Asymmetric Transfer Hydrogenation of Aryl Heteroaryl Ketones using Noyori-Ikariya Catalysts

Article abstract of DOI:10.1002/cctc.202101027

A range of ketones flanked by a combination of an aromatic and a heterocyclic ring (furan, thiophene, N-methylimidazole) were reduced under asymmetric transfer hydrogenation (ATH) conditions. Using a range of [(arene)Ru(TsDPEN)Cl] precatalysts, including tethered derivatives, the reduction enantioselectivity was high (up to 99 % ee) in cases where the aromatic ring contained an ortho-substituent. The enantioselectivity is influenced by a combination of steric and electronic factors which for the furan and thiophene series, follow literature precedents. In the case of the N-methylimidazole-containing ketones, an unexpected switch in enantioselectivity took place upon variation of the opposing aromatic group. Pyrrole- containing ketones were resistant to reduction. This study demonstrates the asymmetric transfer hydrogenation (ATH) of a range of hindered heterocyclic ketones, in high conversion and ee, using Noyori-Ikariya catalysts.

Full text of DOI:10.1002/cctc.202101027

The European Society Journal for Catalysis
Supported by
Accepted Article
Title: Asymmetric transfer hydrogenation of aryl heteroaryl ketones
using Noyori-Ikariya catalysts
Authors: Martin Wills, Ye Zheng, Jaime Martinez-Acosta, Mohammed
Khimji, Luiz Claudio Barbosa, and Guy Clarkson
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To be cited as: ChemCatChem 10.1002/cctc.202101027
Link to VoR: https://doi.org/10.1002/cctc.202101027
01/2020

10.1002/cctc.202101027
ChemCatChem
FULL PAPER
Asymmetric transfer hydrogenation of aryl heteroaryl ketones
using Noyori-Ikariya catalysts
Ye Zheng,[a] Jaime A. Martinez-Acosta,[b] Mohammed Khimji,[a] Luiz C. A. Barbosa,[b] Guy J. Clarkson[a]
and Martin Wills.[a]*
[a]
[b]
Y. Zheng, M. Khimji, Dr G.J. Clarkson, Prof. Dr. M. Wills,
Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, UK m.wills@warwick.ac.uk: https://twitter.com/WarwickChem
Dr J. A. Martinez-Acosta, Prof. Dr L. C. A. Barbosa,
Universidade Federal de Minas Gerais, Dept Chem, ICEx, Av Presidente Antonio Carlos 6627, Campus Pampulha, BR-31270901 Belo Horizonte, MG,
Brazil
Supporting information for this article is given via a link at the end of the document
Abstract: A range of ketones flanked by a combination of an
aromatic and heterocyclic ring (furan, thiophene, N-
methylimidazole) were reduced under asymmetric transfer
hydrogenation (ATH) conditions. Using range of
excellent example of where highly enantioselective reduction
can be achieved (Figure 2) by applying the desirable design
features to the substrates.6
a
a
[(arene)Ru(TsDPEN)Cl] precatalysts, including tethered derivatives,
the reduction enantioselectivity was high (up to 99% ee) in cases
where the aromatic ring contained an ortho-substituent. The
enantioselectivity is influenced by a combination of steric and
electronic factors which for the furan and thiophene series, follow
literature precedents. In the case of the N-methylimidazole-
containing ketones, an unexpected switch in enantioselectivity took
place upon variation of the opposing aromatic group. Pyrrole-
containing ketones were resistant to reduction. This study
demonstrates the asymmetric transfer hydrogenation (ATH) of a
range of hindered heterocyclic ketones, in high conversion and ee,
using Noyori-Ikariya catalysts.
Figure 1. [(arene)Ru(TsDPEN)Cl] complexes for ATH of ketones.
Introduction
Asymmetric transfer hydrogenation (ATH) of ketones, using
formic acid / triethylamine azeotrope (FA:TEA, 5:2) provides an
efficient route for the enantioselective synthesis of alcohols.1-6
Numerous ketone reduction applications using ATH with
ruthenium-based Noyori-Ikariya type catalysts such as 1 – 6
(Figure 1) have been published in recent years. Acetophenone
derivatives,2 propargylic ketones3 and perfluorinated ketones4
are well suited to ATH using Noyori-Ikariya catalysts and have
provided the basis for numerous successful ATH studies, as has
dynamic kinetic resolution (DKR) coupled with ATH.4c,5 However
it would be desirable to continue to expand the methodology to a
wider range of substrates, including what might traditionally be
considered to be challenging ketones for ATH. In the case of
benzophenones, which have similar groups flanking the ketone,
significant electronic differences between substituents can
improve the reduction enantioselectivity, as can differences in
steric hindrance (Figure 2).6 The use of substrates containing an
ortho-substituted aromatic ring adjacent to the ketone to
facilitate enantioselective reduction has also been applied to
propargylic ketones.3b There have been relatively few reports on
the asymmetric reductions of analogous heteroaromatic ketones,
despite the known compatibility of heteroaromatics with ATH
conditions,6b,6c,7 including DKR-ATH applications (Figure 2).8 The
application of ATH to the reduction of pyridine and pyridine N-
oxide analogues of benzophenones by Zhou et al represents an
Figure 2. A. reduction of ketones by ATH using formic acid/triethylamine. B.
Reduction products of benzophenones and heterocyclic ketones using ((R,R)-
configuration catalysts) catalysts 1 - 6. Electronic or steric differences between
1
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10.1002/cctc.202101027
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the substituents facilitate high asymmetric induction. C. Likely mode of
hydrogen transfer illustrated for (R,R)-configuration catalyst. (S,S)-
Configuration catalyst will give the opposite absolute configuration product but
via the same directing effects.
The more electron-rich OMe-substituted catalyst (R,R)-5 was
much less active and the benzyl-tethered (R,R)-4 was of
intermediate activity. All tethered catalysts were more active or
comparable to the non-tethered catalyst (S,S)-6, which gave
products of opposite configuration to the other catalysts, i.e.
indicating that a common mechanism is operating between all
catalysts.1 The pyrrole-containing substrate 20 was not reduced
by any catalysts however, or even when 5 mol% of catalyst
(R,R)-2 was used. Ketone 21 (Figure 4), designed to be less
electron rich, was also not reduced using (R,R)-2.
