Enantioselective Benzylic Hydroxylation of Arylalkanes with H2O2 in Fluorinated Alcohols in the Presence of Chiral Mn Aminopyridine Complexes

Article abstract of DOI:10.1002/cctc.201801476

A series of chiral bioinspired Mn-aminopyridine complexes of the type [L*Mn^II(OTf)₂] (where L* is 2,2′-bipyrrolidine derived ligand, bearing trifluoroalkoxy and alkyl substituents) have been tested as catalysts in benzylic C?H hydroxylation of arylalkanes with H₂O₂ in fluorinated ethanols media. In 2,2,2-trifuoroethanol, the yield of the target ethylbenzene oxidation product, chiral 1-phenylethanol, reaches 45 %, which is much better than in the common solvent CH₃CN (5-6 %). The selectivity for 1-phenylethanol formation increases in the following order: CH₃CN<2-fluoroethanol<2,2-difluoroethanol<2,2,2-trifuoroethanol, while 2,2-difluoroethanol ensures the highest asymmetric induction in this series, affording chiral benzylic alcohols with up to 89 % ee. In trifluoroethanol, the observed primary k_H/k_D value of 2.3 has been measured for the oxidation of 1-phenylethanol/α-D-1-phenylethanol, which is similar to that in CH₃CN (2.2). At the same time, depending on the solvent, CH₃CN or 2,2,2-trifuoroethanol, the oxidations of 1-phenylethanol demonstrates drastically different linear free-energy relationships; possible effect of the hydrogen-bond donor (HBD) nature of CF₃CH₂OH is discussed in this context. Noticeably, it has been shown that by switching the absolute chirality ((S,S)? or (R,R)?) of the catalyst, the oxidation of complex substrate of natural origin, estrone acetate, can be diverted to predominant formation of either the tertiary C9-alcohol or of the C6-ketone, respectively.

Full text of DOI:10.1002/cctc.201801476

Accepted Article
Title: Enantioselective Benzylic Hydroxylation of Arylalkanes with
H2O2 in Fluorinated Alcohols in the Presence of Chiral Mn
Aminopyridine Complexes
Authors: Roman Ottenbacher, Evgenii Talsi, Tatyana Rybalova, and
Konstantin Petrovich Bryliakov
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.201801476
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ChemCatChem
10.1002/cctc.201801476
Enantioselective Benzylic Hydroxylation of Arylalkanes with H O in
2
2
Fluorinated Alcohols in the Presence of Chiral Mn Aminopyridine Complexes
[
a,b]
[a,b]
[a,c]
Dr. Roman V. Ottenbacher, Prof. Dr. Evgenii P. Talsi,
Mrs. Tatyana V. Rybalova,
and
[
a,b]
Prof. Dr. Konstantin P. Bryliakov
*
a
Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation
b
c
Boreskov Institute of Catalysis, Pr. Lavrentieva 5, Novosibirsk 630090, Russian Federation
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Pr. Lavrentieva 9, Novosibirsk 630090,
Russian Federation
E-mail: bryliako@catalysis.ru
Abstract
II
A series of chiral bioinspired Mn-aminopyridine complexes of the type [L*Mn (OTf) ] (where
2
L* is 2,2'-bipyrrolidine derived ligand, bearing trifluoroalkoxy and alkyl substituents) have been
tested as catalysts in benzylic C-H hydroxylation of arylalkanes with H O in the media of
2
2
fluorinated ethanols. In 2,2,2-trifuoroethanol, the yield of the target ethylbenzene oxidation product,
chiral 1-phenylethanol, reaches 45 %, which is much better than in the common solvent CH CN (5-
3
6
%). The selectivity for 1-phenylethanol formation increases in the following order: CH CN < 2-
3
fluoroethanol < 2,2-difluoroethanol < 2,2,2-trifuoroethanol, while 2,2-difluoroethanol ensures the
highest asymmetric induction in this series, affording chiral benzylic alcohols with up to 89 % ee. In
trifluoroethanol, the observed primary k /k value of 2.3 has been measured for the oxidation of 1-
H
D
phenylethanol/α-D-1-phenylethanol, which is similar to that in CH CN (2.2). At the same time,
3
depending on the solvent, CH CN or 2,2,2-trifuoroethanol, the oxidations of 1-phenylethanol
3
demonstrates drastically different linear free-energy relationships; possible effect of the hydrogen-
bond donor (HBD) nature of CF CH OH is discussed in this context. Noticeably, it has been shown
3
2
that by switching the absolute chirality ((S,S)- or (R,R)-) of the catalyst, the oxidation of complex
substrate of natural origin, estrone acetate, can be diverted to predominant formation of either the
tertiary C9-alcohol or of the C6-ketone, respectively.
