Asymmetric Transfer Hydrogenation of (Hetero)arylketones with Tethered Rh(III)-N-(p-Tolylsulfonyl)-1,2-diphenylethylene-1,2-diamine Complexes: Scope and Limitations

Article abstract of DOI:10.1021/acs.joc.7b00436

A series of new tethered Rh(III)/Cp? complexes containing the N-(p-tolylsulfonyl)-1,2-diphenylethylene-1,2-diamine ligand have been prepared, characterized, and evaluated in the asymmetric transfer hydrogenation (ATH) of a wide range of (hetero)aryl ketones. The reaction was performed under mild conditions with the formic acid/triethylamine (5:2) system as the hydrogen source and provided enantiomerically enriched alcohols with good yields and high to excellent enantioselectivities. Although the nature of the substituents on the phenyl tethering ring did not alter the stereochemical outcome of the reaction, complexes bearing electron-donating groups exhibited a higher catalytic activity than those having electron-withdrawing groups. A scale-up of the ATH of 4-chromanone to the gram scale quantitatively delivered the reduced product with excellent enantioselectivity, demonstrating the potential usefulness of these new complexes.

Full text of DOI:10.1021/acs.joc.7b00436

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Article
Asymmetric Transfer Hydrogenation of (Hetero)Arylketones with
Tethered Rh(III)-TsDPEN Complexes: Scope and Limitations
Longsheng Zheng, Quentin Llopis, Pierre-Georges Echeverria, Charlène Férard,
Gérard Guillamot, Phannarath Phansavath, and Virginie Ratovelomanana-Vidal
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 May 2017
Downloaded from http://pubs.acs.org on May 5, 2017
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Asymmetric Transfer Hydrogenation of (Hetero)Arylketones with
Tethered Rh(III)-TsDPEN Complexes: Scope and Limitations
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Longsheng Zheng,† Quentin Llopis,† PierreꢀGeorges Echeverria,† Charlène Férard,† Gérard
Guillamot,‡ Phannarath Phansavath*† and Virginie RatovelomananaꢀVidal*†
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† PSL Research University, Chimie ParisTechꢀCNRS, Institut de Recherche de Chimie Paris,
75005 Paris, France
‡ PCAS, 23 rue Bossuet, Z.I. de la vigne aux Loups, 91160 Longjumeau, France
Eꢀmail: phannarath.phansavath@chimieꢀparistech.fr; virginie.vidal@chimieꢀparistech.fr
(R,R)ꢀ8b–8e (0.5 mol%)
HCO2H/Et3N (5:2), 30 °C
O
HO
R1
H
R2
R1
R2
Rh
N
up to quant. yield
Cl
28 examples
up to >99% ee
R
TsN
H
Ph
Ph
(R,R)ꢀ8b: R = MeO
(R,R)ꢀ8c: R = Me
(R,R)ꢀ8d: R = F
(R,R)ꢀ8e: R = CF3
Abstract. A series of new tethered Rh(III)/Cp* complexes containing the TsDPEN ligand
has been prepared, characterized and evaluated in the asymmetric transfer hydrogenation of a
wide range of (hetero)aryl ketones. The reaction was performed under mild conditions with
the formic acid/triethylamine (5:2) system as the hydrogen source and provided
enantiomerically enriched alcohols with good yields and high to excellent enantioselectivities.
Although the nature of the substituents on the phenyl tethering ring did not alter the
stereochemical outcome of the reaction, complexes bearing electronꢀdonating groups
exhibited a higher catalytic activity than those having electronꢀwithdrawing groups. A scaleꢀ
up of the ATH of 4ꢀchromanone to gram scale quantitatively delivered the reduced product
with excellent enantioselectivity, demonstrating the potential usefulness of these new
complexes.
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Introduction
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8
Because enantiomerically pure alcohols are important synthetic building blocks in the
manufacturing of pharmaceuticals, flavors and fragrances, significant efforts have been made
to develop efficient and atomꢀeconomical stereoselective processes for the synthesis of these
compounds.1 In this area, transitionꢀmetalꢀcatalyzed asymmetric transfer hydrogenation
(ATH) is one of the most powerful and useful methods for the generation of enantiomerically
enriched secondary alcohols from the corresponding prochiral ketones, owing not only to its
high performance in terms of activity and selectivity, but also to its operational simplicity.2
Moreover, a variety of convenient, safe and inexpensive nonꢀH2 hydrogen sources can be
used for this reaction, typically isopropanol, formic acid/triethylamine mixtures or formate
salts. Since the seminal report in 1995 by Noyori and Ikariya of the [RuCl(η6ꢀarene)(Nꢀ
TsDPEN)] complexes 13 (named Noyori catalysts; TsDPEN = pꢀtoluenesulfonylꢀ1,2ꢀ
diphenylethyleneꢀ1,2ꢀdiamine), rutheniumꢀbased catalysts have been widely used in the ATH
of ketones and imines (Figure 1). Rhodium and iridium derivatives 2 and 3, respectively,
bearing Cp* as a ligand in place of the benzene ring were also studied and successfully
employed for these transformations.1a,2g,4 Numerous investigations aimed at diversifying the
ligands were undertaken in order to achieve more efficient catalytic performances, and
various derivatives of the Noyori catalysts have been reported.2 Notably, Wills et al.
introduced a series of ruthenium complexes 4 and 5 bearing a tether between the η6ꢀarene and
the diamine unit,5 and developed the isoelectronic Rh(III) derivatives 6,6 77 and 8a,8 which
proved effective for the asymmetric catalytic reduction of imines and functionalized ketones.
As part of our ongoing studies toward the development of efficient catalysts for the
asymmetric reduction of unsaturated compounds,9 we reported the synthesis and catalytic
performances of the rhodium(III)ꢀTsDPENꢀbased tethered catalyst 8b bearing a methoxy
group on the tethering phenyl ring (Figure 1).
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Rn
( )n
Cl
M
Ru
N
Ru
5
6
7
8
Cl
Cl
TsN
TsN
TsN
NH2
NH2
H
Ph
Ph
Ph
Ph
Ph
Ph
2: M = Rh
3: M = Ir
1
4 (n = 0,1,2,3)
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Rh
Rh
Ru
Cl
O
S
Cl
R
Cl
TsN
H
N
TsN
N
N
O
NH2
H
H
Ph
Ph
8a
Ph
H
Ph
6: R = H
5
7: R = MeO
This work:
Rh
Cl
Rh
Cl
MeO
Me
TsN
TsN
N
N
H
H
Ph
Ph
Ph
8c
Ph
8b
Rh
Rh
Cl
Cl
F3C
F
TsN
N
TsN
N
H
H
Ph
Ph
8e
Ph
Ph
8d
Figure 1. Transitionꢀmetal complexes used in ATH.
This new complex showed a good catalytic behaviour in the asymmetric transfer
hydrogenation of ketones10 and αꢀamino βꢀketo ester hydrochlorides.11 Following these initial
reports, we now describe herein the synthesis, characterization and evaluation of the novel
RhꢀTsDPENꢀbased tethered complexes 8c–8e having electron donating methyl, and electronꢀ
withdrawing fluorine and trifluoromethyl substituents respectively on the 2ꢀbenzyl tether
(Figure 1). In order to evaluate the electronic effect of the 2ꢀbenzyl tether substituent on the
catalytic performance of the resulting complexes, a complete comparative study of Wills'
complex 8a,8 and complexes 8b-8e in the ATH of a wide range of aromatic ketones is
disclosed.
Results and Discussion
Novel complexes (R,R)ꢀ8b–8e were prepared from commercially available 2ꢀbromoꢀ5ꢀ
methoxybenzaldehyde 9, 2ꢀbromoꢀ5ꢀmethylbenzaldehyde 10, 2ꢀbromoꢀ5ꢀfluorobenzaldehyde
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11 and 2ꢀbromoꢀ5ꢀtrifluoromethylbenzaldehyde 12, which were protected as their 1,3ꢀ
dioxolane derivatives 13–16 (Scheme 1).