Whilst the factors which control the sense of ATH reductions are
known to be complex,9 for the examples illustrated the model in
Figure 2C serves to summarise the likely approach of substrate
to catalyst in the key hydride-transfer step.6,7 Other catalyst
systems have also been applied to the successful asymmetric
reduction of benzophenones and their heterocyclic derivatives.10
Apart from the examples which have been reported, the ATH of
substrates containing
a combination of heterocyclic and
aromatic groups is relatively under-explored to date.
Results and Discussion
Given the lack of information on the ATH of ketones containing a
combination of aromatic and heterocyclic groups flanking the
ketone, we undertook a study on a systematic group of
substrates (Figure 3).
Figure 3. ATH reactions which were investigated in this study.
As well as investigating the effect of substrate structure, we also
took the opportunity to compare the activity and selectivity of a
number of ATH catalysts. Therefore we focussed on the use of
the ‘3C-tethered’ 2,1 ‘benzyl-linked’ 4,1b ‘OMe-substituted’ 51b
and the untethered catalyst 6.1 The (R,R)- form of the catalysts 2,
4 and 5 were used, however the (S,S)- enantiomer of 6 was
employed. As substrates, we selected ketones where Ar = Ph, o-
(MeO)C6H4 (oOMe), o-(Me)C6H4 (oMe), o-(Br)C6H4 (oBr), o-
(Br)C6H4 (oCl) and -naphthyl (Np) versus Het = 2-furyl (Fu), 2-
thienyl (Thio), 2-N-methylimidazole (Im) and 2-N-methylpyrrole
(PyMe) (Figure 4), these being designed to test the effect of
aromatic ring size and heterocycle type across a range of
substrates. The ketones were prepared either by the addition of
a Grignard reagent to the corresponding aldehyde followed by
oxidation or by acylation of N–methylimidazole (Supporting
Information). Products 7 – 19, formed from the ATH reactions
are shown in Figure 4 (for reductions with (R,R(-2) / Table 1 (for
reductions with other catalysts). Conversion and ee vs time
graphs for several reductions are given in the Supporting
Information. Reactions were consistently carried out at loadings
of 1 mol% catalyst in FA:TEA (5:2 azeotropic mixture) as the
hydrogen source and DCM (due to the limited solubility of the
substrates in pure FA/TEA), at room temperature.
Figure 4. Products of ATH formed in this study using catalyst (R,R)-2, and
ketones which were not reduced. Products have configuration either known or
speculated to be formed. The method used for determination of the absolute
configuration is given in brackets. Products are depicted with the group
speculated to be closest to the catalyst6-arene ring during the hydrogen
transfer (Figure 2C) on the right-hand side. Table 1 illustrates the results of
reductions using alternative catalysts, where studied.
Substrates
containing
furan,
thiophene
and
methylimidazole groups were all reduced with one or more of the
catalysts however there was a significant variation in both the
activity and the enantioselectivity. The 3C tethered complex
(R,R)-2 proved to be the most enantioselective catalyst for most
substrates, also delivering products in almost quantitative
conversions at rt in most cases. This catalyst was therefore used
as for reduction of each substrate we tested, to provide a
comparison of activity and enantioselectivity between substrates.
2
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10.1002/cctc.202101027
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Table 1. ATH of aromatic/heterocyclic substrates; results not illustrated in
this suggests a slight preference for the furan or thiophene to
adopt the position proximal to the6-arene in the complex.
Introduction of an ortho-methoxy group to the aromatic ring in
the substrate provided a route to products 8a (oOMe/Fu) and 11
(oOMe/Thio) in higher ees of 97% and 96% respectively.
Although the configurations could not be proven unambiguously,
we tentatively assign R- configuration to these products by
analogy with the non-methoxylated products and would suggest
that the higher ee arises from increased hindrance placing the
aromatic ring in the position distal from the6-arene, i.e.
following on from previous observations (Figure 2C).5,6 The
structurally-related products 8b-8d were also formed in very high
Figure 4.*
ATH product
Catalyst
Temp./
oC
rt
time
/h
Conv.
/%
100
100
99
99
28
58
100
27
47
97
39
30
62
98
37
99
0
ee
/%
7 Ph/Fu [a]
(R,R)-4
(R,R)-5
(S,S)-6
(R,R)-4
(R,R)-5
(S,S)-6
(R,R)-4
(R,R)-5
(S,S)-6
(R,R)-4
(R,R)-5
(S,S)-6
(R,R)-4
(R,R)-5
(S,S)-6
(R,R)-4
(R,R)-5
(S,S)-6
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-4
(R,R)-5
(R,R)-6
(S,S)-6
(R,R)-4
(R,R)-5
(S,S)-6
(S,S)-6
(R,R)-2
(R,R)-6
(R,R)-4
(R,R)-5
(S,S)-6
(R,R)-2
(S,S)-6
(R,R)-2
(R,R)-4
(R,R)-5
(S,S)-6
(R,R)-2
158
120
163
164
164
159
47
61 (R)
27 (R)
43 (S)
89 (R)
56 (R)
88 (S)
91 (R)
31 (R)
94 (S)
69 (R)
25 (R)
28 (S)
88 (R)
48 (R)
89 (S)
99 (R)
-
“
rt
“
rt
8a oOMe/Fu [c]
rt
“
rt
“
rt
9 Np/Fu [b][c]
rt
“
rt
76
ee (90-98% ee), indicating
a useful level of generality.
“
rt
144
160
187
160
186
189
217
162
165
165
16
10 Ph/Thio [a]
rt
Continuing this trend and using catalyst (R,R)-2, products 9
(Np/Fu) and 12 (Np/Thio) were also formed in excellent ees of
87% and 99% respectively. The absolute configuration of the
major 9 (Np/Fu) product was confirmed by X-ray crystallographic
analysis (Figure 6A) and that of 12 (Np/Thio) was assigned by
analogy with this. Again, these results fit the accepted model for
hydrogen transfer (Figure 7A), with more hindered substrates
giving products of highest ee. The sense of reduction for the
furan and thiophene-containing substrates aligns with that
reported in precedents (Figure 2) which the more electron-rich
heterocycle adopts the position adjacent to the 6-arene of the
catalyst as illustrated in Figure 7A and 7B. For the 1-Np
products 9 and 12, there is precedent in the reported ATH of
PhCO(1-Np) using a closely-related ansa-Ru sulfamoyl-(S,S)-
DPEN catalyst (Figure 7E).2e In this example, the Np ring adopts
the position distal to the 6-arene of the catalyst. This is in
contrast to the reduction mode of 1-acetylnapthylene (Figure 7F)
in which the Np ring occupies the expected position adjacent to
the 6-arene of the catalyst during the reduction. Notably,
catalyst (R,R)-4 gave 7 (Ph/Fu) and 9 (Np/Fu) in slightly higher
61% ee and 91% ee respectively, and full conversion. Catalyst
(S,S)-6 gave 9 (Np/Fu) in 94% ee, which was the highest for this
product, but only 47% yield. Surprisingly, catalyst (R,R)-5 did not
give any 12 (Np/Thio), possibly due to a specific destabilising
effect involving the methoxy substituent. However the catalyst
proved to be effective at slightly elevated temperature (see
below).