1
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ChemCatChem
10.1002/cctc.201801476
Introduction
In the last 30 years, transition-metal based catalyst systems for the selective oxidation of C-H
groups with the environmentally benign oxidants, such as H O and O , have experienced
2
2
2
[
1]
remarkable progress, with the most impressive achievement being the discovery of bipyrrolidine
derived iron complexes by White and co-workers, who proposed the procedures for the oxidation of
non-activated aliphatic C-H groups in complex organic molecules with H O with practically
2
2
[
2]
attractive selectivity. At the same time, transition metal catalyzed enantioselective oxidations of
C-H groups have so far been challenging: while several papers reporting asymmetric C-H
oxidations with 2,6-dichloropyridine N-oxide, iodosylarenes, or iodobenzene diacetate were
[
3]
published after 1989, such oxidations with H O and O were not known until rather recently.
2
2
2
The pioneering contribution by Simonneaux and co-workers presented the asymmetric
benzylic hydroxylation of several arylalkanes with H O (5 equiv. relative to alkane) in the presence
2
2
of the water-soluble chiral Halterman porphyrin (2.5 mol % catalyst loading), with moderate
[
4a,b]
[4c]
[4d]
enantioselectivities (32–57 % ee).
Recently, Costas and Bietti,
and Sun
proposed
alternative approaches to asymmetric C-H oxidations with H O , consisting in the oxidative
2
2
desymmetrization-ketonization of prochiral substrates, namely substituted cyclohexanes and
spirocyclic β-ketones, respectively, in the presence of chiral aminopyridine manganese complexes.
Compared with the catalyst system of Simonneaux, the latter systems required much lower catalyst
[
4c]
[4d]
loadings (1 mol. % and 0.5 mol. % ) and demonstrated much higher enantioselectivities (up to
[
4c]
[4d]
9
6 % ee and 98 % ee, respectively). However, both systems have so far been applicable to
specific classes of substrates, affording chiral ketones as the main reaction products.
Recently, we developed the catalytic protocol for the asymmetric benzylic hydroxylation of
arylalkanes with H O in acetonitrile in the presence of bipyrrolidine derived manganese complexes
2
2
[
4e,f]
(S,S)-1 and (R,R)-1 (Figure 1), affording the desired chiral 1-arylalkanols with up to 86 % ee.
The catalysts (0.1 mol. % loading) were able to perform several hundreds of turnovers; however,
owing to the facile overoxidation to ketone, the reaction procedure required that high substrate
2
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ChemCatChem
10.1002/cctc.201801476
excess conditions be used, and the reaction be stopped at low conversion levels (∼ 10 %), the yield
of the target chiral alcohol typically not exceeding 5-6 %. It was a serious practical drawback,
[
4e,f]
unsolvable at the time of publication of our reports.
Encouragingly, very recently, Company,
Bietti, and Costas introduced the replacement of CH CN with 2,2,2-trifluoroethanol (TFE) as
3
reaction solvent, which improvement substantially enhanced the aliphatic hydroxylation selectivity
in the presence of manganese based catalysts, further ketonization step being dramatically
[
4g]
suppressed.
Figure 1. Structures of manganese complexes discussed in this study.
In this work, we present the improved Mn-catalyzed asymmetric benzylic oxidation protocol
with H O in fluorinated ethanols, with the yield of the chiral 1-alkanol approaching 45 %, and with
2
2
up to 89 % ee optical purity. The effect of solvents and catalytic additives on the hydroxylation
yield and enantioselectivity, as well as the mechanistic peculiarities of the oxidations are discussed.
Results and discussion
3
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ChemCatChem
10.1002/cctc.201801476
Very recently, Company, Bietti, and Costas have shown that the replacement of acetonitrile as
solvent with 2,2,2-trifluoroethanol or heptafluoroisopropanol substantially enhanced the aliphatic
C-H hydroxylation selectivity by suppressing the overoxidation of the resulting alkanol to the
[
4g]
ketone. This effect has been ascribed to deactivation of electron-rich functional groups (such as
CH(OH)) by virtue of hydrogen bonding interactions with the hydrogen-bond donor solvents, thus
directing the oxidation towards the stronger non-activated C−H bonds. This work was initiated
aiming at adapting this approach for the asymmetric aromatic benzylic hydroxylations.
First of all, the effect of degree of solvent fluorination on the hydroxylation selectivity in the
course of ethylbenzene oxidation with H O , catalyzed by (R,R)-1, has been tested. To this end, the
2
2
oxidation of ethylbenzene in ethanols CF H CH OH with different degree of fluorination
n
3-n
2
(n = 1…3) was monitored, providing the following plots of 1-phenylethanol vs. ethylbenzene
conversion (Figure 2). Using the experimental curves, the ratios of the observed constants for the
first and second oxidation stages (k /k ) have been evaluated (Figure 1; for fitting details see SI).
