N-Functionalised TsDPEN catalysts for asymmetric transfer hydrogenation; Synthesis and applications

Article abstract of DOI:10.1016/j.tetlet.2015.09.135

A series of Ru(II)/arene complexes containing N-alkylated derivatives of TsDPEN were prepared and tested in the asymmetric transfer hydrogenation (ATH) of ketones. The results demonstrated that a wide variety of functionality were tolerated on the basic amine of the TsDPEN ligand, without significantly disrupting the ability of the catalyst to catalyse hydrogen transfer reactions.

Full text of DOI:10.1016/j.tetlet.2015.09.135

Tetrahedron Letters 56 (2015) 6397–6401
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
N-Functionalised TsDPEN catalysts for asymmetric transfer
hydrogenation; synthesis and applications
⇑
Rina Soni, Thomas H. Hall, David J. Morris, Guy J. Clarkson, Matthew R. Owen, Martin Wills
Department of Chemistry, The University of Warwick, Coventry CV4 7AL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2015
Revised 24 September 2015
Accepted 28 September 2015
Available online 30 September 2015
A series of Ru(II)/arene complexes containing N-alkylated derivatives of TsDPEN were prepared and
tested in the asymmetric transfer hydrogenation (ATH) of ketones. The results demonstrated that a wide
variety of functionality were tolerated on the basic amine of the TsDPEN ligand, without significantly
disrupting the ability of the catalyst to catalyse hydrogen transfer reactions.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric
Transfer
Hydrogenation
Ketone
TsDPEN
Alcohol
Introduction
afford improved aqueous solubility and activity in the reduction
of ketones in water.10 Applications of N0-alkylated derivatives of
The application of [(arene)Ru(TsDPEN)Cl] (TsDPEN = N-Tosyl-
1,2-diphenylethyl-1,2-diamine) complexes of type 1 to asymmet-
ric transfer hydrogenation (ATH) and asymmetric hydrogenation
(AH) of ketones and imines is now well-established.1–4 These cat-
alysts have been widely applied in synthetic chemistry5 and their
mechanisms of action have been studied in detail.6
N-tosyl-1,2-diaminocyclohexane to ATH have been reported,11a,b
as have secondary amine ligands derived from proline.11c,d The
ATH of some (electron poor) alkene bonds using N-alkylated
TsDPEN derivatives has also been reported.12
In our work, we have found that it was important to use ben-
zene as the arene for best results,9 however others have found that
p-cymene may be used.10,11 N-Alkylated complexes of type 2 still
work effectively because in the active hydride species 4, the ‘R’
The majority of applications of this class of catalysts involve the
use of 1, or close derivatives, which contain a ligand with a primary
amine group, and a p-cymene arene group.7 However complexes
derived from TsDPEN ligands containing secondary amine groups,
for example, complexes 2a–2g, are also viable, although less well
studied despite the obvious scope for the attachment of function-
ality at this position. Ikariya and Kioke8 have described the process
of hydride transfer from formate to the Ru atom within N-methy-
lated complex 2a, whilst we have reported the preparation and
applications to ketone and imine reduction of a series of N-alky-
lated complexes 2a–2g.9 Scheme 1 illustrates some examples of
ketone reduction using formic acid/triethylamine 5:2 azeotrope
(FA/TEA) as the reducing agent, however isopropanol and molecu-
lar hydrogen have also been employed.1–6 Li et al. reported the use
of catalyst 3, and close derivatives containing an N-PEG chain to
group can occupy a position in which it is proximal to the
g
6-arene
ring.9a This allows the remaining N-H bond to form a productive
interaction with the ketone substrate (as illustrated by structure
5), which is essential for the hydrogen transfer step. Tethered
complexes such as 6 and 79c,13 also contain an N-alkylated group
although this is conformationally locked in a position which
permits the N–H of the hydride form to operate in the required
manner for reduction.
The ability to N-functionalise the basic nitrogen atom of the
ligand in TsDPEN/Ru/arene complexes provides a valuable route
for productive functionalisation, as illustrated by 3,10 and also pro-
vides a means to introduce groups which could allow the catalyst
to be attached to other groups such as polymeric supports. Linking
through this position appears to have found limited application to
form solid-supported reagents14 which is in contrast to the many
examples of linking through the sulfonamide function of the
ligand.15 In this Letter we describe the synthesis of a number of
⇑
Corresponding author.
E-mail address: m.wills@warwick.ac.uk (M. Wills).
http://dx.doi.org/10.1016/j.tetlet.2015.09.135
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