6
7
8
R
R
1. nBuLi, Et2O, –90 °C, 1 h
then 2,3,4,5ꢀtetramethylꢀ
cyclopentꢀ2ꢀenone, rt, 3 h
HOCH2CH2OH
PTSA
toluene, ∆, 24 h
9
H
O
84–100%
2. 3% HCl, acetone, rt, 18 h
26–65% (2 steps)
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O
Br
O
Br
9: R = MeO
10: R = Me
11: R = F
13: R = MeO
14: R = Me
15: R = F
12: R = CF3
16: R = CF3
R
1. (R,R)ꢀTsDPEN
Rh
NaBH3CN, AcOH
4Å MS, MeOH, rt, 16 h
Cl
R
OHC
TsN
N
H
2. RhCl3.H2O, MeOH, ∆, 24 h
then Et3N, ∆, 24 h
Ph
Ph
18–36% (2 steps)
(R,R)ꢀ8b: R = MeO
(R,R)ꢀ8c: R = Me
(R,R)ꢀ8d: R = F
17: R = MeO
18: R = Me
19: R = F
(R,R)ꢀ8e: R = CF3
20: R = CF3
Scheme 1. Synthesis of complexes (R,R)ꢀ8b–8e.
Treatment of these compounds with nꢀBuLi followed by addition of 2,3,4,5ꢀ
tetramethylcyclopentꢀ2ꢀenone furnished the corresponding alcohols, which were then
subjected to 3% hydrochloric acid in acetone. The latter conditions led to both deprotection of
the aldehyde function and dehydration of the tertiary alcohol providing compounds 17–20.
Subsequent reductive amination using (R,R)ꢀTsDPEN in the presence of sodium
cyanoborohydride then delivered the corresponding diamines and the targeted complexes
(R,R)ꢀ8b–8e were obtained through heating the latter in refluxing methanol in the presence of
rhodium(III) chloride followed by treatment with triethylamine. The four complexes were
isolated after flash chromatography as orange solids and as single diastereomers whereas their
structures were confirmed by Xꢀray crystallographic analysis in the case of (R,R)ꢀ8b, (R,R)ꢀ8c
and (R,R)ꢀ8d (Figures 2–4).12
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Figure 2. Xꢀray structure of complex (R,R)ꢀ8b.12
Figure 3. Xꢀray structure of complex (R,R)ꢀ8c.12
Figure 4. Xꢀray structure of complex (R,R)ꢀ8d.12
Evaluation of these complexes started with the ATH of acetophenone as the standard
substrate using (R,R)ꢀ8b in combination with various hydrogen donor systems (Table 1). The
reaction was carried out at 24–30 °C with 0.5 mol% of (R,R)ꢀ8b. A comparison of various
hydrogen donor sources highlighted the choice of a formic acid/triethylamine (5:2) system in
preference to either sodium hypophosphite, ammonium formate, or an iꢀPrOH/tꢀBuOK
system. Indeed, in the presence of a formic acid/triethylamine (5:2) system, a full conversion
was attained within 5 h, and the reduced compound, (R)ꢀ1ꢀphenylethanol, was obtained with a
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very high enantiomeric excess of 98% (entry 1). On the other hand, in the presence of sodium
hypophosphite, the conversion dramatically decreased to 7% (entry 2). In the same manner,
an unsatisfactory conversion of 53% was observed with ammonium formate (entry 3). Upon
using the iꢀPrOH/tꢀBuOK system as the reducing agent, only degradation products were
formed (entry 4). Finally, the optimized reaction conditions for the ATH of acetophenone
with (R,R)ꢀ8b were set as follows: 0.5 mol% of the tethered Rh complex (R,R)ꢀ8b in neat
HCO2H/Et3N (5:2) at 24–30 °C. With these optimized set of conditions in hands, and to
establish the scope and limitations of the (R,R)ꢀ8b–8eꢀcatalyzed ATH reaction, a series of aryl
ketones was first examined (Table 2). A comparison with the rhodium complex (R,R)ꢀ8a8 was
carried out as well. It should be noted that, with the exception of four substrates (entries 1, 3,
10 and 11) indicated in Table 2, none of the ketones described in this paper has been
previously reduced using the Wills' complex (R,R)ꢀ8a so that the range of ketones has been
consistently expanded in this comparative study.
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Table 1. Optimization of the reaction conditions for the ATH of acetophenone with (R,R)ꢀ
8b.a
O
HO
H
(R,R)ꢀ8b, hydrogen donor, 24–30 °C, t (h)
S/C = 200
Entry
Hydrogen donor
t [h]
5
Conv [%]b
ee [%]c
1
2
3
4
HCO2H/Et3N (5:2)d
NaH2PO2.H2Oe
100
7
98
–
29
29
29
f
HCO2NH4
53
–
98
–
iꢀPrOH/tꢀBuOKg
a Conditions: acetophenone (126
ꢀL, 1.08 mmol), (R,R)ꢀ8b (4 mg, 0.0054 mmol).
b Determined by 1H NMR of the crude product.
c Determined by HPLC analysis.
d 580
ꢀL of HCO2H/Et3N (5:2).
e NaH2PO2.H2O (2.7 mmol), THF used as a solvent.
f HCO2NH4 (2.4 mmol), CH2Cl2 used as a solvent.
g iꢀPrOH (0.026 mmol) in tBuOK (11 mL).
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Acetophenone underwent a faster reduction with (R,R)ꢀ8b and (R,R)ꢀ8c than with the other
parent complexes (R,R)ꢀ8a, (R,R)ꢀ8d and (R,R)ꢀ8e, excellent yields and enantioselectivities
being observed in all cases (entry 1). The ATH of propiophenone proceeded similarly except
for (R,R)ꢀ8e which failed to afford complete conversion even after a prolonged reaction time
of 96 h, and with a significantly higher catalytic activity observed for complexes (R,R)ꢀ8b and
(R,R)ꢀ8c which gave full conversions in only 6 h as compared to 22h with (R,R)ꢀ8a (entry 2).
On the other hand, 2ꢀchloroacetophenone was readily reduced with all five complexes with ee
values ranging from 95% to >99%, (entry 3). The catalytic reduction of acetophenones
bearing substituents in the para or meta positions of the phenyl ring led to high levels of
stereoselectivity as well (entries 4–7) with a higher catalytic activity observed with (R,R)ꢀ8b
and (R,R)ꢀ8c (entries 4 and 5), whereas complex (R,R)ꢀ8e led only to 62–64% conversions
after 100–110 h of reaction for 4'ꢀbenzyloxyꢀacetophenone and 3',5'ꢀdimethoxyacetophenone
(entries 6 and 7). In contrast, lower enantiofacial discriminations were observed for aryl
ketones possessing an ortho substituent as for 2'ꢀbromoacetophenone (entry 8, 64–71% ee)
and 1ꢀacetonaphtone (entry 10, 78–85% ee). In both instances, compared to complex (R,R)ꢀ
8a, slightly higher ee values could be attained with complexes (R,R)ꢀ8b, (R,R)ꢀ8c and (R,R)ꢀ
8d (entries 8 and 10). Whereas fair enantioselectivities were reached within a short reaction
time for 4'ꢀnitroacetophenone (88% ee, entry 9), polycyclic aryl ketones afforded uniformly
high enantioinductions with ee values ranging from 92% to >99% (entries 11–16). A gramꢀ
scale ATH of 4ꢀchromanone was also carried out with complex (R,R)ꢀ8b under the standard
conditions and furnished quantitatively the desired (R)ꢀchromanꢀ4ꢀol with the same
enantiomeric purity (>99% ee, cf entry 14).