1
2
Trifluoroethanol has been established as the best solvent in terms of alcohol yield, the maximum 1-
phenylethanol yield approaching 45 % at 75 % ethylbenzene conversion (Figure 1). At the same
time, the hydroxylation enantioselectivity, achieved at maximum conversion, was somewhat higher
for the oxidation in difluoroethanol (DFE); in effect, both these solvents were chosen for further
catalytic experiments.
Noticeably, while in CH CN, the oxidation enantioselectivity demonstrated initial increase
3
and then remained in the range 52-54 % ee at 50-70% conversion, Figure S1A, SI), in di- and
trifluorinated ethanols, the ee began to decline when the 1-phenylethanol yield passed through the
maximum (Figure S1C, D). In monofluoroethanol (MFE), the 1-phenylethanol ee monotonously
declined from the very beginning of the reaction (from 50 % ee at 10 % conversion to 19 % ee at 80
%
conversion, Figure S1B).
4
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ChemCatChem
10.1002/cctc.201801476
k /k = 1.61
50
40
30
20
10
0
1
2
k /k = 0.84
1
2
k /k = 0.24
1
2
k /k = 0.07
1
2
0
20
40
60
80
100
ethylbenzene conversion, %
Solvent
maximum
yield, % (at
conversion, %)
% ee at
maximum
yield
k1/k2
CH CN
6.5 (19)
39
0.07
0.24
3
1
3
7 (51)
3 (58)
38
61
59
0.84
1.61
4
5 (75)
Figure 2. 1-Phenylethanol yield vs. conversion for the oxidation of ethylbenzene (0.1 mmol) in the
presence of (R,R)-1 (0.2 mol. %) and 2-ethylhexanoic acid (0.1 mmol) at -30 °C in acetonitrile
(black), 2-fluoroethanol (olive), 2,2-difluoroethanol (red) and 2,2,2-trifluoroethanol (blue).
Further, we have screened a series of carboxylic acids as catalytic additives, using TFE and
DFE as solvents. A series of experiments were conducted at -30 °C, using different carboxylic
acids, where 1 equiv. (vs. substrate) of H O in TFE or DFE (0.1 mL) was added with syringe pump
2
2
to a mixture of ethylbenzene and the catalyst (0.2 mol. %) in 0.1 mL of the same solvent. The
results, summarized in Table 1, have witnessed superiority of commercial 2-ethylehexanoic acid
over the range of common achiral/racemic carboxylic acids in terms of achieving high
enantioselectivity, in line with that previously established for the processes of asymmetric
[
5]
[4e-g]
epoxidation and C-H oxidation,
mediated by bioinspired Mn and Fe complexes. In the case of
5
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ChemCatChem
10.1002/cctc.201801476
C-H oxidation, the relationship between the acid structure and enantioselectivity is not as
[5c]
straightforward as in the case of epoxidation; in general, heavier carboxylic acids, bearing one
substituent at the α-C atom, showed higher enantioselectivities. In DFE, the alcohol yield and
optical purity of the alcohol were several per cent higher than in TFE, yet at somewhat different
conversions (cf. entries 10 vs. 12 and 1 vs. 11 of Table 1). Formation of minor (2-5 %) byproduct –
trifluoroethyl ethers of 1-phenylethanol – has been observed (SI).
[
a]
Table 1. Oxidation of ethylbenzene with H O in the presence of complex (S,S)-1.
2
2
HO
O
Mn cat.
+
solvent
RCOOH
H O
2
2
O
O
O
O
O
OH
OH
OH
OH
OH
AA
CHA
PA
IBA
DMBA
O
O
O
O
O
OH
OH
OH
OH
OH
CA
IVA
EBA
PVA
EHA
[b]
No catalyst
Solvent
additive (µmol)
substrate
alcohol yield A / K alcohol ee config.
c
[d]
[c]
conversion
(µmol)
(%)
[
c]
(
µmol)
1
9
3
4
6
2
5
7
8
1
1
1
(S,S)-1
(S,S)-1
(S,S)-1
(S,S)-1
(S,S)-1
(S,S)-1
(S,S)-1
(S,S)-1
(S,S)-1
(S,S)-1
(S,S)-1
(S,S)-1
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
DFE
DFE
AA (100)
CHA (100)
PA (100)
28
22
34
18.2
7.3
8.7
9.5
5.9
6.3
11.3
3.5
4.1
6.8
1.9
1.9
31.5
30
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
45
34
28
35.5
35.5
39
IBA (100)
DMBA (100)
CA (100)
36
28.5
38
48
33
26
43
IVA (100)
EBA (100)
PVA (100)
EHA (100)
AA (100)
25
20
46
56
40.5
40
52.5
53
54
0
1
2
35
28
58
56
31
40
EHA (100)
47.5
29.5
60
[
a]
At -30 °C; [substrate] : [H O ] : [Mn] = 100 µmol : 100 µmol : 0.2 µmol, solvent (0.1 mL),
2
2
oxidant was added with a syringe pump over 30 min, and the mixture was stirred for an additional 2
6
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ChemCatChem
10.1002/cctc.201801476
[
b]
h, followed by taking 2 µmol aliquot for chiral HPLC analysis. See abbreviations used at the end
[
c]
[d]
of this paper. Determined by chiral HPLC. Alcohol/ketone ratio.