6398
R. Soni et al. / Tetrahedron Letters 56 (2015) 6397–6401
(R1 = Me, R2 = iPr, 1 mol%)
Time= 26 h, Conv = 99%, 95% ee
2a
1
R1
R2
Cl
OH
(R1 = R2 = H, 1 mol%)
O
i)
Ru
N
Time= 11 h, Conv = 99%, 96% ee
(R)
TsN
Ph
Ph
(R,R) catalyst
2e (R1 = R2 = H, 1 mol%)
R
Time= 8 d, Conv = 95%, 95% ee
3 (R1 = Me, R2 = iPr, 1 mol%)
Time = 15 h, Conv = >99%, 95% ee
H
Scheme 1. ATH of acetophenone using N-alkylated Ru complexes. Reagents and conditions: (i) catalyst, FA/TEA, 28 °C.
N-alkylated complexes and demonstrate their viability as catalysts
for ketone reduction.
2a R = Me
2b R = Et
2c R = nPr
2d R = iBu
2e R = CH2Ph
R
Cl
H
H
Cl
H
Ru
N
Ru
N
TsN
Ph
TsN
Ph
Results and discussion
Ph
Ph
2f
2g
(CH2)2Ph
R = (CH2)nOH (n=2-4)
1
We first investigated the synthesis of an ester-functionalised
catalyst 8, in order to establish a synthetic route and the compat-
ibility of an ester-containing group with the ATH conditions
(Scheme 2). Using a literature procedure, allyl alcohol was coupled
to 4-iodo ethylbenzoate 9 to form aldehyde 10.16 A side reaction
also occurred to form an unsaturated 3-carbon chain as a side pro-
duct (ca. 6–20%, see ESI).
OH/OMe
R
Ru
O
TsN
Ph
Ru
TsN
n
H
H
Cl
N
Ph
N
Ph
H
Ph
3
4 (R defined as for 2)
The reductive amination of 10 with (R,R)-TsDPEN, was achieved
using sodium cyanoborohydride as reductant to give the product
amine 11 as a crystalline and air stable solid. Complexation with
[(benzene)RuCl2]2 was achieved by treating 11 at reflux in IPA with
triethylamine;2d formation of 8 was straightforward and the
product was purified on silica gel. Suitable single crystals for X-
ray analysis were obtained by recrystallisation and the resulting
crystal structure confirmed the assigned stereochemistry
(Fig. 2).17 As expected for complexes of this type, the (R,R) carbon
backbone led to an (S) configuration at the ruthenium atom.2d
It was hoped that the ethyl ester in 8 could be directly hydrol-
ysed to generate the carboxylic acid complex 12. However,
although hydrolysis with both KOH/DCM/H2O and LiOH/THF/H2O
generated the known 16 electron species through elimination of
HCl,2d as characterised by a colour change from orange to bright
purple, ESI MS and NMR showed no effect on the ester
functionality. Acidic workup with HCl resulted in recovery of the
18 electron chloride complex 8. However, treatment of 11 with
KOH in refluxing MeOH/H2O gave 13 in high yield. Complexation
of 13 with [(benzene)RuCl2]2 was attempted and a catalytically
δ-
δ+
H
O
Ru
N
Cl
Ru
N
Cl
R
H
H
Ru
N
TsN
Ph
TsN
Ph
TsN
Ph
Ph
H
H
Ph
O
Ph
7
6
Me
5
Figure 1. TsDPEN/Ru(II) complexes (1–4, 6, 7) for the ATH of ketones and imines,
and the proposed mode of hydrogen transfer to ketone substrates (5).
I
i)
ii)
O
37%
85%
CO2Et
CO2Et
Figure 2. Single crystal X-ray structure of 8; hydrogen atoms have been omitted for
clarity, except at stereocentres.
10
9
Ph NHTs
iii)
63%
Ru
TsN
Ph
Ph
N
H
Cl
H
Table 1
N
Ph
CO2Et
Optimisation of conditions for the reduction of acetophenone using 8a
CO2Et
11
8
Entry
T (°C)
S/C
Time (h)
Conv (%)
ee (%)
iv)
94%
v) or vi)
1
2
3
4
60
45
45
28
1000
500
100
100
48
48
6
65
92
99
97 (R,R)
95 (R,R)
95 (R,R)
96 (R,R)
Ph NHTs
21
100
iii)
18%
Ru
N
TsN
Ph
Ph
N
H
a
Cl
H
Conversion and ee were determined by chiral GC.
Ph
CO2H
CO2H
13
12
not isolated
active complex was formed by combining the reagents in situ. A
product was isolated which gave a 1H NMR spectrum of what
appeared to be the triethylammonium adduct of 12, however in
a DCM solution the complex decomposed over ꢀ24 h, forming a
Scheme 2. Reagents and conditions: (i) allyl alcohol, Pd(OAc)2 (6 mol %), TBAB,
NaHCO3, 3 Å MS, DMF, 70 °C, sealed tube; (ii) (R,R)-TsDPEN, AcOH, 4 Å MS, MeOH,
then NaBH3CN, rt; (iii) [(C6H6)RuCl2]2, NEt3, iPrOH, 80 °C, reflux; (iv) KOH, MeOH/
H2O, 70 °C, 1 h; (v) KOH/DCM/H2O; (vi) LiOH/THF/H2O.

