Probing the Effects of Heterocyclic Functionality in [(Benzene)Ru(TsDPENR)Cl] Catalysts for Asymmetric Transfer Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.9b02339

A range of TsDPEN catalysts containing heterocyclic groups on the amine nitrogen atom were prepared and evaluated in the asymmetric transfer hydrogenation of ketones. Bidentate and tridentate ligands demonstrated a mutual exclusivity directly related to their function as catalysts. A broad series of ketones were reduced with these new catalysts, permitting the ready identification of an optimal catalyst for each substrate and revealing the subtle effects that changes to nearby donor groups can exhibit.

Full text of DOI:10.1021/acs.orglett.9b02339

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Probing the Effects of Heterocyclic Functionality in
[(Benzene)Ru(TsDPENR)Cl] Catalysts for Asymmetric Transfer
Hydrogenation
Jonathan Barrios-Rivera,† Yingjian Xu,*,‡ and Martin Wills*,†
†Department of Chemistry, University of Warwick, Coventry, CV4 7AL, United Kingdom
‡GoldenKeys High-Tech Materials Co., Ltd., Building B, Innovation & Entrepreneurship Park, Guian New Area, Guizhou Province
550025, China
S
* Supporting Information
ABSTRACT: A range of TsDPEN catalysts containing heterocyclic groups on the amine nitrogen atom were prepared and
evaluated in the asymmetric transfer hydrogenation of ketones. Bidentate and tridentate ligands demonstrated a mutual
exclusivity directly related to their function as catalysts. A broad series of ketones were reduced with these new catalysts,
permitting the ready identification of an optimal catalyst for each substrate and revealing the subtle effects that changes to
nearby donor groups can exhibit.
he [(arene)Ru(TsDPEN)Cl] class of precatalyst (1) for
Tasymmetric transfer hydrogenation (ATH) of ketones
and imines, first reported by Noyori et al.,1 are now established
reagents for synthetic chemists.2 Although the parent
compounds contain a TsDPEN ligand with a primary amine
bound to the Ru(II), it is known that one substituent can be
added to the amine atom, i.e., in complexes 2, without causing
lack of activity (Figure 1),3−13 and in some cases a higher
activity, notably to CN reduction, is observed.5,6,11−13
Functional groups on the amine atom of TsDPEN can also
provide a means for tuning the structures of complexes to
particular substrates6,11−13 and to modify the properties of the
complexes, e.g., to improve their water solubility or assist
extraction from a mixture.9,10,14
Figure 2. Reported ligands for ATH using Ru3(CO)12.
However, very little work has been reported on the
functionalization of Ru/TsDPEN catalysts with heterocyclic
functionality on the amine atom, which would offer further
possibilities for wider synthetic applications. We previously
reported that TsDPEN derivatives 4 and 5, containing a
triazole or pyridine group, respectively, form active complexes
for ATH with Ru3(CO)12 which are capable of ATH of
ketones in IPA (Figure 2).15,16 However, these have not been
investigated as components of [(arene)Ru(TsDPENR)Cl]
precatalysts, and neither has the wider applications of these
ligands.
To gain a further understanding of the effect of
functionalizing the TsDPEN ligand with a heterocyclic group
on catalysis with both [(arene)Ru(TsDPENR)Cl] and
Received: July 8, 2019
Figure 1. [(Arene)Ru(TsDPEN)Cl] ATH precatalyst derivatives.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02339
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Table 2. Application of Catalysts in Figure 5 to ATH of
Acetophenone in [(Benzene)Ru(TsDPENR)Cl]
a
Complexes
b
ligand
[S] (M)
time (h)
conv (%)
ee (%)
Ts/Furan 17
Ts/Thio 18
Ts/Isox 19
Ts/ester 20
Ts/BrFuran 21
Ts/Furan 17
Ts/Thio 18
Ts/Isox 19
1
1
1
1
1
2
2
2
2
72
72
72
95
86
24
24
72
156
95
56
99
60
73
99
98
96
90
90
93
95
96
95
92
92
90
93
Ts/ester 20
a
b
1 mol % 17−21, 5:2 HCO2H/Et3N, rt. R-configuration product
formed.