Further, following the approach previously developed for the C-H oxidations in CH CN, we
3
have attempted the use of chiral catalytic additives, derived from enantiomerically pure proline
(Table 2). In order to analyze the product yield and ee at different conversions, the experiments
were conducted as follows: to a solution of the substrate (0.1 mmol), the Mn complex (0.2 µmol),
and the additive in TFE or DFE (0.2 mL), 30 % H O was added portionwise (in 15-20 µmol
2
2
portions), the mixture was stirred for 0.5 h after each addition, followed by taking 2 µmol aliquots,
[
6]
that were subject to chiral HPLC analysis. Unless otherwise noted, in Table 2, the maximum
achieved alcohol yields and the corresponding ees are reported. When using (S,S)-1 as catalyst in
TFE, the replacement of EHA (0.1 mmol) with chiral additives - N-protected prolines (0.03 mmol)
did not give any improvement in terms of alcohol yield and enantioselectivity (cf. entries 1 and 3 of
Table 2). In turn, the combination (S,S)-1/Cbz-D-proline afforded 1-phenylethanol with several per
cent higher optical purity than (S,S)-1/EHA (cf. entries 1 and 4 of Table 2).
In DFE, the replacement of EHA (0.1 mmol) with chiral additives - N-protected prolines
(0.03 mmol) - allowed the improvement of the oxidation enantioselectivity from ca. 60 % ee to >
70 % ee, the right (“matched”) combinations being (S,S)-1/protected D-proline and (R,R)-
1/protected L-proline (cf. Table 2, entries 5-8 vs. 1-2). Replacing DFE solvent with TFE in the
system (R,R)-1/N-Boc-L-proline/ethylbenzene improved the alcohol yield from 34 to 43 %, but
deteriorated the enantioselectivity from 74 to 62 % ee (entry 9 vs. 8). In a 1:1 DFE/TFE mixture,
the alcohol yield was only slightly better than in DFE (entry 10 vs. 8), with the same
enantioselectivity level (74 % ee). The increase of the amount of additive up to 0.05 mmol did not
improve the enantioselectivity (entry 11 vs. 8). At the same time, in the system (R,R)-1/N-Boc-L-
proline/ethylbenzene, extending the reaction to higher conversions slightly enhanced the
enantiomeric excess from 73-74 % ee to 77 % ee, yet deteriorating its chemical yield (entries 12 vs.
8
and 13 vs. 11). This apparently indicates contribution of kinetic resolution into the resulting
7
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10.1002/cctc.201801476
optical purity of the resulting 1-phenylethanol. The alcohol yield and ee plots vs. ethylbenzene
conversion for the experiment in entry 12 of Table 2 corroborate this hypothesis (Figure 3A).
In contrast, for the catalyst system (S,S)-1/Cbz-D-proline, the enantiomeric excess of 1-
phenylethanol demonstrated very small deviation from 70 % ee over the reaction course (Figure
3B), suggesting that when using N-carbobenzyloxy-D-proline as additive, the contribution of
kinetic resolution is not significant.
[
a]
Table 2. Oxidation of ethylbenzene with H O in the presence of chiral manganese complexes.
2
2
HO
O
Mn cat.
+
solvent
RCOOH
H O
2
2
No catalyst
Solvent
additive (µmol)
substrate alcohol yield A / K alcohol config.
