Chelate ring size effects of Ir(P,N,N) complexes: Chemoselectivity switch in the asymmetric hydrogenation of α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.catcom.2020.106128

A novel, highly modular approach has been developed for the synthesis of new chiral P,N,N ligands with the general formula Ph₂P(CH₃)CH(CH₂)_mCH(CH₃)NHCH₂CH₂(CH₂)_nN(CH₃)₂ and Ph₂P(CH₃)CHCH₂CH(CH₃)NHCH₂(CH₂)_n-2-Py (m, n = 0, 1). The systematic variation of their P–N and N–N backbone led to the conclusion that the activity, chemo- and enantioselectivity in the hydrogenation of α,β-unsaturated ketones are highly dependent on the combination of the two bridge lengths. It has been found that a minor change in the ligand's structure, i. e. varying the value of m from 1 to 0, can switch the chemoselectivity of the reaction, from 80percent C[dbnd]O to 97percent C[dbnd]C selectivity.

Full text of DOI:10.1016/j.catcom.2020.106128

CatalysisCommunications146(2020)106128
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Short communication
Chelate ring size effects of Ir(P,N,N) complexes: Chemoselectivity switch in
the asymmetric hydrogenation of α,β-unsaturated ketones
⁎
Zsófia Császára, Eszter Z. Szabóa, Attila C. Bényeib, József Bakosa, Gergely Farkasa,
a Department of Organic Chemistry, University of Pannonia, Egyetem u. 10., H-8200 Veszprém, Hungary
b Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
A R T I C L E I N F O
A B S T R A C T
Keywords:
A novel, highly modular approach has been developed for the synthesis of new chiral P,N,N ligands with the general
formula Ph2P(CH3)CH(CH2)mCH(CH3)NHCH2CH2(CH2)nN(CH3)2 and Ph2P(CH3)CHCH2CH(CH3)NHCH2(CH2)n-2-Py
(m, n = 0, 1). The systematic variation of their PeN and NeN backbone led to the conclusion that the activity,
chemo- and enantioselectivity in the hydrogenation of α,β-unsaturated ketones are highly dependent on the com-
bination of the two bridge lengths. It has been found that a minor change in the ligand's structure, i. e. varying the
value of m from 1 to 0, can switch the chemoselectivity of the reaction, from 80% C]O to 97% C]C selectivity.
Chelate ring size
P,N,N ligand
Asymmetric hydrogenation
α,β-unsaturated ketones
1. Introduction
chiral ligands (f-Amphox) and sucessfully used them in the en-
antioselective hydrogenation of simple ketones [16], α-hydroxy- [17]
Transition metal catalyzed asymmetric hydrogenation of ketones is
one of the simplest chemical transformations affording optically active
secondary alcohols that serve as useful intermediates for the synthesis
of biologically active compounds such as medicines, perfumes, and
agrochemicals [1–4]. Since the development of highly efficient chiral
ruthenium-diphosphine/diamine complexes by Noyori et al. for the
asymmetric hydrogenation of ketones in the 1990s [5], the design and
synthesis of novel and even more efficient transition metal catalysts still
represents a challenging direction in this research area [6,7]. Besides
ruthenium-based systems, chiral iridium-complexes proved to be highly
active, selective and robust catalysts in the asymmetric hydrogenation
of a broad range of ketonic substrates. In this contribution, Ir-complexes
modified by potentially tridentate P,N,N ligands constitute a unique
class of chiral catalysts due to their extremely high activity and se-
lectivity, structural modularity and high substrate tolerance (Fig. 1).