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Table 2. Asymmetric transfer hydrogenation of aryl ketones mediated by complexes (R,R)ꢀ
8a–8e.a
Entry/ATH
productb
Cat. Time
Yield
[%]c
ee
Entry/ ATH productb Cat. Time
Yield
[%]c
ee
[h]
[%]d
[h]
[%]d
8
8ae
8
1
10
100
98
9
1
99
88
8a
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OH
OH
5
99
99
97
99
98
97
98
98
0.5
1
0.5
2.5
99
99
99
99
88
88
88
88
8b
8c
8d
8e
8b
8c
8d
8e
8ae
8b
8c
8d
8e
8ae
8b
8c
O2N
8.5
22
24
2
22
6
6
30
96
90
79
100
100
(89)
98
97
97
97
97
10
11
12
8
35
94
100
98
(68)
80
82
84
85
78
8a
8b
8c
8d
8e
8ae
8b
8c
OH
27
30
39
110
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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3[f]
2
1.5
1
4
5
100
99
93
95
88
99.6
99
95
95
95
9
7
9
39
24
100
92
100
98
99.9
>99
>99
>99
99
OH
OH
Cl
8d
8e
8d
8e
100
4
22
7
7
27
96
100
98
93
97
90
98
98
97
98
98
48
29
24
96
96
97
72
100
(94)
(81)
>99
>99
99
92
99
8a
8b
8c
8d
8e
8a
8b
8c
8d
8e
OH
OH
MeO
5
22
3
24
30
96
97
99
99
99
91
95
96
94
94
95
13
24
5.5
22
22
55
62
95
100
100
76
98
98
97
97
98
8a
8b
8c
8d
8e
8a
8b
8c
8d
8e
OH
OH
Br
6g
22
23
39
48
100
97
100
84
98
99
99
99
98
14
15
16
6
4
4.5
10
96
100
100
100
100
79
99
8a
8b
8c
8d
8e
8a
8b
8c
8d
8e
OH
OH
>99
>99
>99
>99
BnO
O
110
(64)
7
7
2
2.5
72
100
99
90
100
100
(62)
96
96
94
94
96
7
5.5
5
7
6.5
97
>99
>99
>99
>99
99
8a
8b
8c
8d
8e
8a
8b
8c
8d
8e
MeO
OH
100
100
100
99
OH
MeO
8
22
27
30
88
88
98
99
93
64
70
65
71
66
23
22
4
6
65
95
79
100
100
84
99
8a
8b
8c
8d
8e
8a
8b
8c
8d
8e
OH
Br
>99
>99
>99
>99
OH
Br
110
(82)
17g
30
30
99
99
99
99
8a
8b
OH
N
O
a
Reaction conditions: ketone (0.8 mmol) in neat HCO2H/Et3N (5:2) (430 ꢀL), (R,R)ꢀ8a–8e (0.004 mmol, 0.5
mol%), 24–30 °C. Except where indicated, complete conversions were observed.
Absolute configuration assigned by comparing optical rotation with literature data and on the basis of the
general trends in enantioselectivity observed for the Rhꢀcatalyzed ATH of ketones.
b
c
Isolated yields after filtration through a short pad of silica gel. Values in brackets refer to incomplete
conversions.
d Determined by HPLC or SFC analysis.
e Results described by Wills et al.8 Conversion is reported in place of yield.
f Ethyl acetate was used as a coꢀsolvent to allow solubilization of the reaction mixture.
g Dichloromethane was used as a coꢀsolvent to allow solubilization of the reaction mixture.
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Additionally, we studied the ATH of a highly electronꢀrich aryl ketone bearing a
morpholine substituent in the para position. Although this challenging family of substrates
was recently efficiently reduced through ATH with tethered rutheniumꢀTsDPEN catalysts,13
no example of catalytic reduction with a rhodium catalyst has been reported to our
knowledge. The use of complexes (R,R)ꢀ8a and (R,R)ꢀ8b under the defined standard
conditions smoothly afforded the desired reduced compound in quantitative yield and with an
excellent enantiopurity (entry 17). It appears from this survey that complexes (R,R)ꢀ8a–8e
exhibited comparable stereoselectivities, providing the corresponding alcohols with mainly
high enantioselectivities for paraꢀ and metaꢀsubstituted ketones (ee values up to >99%)
whereas lower enantioinductions were observed for the orthoꢀsubstituted compounds. Of note,
a lower catalytic activity was displayed by complex (R,R)ꢀ8e, possessing an electronꢀ
withdrawing trifluoromethyl substituent, which generally required longer reaction times.
To test the substrate scope further, we next explored the (R,R)ꢀ8a–8eꢀmediated ATH of
heteroaryl and alkyl ketones (Table 3). The former compounds underwent the catalytic
reduction in good yields with systematically high asymmetric inductions observed with all the
examined tethered Rh(III)/Cp* complexes, for (R)ꢀ1ꢀ(2ꢀfuryl)ethanol, (R)ꢀ1ꢀ(2ꢀ
thienyl)ethanol, (1R)ꢀ1ꢀ(benzofuranꢀ2ꢀyl)ethanol and (R)ꢀ1ꢀ(2ꢀpyridyl)ethanol (entries 1–4).
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With regard to nonꢀaromatic ketones, βꢀtetralone yielded moderate ee values (80–83%, entry
5), whereas high stereoselectivities were obtained for the ATH of acetylcyclohexane (entry 6,
93–95% ee) albeit lower ee values of 84 and 87%, were respectively observed using parent
tethered rhodium complexes.6,7
Table 3. (R,R)ꢀ8a–8eꢀmediated ATH of heteroaryl and aliphatic ketones.a
Entry/ATH
productb
Cat. 8
Time
[h]
Yield
[%]c
ee [%]d
1
5.5
5.5
8
27
24
82
99
98
>99
>99
99
8a
8b
8c
8d
8e
OH
O
100
100
92
85
2
23
100
99
8a
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OH
23
17
20
65
76
98
100
84
98
99
99
>99
8b
8c
8d
8e
S
6
7
8
9
3
4
5
5.5
3
3
3.5
6.5
100
100
100
100
100
97
98
98
99
98
8a
8b
8c
8d
8e
OH
O
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6
89
99
100
98
70
97
94
96
99
96
8a
8b
8c
8d
8e
N
OH
4.5
6.5
9
24
24
3
3
27
30
53
96
81
83
83
80
80
94f
95f
93f
94f
94f
8a
8b
8c
8d
8e
OH
100
100
89
71e
68e
73e
72e
58e
22
7
7
30
24
8a
8b
8c
8d
8e
6
OH
a Reaction conditions: see Table 2.
b Absolute configuration assigned by comparing optical rotation with literature data.
c Isolated yields after filtration through a pad of silica gel.
d Determined by HPLC or SFC analysis.
e Isolated yield (two steps) after conversion of the alcohol into the benzoyl ester.
f Determined by HPLC on the related benzoyl ester.
In addition, because the catalytic asymmetric reduction of unsymmetrical benzophenones
has been less investigated,14 we were keen to evaluate the catalytic performance of our new
complexes in the ATH of these more challenging substrates wherein a catalyst has to
discriminate structural differences in the two aromatic moieties (Scheme 2). Interestingly, the
tethered RhꢀTsDPEN complexes (R,R)ꢀ8a and (R,R)ꢀ8b operated efficiently under the
standard reaction conditions and 4'ꢀnitrobenzophenone underwent the ATH with satisfactory
enantiomeric excesses of 84% and 83%, respectively (Scheme 2). On the other hand, the
asymmetric transfer hydrogenation proceeded with low enantioinductions for 4'ꢀ
chlorobenzophenone and 4'ꢀmethoxybenzophenone. Unsurprisingly, the highest
stereoselectivity was observed with the orthoꢀsubstituted substrate, 2'ꢀmethylbenzophenone,
which was converted into the corresponding alcohol in 99% ee.