“
rt
“
rt
11 oOMe/Thio [c]
rt
“
rt
“
rt
12 Np/Thio [c]
rt
“
rt
“
rt
90
100
100
88
100
100
100
55
28
6
97 (S)
96 (R)
98 (R)
95 (R)
95 (R)
94 (R)
97 (R)
80 (R)
94 (R)
14 (R)
50 (S)
13 (S)
48 (R)
43 (R)
14 (S)
38 (S)
93 (S)
91 (S)
42 (R)
57 (S)
93 (R)
81 (S)
93 (R)
85 (R)
18 (S)
89 (R)
12 Np/Thio [c]
12 Np/Thio [c][e]
12 Np/Thio [c][f]
12 Np/Thio [c][e]
12 Np/Thio [c][f]
12 Np/Thio [c][e]
12 Np/Thio [c][e]
12 Np/Thio [c][e]
13 pOMe/Im [c]
14 Ph/Im [c]
“
38
40
40
60
60
40
40
40
rt
16
16
4
6
16
16
16
168
165
168
168
168
16
rt
30
14
6
rt
“
rt
15 pCl/Im [c]
15 pCl/Im [c][e]
15 pCl/Im [c][e]
16 oOMe/Im [b][d]
“
rt
22
100
10
68
61
5
40
40
rt
16
169
168
169
16
rt
“
rt
Although the reductions of 7-12 proceeded to complete or
almost complete conversion, we investigated the formation of 12
(Np/Thio), as a representative substrate, at slightly elevated
temperature. ATH reactions at temperatures of 40 and 60 oC
have been reported to proceed successfully with minimal loss of
enantioselectivity.1-6 Using catalyst (R,R)-2, using the standard
16 oOMe/Im [b][d][e]
18a oCl/Im [d]
18c oMe/Im [d][e]
19 Np/Im [b][d]
“
40
rt
100
14
31
60
26
8
168
16
40
rt
168
168
168
16
rt
“
rt
o
reaction conditions at 38 C led to full reduction in 16h, as did
19 Np/Im [b][d][e]
40
98
o
the reduction at 40 C in only FA/TEA. Using DCE as a solvent
*Reaction conditions are as given in Figure 3, at rt (ca. 20 oC) in FA/TEA/DCM
unless otherwise stated. [a] Configuration confirmed by comparison of optical
rotation to that reported. [b] Configuration established by X-ray crystallography.
[c] reported in racemic form/configuration not previously established. [d] novel
[e] reaction in FA/TEA alone. [f] reaction in 1,2-dichloroethane (DCE).
o
at 40 C gave 88% conversion after 16h. In these cases, the
products were formed in 96, 98 and 95% ee respectively, i.e.
slightly lower than at rt. At a higher temperature of 60 oC, in
FA/TEA alone, 100% reduction was achieved in 4h (95% ee)
o
and in 6h when DCE was used as cosolvent at 60 C (94% ee).
Extending the 40 oC, cosolvent-free conditions to the other
catalysts gave, in 16h, full conversion (97% ee) using 4, 55%
conversion (80% ee) with 5 and 28% conversion (94% ee) with 6.
The result with 5 was particularly significant as the rt reaction
had given no conversion, even over an extended reaction time,
for this sluggish substrate/catalyst combination. Hence, slightly
higher temperatures can accelerate the reactions, with slight
In the following discussion, the focus will be on the results
from the use of (R,R)-2, with others described if they gave
superior results. Taking the reductions of the furan- and
thiophene- containing substrates first, the configuration (R) of
the products 7 (Ph/Fu) and 10 (Ph/Thio) (Figure 4) were
assigned by comparison of the sign of their optical rotations with
those previously reported. Based on the model for ATH
reductions with this class of catalyst (Figure 2C and Figure 7),
3
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10.1002/cctc.202101027
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loss of enantioselectivity, and hence the conditions can be
selected for optimisation of rate or ee.
with the carbonyl group (Figure 6D). This would be in
accordance with the general suggestion that bulky aromatic
groups create a high level of steric hindrance which favours their
positioning distal to the6-arene in most cases (Figure 2).
The pattern of results for the methylimidazole series was
more complicated. Three alcohols (13-15), containing a para-
substituted or unsubstituted aromatic ring, were formed in 0% -
70% ee. Since the more electron-rich (OMe substituted)
substrate gave the highest ee product, and the electron-poor (Cl
substituted) the lowest, it is speculated that S- configuration
products were formed, via an approach of substrate to catalyst
in which the aromatic group is proximal to the 6-arene of the
catalyst (Figure 7C). Catalyst (S,S)-6 gave 15 (pCl/Im) in an
improved ee of 43% but just 22% conversion. The racemic
reduction using catalyst 2 at rt was improved at 40 oC in FA/TEA
alone; 100% conversion in 16h but still only 14% ee, In this case,
o
catalyst 6 gave just 10% conversion in 16h at 40 C vs 22% at
168h at rt. ortho-Methoxyphenyl-substituted product 16
(oOMe/Im) was formed in a very high ee of 98% at rt, and S-
configuration, as confirmed by X-ray crystal structure analysis
(Figure 6B). At 40 oC, full conversion was obtained in 16h but in
just 57% ee, representing a sharp drop relative to the rt reaction.
This was also supported by the formation of S-17 (oOH/Im)
under the same conditions, which, upon methylation was
converted to S-16 (oOMe/Im). It has been demonstrated that
ortho-hydroxyphenyl groups have a strong propensity to occupy
the position near the catalyst 6-arene during ketone reduction
(Figure 2C),11 and the same selectivity is likely operating here. In
contrast, ATH of substrate 22 containing two ortho-hydroxy
groups failed (Figure 4). Products 18a-18c, containing ortho-
chloro, bromo and methyl groups respectively, were also formed
in high ee (78%, 85%, 85% respectively) and were tentatively
assigned S configuration by analogy with 16 (oOMe/Im). The ee
of 18c (oMe/Im) dropped slightly, to 81%, but with 100%
o
conversion in 16h, at 40 C. Product 19 (Np/Im), was formed in
93% ee at rt (90% conv in 168h) and this dropped slightly to
o
89% ee when the reaction was run in FA/TEA at 40 C (98%
conversion in 16h), However its X-ray crystal structure revealed
an unexpected switch to the R-configuration (Figure 6C). This
suggests that the N-methylimidazole group occupies the position
near the 6-arene of the catalyst during the reduction (Figure
7D). Hence, how to explain the apparent switch in selectivity?