Figure 3. New ligands investigated in this project.
Table 1. Application of Ligands in Figure 3 to ATH of
a
Acetophenone using Ru3(CO)12
b
ligand
conv (%)
ee (%)
4
5
98
87
90
55
79
95
49
92
92
83
82
73
93
76
Ts/Thia 12
Ms/Py 13
Tris/Py 14
Tf/Py 15
6Me/py 16
a
1 mol % ligand, 0.33 mol % Ru3(CO)12, iPrOH, 80 °C, 48h, [S] =
b
0.1M. R-configuration product formed.
Figure 6. Products of ATH of substituted ketones using 4 or 5/
Ru3(CO)12 and complexes 17−20 (Table 3).
aldehyde. Ligand 8 was prepared by the cycloaddition of the
nitrile oxide PhCNO with a propargyl-substituted TsDPEN.
Ligand 10 was prepared by the reaction of TsDPEN with t-
butylbromoacetate.
Figure 4. (A) Likely active complex formed between tridentate
ligands and Ru3(CO)12.15,16 (B,C) Inert tridentate complexes 22 and
23 formed by reaction of ligands 4 and 5 respectively with
[(benzene)RuCl2]2.
We first evaluated the new ligands in the ATH reaction with
Ru3(CO)12 (Table 1), along with tests of 4 and 5 as control
reactions. We were surprised to find that ligands 6−11 did not
form active catalysts, whereas all of ligands 12−16 did. The
unreactive ligands all contain weaker donor atoms (6−10) or
more distal heteroatoms (11) and cannot form strong
tridentate complexes with Ru3(CO)12. We had previously
found that a benzyl group on the TsDPEN was also not an
effective catalyst, and these results align with this observa-
tion.15 It can be concluded that, for this application, a ligand
requires a third heteroatom containing a strong donor atom
which can form a tridentate complex (Figure 4) which acts as
the catalyst in the reaction. As previously described, the
hydrogen transfer mechanism is likely to involve a bifunctional
catalysis mechanism,15,16 similar to that reported for complex
1.17
Because the results suggested that the non N-donating
heterocycles were weak donors, we examined the preparation
of derivatives of the catalysts with [(Benzene)RuCl2]2 in the
anticipation that, provided the heterocycle did not coordinate
to the metal, that it would not hinder the generation of an
active catalyst. The use of benzene as the η6-ligand in the
complex is important, as we have previously found that the use
Figure 5. Complexes 17−21 prepared from weak donor heterocycle
derivatives of TsDPEN and isolated.
Ru3(CO)12, we prepared a diverse series of derivatives (R,R)-
6−16 which contain alternative donor groups (Figure 3).
