, S.; Ryan, K.; Kargbo, R. B. J. Am. Chem. Soc. 2017, 139,
11630−11641.
S
(4) Troutman, M. V.; Appella, D. H.; Buchwald, S. L. J. Am. Chem.
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(5) Even small changes such as replacing the methyl group by an
ethyl had a deleterious effect on enantioselectivity. Thus, ee’s drops
from 93% (Me) to 52% (Et).
Experimental procedure for the preparation of substrates
and for the hydrogenation reactions; copies of NMR
spectra of the new substrates and hydrogenation
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Neumann, E.; Pfaltz, A. Angew. Chem., Int. Ed. 2007, 46, 8274−8276.
D
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̌
(b) Busacca, C. A.; Qu, B.; Gret, N.; Fandrick, K. R.; Saha, A. K.;
Marsini, M.; Reeves, D.; Haddad, N.; Eriksson, M.; Wu, J. P.;
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Senanayake, C. H. Adv. Synth. Catal. 2013, 355, 1455−1463. During
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application of Ir/phosphinite-oxazoline catalysts in the AH of some
cyclic and acyclic tetrasubstituted olefins. It was also found that the
simple substitution of the phosphinite moiety by a phosphite group
has an extremely negative effect on enantioselectivity, reinforcing the
̀
need of specific ligand design. Biosca, M.; Magre, M.; Pamies, O.;
́
Dieguez, M. ACS Catal. 2018, 8, 10316−10320. (d) The second
publication reported by Andersson’s group showed the successful AH
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catalysts for the AH of trisubstituted olefins, with a small modification
in the P group. However, this catalyst was not successful for the other
classes of cyclic and acyclic tetrasubstituted olefins reported in this
paper and also required the use of high H2 pressure (20−100 bar).
Ponra, S.; Rabten, W.; Yang, J.; Wu, H.; Kerdphon, S.; Andersson, P.
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́
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(9) (a) Orgue, S.; Flores, A.; Biosca, M.; Pamies, O.; Dieguez, M.;
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The Ir−MaxPHOX complexes have recently been successfully applied
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́
́
enamides and imines. See: (b) Salomo, E.; Orgue, S.; Riera, A.;
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́
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(c) Salomo, E.; Rojo, P.; Hernandez-Llado, P.; Riera, A.;
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been reported by Pfaltz and co-workers. See ref 6a.
(11) During the last decade, the synthesis of chiral fluorinated
molecules with two vicinal chiral centers has received a great deal of
attention because of their presence in several drugs, such as
dexamethasone and fluticasone propionate. Despite this, the number
of successful methods for their preparation is very limited, and those
methods also require high catalyst loading, drastic reaction conditions,
and multiple steps, among other drawbacks. See, for instance: Ma, J.-
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