The N-methyl imidazole is likely to be protonated under the
mildly acidic reaction conditions; attempted ATH to form 16
(oOMe/Im) under neutral conditions in iPrOH/KOH gave no
product formation. In addition, the N-methyl substituent will
create further steric hindrance which may favour its positioning
as indicated in Figure 7C for the formation of 13, 14, 16, 17,
18a-18c and 17. However the bulkier Np structure may
overwhelm this preference when 19 is formed, as observed for
the reduction of PhCO(1-Np) (Figure 7E).2e It would appear that
the Ph ring opposing the 1-Np group prevents this substrate
from adopting a conformation which allows the 1-Np to adopt the
position observed for less-hindered substrates (Figure 7F). In
the reduction to form 19, we hypothesise that the protonated
methylimidazole, whilst likely to be less electron-rich, controls
the conformation of the substrate in a similar manner and this
leads to an analogous directing effect (Figure 7D). It is also
noteworthy that the ees were moderated by other catalysts,
indicating that some important, and more subtle, secondary
control factors also influence the reduction enantioselectivity.
An X-ray crystallographic structure of the ketone precursor
of 12 (Np/Thio ) revealed the naphthyl ring to be out of plane
Figure 6. X-ray crystal structures of major enantiomer of alcohols formed by
reduction with (R,R)-catalyst and one ketone precursor.
Figure 7. Reduction modes using catalyst (R,R)-2; A, B. Furan/thiophene
generally adopts the position adjacent to the 6-arene group. C, D. The N-
4
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10.1002/cctc.202101027
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(3.18 g, 36.6 mmol). The reaction mixture was left to stir under a nitrogen
atmosphere overnight. TLC (9:1 hexane: EtOAc) after this time indicated
full conversion. The solids were removed by gravity filtration and washed
with DCM. The combined solvent was removed to give the product as a
yellow oil (369 mg, 2.15 mmol, 88%). TLC: Rf ca 0.30 (9:1 hexane:
EtOAc), strong UV and KMnO4; 1H NMR (500 MHz, CDCl3): δ=7.97 (d,
3JH,H=7.3 Hz, 2H; Ar-H), 7.71 (s, 1H; Ar-H), 7.59 (t, 3JH,H=7.4 Hz, 1H; Ar-
H), 7.49 (t, JH,H=7.7 Hz, 2H; Ar-H + C4H3O), 7.23 (d, JH,H=3.5 Hz, 1H;
C4H3O), 6.60-6.59 ppm (m, 1H; C4H3O); 13C NMR (125 MHz, CDCl3):
δ=182.60 (C), 152.31 (C), 147.14 (CH), 137.28 (C), 132.60 (CH), 129.30
(CH), 128.44 (CH), 120.59 (CH), 112.23 ppm (CH). Data matched that
reported.
methylimidazole series exhibits
a more complex balance of selectivities
depending on the nature of the aromatic group on the opposing side of the
ketone. E,F. favoured modes of reduction of related 1-Np ketones. In the
original paper, the (S,S)-catalyst was employed however the sense of
reduction using the (R,R)-catalyst is illustrated for ease of comparison.2e
3
3
Conclusion
In conclusion, a series of hindered ketones flanked by a
combination of aromatic and heterocyclic groups have been
reduced efficiently by ATH using Ru(II) Noyori-Ikariya type
catalysts. In the case of furan and thiophene-containing
substrates, the products follow a selectivity which has been
established in previous studies in this area, for related ketones.
The ATH of N-methylimidazole-containing ketones, where the
heterocyclic group is likely protonated under the reaction
conditions, follows a more complex pattern of selectivity. This is
speculated to be due to a closer balance of steric and electronic
control factors, although most products were formed in good-
excellent ee. The heterocyclic alcohol products are of interest
and value to the asymmetric synthesis of challenging
heterocyclic targets, notably pharmaceutical molecules. The
formation of number of novel alcohols which may otherwise be
challenging to prepare, are reported, using a practical and
accessible catalyst system.
Furan-2-yl(phenyl)methanol
7 (Ph/Fu). This compound has been
reported and fully characterized.13,14 Furan-2-carbaldehyde (250 mg, 2.60
mmol) was added to a flask, followed by THF (2.5 mL) and the flask was
placed into an ice bath and cooled to 0°C, with stirring under a nitrogen
atmosphere. Phenyl magnesium bromide (0.950 ml, 3.0 M in diethyl
ether, 2.85 mmol) was added dropwise and the reaction was stirred
under the nitrogen atmosphere at rt overnight. The reaction was followed
by TLC (9:1 hexane: EtOAc). After 17 hours, the reaction was quenched
by the addition of distilled water (20 mL), extracted with EtOAc (3 × 20
ml), and the organic extracts were dried with MgSO4. The solvent was
removed under vacuum to give the product as a yellow oil (423 mg, 2.43
mmol, 92%). TLC: Rf ca 0.20 (9:1 hexane: EtOAc), strong UV and
KMnO4; 1H NMR (500 MHz, CDCl3): δ=7.45-7.33 (m, 6H; Ar-H + C4H3O),
3
3
6.32 (dd, JH,H=3.0 Hz, 1.5 Hz, 1H; C4H3O), 6.12 (d, JH,H=3.0 Hz, 1H;
C4H3O), 5.84 (d, 3JH,H=4.0 Hz, 1H; ArCHOH), 2.40 ppm (d, JH,H=4.0 Hz,
3
1H; OH); 13C NMR (125 MHz, CDCl3): δ=155.94 (C), 142.59 (CH), 140.80
(C), 128.50 (CH), 128.11 (CH), 126.61 (CH), 110.25 (CH), 107.47 (CH),
70.17 ppm (CH). Data matched that reported. The enantiomeric excess
and conversion were determined by HPLC analysis (Chiralcel ODH, 30
cm x 6mm column, hexane:iPrOH 97:3, 1.0 mL/min, T = 25°C) ketone
12.7 min, S isomer 25.5 min, R isomer 29.7 min ((S,S)-Noyori Ru(II)-
TsDPEN catalyst), or S isomer 33.1 min , R isomer 40.1 min ((R,R)-
benzyl-tethered Ru(II)-TsDPEN catalyst), or S isomer 29.6 min, R isomer
34.7 min ((R,R)-3C-tethered, 4-methoxy-Ru(II)-TsDPEN catalyst and
(R,R)-3C-tethered Ru(II)-TsDPEN catalyst).