Ligand 6, 7, 9, and 11−16 were prepared through the
reductive amination of (R,R)-TsDPEN with the corresponding
B
DOI: 10.1021/acs.orglett.9b02339
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Organic Letters
Letter
a
Table 3. Application of Catalysts to ATH for the Synthesis of Products 24−35
reduction product/
catalyst
reduction product/
catalyst
time (h) conv (%) yield (%) ee (%) R/S
time (h) conv (%) yield (%) ee (%) R/S
b
,
c
24/4/Ru3(CO)12
24/5/Ru3(CO)12
24/Furan 17
24/Thio 18
24/Isox 19
24/Ester 20
25/4/Ru3(CO)12
25/5/Ru3(CO)12
25/Furan 17
25/Thio 18
25/Isox 19
25/Ester 20
26/4/Ru3(CO)12
26/5/Ru3(CO)12
26/Furan 17
26/Thio 18
26/Isox 19
26/Ester 20
27/4/Ru3(CO)12
27/5/Ru3(CO)12
27/Furan 17
27/Thio 18
27/Isox 19
27/Ester 20
28/4/Ru3(CO)12
28/5/Ru3(CO)12
28/Furan 17
28/Thio 18
28/Isox 19
28/Ester 20
29/4/Ru3(CO)12
29/5/Ru3(CO)12
29/Furan 17
29/Thio 18
29/Isox 19
29/Ester 20
nr
nr
30/Furan 17
30/Thio 18
30/Isox 19
120
120
144
144
72
95
52
85
96
99
71
89
55
66
71
100
95
93
88
41
84
92
91
66
70
49
57
66
98
89
93
61
96
48
99
92
92
45
73
45
91
91
92
96
83
92
88
84
90
92
90
89
90
87
89
93
92
91
93
88
76
90
94
88
93
92
93
90
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
b
,
c
120
120
144
168
72
72
72
120
96
84
41
74
79
94
96
71
89
91
97
94
91
92
91
81
53
92
94
90
92
S
S
S
S
S
S
S
S
S
S
30/Ester 20
31/4/Ru3(CO)12
31/5/Ru3(CO)12
31/Furan 17
31/Thio 18
31/Isox 19
31/Ester 20
32/4/Ru3(CO)12
32/5/Ru3(CO)12
32/Furan 17
32/Thio 18
32/Isox 19
32/Ester 20
33/4/Ru3(CO)12
33/5/Ru3(CO)12
33/Furan 17
33/Thio 18
33/Isox 19
33/Ester 20
34/4/Ru3(CO)12
34/5/Ru3(CO)12
34/Furan 17
34/Thio 18
34/Isox 19
34/Ester 20
82
100
100
100
98
72
144
144
168
168
72
72
72
168
144
168
72
72
80
144
144
168
48
100
100
144
b
,
c
nr
nr
b
,
c
96
96
96
168
72
99
100
99
91
79
87
86
99
92
94
95
95
91
95
96
70
45
73
41
98
96
94
41
93
70
95
88
90
89
91
91
97
94
95
96
93
95
99
99
89
92
94
96
86
90
91
87
91
90
92
91
S
S
S
S
S
S
S
S
S
100
50
100
100
100
55
77
50
98
99
94
100
100
100
100
100
98
100
100
80
52
87
55
100
100
98
50
100
72
72
120
120
120
168
72
S
48
96
R
R
R
R
R
R
R
R
R
R
R
R
R
R
100
94
94
81
74
86
87
72
144
144
96
120
132
120
168
72
99
b
35/4/Ru3(CO)12
35/5/Ru3(CO)12
35/Furan 17
35/Thio 18
35/Isox 19
35/Ester 20
nr
nr
b
96
80
57
65
45
86
89
86
84
R
R
R
R
72
120
120
120
120
120
144
168
72
56
a
Either 5 mol % ligand 4 or 5, 1.67 mol % Ru3(CO)12, iPrOH, 80 °C,
30/4/Ru3(CO)12
30/5/Ru3(CO)12
48h, [S] = 0.1 M or 1 mol % 17−20, 5:2 HCO2H/Et3N, DCM,, [S] =
b
c
72
1 M rt. nr = no reduction. Catalyst inhibition observed.
of a more substituted arene in the complex can reduce its
activity.5 In all cases of ligands 6−10, we were pleased to find
that complexes, 17−21, respectively, were formed in the
reactions (Figure 5), the spectroscopic data for which
indicated the formation of [(benzene)Ru(TsDPENR)Cl].
Each of these complexes also proved to be effective at the
asymmetric ketone hydrogenation of acetophenone in good ee
(Table 2). Ligand 11 did not form a stable complex.