R. Soni et al. / Tetrahedron Letters 56 (2015) 6397–6401
6399
O
O
the (R) enantiomer would be the major product. Using a standard
substrate concentration of 2M in FA/TEA (5:2 azeotrope), the
temperature and substrate to catalyst ratio were varied as shown
in Table 1.
MeO
O
O
O
Cl
MeO
MeO
14
18
15
16
17
Initial attempts focused on the use of high temperature and low
catalyst loading. However this required long reaction times and
gave incomplete conversion. Increasing the loading to 1 mol % gave
almost complete conversion after 6 h at 45 °C and 21 h at 28 °C,
with almost no loss of enantioselectivity. Hence the conditions in
entry 3 were selected for further applications. Under the optimised
conditions, the new ester catalyst 8, along with its acid analogue 12
were tested in the ATH of a series of ketones 14–18 (Fig. 3).
The effect of varying the substrate substitution pattern was
Figure 3. Substrates for ATH by complex 8.
Table 2
Ketone reduction using catalysts 8 and 12a
Entry
Ketone
Catalyst
Time (h)
Convb (%)
eeb (%)
1
Acetophenone
Acetophenone
8
12
8
12
8
6
20
99
99
100
100
98
95 (R)
95 (R)
88 (S)
89 (S)
79 (R)
79 (R)
95 (R)
96 (R)
92 (R)
95 (R)
42d (S)
42d (S)
2c
3
14
14
15
15
16
16
17
17
18
18
1.5
1.5
5.5
5.5
5
explored by the use of a-chloro acetophenone 14, as well as ortho,
4
5
6
7
8
9
10
11
12
meta and para (15, 16, 17) isomers of methoxyacetophenone.
Cyclohexylmethylketone 18 was also chosen to investigate how
the selectivity changed when reducing di-alkyl ketones (Table 2).
12
8
97
92
12
8
12
8
5
95
88
89
99
As expected, an
a-chloro substituent on the ketone increases the
23.5
23.5
22
rate of reaction due to the increased electrophilicity of the carbonyl
carbon. This increased rate came at the penalty of selectivity,
with reduced enantiomeric excess when compared to those for
acetophenone. Upon introducing a methoxy substituent onto the
aromatic ring at the meta position there was little effect other than
reducing the reaction rate; which was due to the increased
electron density on the aromatic ring making the carbonyl less
electrophilic.13g This effect was strongly increased at the para
position, where full conversions could not be achieved even after
24 h. Enantioselectivity was unaffected however and the
obtained ee remained high. Ortho substitution appeared to have
no additional effect on the rate, but significantly reduced the
enantiomeric excess, as had been seen before,2,13 possibly due to
a steric clash with the catalyst.
12
22
96
a
b
c
Reaction conditions: Ru-Catalyst (1 mol %), FA/TEA (5/2 azeotrope), 45 °C.
Conversion and ee determined by chiral GC.
Reduction performed at 28 °C.
d
ee determined by chiral GC after acetylation of the alcohol product.
Ru
N
TsN
Ph
Ru
N
TsN
Ph
Cl
Cl
Ph
Ph
OMe
H
H
19
20
Reduction of cyclohexyl methyl ketone is challenging for most
ATH catalysts, as the high enantioselectivities achieved in reduc-
tion of aryl alkyl ketones are generally dependent on the aromatic
Ph NHTs
N
Ru
N
TsN
N
N
N
Ph
N
H
Cl
CH-p interaction with the ruthenium arene (5, Fig. 1). Without this
Ru2+
Ph
OMe
H
N
2Cl-
interaction the two faces of the ketone are solely distinguished by
the steric bulk of its substituents, hence the ee is frequently lower,
and selectivity is reversed, as observed.2–4
Ph
22
21
N
The basic nitrogen atom of the TsDPEN ligand was also func-
tionalised through the addition of a number of other groups with
potential functionality including a cyclohexadiene (19), anthracene
(20), and even a ruthenium complex (21) (Fig. 4).
Complex 19 was prepared by the reaction between 22 and
[(C6H6)RuCl2]2. Complex 20 was synthesised through in situ forma-
tion of the triflate derived from 3-(1-anthracen-9-yl)propan-1-ol
23,18 followed by reaction with TsDPEN, and reaction of the result-
ing ligand 24 with [(C6H6)RuCl2]2 (Scheme 3). The BIPY–containing
Figure 4. N-Alkylated catalysts for ATH.
black solution from the original bright orange. Hence 12 was used
in its crude form.
Reduction of acetophenone to 1-phenylethanol (Scheme 1) is
the standard benchmark to evaluate the performance of ATH
catalysts, hence this reaction was used for the optimisation of
reduction conditions. Using the (R,R) catalyst it was expected that
ii)
i)
73%
45%
CO2Me
Cl
CO2Me
CO2Me
91%
Ru Cl
TsN
iii)
H
Ph
Ph
NHTs
N
Ph
v)
iv)
Ph
N
H
75%
68%
20
24
23
OH
Scheme 3. Reagents and conditions: (i) dimethyl malonate, NaOMe, MeOH, reflux, 30 h; (ii) LiCl, H2O, DMSO, 130 °C, 18 h; (iii) LiAlH4, THF, 0 °C–rt, 5 h; (iv) 2,6-lutidine, triflic
anhydride, DCM, 0 °C, 30 min, rt, 60 min, then (R,R)-TsDPEN, TEA, DCM, 0 °C, 30 min, rt, 18 h; (v) [C6H6)RuCl2]2, IPA, TEA, 80 °C, 1 h.