Experimental Section
General experimental details.
Reagents and solvents were used as purchased and without further
purification. Reactions were carried out under a nitrogen atmosphere
unless otherwise specified. Reactions at elevated temperature were
maintained by thermostatically controlled oil-baths or aluminium heating
blocks. A temperature of 0 °C refers to an ice slush bath, -78 °C to a dry
ice acetone bath. NMR spectra were recorded on a Bruker AV (250 MHz),
Bruker DPX (300 or 400MHz) or Bruker DRX (500 MHz). Chemical shifts
are rounded to the nearest 0.01 ppm for 1H spectra and the nearest 0.1
ppm for 13C spectra and are referenced to the solvent chemical shift.
Coupling constants are rounded to the nearest 0.1 Hz. Mass spectra
were recorded on an Esquire 2000 and high-resolution mass spectra
were recorded on a Bruker Micro ToF or MaXis. IR spectra were
recorded on a PerkinElmer spectrum100 and peaks are reported in
wavenumbers. Optical rotations were measured on an Optical Activity Ltd.
AA-1000 Polarimeter and are reported in deg dm−1 cm3 g−1. The chiral
ATH of furan-2-yl(phenyl)methanone: Catalyst (0.00233 mmol, 1.0 mol%)
was added to FA: TEA (5:2 azeotropic mixture, 0.18 mL) at rt and the
mixture was stirred at rt under a nitrogen atmosphere for 10-15 minutes;
after which a solution of furan-2-yl(phenyl)methanone (40 mg, 0.233
mmol) in DCM (0.25 mL) was added, and the reaction mixture was
strirred at rt, followed by TLC (9:1 hexane: EtOAc). After 64 hours, the
reaction was quenched by saturated NaHCO3 solution (20 mL). EtOAc
(20 mL) was added and the organic layer was separated. The aqueous
layer was extracted with EtOAc (3 x 20 mL) and the combined organic
layers were dried (MgSO4) and filtered. The solvent was removed under
vacuum to give the crude product. The product was isolated via flash
chromatography on silica eluted with 0-20% EtOAc in hexane to give
furan-2-yl(phenyl)methanol 7 (13.9 mg, 0.080 mmol, 34%; (R,R)-3C-
tethered Ru(II)-TsDPEN catalyst example). The reaction was also
followed by HPLC (Chiralcel ODH, 30 cm x 6mm column, hexane:iPrOH
97:3, 1.0 mL/min, T = 25°C); (R,R)-3C-tethered Ru(II)-TsDPEN catalyst:
GC measurements were performed using
a Hewlett-Packard 1050
instrument linked to a PC running DataApex Clarity software. HPLC
measurements were performed out using a Hewlett Packard 1050 Series
with a quaternary pump, autosampler and variable wavelength detector
linked to a PC running DataApex Clarity software. Melting points were
determined on a Stuart scientific melting point apparatus and are
uncorrected. Flash column chromatography was performed using silica
gel of 230-400 mesh size. Thin layer chromatography was carried out on
aluminium backed silica gel 60(F254) plates, visualised using 254nm UV
light, potassium permanganate or cerium ammonium molybdate (CAM).
Column chromatography was performed either by gradient elution
(reported as a range, eg EtOAc/Petroleum ether (2-12%), or by isocratic
elution.
23
[α]D +2.35 (c 0.5 in CHCl3) 99.9% conversion (HPLC calibration: 1:1
furan-2-yl(phenyl)methanone: furan-2-yl(phenyl)methanol gives 25.3:1
20
ratio of absorption at 254 nm); 47% ee (R) (lit.14 [α]D -1.4 (c 0.15 in
CHCl3) 20% ee (S)).
Phenyl(thiophen-2-yl)methanone. This compound has been reported
and fully characterized.15 To a solution of phenyl(thiophen-2-yl)methanol
10 (360 mg, 1.89 mmol) in DCM (10 mL) at rt was added manganese
dioxide (2.47 g, 28.4 mmol). The reaction mixture was left to stir under a
nitrogen inert atmosphere overnight; TLC (9:1 hexane: EtOAc) after this
time indicated full conversion. The remaining manganese dioxide was
removed by gravity filtration. The solids were removed by gravity filtration
and washed with DCM. The combined solvent was removed to give the
Furan-2-yl(phenyl)methanone. This compound has been reported and
fully characterized.12 To a solution of furan-2-yl(phenyl)methanol 7 (424
mg, 2.44 mmol) in DCM (10 mL) at rt was added manganese dioxide
5
This article is protected by copyright. All rights reserved.

10.1002/cctc.202101027
ChemCatChem
FULL PAPER
product as a white solid (260 mg, 1.38 mmol, 73%). TLC: Rf ca 0.30 (9:1
hexane: EtOAc), strong UV and KMnO4; m.p. 54°C; 1H NMR (500 MHz,
CDCl3): δ=7.87 (d, 3JH,H=7.2 Hz, 2H; Ar-H), 7.73 (d, 3JH,H=4.7 Hz, 1H; Ar-
H), 7.65 (d, 3JH,H=3.3 Hz, 1H; Ar-H), 7.59 (t, 3JH,H=7.5 Hz, 1H; Ar-H), 7.50
(t, JH,H=7.5 Hz, 2H; C4H3S), 7.17 ppm (t, JH,H=5.0 Hz, 1H; C4H3S); 13C
NMR (125 MHz, CDCl3): δ=188.27 (C), 143.66 (C), 138.16 (C), 134.88
(CH), 134.24 (CH), 132.29 (CH), 129.19 (2×CH), 128.43 (2×CH), 127.98
ppm (CH). Data matched that reported.