Recently, Zhou and coworkers developed spiro pyridine-aminopho-
sphine (SpiroPAP) based Ir-catalysts that were utilized in the asym-
metric hydrogenation of simple [8] and functionalized ketones (ke-
toesters [9–11], ketoacids [12], α-amino-ketones [13]) with
outstanding activities (eg. TOF > 100,000 h−1 for acetophenone) and
enantioselectivities (> 99% ee). To date the Ir-SpiroPAP system is the
only Ir(P,N,N) catalyst used in the hydrogenation of α,β-unsaturated
ketones toward enantioselective preparation of chiral 2-substituted
acyclic allylic alcohols [14,15]. Zhang et al. synthesized IreP,N,N cat-
alysts containing ferrocene based aminophosphine-oxazoline type
and halogenated ketones [18] and β-ketoesters [19] with remarkably
high enantioselectivity and activity. Another ferrocene-containing li-
gand family has been developed by the workgroups of Hu and Zhang
and applied in the Ir-catalyzed hydrogenation of aromatic ketones
[20,21] and β-ketoesters [22] as well as for the hydrogenation of α-
alkyl-β-ketoesters [23] via dynamic kinetic resolution. In addition to
these systems Hu et al. reported on the synthesis of an oxazoline-con-
taining tridentate ligand that exhibited good performance in the hy-
drogenation of β-ketoesters [24]. It should be pointed out that all of
these ligands include aromatic moieties in the backbone which might
decrease the conformational flexibility of the chelate ring. The Ir-
complexes of these ligands are capable of producing chiral secondary
alcohols with the same efficiency as the corresponding Ru-based sys-
tems, and in several cases even outperform their catalytic efficiency in
terms of both activity and enantioselectivity.
A key factor in an efficient catalyst design is the careful stereo-
electronic fine tuning of the ligands structure. In asymmetric transition
metal catalysis, the majority of reports on ligand modifications have
followed systematic variation of the simple spatial demands of the
catalyst, and/or substituent controlled electronic tuning of the chiral
ligands. Indeed, this trend can nicely be recognized regarding the above
examples, as the structural modifications, marked with red color in
Fig. 1, involve (i) the alteration of the phosphorus substituents (PAr2),
(ii) the modification of pendant side groups (R or X) or (iii) the varia-
tion of the relative configurations of the stereogenic elements.
⁎ Corresponding author.
E-mail address: gerifarkas@almos.uni-pannon.hu (G. Farkas).
https://doi.org/10.1016/j.catcom.2020.106128
Received 6 July 2020; Received in revised form 28 July 2020; Accepted 29 July 2020
Availableonline03August2020
1566-7367/©2020TheAuthor(s).PublishedbyElsevierB.V.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).

Z. Császár, et al.
CatalysisCommunications146(2020)106128
reaction of the cyclic sulfate with the amine and the second substitution
reaction take place with complete inversion at the stereogenic centers. The
31P{1H} NMR spectra of the compounds L1-L6 exhibit one singlet line
indicating the formation of one single diastereomer. It is important to note
that the present synthetic methodology is of high modularity and does not
require tedious multiple reactions steps. Concerning the structural versa-
tility of the commercially available chiral (or non-chiral) cyclic sulfates
and diamines the structural fine tuning of the corresponding ligands can
easily be implemented without tedious workup procedures.
2.2. Catalytic studies
At first, we chose (E)-chalcone (S1) as a standard substrate for the
Ir-catalyzed hydrogenation to screen ligands L1-L6 (Scheme 2). Hy-
drogenation of S1 in methanol in the presence of the Ir catalyst, syn-
thesized in situ from [Ir(COD)Cl]2 and chiral P,N,N ligand (P,N,N/
Ir = 1), at a substrate catalyst molar ratio of 1000, 5 bar hydrogen
pressure and room temperature afforded hydrogenation products A1,
B1 and C1 in different ratio.
Fig. 1. Subclasses of chiral P,N,N ligands used in Ir-catalyzed asymmetric hy-
drogenation.
Generally, less common are instances of the manipulation of the
chelate ring size, despite the fact that such changes can be, in many
cases, readily implemented resulting in steric and also electronic al-
teration and producing similarly dramatic improvements in catalytic
activity and enantioselectivity [25–27]. Surprisingly, the variation of
the ring size of potentially tridentate ligands in catalysis is very rare
[28–31] and to the best of our knowledge there is no such example
concerning asymmetric catalytic transformations. However, as it was
underlined by Crabtree and Peris, “this little studied area, analogous to
bite angle effects in chelates, seems worth further efforts” [32].
In the present study we report on the development of a highly
modular synthetic approach leading to a novel class of chiral P,N,N
ligands based on two alkane-diyl backbones of different P,N and N,N
tether lengths (Fig. 1). In order to compare the catalytic behavior of the
new ligands, they were tested in the iridium catalyzed chemo- and
enantioselective hydrogenation of enones, a challenging substrate class,
with the intention to compare their activity, chemo- and enantioselec-
tivity. Our primary aim was to vary the chelate ring size formed by the
ligands and hence influence the bite angle and the conformational
flexibility of the catalysts. Additionally, the effect of the reaction con-
ditions and the substrate scope was carefully screened.