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O
OH
(R,R)ꢀ8a-8b (0.5 mol%)
HCO2H/Et3N (5:2), 30 °C
*
R
R
8
9
R
t
(R,R)ꢀ8a
(R,R)ꢀ8b
pꢀNO2 32 h 52% yield, 84% ee (S)
pꢀCl
30 h 100% yield, 54% ee (S)
pꢀMeO 7 d 79% yield, 9% ee (R)
oꢀMe
7 d 60% yield, >99% ee (S)
92% yield, 83% ee (S)
99% yield, 50% ee (S)
72% yield, 9% ee (R)
65% yield, 99% ee (S)
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Scheme 2. (R,R)ꢀ8a–8bꢀmediated ATH of diaryl ketones
The ATH reaction was also carried out with a 1,4ꢀdiaryldiketone (Scheme 3). Thus 1,4ꢀ
diphenylꢀ1,4ꢀbutanedione was successfully reduced with (R,R)ꢀ8b under the standard
conditions giving the corresponding (1R,4R)ꢀ1,4ꢀdiphenylbutanꢀ1,4ꢀdiol with a very high
dl/meso ratio (96:4) and an excellent enantioselectivity (> 99% ee).
(R,R)ꢀ8b (0.5 mol%)
HCO2H/Et3N (5:2)
24 °C, 27 h
O
O
OH OH
( )
( )
2
2
100% conversion
96% isolated yield
dl/meso: 96/4
ee > 99%
Scheme 3. (R,R)ꢀ8bꢀmediated ATH of 1,4ꢀdiphenylꢀ1,4ꢀbutanedione.
When the reaction was performed with (R,R)ꢀ8a, an incomplete conversion was observed
even after a prolonged reaction time of 48 h (48% conversion, 41% isolated yield) whereas
the stereochemical outcome remained unchanged. This compound is a precursor of (2R,5R)ꢀ
diphenylpyrrolidine which is commonly used in asymmetric organocatalytic reactions.15
Conclusion
In conclusion, the synthesis, characterization and evaluation of novel tethered Rh(III)
complexes (R,R)ꢀ8b–8e having electronꢀdonating groups as well as electronꢀwithdrawing
substituents on the tetheringꢀphenyl ring were successfully accomplished. These new
complexes showed high stability and were easy to handle. As far as the synthesis,
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characterization and applications of novel tethered Rh(III) complexes is concerned, a
complete comparative study of the catalytic performances of complexes (R,R)ꢀ8b–8e was
conducted. This study demonstrated that these complexes exhibited excellent activities for the
asymmetric transfer hydrogenation of a wide range of functionalized ketones. In this survey,
the catalytic performance of the Wills' complex (R,R)ꢀ8a was also evaluated on a broad scope
of new substrates. Selectivities obtained with complexes (R,R)ꢀ8b–8e were comparable to
those obtained with (R,R)ꢀ8a or slightly higher in a few instances, and with a better catalytic
activity observed in several cases. A wide range of (hetero)aryl ketones underwent the (R,R)ꢀ
8b–8eꢀpromoted ATH using formic acid/triethylamine with high levels of enantioselectivities
under mild reaction conditions at a low catalyst loading. The scope of the prochiral ketones
for the ATH promoted by tethered Rh/TsDPEN/Cp* complexes has been consistently
expanded, including notably unsymmetrical benzophenones, a highly electronꢀrich
acetophenone bearing a morpholine substituent and a highly electronꢀpoor aryl ketone
possessing a nitro substituent. Moreover, 1,4ꢀdiphenylꢀ1,4ꢀbutanedione was efficiently
reduced upon using the RhꢀTsDPEN complex (R,R)ꢀ8b, into the enantiomerically pure 1,4ꢀ
diphenylꢀ1,4ꢀbutanediol, a valuable intermediate in the preparation of the (2R,5R)ꢀ
diphenylpyrrolidine organocatalyst. In addition, the ATH of 4ꢀchromanone was performed
with (R,R)ꢀ8b on gram scale without detrimental impact on the yield and the stereochemical
outcome of the reaction, demonstrating the potential usefulness of these new complexes.
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Experimental Section
Synthesis of complexes (R,R)-8b–8e:
Compound 13:16 A mixture of 2ꢀbromoꢀ5ꢀmethoxybenzaldehyde 9 (5.0 g, 23.2 mmol),
ethylene glycol (3.1 mL, 56.6 mmol) and pꢀtoluenesulfonic acid (56 mg, 0.32 mmol) in
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toluene (40 mL) was refluxed in a DeanꢀStark apparatus using an oil bath for 24 h. The cooled
mixture was washed with H2O and brine. The organic layer was dried over MgSO4, filtered
and concentrated. Purification of the residue by flash chromatography (SiO2, petroleum
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ether/EtOAc: 95/5) afforded 13 (6.01 g, quant.) as a colorless oil. H NMR (300 MHz,
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CDCl3): δ 7.44 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 3.1 Hz, 1H), 6.78 (dd, J = 8.8, 3.1 Hz, 1H),
6.04 (s, 1H), 4.18–4.03 (m, 4H), 3.79 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 158.9, 137.3,
133.6, 116.6, 113.1, 112.9, 102.4, 65.4 (2C), 55.5. MS (DCI/NH3): m/z = 259 [M+H]+.
Compound 14:17 Following the general procedure described for 13, and starting from 2ꢀ
bromoꢀ5ꢀmethylbenzaldehyde 10 (4.2 g, 21.3 mmol), compound 14 (4.8 g, 92%) was obtained
1
as a colorless oil. H NMR (300 MHz, CDCl3): δ 7.52–7.32 (m, 2H), 7.03 (dd, J = 8.2, 2.3
Hz, 1H), 6.06 (s, 1H), 4.31–3.93 (m, 4H), 2.32 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 137.5,
136.2, 132.8, 131.6, 128.5, 119.7, 102.8, 65.6 (2C), 21.1. MS (DCI/NH3): m/z = 244 [M+H]+.
Compound 15:18 Following the general procedure described for 13, and starting from 2ꢀ
fluoroꢀ5ꢀmethylbenzaldehyde 11 (5.0 g, 25.0 mmol), compound 15 (5.2 g, 84%) was obtained
as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.50 (dd, J = 8.8, 5.1 Hz, 1H), 7.32 (dd, J =
9.3, 3.1 Hz, 1H), 6.94 (ddd, J = 8.8, 7.8, 3.1 Hz, 1H), 6.03 (d, J = 1.3 Hz, 1H), 4.27–3.94 (m,
4H). 13C NMR (75 MHz, CDCl3): δ 162.1 (d, JCF = 247.3 Hz), 139.1 (d, JCF = 6.2 Hz), 134.3
(d, JCF = 7.6 Hz), 117.8 (d, JCF = 22.7 Hz), 116.9 (d, JCF = 3.2 Hz), 115.2 (d, JCF = 24.4 Hz),
102.1, 65.6 (2C). MS (DCI/NH3): m/z = 248 [M+H]+.
Compound 16:19 Following the general procedure described for 13, and starting from 2ꢀ
bromoꢀ5ꢀtrifluoromethylbenzaldehyde 12 (5.0 g, 19.8 mmol), compound 16 (5.8 g, 99%) was
obtained as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 8.00–7.78 (m, 1H), 7.78–7.62 (m,
1H), 7.47 (dt, J = 8.3, 1.5 Hz, 1H), 6.09 (s, 1H), 4.33–3.89 (m, 4H). 13C NMR (75 MHz,
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CDCl3): δ 138.1, 133.7, 130.2 (q, JCF = 33.0 Hz), 127.2 (q, JCF = 3.9 Hz), 125.0 (q, JCF = 3.6
Hz), 123.8 (q, JCF = 272.5 Hz), 102.0, 65.7 (2C). MS (DCI/NH3): m/z = 299 [M+H]+.