(2-methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanone as a white solid
(292 mg, 1.35 mmol, 44%). TLC: Rf ca 0.20 (1:1 hexane: EtOAc), strong
UV and KMnO4; m.p. 74°C; 1H NMR (500 MHz, CDCl3): δ=7.53 (dd,
3JH,H=7.5 Hz, 1.5 Hz, 1H; Ar-H), 7.48-7.43 (m, 1H; Ar-H), 7.16 (s, 1H; Ar-
H), 7.07-7.00 (m, 3H; Ar-H + NCHCHN), 4.11 (s, 3H; OCH3), 3.80 ppm (s,
3H; NCH3); 13C NMR (125 MHz, CDCl3): δ=186.19 (C), 157.79 (C),
143.84 (CH), 132.20 (CH), 130.22 (CH), 129.76 (CH), 128.48 (CH),
126.79 (CH), 120.10 (CH), 111.79 (CH), 55.89 (CH3), 36.25 ppm (CH3);
IR: ν˜=3116, 3067, 1648 (C=O), 1596, 1437, 1392, 1282, 1238, 1020,
753 cm-1; m/z (ES-API+) 239.2 (M+ + 23, 100%); HRMS: (found (ESI+):
[M+H]+, Calcd for C12H13N2O2 217.0967; Found 217.0972; 1.9 ppm error).
3
3
Phenyl(thiophen-2-yl)methanol 10 (Ph/Thio). This compound has been
reported and fully characterized.14,16 Thiophene-2-carbaldehyde (250 mg,
2.23 mmol) was added to a flask, THF (2.5 ml) was added and the flask
was placed into an ice bath to cool down to 0°C, and the reaction was
(2-Methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanol
16
stirred under
a
nitrogen atmosphere. Phenyl magnesium bromide
(oOMe/Im). This compound is novel. To solution of (2-
a
solution (0.813 ml, 3.0M in diethyl ether, 2.44 mmol) was added dropwise
and the reaction was stirred under a nitrogen atmosphere at rt overnight.
TLC (9:1 hexane: EtOAc) after this time indicated full conversion. After
17 hours, distilled water (20 mL) was added, and the mixture was
extracted with EtOAc (3 × 20ml), the combined extracts were dried with
MgSO4, and the solvent was removed under vacuum to give the product
as a yellow solid (407.5 mg, 2.14 mmol, 96.1%). TLC: Rf ca 0.20 (9:1
hexane: EtOAc), strong UV and KMnO4; m.p. 62°C; 1H NMR (500 MHz,
methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanone (200 mg, 0.93
mmol) in MeOH (5 mL) was added sodium borohydride (70.4 mg, 1.85
mmol). The reaction was stirred for 4 hours. TLC (1:1 hexane: EtOAc)
after this time indicated full conversion. Distilled water (20 mL) was
added, and the mixture was extracted with EtOAc (3 × 20ml), dried with
MgSO4, and the solvent was removed under vacuum to give (2-
methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanol 16 as a white solid
(167 mg, 0.766 mmol, 83%). TLC: Rf ca 0.20 (1:1 hexane: EtOAc),
strong UV and KMnO4; m.p.133°C; 1H NMR (500 MHz, CDCl3): δ=7.29-
3
CDCl3): δ=7.35 (d, 3JH,H=7.5 Hz, 2H; Ar-H), 7.28 (t, JH,H=7.4 Hz, 2H; Ar-
3
3
3
H), 7.21 (t, JH,H=7.2 Hz, 1H; Ar-H), 7.16 (d, JH,H=5.6 Hz, 1H; C4H3S),
7.26 (m, 1H; Ar-H), 7.15 (d, JH,H=7.5 Hz, 1H; Ar-H), 6.97-6.90 (m, 3H;
3
6.90-6.81 (m, 1H; C4H3S), 6.79 (d, JH,H=3.2 Hz, 1H; C4H3S), 5.96 (d,
3JH,H=3.4 Hz, 1H; ArCHOH), 2.31 ppm (d, JH,H=3.8 Hz, 1H; OH); 13C
Ar-H + NCHCHN), 6.82 (s, 1H; NCHCHN), 6.20 (s, 1H; ArCHOH), 3.86 (s,
3H; OCH3), 3.50 ppm (s, 3H; NCH3); 13C NMR (125 MHz, CDCl3):
δ=156.68 (C), 148.78 (C), 129.33 (C), 129.11 (CH), 127.87 (CH), 126.96
(CH), 121.58 (CH), 121.06 (CH), 110.82 (CH), 64.19 (CH), 55.66 (CH3),
32.83 ppm (CH3); IR: ν˜=3037 (br), 2970, 2839, 1600, 1489, 1243, 1041,
747, 716 cm-1; m/z (ES-API+) 219.2 (M+ + 1, 100%); HRMS: (found
(ESI+): [M+H]+, Calcd for C12H15N2O2 219.1128; Found 219.1128; 0.1
ppm error). Enantiomeric excess and conversion determined by HPLC
analysis (Chiralcel ODH, 30 cm x 6mm column, hexane:iPrOH 9:1, 0.8
mL/min, T = 25°C) ketone 33.9 min, R isomer 19.5 min and S isomer
29.3 min. The configuration was assigned by X-ray crystallographic
analysis of the ATH product.
3
NMR (125 MHz, CDCl3): δ=148.13 (C), 143.12 (C), 128.57 (CH), 128.04
(CH), 126.68 (CH), 126.31 (CH), 125.46 (CH), 124.92 (CH), 72.46 ppm
(CH); m/z (ES-API+) 190.8 (M+, 100%). Data matched that reported.
Enantiomeric excess and conversion determined by GC (Chrompac
cyclodextrin-β-236M-19 50m
× 0.25mm × 0.25µm, column head
pressure: 15psi, carrier gas: hydrogen, oven temperature: 140 °C,
injection temperature: 220 °C, FID detector temperature: 250 °C) ketone
66.7 min, S isomer 98.6 min., R isomer 100.2 min.
ATH of phenyl(thiophen-2-yl)methanone. Catalyst (0.00213 mmol, 1
mol%) was added to FA: TEA (5:2 azeotropic mixture, 0.18 mL) at rt and
the mixture was stirred under a nitrogen atmosphere for 10-15 minutes;
after which a solution of phenyl(thiophen-2-yl)methanone (40 mg, 0.213
mmol) in DCM (0.25 mL) was added. The reaction mixture was stirred at
rt, followed by TLC (9:1 hexane: EtOAc). After 117 hours, the reaction
was quenched using saturated NaHCO3 solution (20 mL). EtOAc (20 mL)
was added and the organic layer was separated. The aqueous layer was
extracted with EtOAc (3 x 20 mL) and the combined organic layers were
dried (MgSO4) and filtered. The solvent was removed to give the crude
product. The product was isolated via flash chromatography on silica
eluted with 0-20% EtOAc in hexane to give phenyl(thiophen-2-
yl)methanol 10 (32.0 mg, 0.168 mmol, 79%; (R,R)-3C-tethered Ru(II)-
TsDPEN catalyst example). The reaction was also followed by GC
(Chrompac cyclodextrin-β-236M-19 50m × 0.25mm × 0.25µm, column
head pressure: 15psi, carrier gas: hydrogen, oven temperature: 140 °C,
injection temperature: 220 °C, FID detector temperature: 250 °C); (R,R)-
ATH
of
(2-methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanone.