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R. Soni et al. / Tetrahedron Letters 56 (2015) 6397–6401
iii)
iv)
N
NHTs
N
N
N
N
R
100%
92%
N
N
Ph
O
i)
R=H
H
R=CH2CO2Me 70%
R=CH2CH2OH 100%
Ph
25
ii)
26
v)
86%
N
vi)
NHTs
N
N
N
N
Ru
TsN
Ph
N
N
N
Ph
Ru2+
N
Cl
H
Ru2+
N
Ph
2Cl-
Ph
N
H
2Cl-
N
N
27
21
N
Scheme 4. Reagents and Conditions: (i) LDA, THF, ꢁ78 °C to rt then BrCH2CO2Me, ꢁ78 °C; (ii) DIBAL, ꢁ78 °C to rt, 18 h; (iii) (COCl)2, DCM, DMSO, ꢁ78 °C, Et3N; (iv) TsDPEN,
MeOH, AcOH, rt, 4.5 h, then NaBH3CN, 4A MS, rt, 18 h; (v) [Ru(bipy)2Cl2], MeOH, water, 95 °C, 17 h; (vi) [(C6H6)RuCl2]2, iPrOH, Et3N, 80 °C, 1 h, crude product used in reduction
reactions.
Table 3
References and notes
Acetophenone reduction using complexes 19–21a
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Entry
Catalyst
Temp (°C)
Time (h)
Conva (%)
eea (%)
1
2
3
4
5
6
7
19
20
20
20
21
21
21
28
28
28
28
28
28
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20
4
8
23
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22
39
99
70
93
100
68
81
96 (R)
97 (R)
97 (R)
97 (R)
93 (R)
93 (R)
93 (R)
89
a
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ligand was prepared via aldehyde 2519 which was coupled by
reductive amination with (R,R)-TsDPEN to give 26, conversion to
ter(BIPY) complex 27 and subsequently reaction with [(C6H6)
RuCl2]2 to give 21 (Scheme 4). Complex 21 was not fully charac-
terised but used directly as the in situ-formed material, although
1H-NMR spectroscopy indicated the correct composition.
A summary of the results from the ATH studies on ace-
tophenone using complexes 19–21 is given in Table 3. All of
these worked as effective catalysts, including those formed
and used in situ, and products of high ee were formed in each
case. This highlights the versatility and functional group toler-
ance to substitution on the N atom of TsDPEN-derived Ru(II)
catalysts.
In conclusion, complexes 8, 12 and 19–21, containing a range of
functional groups on the basic nitrogen atom of the TsDPEN ligand,
were synthesised and applied to the ATH of ketones using formic
acid/trimethylamine (FA/TEA) as the reducing agent. All demon-
strated good activity for the ATH of ketones under the conditions
used. In principle it should be possible to utilise this linkage to
combine the catalyst to other useful molecules, such as secondary
catalysts, fluorescent tags or polymeric supports.
Acknowledgements
We thank the Leverhulme Trust (Grant no RPG-374) for support
to R.S. and the ESPRC for funding of D.J.M. (Grant EP/F061420/1).
M.R.O. was supported by the Warwick University URSS scheme
and THH was a final year project student supported by Warwick
University.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
135.

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a
= 90°, b = 90°,
5908 reflection positions), T = 150(2)K, k = 1.54184 Å, Z = 4, D(cal)
= 1.414 Mg mꢁ3, F(000) = 1592. ) = 5.063 mmꢁ1
(MoK-
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= 90°, U = 3618.5(7) Å3 (by least squares refinement on
l
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