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Compound 17:7 To a solution of 13 (6.0 g, 23.2 mmol) in Et2O (42 mL) was added dropwise
nꢀBuLi (9.7 mL, 2.5 M in hexane, 24.4 mmol) at −90 °C. After 1 h at this temperature,
2,3,4,5ꢀtetramethylcyclopentꢀ2ꢀenone (3.7 mL, 24.4 mmol) was added dropwise and the
reaction was allowed to warm to rt and stirred for 3 h. Toluene and water (30 mL/30 mL)
were added and the aqueous layer was extracted with toluene. The combined organic layers
were washed with brine, dried over MgSO4, filtered and concentrated to afford the crude
alcohol. THF (140 mL), acetone (18 mL) and 3% aqueous HCl solution (60 mL) were added
and the mixture was stirred overnight at rt. Toluene was added, the organic layer was washed
with H2O then brine, dried over MgSO4, filtered and concentrated. The crude residue was
purified by flash chromatography (SiO2, petroleum ether/EtOAc: 98/2) to give 17 (3.9 g,
65%) as a bright yellow oil. 1H NMR (300 MHz, CDCl3): δ 9.81 (br s, 1H), 7.44 (dd, J = 2.3,
0.8 Hz, 1H), 7.15–7.14 (m, 2H), 3.88 (s, 1H), 3.87 (s, 3H), 1.92 (s, 3H), 1.85 (s, 3H), 1.71 (s,
3H), 0.93 (d, J = 7.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 192.9, 158.3, 141.8 (2C), 138.2,
135.3, 134.5, 132.0, 121.8 (2C), 109.0, 55.5 (2C), 14.2, 12.3, 11.9, 11.0. MS (DCI/NH3): m/z
= 257 [M+H]+.
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Compound 18: Following the general procedure described for 17, and starting from 14 (4.8
g, 19.6 mmol), compound 18 (2.6 g, 55%) was obtained as a bright yellow oil. 1H NMR (300
MHz, CDCl3): δ 9.87 (br s, 1H), 7.90–7.66 (m, 1H), 7.40 (dd, J = 7.8, 2.0 Hz, 1H), 7.13 (d, J
= 7.8 Hz, 1H), 3.20 (br s, 1H), 2.42 (s, 3H), 1.94 (s, 3H), 1.87 (s, 3H), 1.73 (s, 3H), 0.95 (d, J
= 7.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 193.2, 144.4, 141.9, 139.3, 138.8, 137.1, 136.5,
134.5, 134.4, 130.8, 127.3, 52.5, 21.0, 14.2, 12.4, 11.9, 11.1. HRMS (ESI/ion trap) m/z:
[M+Na]+ calcd for C17H20ONa: 263.1406, found: 263.1408.
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Compound 19: Following the general procedure described for 17, and starting from 15 (5.2
g, 21.0 mmol), compound 23 (2.5 g, 49%) was obtained as a bright yellow oil. 1H NMR (300
MHz, CDCl3): δ 9.80 (br s, 1H), 7.62 (dd, J = 8.9, 2.6 Hz, 1H), 7.37 – 7.16 (m, 2H), 3.18 (br
s, 1H), 1.93 (s, 3H), 1.86 (s, 3H), 1.71 (s, 3H), 0.94 (d, J = 7.7 Hz, 3H). 13C NMR (75 MHz,
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CDCl3): δ 191.9, 161.7 (d, JCF = 247.9 Hz), 145.1 (d, JCF = 19.4Hz), 142.4, 139.9 (d, JCF
=
14.0 Hz), 137.6, 136.2, 134.6, 132.8 (d, JCF = 6.5 Hz), 121.0 (d, JCF = 22.1 Hz), 113.1 (d, JCF
= 22.0 Hz), 52.6 14.2, 12.4, 12.0, 11.1. HRMS (ESI/ion trap) m/z: [M+Na]+ calcd for
C16H17FONa: 267.1156, found: 267.1157.
Compound 20: Following the general procedure described for 17, and starting from 16 (5.2
g, 17.5 mmol), compound 20 (1.4 g, 26%) was obtained as a bright yellow oil. 1H NMR (300
MHz, CDCl3): δ 9.87 (br s, 1H), 8.30–8.10 (m, 1H), 7.79 (ddd, J = 8.1, 2.1, 0.8 Hz, 1H), 7.36
(d, J = 8.1 Hz, 1H), 3.26 (br s, 1H), 1.96 (s, 3H), 1.87 (s, 3H), 1.74 (s, 3H), 0.96 (d, J = 7.7
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 191.6, 145.1, 143.5, 137.5, 134.9, 134.8, 131.7,
131.6, 129.6 (q, JCF = 3.2 Hz), 129.1 (q, JCF = 33.6 Hz), 124.6 (q, JCF = 3.7 Hz), 123.9 (q, JCF
= 272.2 Hz), 52.5, 14.1, 12.6, 12.0, 11.1. MS (DCI/NH3): m/z = 295 [M+H]+. HRMS (APCI)
m/z: [M+H]+ calcd for C17H18F3O: 295.1304, found: 295.1310.
Complex (R,R)-8b: To a solution of compound 17 (538 mg, 2.1 mmol) in dry MeOH (24
mL) was added (R,R)ꢀTsDPEN (900 mg, 2.5 mmol) followed by the addition of 700 mg of
molecular sieves (4 Å) and 2 drops of glacial acetic acid. The mixture was stirred at rt for 5 h
then NaBH3CN (170 mg, 2.7 mmol) was added and the reaction was stirred overnight at rt.
After removal of the molecular sieves and evaporation of MeOH, the residue was dissolved in
EtOAc (40 mL). The organic layer was washed with saturated NaHCO3 then brine, dried over
MgSO4, filtered and concentrated. Purification of the residue by flash chromatography (SiO2,
pentane/EtOAc: 9/1 to 8/2) afforded the diamine (786 mg, 60%) as a white solid. To a
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solution of the diamine (740 mg, 1.2 mmol) in MeOH (28 mL) was added RhCl3.H2O (255
mg, 1.2 mmol) and the reaction mixture was heated under reflux using an oil bath for 23 h.
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Et3N (340 ꢀL, 2.4 mmol) was then added and the mixture was refluxed for a further 20 h and
9
concentrated. The residue was triturated with H2O and the solid was filtered, washed with
H2O and dried under vacuum. Purification of the black solid by flash chromatography (SiO2,
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EtOAc/cyclohexane: 1/1 to EtOAc/MeOH: 95/5) afforded (R,R)
−
8b (455 mg, 50%) as an
25
orange solid. mp > 260 °C (decomposition). Rf 0.51 (CH2Cl2/MeOH:9/1, UV, KMnO4). [α]D
= −154.4 (c 0.12, CHCl3). IR (neat): 2360, 2339, 1608, 1513, 1489, 1455, 1397, 1372, 1277,
1239, 1131, 1098, 1086, 1040, 1023, 940, 895, 812, 796, 766, 700, 682, 661, 646, 635, 622,
1
606 cm–1. H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H),
7.19–7.16 (m, 3H), 7.02 (dd, J = 8.4, 2.5 Hz, 1H), 6.73 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 7.3
Hz, 2H), 6.59 (t, J = 7.8 Hz, 2H), 6.48 (d, J = 7.4 Hz, 2H), 6.42 (br d, J = 2.4 Hz, 2H), 4.98
(d, J = 12.4 Hz, 1H), 4.32 (d, J = 11.0 Hz, 1H), 4.22 (dd, J = 14.0, 2.9 Hz, 1H), 3.73 (s, 3H),
3.60 (d, J = 14.0 Hz, 1H), 3.26 (t, J = 12.4 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.97 (s, 3H),
13
1.83 (s, 3H), 1.54 (s, 3H). C NMR (100 MHz, CDCl3): δ 160.2, 142.3, 139.0, 138.6, 137.5,
135.7, 131.2, 128.8, 128.7, 127.9, 127.7, 127.1, 126.2, 118.6, 117.0, 115.0, 106.4 (d, JCRh
=
6.6 Hz), 99.2 (d, JCRh = 6.6 Hz), 97.0 (d, JCRh = 8.8 Hz), 88.7 (d, JCRh = 9.5 Hz), 80.6 (d, JCRh
= 8.0 Hz), 75.9, 69.8, 55.5, 52.5, 21.3, 10.8, 10.7, 10.4, 8.3. HRMS (ESI/ion trap) m/z: [M–
Cl]+ calcd for C38H40N2O3RhS: 707.1809, found: 707.1813.