[
b]
[c]
[b]
conversion (µmol)
ee (%)
[
b]
(
µmol)
1
2
3
4
5
6
(S,S)-1
(R,R)-1
(S,S)-1
(S,S)-1
(S,S)-1
(R,R)-1
TFE
DFE
TFE
TFE
DFE
DFE
EHA (100)
EHA (100)
75
45
32
46
41
39
37
1.6
1.4
1.9
1.9
1.5
1.1
59
61
(S)
(R)
(S)
(S)
(S)
(R)
59.5
80
Boc-L-Pro (30)
59
Cbz-D-Pro (30)
Boc-L-Pro (30)
Cbz-D-Pro (30)
71
66.5
59
69
73
60.5
7
8
9
1
1
1
1
(S,S)-1
(R,R)-1
(R,R)-1
DFE
DFE
TFE
Cbz-D-Pro (30)
Boc-L-Pro (30)
Boc-L-Pro (30)
Boc-L-Pro (30)
Boc-L-Pro (50)
78
75
77
88
80
90
90
37
34
1.1
1.0
1.7
0.8
1.0
0.6
0.6
70
74
(S)
(R)
(R)
(R)
(R)
(R)
(R)
43
62
0
1
2
3
(R,R)-1 1:1 DFE/TFE
36
74
(R,R)-1
(R,R)-1
(R,R)-1
DFE
DFE
DFE
38
73
[d]
Boc-L-Pro (30)
Boc-L-Pro (50)
31
77
[e]
32.5
77.5
1
1
1
4
5
6
(S,S)-2
(S,S)-3
(S,S)-4
DFE
DFE
DFE
Cbz-D-Pro (30)
Cbz-D-Pro (30)
Cbz-D-Pro (30)
78
80
55
36
37
32
0.9
0.9
1.8
66
62
(S)
(S)
(S)
61.5
[
a]
At -30 °C; [substrate] : [Mn] = 100 µmol : 0.2 µmol, solvent (0.2 mL), oxidant was added
portionwise (in several 15-20 µmol portions) and the mixture stirred for an additional 0.5 h, and 2
[
b]
[c]
µmol aliquots were analyzed by chiral HPLC.
Determined by chiral HPLC. Alcohol/ketone
8
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ChemCatChem
10.1002/cctc.201801476
[
d]
[e]
ratio.
Experiment in entry 8, continued to higher conversions.
Experiment in entry 11,
continued to higher conversions.
90
80
70
60
50
40
30
20
10
0
90
A
80
70
60
50
40
30
20
10
0
µ
0
10 20 30 40 50 60 70 80 90 100
ethylbenzene conversion, %
90
80
70
60
50
40
30
20
10
0
90
80
70
60
50
40
30
20
10
B
µ
0
10 20 30 40 50 60 70 80 90 100
ethylbenzene conversion, %
Figure 3. Plots of the amounts of alcohol (blue), ketone (black), and of alcohol ee (red) in the
course of ethylbenzene oxidation by the systems (R,R)-1/Boc-(L)-Pro/H O (A) and (S,S)-1/Cbz-
2
2
(
D)-Pro/H O (B) ([substrate]:[Mn]:[protected proline] = 100 µmol : 0.1 µmol : 30 µmol) at -30 °C
2
2
vs. ethylbenzene conversion.
Next, the influence of ligand structure on the catalytic properties of Mn complexes has been
tested. Given the established efficiency of bipyrrolidine-derived aminopyridine complexes with
trifluoroethoxy substituents, we have probed the effect of additional steric bulk by introducing
methyl and ethyl substituents at the aryl C5 positions (complexes (S,S)-2 and (S,S)-3, respectively).
Unfortunately, both complexes have demonstrated somewhat lower enantioselectivities compared
9
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ChemCatChem
10.1002/cctc.201801476
with complexes (S,S)-1 and (R,R)-1. New complex (S,S)-4 (for X-ray data see SI) without alkyls at
C5, and bearing different 4,4′-polyfluoroalkoxy substituents, demonstrated both lower alcohol
yields and lower enantioselectivities (cf. entries 14-16 vs. entry 7, Table 2).
The oxidation of several substituted ethylbenzenes in the presence of (R,R)-1 and N-Boc-L-
proline (Table 3), with the ee values measured at the maximum alcohol yield, has witnessed in most
cases rather similar enantioselectivities, ranging from 73 to 76 % ee (of Table 3), except the case of
oxidation of 2-ethyltoluene which occurred in lower ee (entry 4 of Table 3). On the contrary, the
oxidation of N-Boc-protected 3,4-dihydro-2(1H)-quinolinone under these conditions has
demonstrated higher enantioselectivity of 83 % ee (entry 6). Encouragingly, the oxidation of the
same substrate in the presence of (S,S)-1/N-carbobenzyloxy-D-proline has afforded the product
having even higher optical purity of 89 % ee (entry 7). To the best of our knowledge, this
enantioselectivity is the highest ever reported in non-enzymatic enantioselective hydroxylation of
[1l,1m]
methylenic groups with the environmentally benign oxidants such as H O and O .
2
2
2
Table 3. Oxidation of substituted ethylbenzene with H O in the presence of chiral manganese
2
2
[a]
complex (R,R)-1.
R
X
HO
R
O
R
(
R,R)-1 (0.2 mol. %)
+
DFE
Boc-L-Pro
X
X
H O
2
2
[c,b]
No
substrate
substrate
alcohol yield A / K
alcohol ee
(%)
[
b]
[d]
conversion
(%)
[
b]
(
%)
[
d]
[d]
1
2
75
34
1.0
0.4
74
74
79
21
3
4
5
90
94
72
28
30
22
0.75
1.3
76
56
0.65
73.5
1
0
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10.1002/cctc.201801476
[
e]
f]
[g]
[g]
6
7
n.d.
n.d.