The reactions completed within 60 min with ligands L2 and L4
(Table 1, entries 2 and 4) and 87% conversion could be achieved with
L3 (entry 3). Catalysts with more rigid skeleton, i.e. ligands of shorter
backbone(s) (L1) or pyridyl containing side chain (L5 and L6), provided
low turnovers. For the sake of comparison, we tested the bidentate
analogue of ligand L3, with a simple N-ethyl substituent, under iden-
tical conditions in the hydrogenation reaction of S1 (entry 7). No
conversion could be achieved, indicating that the presence of the third
coordination site is necessary to obtain catalytic turnover. Furthermore,
it also suggests that the N atom of the side arm coordinates to the metal
during the catalytic reaction forming an N,N chelate in addition to the
P,N cycle. Zhou et al. reported that the introduction of a third co-
ordination site to a P,N/Ir system (SpiroAP/Ir) lead to increased sta-
bility and activity (SpiroPAP/Ir) [8]. In this case the pronounced dif-
ference between the P,N and P,N,N systems was attributed to the ability
of the former system to irreversibly form inactive dimers or trimers
under hydrogenation conditions [33].
As the bidentate system was totally inactive in our case (entry 7), it
was surmised that the introduction of the third coordination site not
only prevents the formation of inactive metal species but through co-
ordination to the metal may also change the conformation of the P,N
chelate, thus potentially changing the substrate-catalyst interaction in
the catalytic cycle. This is also in line with the data of Table 1, where
the activity of the catalysts depends both on the structure of the P,N and
the N,N backbone. The highest conversions could be achieved with li-
gands L2 and L4 (Table 1, entries 2 and 4) having the most flexible
dimethylaminopropyl side chain.
2. Results and discussion
2.1. Synthesis of the ligands
The novel ligands were synthesized in two simple steps. At first, en-
antiomerically pure (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide
(1a) or (4R,6R)- or (4S,6S)-4,6-dimethyl-1,3,2-dioxathiane-2,2-dioxide
(1b) and the corresponding diamine were mixed in THF leading to ami-
noalkyl sulfates 2a-f (Scheme 1). A remarkable feature of this metho-
dology is that strong bases as deprotonating agents for the amines can be
avoided. The addition of three equivalents of LiPPh2 in THF provided the
desired P,N,N (L1-L6) ligands in good yields. Both the ring opening
The chemoselectivity of the reaction drastically changes with the
length of the P,N backbone. Butane-2,3-diyl based systems L1 and L2 are
less selective toward allylic alcohol A1 (entries 1 and 2). In fact, L2
provided saturated ketone B1 with 94% chemoselectivity. Contrarily,
ligands with pentane-2,4-diyl backbone and sp3 N-atoms, L3 and L4,
proved to be rather selective to A1, giving 66 and 80% chemoselectivity,
respectively (entries 3 and 4).
Scheme 1. Synthesis of chiral ligands L1-L6
2

Z. Császár, et al.
CatalysisCommunications146(2020)106128
Scheme 2. Chemo- and enantioselective hydrogena-
tion of (E)-chalcone (S1)
Ligands L3 and L4 were also highly enantioselective as the allylic
alcohol A1 was produced with 90 and 94% ee, respectively.
Interestingly, increasing the length of the side chain, i.e. the ring size of
the N,N-chelate, slightly increases the enantioselectivity. Ligands L5
and L6 with more rigid pyridyl-containing pendant side arm gave lower
chemo- and enantioselectivities (entries 5 and 6).
In order to gain a deeper insight into the reaction pathways leading
to the formation of B1 and C1, racemic allylic alcohol A1 as starting
material was subjected to hydrogenation by using ligands L2 and L4
under identical conditions as in the first set of experiments (Table 1).