Complex (R,R)-8c: Following the general procedure described for (R,R)ꢀ8b, and starting
from 18 (546 mg, 2.3 mmol), complex (R,R)ꢀ8c (590 mg, 36%, 2 steps) was obtained as an
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orange solid. mp 274 °C (decomposition). Rf 0.58 (CH2Cl2/MeOH:9/1, UV, KMnO4). [α]D
=
–112 (c 0.15, CHCl3). IR (neat): 1456, 1277, 1133, 1107, 1085, 1036, 1021, 938, 894, 809,
751, 701, 682, 670, 661, 647, 601 cmꢀ1.1H NMR (400 MHz, CDCl3): δ 7.39–7.23 (m, 5H),
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7.23–7.06 (m, 3H), 6.81–6.66 (m, 5H), 6.59 (dd, J = 8.2, 7.1 Hz, 2H), 6.48 (d, J = 7.6 Hz,
2H), 4.99 (d, J = 12.8 Hz, 1H), 4.30 (d, J = 11.0 Hz, 1H), 4.20 (dd, J = 14.0, 3.3 Hz, 1H), 3.62
(d, J = 14.0 Hz, 1H), 3.25 (dd, J = 12.8, 10.9 Hz, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 2.09 (s, 3H),
1.98 (s, 3H), 1.82 (s, 3H), 1.54 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 142.2, 139.9, 139.1,
138.7, 135.9, 135.8, 132.4, 130.3, 129.8, 128.7, 127.9, 127.8, 127.0, 126.2, 123.9, 106.3 (d,
JCRh = 6.1 Hz), 99.5 (d, JCRh = 7.0 Hz), 97.2 (d, JCRh = 9.0 Hz), 88.2 (d, JCRh = 9.2 Hz), 80.9
(d, JCRh = 8.6 Hz), 75.9, 69.9, 52.2, 21.3, 21.2, 10.8, 10.6, 10.4, 8.3. HRMS (ESI/ion trap)
m/z: [MꢀCl]+ calcd for C38H40N2O2RhS: 691.1860, found: 691.1870.
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Complex (R,R)-8d: Following the general procedure described for (R,R)ꢀ8b, and starting
from 19 (555 mg, 2.3 mmol), complex (R,R)ꢀ8d (297 mg, 19%, 2 steps) was obtained as an
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orange solid. mp 280 °C (decomposition). Rf 0.55 (CH2Cl2/MeOH:9/1, UV, KMnO4). [α]D
=
–151 (c 0.14, CHCl3). IR (neat): 1736, 1608, 1585, 1511, 1492, 1455, 1373, 1275, 1235,
1216, 1158, 1132, 1023, 940, 894, 868, 852, 842, 811, 793, 779, 757, 730, 699, 677, 657, 645,
1
636, 607 cmꢀ1. H NMR (400 MHz, CDCl3): δ 7.45 (dd, J = 8.5, 5.5 Hz, 1H), 7.33–7.10 (m,
7H), 6.74 (d, J = 8.0 Hz, 3H), 6.71–6.55 (m, 4H), 6.48 (d, J = 7.3 Hz, 2H), 5.04 (d, J = 12.8
Hz, 1H), 4.32 (d, J = 10.9 Hz, 1H), 4.22 (d, J = 14.2 Hz, 1H), 3.64 (d, J = 14.3 Hz, 1H), 3.34–
3.13 (m, 1H), 2.17 (s, 3H), 2.10 (s, 3H), 1.98 (s, 3H), 1.83 (s, 3H), 1.55 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 162.8 (d, JCF = 251.3 Hz), 142.1, 139.2, 138.7 (d, JCF = 7.7 Hz), 138.4,
135.4, 131.9 (d, JCF = 8.4 Hz), 129.0, 128.9, 128.6, 127.9, 127.7, 127.1, 127.0, 126.3, 123.1
(d, JCF = 3.2 Hz), 118.7 (d, JCF = 22.3 Hz), 116.8 (d, JCF = 21.4 Hz), 106.5 (d, JCRh = 6.4 Hz),
99.9 (d, JCRh = 7.0 Hz), 96.0 (d, JCRh = 9.2 Hz), 88.2 (d, JCRh = 9.5 Hz), 81.1 (d, JCRh = 8.5
Hz), 76.3, 69.9, 52.2, 21.3, 10.8, 10.6, 10.4, 8.3. HRMS (ESI/ion trap) m/z: [M–Cl]+ calcd for
C37H37FN2O2RhS: 695.1609, found: 695.1616.
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Complex (
R
,
R
)-8e: Following the general procedure described for (R,R)ꢀ8b, and starting
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from 20 (656 mg, 2.2 mmol), compound (R,R)ꢀ8e (310 mg, 18%, 2 steps) was obtained as an
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orange solid. mp 284 °C (decomposition). Rf 0.56 (CH2Cl2/MeOH:9/1, UV, KMnO4). [α]D
=
9
–172 (c 0.14, CHCl3). IR (neat): 2359, 2341, 1329, 1275, 1168, 1132, 1082, 938, 906, 896,
881, 870, 808, 791, 766, 756, 713, 699, 687, 679, 671, 659, 641, 622, 614, 605 cmꢀ1. 1H NMR
(400 MHz, CDCl3): δ 7.78 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.2 Hz,
2H), 7.23–7.09 (m, 4H), 6.73 (d, J = 8.0 Hz, 2H), 6.76–6.66 (m, 3H), 6.65–6.54 (m, 2H), 6.47
(d, J = 7.6 Hz, 2H), 5.04 (d, J = 12.7 Hz, 1H), 4.35 (d, J = 10.9 Hz, 1H), 4.26 (dd, J = 14.0,
3.3 Hz, 1H), 3.73 (d, J = 14.1 Hz, 1H), 3.19 (dd, J = 12.7, 10.9 Hz, 1H), 2.17 (s, 3H), 2.10 (s,
3H), 1.98 (s, 3H), 1.83 (s, 3H), 1.56 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 141.9, 139.2,
138.1, 137.0, 135.1, 131.8 (q, JCF = 33.2 Hz), 131.5, 131.3, 130.7, 129.1, 128.9, 128.6, 128.6
(q, JCF = 3.2 Hz), 127.8, 127.6, 127.1, 126.5 (q, JCF = 3.2 Hz), 126.3, 123.3 (q, JCF = 272.7
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Hz), 106.5 (d, JCRh = 6.3 Hz), 100.1 (d, JCRh = 7.0 Hz), 95.5 (d, JCRh = 9.2 Hz), 87.8 (d, JCRh
=
9.1 Hz), 81.4 (d, JCRh = 8.4 Hz), 76.4, 69.5, 52.1, 21.2, 10.6, 10.5, 10.3, 8.2. HRMS (ESI/ion
trap) m/z: [M–Cl]+ calcd for C38H37F3N2O2RhS: 745.1577, found: 745.1585.
General procedure for the ATH of ketones with complexes (R,R)-8a–8e: To a roundꢀ
bottom tube containing complex (R,R)ꢀ8 (4 ꢁmol, 0.5 mol%) was added at room temperature,
an HCO2H/Et3N (5:2) azeotropic mixture (430 ꢁL, 7.2 mmol) and 3 vacuum/argon cycles
were used to insure an inert atmosphere. The orange mixture was stirred for 10–15 min before
the ketone (0.8 mmol) was added. The reaction mixture was stirred at 24–30 °C until the
starting material was consumed as determined by TLC, then the reaction mixture was purified
by filtration through a pad of silica gel using pentane/EtOAc (8/2). The filtrate was
concentrated under vacuum to give the reduced product. Enantiomeric excess was determined
by SFC (Chiralpak ODꢀH and Chiralpak ADꢀH, ASꢀH, IA, IC or ID) or HPLC (Chiralpak IB,
IC, ID column) analysis.