25
30
n.d.
n.d.
83
N
Boc
O
O
[
[h]
89
N
Boc
[
a]
At -30 °C; [substrate] : [additive] : [Mn] = 100 µmol : 30 µmol : 0.2 µmol; solvent: 0.2 mL
entries 1, 4), 0.8 mL (entry 2), 0.3 mL (entry 3), 0.4 mL (entry 5), oxidant was added portionwise
in several 15-20 µmol portions), the mixture was stirred for an additional 0.5 h, and 2 µmol
(
(
[
b]
[c]
[d]
aliquots were analyzed by chiral HPLC.
Determined by GC-MS.
Alcohol/ketone ratio.
[
e]
[f]
Determined by chiral HPLC. 0.2 mmol substrate, for conditions see SI. 0.2 mmol substrate,
[
g]
[h]
(
S,S)-1/Cbz-D-Pro as catalyst/additive; for conditions see SI. Isolated yield. Products in entries 6
and 7 had opposite optical configuration (see HPLC traces at the end of the SI). n.d. – not determined
ketone was not isolated).
(
In their contribution, Company, Bietti, and Costas hypothesized that the effect of fluorinated
solvents on diverting the reactivity of manganese based catalysts toward stronger C-H bonds could
[
4g]
be due to the ability of these hydrogen-bond donor solvents to stabilize charged intermediates.
To get some insight into the nature of the intermediates, we have conducted competitive oxidations
of a series of substituted ethylbenzenes and substituted 1-phenylethanols with H O in TFE, and
2
2
drawn up the corresponding Hammett-Brown correlations (Figure 4). Quite surprisingly, the
oxidations of substituted ethylbenzenes in TFE have shown good correlation with the regular, non-
polar Hammett substituent parameter σ (ρ = -2.74±0.06, Figure 4A), which is different from the
[
7]
previously reported results obtained in CH CN. Contrariwise, the oxidation of substituted 1-
3
+
+
phenylethanols in TFE has shown correlation with polar Brown-Okamoto parameter σ (ρ = -
0.60±0.03 Figure 4B), reflecting electron-deficient transition state, which is different from the
[8]
+
oxidations in CH CN. Correlations with σ (for substituted ethylbenzenes) and σ (for substituted
3
1
-phenylethanols) were much poorer, especially because of large nonzero intercepts (Figure S3,
Supporting Information).
This result deserves some discussion. First of all, the oxidation of substituted ethylbenzenes
shows rather high slope ρ of -2.74. This is higher than the values of -1 to -2, typically observed in
1
1
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ChemCatChem
10.1002/cctc.201801476
[4f,9]
electrophilic transition-metal mediated C-H oxidations,
reflecting substantially higher
sensitivity of the Mn-catalyzed oxidation in TFE to electronic effects. On the contrary, the oxidation
+
of substituted alcohols in TFE exhibits the slope ρ of -0.60, which is smaller than typical values of
[
4e,10]
-0.8 to -2.0.
p-Ме
A
0,5
,0
p-H
0
m-Me
p-Br
-0,5
-1,0
-1,5
-2,0
-2,5
y = −2.74x - 0.03
R = 0.998
p-NO
2
2
-0,2
0,0
0,2
0,4
0,6
0,8
σp
0
B
0,6
0,4
0,2
0,0
p-OМе
p-Ме
p-F
p-H
p-Cl
-0,2
y = −0.60x - 0.0003
R = 0.988
2
p-CF
3
-0,4
-0,8 -0,6 -0,4 -0,2 0,0 0,2 0,4 0,6 0,8
+
σp
Figure 4. Hammett plots for the competitive oxidation of substituted ethylbenzenes (A) and
substituted 1-phenyl ethanols (B) with H O in the presence of (R,R)-1 in 2,2,2-trifluoroethanol.