Catalyst (0.00185 mmol, 1 mol%) was added to FA: TEA (5:2 azeotropic
mixture, 0.18 mL) at rt and the mixture was stirred under a nitrogen
atmosphere for 10-15 minutes; after which
a
solution of 2-
methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanone (40 mg, 0.185
mmol) in DCM (0.25 mL) was added. The reaction mixture was stirred at
rt, followed by TLC (1:1 hexane: EtOAc). After 168 hours, the reaction
was quenched using saturated NaHCO3 solution (20 mL). EtOAc (20 mL)
was added and the organic layer was separated. The aqueous layer was
extracted with EtOAc (3 x 20 mL) and the combined organic layers were
dried (MgSO4) and filtered. The solvent was removed to give the crude
product. The product was isolated via flash chromatography on silica
eluted with 50%-100% ethyl acetate in hexane to give (2-
methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanol 16 (17.4 mg, 0.0798
mmol, 43%; (R,R)-3C-tethered Ru(II)-TsDPEN catalyst example). The
reaction was also followed by HPLC (Chiralcel ODH, 30 cm x 6mm
column, hexane:iPrOH 9:1, 0.8 mL/min, T = 25°C); (R,R)-3C-tethered
Ru(II)-TsDPEN catalyst: 95% conversion (HPLC calibration: 1:1 (2-
23
3C-tethered Ru(II)-TsDPEN catalyst: 97% conversion; [α]D -2.034 (c
20
0.0885 in CHCl3) 48% ee (R) (lit.14 [α]D -1.7 (c 0.3 in CHCl3) 19% ee
(R)).
methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanone:
(2-
methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanol gives 7.62:1 ratio of
(2-Methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanone.
This
absorption at 254 nm) [α]D26 +21.6 (c 0.03 in CHCl3) 98% ee (S).
compound is novel. To a solution of 1-methylimidazole (250 mg, 3.05
mmol) in MeCN (9 mL) at 0 °C was added 2-methoxybenzoyl chloride
(780 mg, 4.58 mmol), followed by the addition of Et3N (462 mg, 4.58
mmol). The reaction mixture was stirred under a nitrogen atmosphere
overnight; and the conversion was monitored by TLC (1:1 hexane:
EtOAc). The mixture was quenched by dropwise addition of water (20
mL). EtOAc (20 mL) was added and the organic layer was separated.
The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined
organic layers were dried (MgSO4) and filtered. The solvent was removed
to give the crude product. The product was isolated via flash
chromatography on silica eluted with 50-100% EtOAc in hexane to give
(2-Hydroxyphenyl)(1-methyl-1H-imidazol-2-yl)methanone.
This
compound is novel. To a solution of 2-(hydroxy(1-methyl-1H-imidazol-2-
yl)methyl)phenol 17 (94 mg, 0.461 mmol) in DCM (5 mL) at rt was added
manganese dioxide (601 g, 6.92 mmol). The reaction mixture was left to
stir under a nitrogen atmosphere overnight. TLC (19:1 DCM: MeOH) after
this time indicated full conversion. The solids were removed by gravity
filtration and washed with DCM. The combined solvent was removed to
give the product as a yellow solid (58.6 mg, 0.290 mmol, 63%). TLC: Rf
ca 0.80 (19:1 DCM: MeOH), strong UV and KMnO4; m.p. 62.5°C; 1H
6
This article is protected by copyright. All rights reserved.

10.1002/cctc.202101027
ChemCatChem
FULL PAPER
3
NMR (500 MHz, CDCl3): δ=13.25 (s, 1H; ArOH), 8.64 (dd, JH,H=8.2 Hz,
The aqueous layer was extracted with EtOAc (3 x 20 mL) and the
combined organic layers were dried (MgSO4) and filtered. The solvent
was removed to give the crude product. The product was isolated via
flash chromatography on silica eluted with 0-10% MeOH in DCM to give
asymmetric (2-methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanol 17
as a colorless oil (8.90 mg, 0.0408 mmol, 41.6%). The reaction also
followed by HPLC analysis (Chiralcel ODH, 30 cm x 6mm column,
hexane:iPrOH 9:1, 0.8 mL/min, T = 25°C): 82% ee.
3
1.7 Hz, 1H; Ar-H), 7.48 (ddd, JH,H=8.6 Hz, 1.7 Hz, 1.7 Hz, 1H; Ar-H),
7.32-7.18 (m, 1H; Ar-H), 7.13 (s, 1H; Ar-H), 7.02 (dd, JH,H=8.3 Hz, 0.9
3
Hz, 1H; NCH=CH), 6.98-6.89 (m, 1H; NCH=CH), 4.07 ppm (s, 3H;
NCH3); 13C NMR (125 MHz, CDCl3): δ=185.10 (C), 161.97 (C), 142.79
(C), 136.09 (CH), 133.79 (CH), 128.19 (CH), 127.07 (CH), 120.93 (C),
118.99 (CH), 36.87 ppm (CH3); IR: ν˜=3141, 3125, 3058, 3016, 1768
(C=O), 1621, 1595, 1457, 1407, 1392, 1298, 1277, 948, 816, 790, 751
cm-1; m/z (ES-API+) 225.2 (M+ + 23, 100%); HRMS: (found (ESI+):
[M+H]+, Calcd for C11H11N2O2 203.0818; Found 203.0815; -1.3 ppm
error).