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(R
)-1-phenylethanol:8 96 mg, 98% yield; Pale yellow oil; [α]D +45.5 (c 1.0, CHCl3, 98%
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9
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ee), lit.:8 [α]D +45.4 (c 0.5, CHCl3, 98% ee); enantiomeric excess determined by HPLC
analysis on Daicel Chiralpak IB column (0.46 x 25 cm), hexane/iꢀPrOH 95:5, 1.0 mL/min, λ =
215 nm, tR: 7.38 min (R), 8.04 min (S). MS (DCI/NH3): m/z = 140 [M+NH4]+.
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)-1-Phenylpropan-1-ol:20 98 mg, 90% yield; Pale yellow oil; [α]D +45 (c 1.0, CHCl3,
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(
R
20
98% ee), lit.:20 [α]D +44.5 (c 1.0, CHCl3, 97% ee); enantiomeric excess determined by SFC
analysis on Daicel Chiralpak ODꢀH column (0.46 x 25 cm), scCO2/MeOH 95:5, 4.0 mL/min,
P = 150 bar, λ = 215 nm, tR: 2.07 min (R), 2.44 min (S). MS (DCI/NH3): m/z = 154
[M+NH4]+.
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(S
)-2-Chloro-1-phenylethan-1-ol:21 119 mg, 95% yield; Colorless oil; [α]D +56 (c 1.09,
CHCl3, 95% ee), lit.:21 [α]D20 +57.8 (c 1.0, CHCl3, 96.6% ee); enantiomeric excess determined
by SFC analysis on Daicel Chiralpak ODꢀH column (0.46 x 25 cm), scCO2/MeOH 95:5, 4.0
mL/min, P = 150 bar, λ = 215 nm, tR: 2.52 min (S), 3.38 min (R). MS (DCI/NH3): m/z = 174
[M+NH4]+.
(R
)-1-(p
-Tolyl)ethan-1-ol:22 109 mg, 100% yield; Pale yellow oil; [α]D25 +53 (c 0.94, CHCl3,
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98% ee), lit.:22 [α]D +55.4 (c 1.01, CHCl3, 98.7% ee); enantiomeric excess determined by
HPLC analysis on Daicel Chiralpak ID column (0.46 x 25 cm), hexane/iꢀPrOH 97:3, 0.5
mL/min, λ = 215 nm, tR: 18.77 min (R), 19.97 min (S). MS (DCI/NH3): m/z = 119 [M+H–
H2O]+.
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(R
)-1-(4-Bromophenyl)ethan-1-ol:23 159 mg, 99% yield; Colorless oil; [α]D +35 (c 1.17,
22
CHCl3, 96% ee), lit.:[23] [α]D +34.8 (c 1.03, CHCl3, 97% ee); enantiomeric excess
determined by HPLC analysis on Daicel Chiralpak IB column (0.46 x 25 cm), hexane/iꢀPrOH
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95:5, 0.5 mL/min, λ = 215 nm, tR: 15.09 min (S), 15.83 min (R). MS (DCI/NH3): m/z = 202
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[M+NH4–H2O]+.
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(R
)-1-(4-(Benzyloxy)phenyl)ethan-1-ol:24 182 mg, 100% yield; White solid; [α]D +33 (c
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1.09, CHCl3, 99% ee), lit.:24 [α]D −31.8 (c 1.2, CHCl3, >99% ee, (S)ꢀisomer); enantiomeric
excess determined by SFC analysis on Daicel Chiralpak ODꢀH column (0.46 x 25 cm),
scCO2/MeOH 98:2, 2.0 mL/min, P = 150 bar, λ = 215 nm, tR: 39.24 min (S), 42.59 min (R).
MS (DCI/NH3): m/z = 211 [M+H–H2O]+.
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(R
)-1-(3,5-Dimethoxyphenyl)ethan-1-ol:25 144 mg, 99% yield; Colorless oil; [α]D +31 (c
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0.95, CHCl3, 96% ee), lit.:25 [α]D −32.7 (c 2.0, CHCl3, 97% ee, (S)ꢀisomer); enantiomeric
excess determined by SFC analysis on Daicel Chiralpak ODꢀH column (0.46 x 25 cm),
scCO2/MeOH 95:5, 4.0 mL/min, P = 150 bar, λ = 215 nm, tR: 3.11 min (R), 3.49 min (S). MS
(DCI/NH3): m/z = 183 [M+H]+.
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(R
)-1-(2-Bromophenyl)ethan-1-ol:26 142 mg, 88% yield; Colorless oil; [α]D +40 (c 0.99,
CHCl3, 64% ee), lit.:26 [α]D +32.7 (c 0.8, CHCl3, 64% ee); enantiomeric excess determined
by SFC analysis on Daicel Chiralpak ID column (0.46 x 25 cm), scCO2/MeOH 90:10, 4.0
mL/min, P = 150 bar, λ = 215 nm, tR: 1.27 min (R), 1.50 min (S). MS (DCI/NH3): m/z = 218
[M+NH4]+.
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22
(R
)-1-(4-Nitrophenyl)ethan-1-ol:27 132 mg, 99% yield; Yellow oil; [α]D +34.9 (c 1.0,
23
CHCl3, 88% ee); lit.:27 [α]D +33.7 (c 1.0, CHCl3, 85% ee); enantiomeric excess determined
by SFC analysis on Daicel Chiralpak ASꢀH column (0.46 x 25 cm), scCO2/MeOH 95/5, 2.0
mL/min, P = 100 bar, λ = 215 nm, tR: 6.30 min (R), 7.33 min (S). MS (DCI/NH3): m/z = 185
[M+NH4]+.
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(R
)-1-(Naphthalen-1-yl)ethan-1-ol:28 135 mg, 98% yield; Colorless oil; [α]D +46.6 (c 1.0,
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9
22
CHCl3, 85% ee), lit.:28 [α]D +55.1 (c 1.0, CHCl3, 92% ee); enantiomeric excess determined
by SFC analysis on Daicel Chiralpak ODꢀH column (0.46 x 25 cm), scCO2/MeOH 95:5, 4.0
mL/min, P = 150 bar, λ = 215 nm, tR: 7.65 min (S), 11.48 min (R). MS (DCI/NH3): m/z = 155
[M+H–H2O]+.
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(R
)-1,2,3,4-Tetrahydro-1-naphthol:5f 141 mg, 100% yield; Colorless oil; [α]D25 −30 (c 0.94,
CHCl3, 99% ee), lit.:5f [α]D −30.7 (c 1.02, CHCl3, 99.2 % ee); enantiomeric excess
determined by SFC analysis on Daicel Chiralpak ODꢀH column (0.46 x 25 cm),
scCO2/MeOH 95:5, 3.0 mL/min, P = 150 bar, λ = 215 nm, tR: 3.80 (S), 4.20 min (R). MS
(DCI/NH3): m/z = 131 [M+H–H2O]+.
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(R
)-6-Methoxy-1,2,3,4-tetrahydro-1-naphthol:29 165 mg, 100% yield; Colorless oil; [α]D
−22 (c 0.92, CHCl3, >99% ee), lit.:29 [α]D −17.2 (c 1.19, CHCl3, 92% ee); enantiomeric
excess determined by SFC analysis on Daicel Chiralpak ADꢀH column (0.46 x 25 cm),
scCO2/MeOH 90:10, 3.0 mL/min, P = 150 bar, λ = 215 nm, tR: 5.37 min (S), 6.23 min (R). MS
(DCI/NH3): m/z = 161 [M+H–H2O]+.