No catalytic turnover could be achieved in either case. This experiment
suggests that, in the catalytic reaction, product B1 is formed by the
direct hydrogenation of the C]C double bond of (E)-chalcone (S1)
instead of the transition metal catalyzed isomerization [34] of the
allylic alcohol A1 (Scheme 3). The saturated alcohol C1 is consequently
a product of the C]O hydrogenation of B1. Consequently, the L2/Ir
system having five-membered P,N chelate exhibits high C]C selectivity
in the hydrogenation reaction, while the L4/Ir catalyst with six-mem-
bered P,N cycle switched chemoselectivity for the hydrogenation of C]
O double bond. This phenomenon proves that the presence of the C]O
double bond is a prerequisite for the hydrogenation of C]C moiety.
Encouraged by these observations, P,N,N ligands L2 and L4 were also
utilized in the chemoselective hydrogenation of α,β-unsaturated car-
bonyl compounds S2-S5 with distinct steric and S6-S7 with different
Scheme 3. Reaction pathways leading to the products of the enantioselective
hydrogenation of S1
electronic properties. Based on the data of Table 2 it is clearly visible that
the activity and selectivity of the two IreP,N,N systems are remarkably
different with each conjugated substrates. This strongly suggest that the
steric nature of the two systems are remarkably different. Albeit the
electronic alteration of the substrate does not significantly change the
activity and the chemoselectivity, the ee of hydrogenation of S6, con-
taining electron withdrawing substituent, could be improved to 96%.
Although the exact explanation for the rather distinct catalytic
performance of ligands L1-L6 with different backbone length is cur-
rently unknown, several factors influencing activity and selectivity can
be highlighted. The (i) fac/mer stereoselectivity in the coordination of
the tridentate ligands [35], (ii) the hemilability of the terminal N-
Table 1
Ir-catalyzed chemo- and enantioselective hydrogenation of (E)-chalcone (S1): catalyst screeninga.
Entry
Ligand
Reaction time (h)
Conversion (%)b
A:B:C molar ratio (%)b
43:41:16
Ee of A (%)c
1
24 h
42
78
2
3
1 h
1 h
> 99 (91)d
87 (47)
2:94:4
–
66:15:19
90
4
5
6
1 h
> 99 (73)
80:8:12
72:23:5
34:60:4
–
94
78
64
–
1 h
20
10
0
1 h
7
a
24 h
Reaction conditions: Catalyst: 12.12 μmol ligand and 5.06 μmol [Ir(COD)Cl]2, substrate: 10 mmol (E)-chalcone, solvent: 6 ml MeOH, base: 100 μmol of tBuOK, H2
pressure: 5 bar, temperature: RT.
b
c
d
The conversion and chemoselectivity were determined by NMR spectroscopy. Values in brackets are isolated yields of A1.
The enantioselectivity was determined by chiral HPLC.
Isolated yield of product B1.
3

Z. Császár, et al.
CatalysisCommunications146(2020)106128
Table 2
Hydrogenation of α,β-unsaturated ketones S2-S7 by using chiral P,N,N ligands L2 and L4.a
Entry
Substrate
Ligand
PH2 (bar)
Conv. (%)b
Molar ratio of A in the product (%)b
Ee of A (%)c
1d
L2
L4
5
5
> 99
23
> 99
> 99
86
70
2d
3e
4e
L2
L4
15
15
98
6
85
–
76
–
5
6
L2
L4
5
5
65
36
97
22
36
> 99
7
8
L2
L4
5
5
> 99
> 99
> 99
> 99
–
–
9
L2
L4
5
5
> 99
> 99
5
–
10
81
96
11
12
L2
L4
5
5
84
95
2
–
77
92
a
b
c
d
e
Reaction conditions: Catalyst: 12.12 μmol ligand and 5.06 μmol [Ir(COD)Cl]2, substrate: 10 mmol, solvent: 6 ml MeOH, base: 100 μmol of tBuOK, reaction time: 1 h.
The conversion and chemoselectivity were determined by NMR spectroscopy.
The enantioselectivity was determined by chiral HPLC.
Substrate: 2 mmol, reaction time: 24 h.
Substrate: 2 mmol.
Table 3
Asymmetric hydrogenation of (E)-chalcone (S1)a.
Entry
Solvent
Ligand
T (°C)
PH2 (bar)
Time (h)
Conv.