2
2
In trifluoroethanol, the observed primary k /k value of 3.2 has been observed for the
H
D
oxidation of ethylbenzene/d -ethylbenzene by the system (R,R)-1/EHA/H O in TFE (0.2 mL) at 0
1
0
2
2
[
4f]
°
C, which is somewhat lower than KIE for the same process in CH CN (3.5…3.6). For the
3
oxidation of 1-phenylethanol/α-D-1-phenylethanol, such difference is negligible: 2.3 in TFE vs. 2.2
[
4e]
in CH CN, respectively. In both cases, however, the sizeable KIEs reflect breaking the benzylic
3
C-H bond as the rate-limiting step. At the same time, the nature of the transition states seems to be
considerably altered by the presence of TFE. Previously, we hypothesized that the correlation with
+
σ (rather than σ ) for the oxidation of 1-phenylethanols in CH CN might be due to the presence of
3
1
2
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ChemCatChem
10.1002/cctc.201801476
an oxygen atom nearby the reaction center, which efficiently assists in compensation of the partial
[8]
electron deficiency at the C-H abstraction step, thus stabilizing the transition state. In TFE, such
stabilization may be less efficient because of the hydrogen bonding between the HBD solvent and
the alcohol hydroxyl group (Scheme 1), thus resulting in relative deactivation of the α-H toward
hydrogen abstraction and eventually resulting in the observed correlation of Log(k /k ) with the
X
H
+
polar parameter σ . This picture fits within the through-hydrogen-bonding polarity reversal model
[4g,11]
of deactivation of adjacent C-H groups in alcohols.
At the same time, in the case of benzylic C-H oxidation of substituted ethylbenzenes, the
[4f,12]
observed alteration of the formally electron-deficient transition state in CH CN
into formally
3
non-electron-deficient one in TFE is at the moment not well understood and will be addressed in
future studies.
O
Ph
Ph
Ph
Ph
LMnV
.
OH
HO
HO
-LMnIII
HO
O
-H O
CH CN
HO
2
H
3
LMnIV
X
O
O
Ph
H
Ph
Ph
Ph
+
O
LMnV
TFE
.
OH
LMnIV
HO
-LMnIII
HO
HO
O
-H O
2
H
H
Scheme 1. Proposed model of the effect of trifluoroethanol on the observed electronic nature of the
transition state. X = CH CF .
2
3
To get more practical insight into the influence of the fluorinated solvent on the oxidation of
complex molecules, we have examined the oxidation of a substrate of natural origin, estrone acetate
(Scheme 2). The experiment was conducted as follows: to the solution of the substrate (0.2 mmol),
Mn catalyst (0.3 mol. %), and 2-ethylhexanoic acid (0.4 mmol) in an appropriate solvent (0.4 mL),
appropriate amount of H O in the same solvent (0.1 mL) was added. After stirring for at least 4 h,
2
2
the mixture was analyzed by chiral HPLC; if necessary, additional H O was introduced in order to
2
2
achieve complete substrate conversion (reflected by disappearance of the HPLC peak of estrone
1
3
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ChemCatChem
10.1002/cctc.201801476
acetate). After completion of the reaction, volatiles were carefully removed in a stream of air, and
the reaction mixture was separated on a SiO column. The major oxidation products, C9-alcohol
2
and C6-ketone, eluted together; the corresponding LC fractions were combined, evaporated, and
[
13]
weighed, affording isolated yield of the two major products. The ratio between the products in
the combined fractions was determined by NMR spectroscopy and HPLC. The oxidations results
are summarized in Scheme 2.
In CH CN, the oxidation, mediated by (S,S)-1 and (S,S)-2, preferentially occurred at C9
3
position, to afford the corresponding alcohol (Scheme 2, entries 1,2). Gratifyingly, the replacement
of CH CN with TFE substantially enhanced the C9-alcohol/C6-ketone (A:K) selectivity, from 5.5:1
3
to 17.3:1 (at 0 °C) and even up to 65:1 (at -30 °C) (entries 3, 4 vs. 1, 2). On the other hand, in the
presence of (R,R)-1, the selectivity was diverted to preferential formation of ketone (entry 5). This
is another example of crucial effect of chirality on the site selectivity in C-H oxidation of complex
[
14]
steroidal substrates.
O
O
O
H
Mn cat. (0.3 mol. %)
H
H
+
+ byproducts
H
O
H
H O
-EHA/solvent
OH
H
2
2
H
H
2
AcO
AcO
AcO
A
K
0.2 mmol
Entry Catalyst
Solvent
t, C
Total H O
Yield (A+K)
A:K
2
2
1
2
3
4
5
(S,S)-1
(S,S)-2
(S,S)-1
(S,S)-1
(R,R)-1
CH CN
0
0
0.9 mmol
0.9 mmol
0.55 mmol
0.55 mmol
0.63 mmol
56 %
50 %
51 %
62 %
43 %
5.5:1
6.2:1
3
CH CN
3
TFE
TFE
TFE
0
17.3:1
65:1
-30
-30
0.67:1
Scheme 2. Results of the oxidation of estrone acetate.