Ligands 4 and 5 were combined with [(benzene)RuCl2]2,
but neither formed an active ATH complex. Analysis of the
spectroscopic data for the resulting complexes indicated the
formation of tridentate cationic species 22 and 23 instead,
both of which were stable and inert (Figure 4). In view of the
observations, the formation of complexes with closely related
ligands 12−16 was not investigated. A recently reported series
of TsDPEN-derived, tridentate ligand-containing (arene)Ru-
(II) complexes have been demonstrated to be effective ATH
catalysts, with reversible formation of one of the Ru−N bonds
being important for reactivity.18
Having established which structural features of a substituted
ligand are essential for formation of specific catalyst types, the
application of both systems (specifically ligands 4 and 5 with
Ru3(CO)12, and complexes 17−20) was extended to a range of
substituted ketone substrates (Figure 6, Table 3). In these
examples, due to lower solubility in FA/TEA, the reactions
with 17−20 were run at [S] = 1 M with DCM as a cosolvent,
and the reactions with 4/5 employed 5 mol % of the catalyst to
ensure full conversion of these more hindered ketones. The
range of results allowed the identification of the best catalyst
for each substrate. In several cases where ligands 4 and 5 were
used, full conversions were observed even though the reaction
in IPA is reversible, presumably due to evaporation of the
acetone side product at the elevated reaction temperature.2d
The furan-substituted catalyst 17 proved to be the most
versatile, giving products of good ee for most substrates,
although the other catalysts gave products in excellent yield
and ee in some cases. For example, for product 26, catalysts 19
and 20 gave excellent results. For products 27 and 28, the
Ru3(CO)12 system worked very well. Ester-containing catalyst
C
DOI: 10.1021/acs.orglett.9b02339
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ligand. The complexes can be generated in situ or isolated
before use, depending on the class of substate under study.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02339.
Experimental procedures, NMR spectra, HPLC and full
table of reductions of 24−35 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: m.wills@warwick.ac.uk
*E-mail: goldenkeys9996@thegoldenkeys.com.cn
ORCID
Martin Wills: 0000-0002-1646-2379
Notes
Figure 7. Products of ATH of substituted ketones using in situ-
generated complexes 17−20. Conditions: 1 mol % ligand 6−9/0.5
mol % [(benzene)RuCl2]2, 5:2 FA:TEA, DCM, [S] = 1M, rt.
The authors declare the following competing financial
interest(s): Author Y Xu is founder and CEO of the company
supporting the work.
20 also gave reduction products 30 and 31 in the highest ees.
The thiophene-containing catalyst 18 was the least versatile
overall but gave one of the best results for product 27. It was
interesting to note that both α-chloro- and α-methoxyaceto-
phenone inhibited the catalysis by 4 and 5, which was
ACKNOWLEDGMENTS
■
We thank Warwick University and GoldenKeys High-Tech
Material Co., Ltd. for funding (of J.B.-R.) via the Warwick
Collaborative Postgraduate Scholarship Scheme. The research
data (and/or materials) supporting this publication can be
accessed at http://wrap.warwick.ac.uk/.
confirmed by
a test using a 1:1 mixture of
PhCOCH2Cl:PhCOMe in which neither ketone was reduced.
This may be due to competing co-ordination of the Ru(II) by
the substrate. However, the other heteroatom-substituted
reagents were compatible with all the catalysts tested. The
attempted reduction of the triple bond-containing ketone 35
was also not successful with 4 or 5. The alcohols in Figure 7
are novel ATH products in many cases and add to the utility of
ATH for the preparation of asymmetric alcohols, hence the
catalyst set described herein represents a valuable toolkit for
identification of suitable catalysts for ATH of diverse
substrates.
In a further demonstration of the value of the new bidentate
ligands, it was also found that catalysts 17−21 could be formed
in situ by combination of the precursor ligands 6−9 with
[(benzene)RuCl2]2. The complexes generated in this way
proved to be effective for the ATH of simple acetophenone
derivatives to give products 36−41 (Figure 7, Supporting
Information, Table S2) that have previously been reported as
substrates for 4/5/Ru3(CO)12.15,16 The use of the in situ
catalysts in these cases gave products in good conversion and
ee’s similar to those previous reported for ATH catalysis,
noting that ortho-substituted acetophenone derivatives are
challenging substrates that often give lower ee’s than less
hindered ketones.1−3,19
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effective catalysts for ATH of a range of functionalized ketones,
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