(%)b
A:B:C molar ratio (%)b
Ee of A (%)c
1
MeOH/H2O 85/15
MeOH/H2O 70/30
MeOH
L2
L4
L2
L4
L2
L4
L2
L4
25
25
25
40
5
2
79
2:98:0
–
2
90
67:18:15
5:93:2
88
–
3
5
2
85
4
91
63:22:15
5:95:0
88
–
5d
6d
7
1
1
78
58
73:21:6
5:95:0
96
–
MeOH
10
5 min
57
8
> 99
74:8:18
94
a
b
c
Reaction conditions: Catalyst: 12.12 μmol ligand and 5.06 μmol [Ir(COD)Cl]2, substrate: 10 mmol, solvent: 6 ml MeOH, base: 100 μmol of tBuOK, reaction time: 1 h.
The conversion and chemoselectivity were determined by NMR spectroscopy.
The enantioselectivity was determined by chiral HPLC.
Substrate: 2 mmol.
d
containing functionality capable of creating vacant coordination sites
reaction was complete after 5 min and the ee remained unchanged
[32], (iii) the mutual interactions between the two (P,N and N,N)
chelates affecting ring conformation and (iv) the magnitude of the bite
angle in the catalytically active species may largely contribute to the
diverse reactivity pattern. Nevertheless, the proper choice of the ligand
backbone enabled the hydrogenation of α,β-unsaturated ketones car-
bonyl compounds with high activity, chemo- and enantioselectivity.
Finally, we compared the catalytic performance of the Ir-catalysts
modified by L2 and L4 under different reaction conditions by varying
the solvent, the pressure and the temperature (Table 3). The catalysts
proved to be active and selective even in 70 V/V% aqueous methanol
(MeOH/H2O 70/30). At 1 bar hydrogen pressure the enantioselectivity
of A1 could be increased to 96% ee, while the chemoselectivity some-
what decreased. Interestingly, increasing the temperature to 40 °C the
compared to the experiment conducted at room temperature. This re-
sult corresponds to a TOF value of higher than 12,000 h−1
.
In conclusion, a novel highly modular synthetic approach has been
developed for the synthesis of chiral tridentate P,N,N type ligands L1-
L6. The new methodology enables the variation of the P,N and N,N
bridge length as well as the stereoselective synthesis of the ligands in
two simple steps. The novel compounds L1-L6 were screened in the Ir-
catalyzed chemo- and enantioselective hydrogenation of enones to in-
vestigate the effects of their backbone length on the activity and se-
lectivity of the catalytic reactions. The rate and the selectivity of the
asymmetric hydrogenation were strongly sensitive to the size of the
formed chelate rings. By simply changing the size of the P,N chelate
switched the chemoselectivity of the reaction. Furthermore, by properly
4

Z. Császár, et al.
CatalysisCommunications146(2020)106128
combining the backbone lengths high enantioselectivities (up to 96%
ee) and chemoselectivities (98%) could be obtained. As a unique feature
of the PNN/Ir systems, the hydrogenation reactions could also be per-
formed in aqueous methanol solutions.
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The substantial improvements of the chemo- and enantioselectivities
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Declaration of Competing Interest
[17] W. Wu, Y. Xie, P. Li, X. Li, Y. Liu, X.-Q. Dong, X. Zhang, Asymmetric hydrogenation
of α-hydroxy ketones with an iridium/f-amphox catalyst: efficient access to chiral
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C6QO00810K.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
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catalyzed asymmetric hydrogenation of halogenated ketones for the efficient con-
struction of chiral Halohydrins, Adv. Synth. Catal. 360 (2018) 2119–2124, https://
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Acknowledgements
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[20] C. Qin, C.-J. Hou, H. Liu, Y.-J. Liu, D.-Z. Huang, X.-P. Hu, Ir-catalyzed asymmetric
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10.1016/j.tetasy.2013.10.012.
We thank Mr. Béla Édes for skillful assistance in analytical mea-
surements and synthetic experiments. The research was supported by the
project NKFIH K128074. The research was also supported by the EU and
co-financed by the European Regional Development Fund under the
projects GINOP-2.3.2-15-2016-00008 and GINOP-2.3.3-15-2016-00004.
Appendix A. Supplementary data
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dynamic kinetic resolution, Org. Lett. 18 (2016) 5592–5595, https://doi.org/10.
1021/acs.orglett.6b02828.
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.catcom.2020.106128.
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