Acknowledgements
Racemic and S-2-(Hydroxy(1-methyl-1H-imidazol-2-yl)methyl)phenol
17 (oOH/Im). This compound is novel. To a solution of 2-(((tert-
butyldimethylsilyl)oxy)(1-methyl-1H-imidazol-2-yl)methyl)phenol (210 mg,
0.660 mmol) in THF (10.5 mL) was added a solution of Tetra-n-
butylammonium fluoride (TBAF) (0.990 mL, 1.0M in THF, 0.990 mmol) at
rt. The reaction mixture was left stirring under the nitrogen atmosphere
and followed by TLC (19:1 DCM: MeOH). Solvent was removed to give
the crude product. The product was isolated via flash chromatography on
silica eluted with 0-50% MeOH in DCM to give 2-(hydroxy(1-methyl-1H-
imidazol-2-yl)methyl)phenol 17 as a white solid (85.3 mg, 0.418 mmol,
63.3%). m.p. 40°C; TLC: Rf ca 0.20 (19:1 DCM: MeOH), strong UV and
KMnO4; 1H NMR (500 MHz, CDCl3): δ=7.24-7.12 (m, 1H; Ar-H), 6.95 (d,
3JH,H=8.1 Hz, 1H; Ar-H), 6.91-6.83 (m, 2H; Ar-H), 6.85-6.71 (m, 2H;
NCH=CHN), 5.89 (s, 1H; ArCHOH), 3.63 ppm (s, 3H; NCH3); 13C NMR
(125 MHz, CDCl3): δ=158.11 (C), 148.81 (C), 129.81 (CH), 128.06 (CH),
125.85 (CH), 125.05 (C), 122.12 (CH), 119.82 (CH), 119.03 (CH), 69.39
(CH), 33.31 ppm (CH3); IR: ν˜=3344 (br), 3113, 3042, 2952, 2871, 1595,
1490, 1453, 1390, 1277, 1233, 1137, 937, 748, 706 cm-1; m/z (ES-API+)
227.2 (M+ + 23, 100%); HRMS: (found (ESI+): [M+H]+, Calcd for
C11H13N2O2 205.0972; Found 205.0972; -0.1 ppm error). Enantiomeric
excess and conversion determined by HPLC analysis (Chiralpak IG, 30
cm x 6mm column, hexane:iPrOH 90:10, 1.0 mL/min, T = 25°C) ketone
13.6 min, R and S isomer 15.1 min and 22.9 min, configuration S
assigned by methylation to OMe/Im previously characterized by X-ray.
The X-ray diffraction instrument was obtained through the
Science City Project with support from Advantage West
Midlands (AWM) and part funded by the European Regional
Development fund (ERDF). The Brazilian Research agencies
Conselho Nacional de Desenvolvimento Científico
e
Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do
Estado de Minas Gerais (Fapemig) are thanked for supporting
LCAB and JAM-A. Warwick University provided
partnership award to support a visit by JAM-A and supported MK
through University undergraduate research scholarship
a Brazil
a
(URSS). We thank Johnson Matthey Ltd for a gift of catalyst 2.
Supporting Information
The Supporting Information contains details of the remaining
experimental procedures, NMR spectra, chiral HPLC spectra, X-
ray crystallographic data for structures CCDC 2071155 –
2071158 and conversion and ee vs time graphs.
Author Contributions
YZ, JM-A and MK carried out the experimental work, MW was
supervisor to YZ and MK and LCAB was supervisor to JAM-A.
YZ, JM-A, MK, LCAB and MW contributed to the design and
planning of the investigation. GJC carried out the X-ray
crystallographic analyses.
ATH
of
(2-Hydroxyphenyl)(1-methyl-1H-imidazol-2-yl)methanone.
Catalyst (0.00198 mmol, 1 mol%) was added to FA: TEA (5:2 azeotropic
mixture, 0.18 mL) at rt and the mixture was stirred under a nitrogen
atmosphere for 10-15 minutes; after which
a
solution of (2-
hydroxyphenyl)(1-methyl-1H-imidazol-2-yl)methanone (40 mg, 0.198
mmol) in DCM (0.25 mL) was added. The reaction mixture was stirred at
rt overnight (20 h). The reaction was followed by TLC (19:1 DCM: MeOH).
Then the reaction was quenched using saturated NaHCO3 solution (20
mL). EtOAc (20 mL) was added and the organic layer was separated.
The aqueous layer was extracted with EtOAc (3 x 20 mL) and the
combined organic layers were dried (MgSO4) and filtered. The solvent
was removed to give the crude product. The product was isolated via
flash chromatography on silica eluted with 0-10% MeOH in DCM to give
2-(hydroxy(1-methyl-1H-imidazol-2-yl)methyl)phenol 17 (20.3 mg, 0.0995
mmol, 50.3%; (R,R)-3C-tethered Ru(II)-TsDPEN catalyst example). The
reaction was also followed by HPLC analysis (Chiralpak IG, 30 cm x
6mm column, hexane:iPrOH 90:10, 1.0 mL/min, T = 25°C); (R,R)-3C-
tethered Ru(II)-TsDPEN catalyst: α]D21 -18.5 (c 0.0600 in CHCl3) 83% ee
(S).
Conflicts of interest
There are no conflicts to declare.
ORCID numbers:
YZ: 0000-0001-9620-7302
LCAB: 0000-0002-5395-9608
GJC: 0000-0003-3076-3191
MW: 0000-0002-1646-2379
Data sharing statement
Formation
of
S-(2-methoxyphenyl)(1-methyl-1H-imidazol-2-
The research data (and/or materials) supporting this publication
can be accessed at http://wrap.warwick.ac.uk/
yl)methanol 16 by methylation of S-2-(hydroxy(1-methyl-1H-
imidazol-2-yl)methyl)phenol 17 to compare with ATH of (2-
methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methanone. To a solution
of asymmetric S-(hydroxy(1-methyl-1H-imidazol-2-yl)methyl)phenol 16
(20 mg, 0.0980 mmol) in DMF (0.98 mL) was added potassium
carbonate (13.6 mg, 0.118 mmol) and iodomethane (13.9 mg, 0.0980
mmol) at rt. The mixture was stirred under a nitrogen atmosphere
overnight. TLC (19:1 DCM: MeOH) after this time indicated full
conversion. Then the reaction was quenched using distilled water (20
mL). EtOAc (20 mL) was added and the organic layer was separated.
Keywords: asymmetric • transfer • hydrogenation • heterocycle
• alcohol
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10.1002/cctc.202101027
ChemCatChem
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A systematic study of the asymmetric transfer hydrogenation (AH), using [arene/Ru(II)/TsDPEN] pre-catalysts, of a range of
heterocyclic ketones is described. The products are formed in very high ee in cases where an ortho-substituted aromatic ring
opposes the heterocycle on the ketone group. This provides a practical and selective access to a range of hetereocyclic alcohols in
high ee, for the by ATH using Noyori-Ikariya catalysts.
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