Conclusions
II
Chiral bipyrrolidine-derived Mn-aminopyridine complexes of the type [L*Mn (OTf) ], bearing
2
trifluoroalkoxy and alkyl substituents at the pyridine moieties, have been shown to efficiently
catalyze the asymmetric benzylic C-H oxidation of ethylbenzene with hydrogen peroxide in
1
4
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ChemCatChem
10.1002/cctc.201801476
different solvents. The replacement of CH CN, the most widely used solvent in bioinspired
3
oxidations, with fluorinated ethanols substantially improves the yield of the target 1-phenylethanol,
from 5-6 % up to 45 % (in CF CH OH). The selectivity for 1-phenylethanol increases in the
3
2
following order: CH CN < 2-fluoroethanol < 2,2-difluoroethanol < 2,2,2-trifuoroethanol. 2,2-
3
Difluoroethanol ensures the highest asymmetric induction in this series, affording chiral benzylic
alcohols with up to 89 % ee optical purity.
Primary KIE data for the oxidations of ethylbenzene/d -ethylbenzene and 1-
1
0
phenylethanol/α-D-1-phenylethanol in TFE witness rate-limiting C-H bond cleavage step.
However, depending on the solvent, CH CN or CF CH OH, the oxidations of substituted
3
3
2
ethylbenzenes and 1-phenylethanol demonstrate drastically different linear free-energy
relationships, which difference in the case of 1-phenylethanol can presumably be ascribed to the
effect of the hydrogen-bond donor (HBD) nature of CF CH OH. Under the catalytic arylalkane
3
2
oxidation conditions, such hydrogen bonding between the initially formed 1-arylalkanol and the
solvent is believed to reduce the alcohol nucleophilicity, thus suppressing its further oxidation to the
corresponding ketone, and improving the alcohol/ketone ratio.
It has been shown that the oxidation of estrone acetate in the presence of the studied Mn
aminopyridine complexes yields the tertiary alcohol (at C9) and the ketone (at C6), as the main
products. In the presence of (S,S)-1, the C9-alcohol is formed preferentially, with the replacement
of CH CN by TFE enhancing the C9-alcohol/C6-ketone ratio up to 65:1. On the other hand, the use
3
of (R,R)-1 instead of (S,S)-1 diverts the oxidation selectivity toward the predominant formation of
the C6-ketone, thus providing another example of determinative effect of chirality on the site
selectivity of bioinspired catalytic C-H oxidations.
Associated content
Supporting information, including description of materials and methods, synthetic procedures,
general procedures for C-H oxidations, HPLC separation details, details of KIE and competitive
1
5
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ChemCatChem
10.1002/cctc.201801476
oxidation experiments, and crystal data for complex (S,S)-4. This information is available free of
charge via the Internet at http://pubs.acs.org/. CCDC 1852416 ((S,S)-4) contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via ww.ccdc.cam.ac.uk/data_request/cif and from the authors.
Abbreviations used:
AA – acetic acid; CA – caproic acid; CHA – cyclohexylcarboxylic acid; EBA – 2-ethylbutyric acid;
EHA – 2-ethylhexanoic acid; DMBA – 2,2-dimetylbutyric acid; PVA – 2-propylvaleric acid, PA –
pivalic aicd; IBA – isobutyric acid; IVA – isovaleric acid; Boc-L-Pro – N-tert-butylcarboxy-L-
proline; Cbz-D-Pro – N-carbobenzyloxy-D-proline.
Author information
Corresponding author
E-mail: bryliako@catalysis.ru.
ORCID
Evgenii P. Talsi: 0000-0003-0756-1401
Roman V. Ottenbacher: 0000-0002-3035-5828
Tatyana V. Rybalova: 0000-0003-2398-5271
Konstantin P. Bryliakov: 0000-0002-7009-8950
Notes
The authors declare no competing financial interest.
Acknowledgments
This work was conducted using the equipment of the Boreskov Institute of Catalysis, within the
framework of the budget project #АААА-А17-117041710080-4. RVO, TVR and KPB
1
6
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ChemCatChem
10.1002/cctc.201801476
acknowledge the financial support form the Russian Foundation for Basic Research, grant 16-29-
0666.
1
Keywords
Asymmetric catalysis; C-H hydroxylation; enzyme models; hydrogen-bond donor; hydrogen
peroxide; manganese
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1
8
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ChemCatChem
10.1002/cctc.201801476
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FULL PAPER
Exploiting polarity reversal effect:
Chiral Mn-aminopyridine complexes
catalyze the benzylic hydroxylation of
prochiral methylenic sites with green
oxidant hydrogen peroxide in the
media of fluorinated ethanols,
affording enantioenriched tertiary
alcohols in up to 45 % yield and
previously unachievable
R. V. Ottenbacher, E. P. Talsi, T. V.
Rybalova, K. P. Bryliakov*
Page No. – Page No.
Highly Enantioselective Benzylic
Hydroxylation of Arylalkanes with
H O in Fluorinated Alcohols in the
2 2
Presence of Chiral Mn Aminopyridine
Complexes
enantioselectivity up to 89 % ee.
2
0
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