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(R
)-1,2-Dihydroacenaphthylen-1-ol:30 129 mg, 95% yield; White solid; [α]D −1.4 (c 0.92,
CHCl3, 98% ee), lit.:30 [α]D20 −1.4 (c 0.5, CHCl3, 98.2% ee); enantiomeric excess determined
by SFC analysis on Daicel Chiralpak ODꢀH column (0.46 x 25 cm), scCO2/iꢀPrOH 93:7, 4.0
mL/min, P = 150 bar, λ = 215 nm, tR: 8.17 min (S), 8.99 min (R). MS (DCI/NH3): m/z = 153
[M+H–H2O]+.
(R
)-Chroman-4-ol:21 120 mg, 100% yield; White solid; [α]D25 +68 (c 0.93, CHCl3, >99% ee),
lit.:21 [α]D20 +66.9 (c 1.0, CHCl3, 99.1% ee); enantiomeric excess determined by SFC analysis
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on Daicel Chiralpak ADꢀH column (0.46 x 25 cm), scCO2/MeOH 97:3, 3.0 mL/min, P = 150
bar, λ = 215 nm, tR: 10.59 min (S), 11.25 min (R). MS (DCI/NH3): m/z = 133 [M+H–H2O]+.
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(R
)-2,3-Dihydro-1H-inden-1-ol:21 107 mg, 100% yield; White solid; [α]D −33 (c 0.85,
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CHCl3, >99% ee), lit.:21 [α]D +29.3 (c 0.967, CHCl3, >99% ee, (S)ꢀisomer); enantiomeric
excess determined by HPLC analysis on Daicel Chiralpak IB column (0.46 x 25 cm),
hexane/iꢀPrOH 98:2, 1.0 mL/min, λ = 215 nm, tR: 14.86 (S), 16.43 min (R). MS (DCI/NH3):
m/z = 117 [M+H–H2O]+.
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(R
)-5-Bromo-2,3-dihydro-1H-inden-1-ol:32 170 mg, 100% yield; White solid. [α]D −16 (c
0.92, CHCl3, >99% ee), lit.:32 [α]D25 +15.8 (c 1.0, CHCl3, 98.1% ee, (S)ꢀisomer); enantiomeric
excess determined by SFC analysis on Daicel Chiralpak ADꢀH column (0.46 x 25 cm),
scCO2/MeOH 90:10, 3.0 mL/min, P = 150 bar, λ = 215 nm, tR: 5.92 (S), 8.21 min (R). MS
(DCI/NH3): m/z = 195 [M+H–H2O]+.
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(R
)-1-(4-Morpholinophenyl)ethan-1-ol:33 164 mg, 99% yield; White solid; [α]D + 43.9 (c
1.16, CHCl3, 99% ee); lit.:33 [α]D + 45.9 (c 1.0, CHCl3, 93% ee); enantiomeric excess
determined by HPLC analysis on Daicel Chiralpak IC column (0.46 x 25 cm), hexane/iꢀPrOH
90:10, 1.0 mL/min, λ = 215 nm, tR: 24.81 min (S), 31.01 min (R). MS (DCI/NH3): m/z = 208
[M+H]+.
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(R
)-1-(2-Furyl)ethanol:34 89 mg, 99% yield; Colorless oil; [α]D +20.0 (c 0.79, CHCl3,
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>99% ee), lit.:34 [α]D +20.7 (c 1.0, CHCl3, 99% ee); enantiomeric excess determined by
HPLC analysis on Daicel Chiralpak IC column (0.46 x 25 cm), hexane/ iꢀPrOH 95:5, 1.0
mL/min, λ = 215 nm, tR: 9.17 min (S), 9.90 min (R). MS (DCI/NH3): m/z = 95 [M+H–H2O]+.
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(R
)-1-(2-Thienyl)ethanol:35 102 mg, 100% yield; Colorless oil; [α]D +23 (c 0.91, CHCl3,
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9
20
99% ee), lit.:35 [α]D +21.6 (c 1.0, CHCl3, 98% ee); enantiomeric excess determined by SFC
analysis on Daicel Chiralpak ID column (0.46 x 25 cm), scCO2/MeOH 93:7, 3.0 mL/min, P =
150 bar, λ = 215 nm, tR: 2.07 min (R), 2.35 min (S). MS (DCI/NH3): m/z = 111 [M+H–H2O]+.
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)-1-(Benzofuran-2-yl)ethanol:36 129 mg, 100% yield; White solid; [α]D +18 (c = 0.88,
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(
R
CHCl3, 97% ee), lit.:36 [α]D23 +18 (c 3.0, CHCl3, 96% ee); enantiomeric excess determined by
HPLC analysis on Daicel Chiralpak ID column (0.46 x 25 cm), hexane/ iꢀPrOH 95:5, 1.0
mL/min, λ = 215 nm, tR: 9.48 min (R), 10.11 min (S). MS (DCI/NH3): m/z = 145 [M+H–
H2O]+.
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(R
)-1-(2-Pyridyl)ethanol:37 98 mg, 100% yield; Pale yellow oil; [α]D +21 (c 0.99, CHCl3,
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96 % ee), lit.:37 [α]D +26.6 (c 1.0, CHCl3, 97.3% ee); enantiomeric excess determined by
HPLC analysis on Daicel Chiralpak ID column (0.46 x 25 cm), hexane/iꢀPrOH 95:5, 1.0
mL/min, λ = 215 nm, tR: 15.23 min (S), 17.10 min (R). MS (DCI/NH3): m/z = 124 [M+H]+.
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(R
)-1,2,3,4-Tetrahydro-2-naphthol:5e 119 mg, 100% yield; Pale yellow oil; [α]D +53 (c
23
0.88, CHCl3, 81% ee), lit.:5e [α]D = +52.7 (c 0.37, CHCl3, 88% ee); enantiomeric excess
determined by SFC analysis on Daicel Chiralpak ADꢀH column (0.46 x 25 cm), scCO2/iꢀ
PrOH 90:10, 3.0 mL/min, P = 150 bar, λ = 215 nm, tR: 4.76 min (S), 5.19 min (R). MS
(DCI/NH3): m/z = 166 [M+NH4]+.
(R
)-1-Cyclohexylethanol:38 80 mg, 100% yield; Colorless oil; [α]D25 +2.1 (c 3.5, CHCl3, 94%
3
ee), lit.:38 [α]D +3.51 (c 3.1, CHCl3, 95% ee); enantiomeric excess determined on the
benzoate derivative by HPLC analysis on Daicel Chiralpak ID column (0.46 x 25 cm),
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hexane/iꢀPrOH 97:3, 0.5 mL/min, λ = 215 nm, tR: 8.87 min (S), 9.37 min (R). MS (DCI/NH3):
m/z = 146 [M+NH4]+.
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(S
)-(4-Nitrophenyl)(phenyl)methanol:39 169 mg, 92% yield; White solid; [α]D + 70.0 (c
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1.0, CHCl3, 83% ee); lit.:39 [α]D +71.0 (c 0.27, CHCl3, 92% ee); enantiomeric excess
determined by HPLC analysis on Daicel Chiralpak IA column (0.46 x 25 cm), hexane/iꢀPrOH
90:10, 1.0 mL/min, λ = 254 nm, tR: 12.17 min (R), 14.49 min (S). MS (DCI/NH3): m/z = 247
[M+NH4]+.
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(S
)-(4-Chlorophenyl)(phenyl)methanol:39 173 mg, 99% yield; White solid; [α]D + 10.9 (c
20
2.0, CHCl3, 50% ee); lit.:39 [α]D + 8.0 (c 1.51, CHCl3, 48% ee); enantiomeric excess
determined by HPLC analysis on Daicel Chiralpak IA column (0.46 x 25 cm), hexane/iꢀPrOH
95:5, 1.0 mL/min, λ = 254 nm, tR: 12.92 min (R), 14.01 min (S). MS (DCI/NH3): m/z = 201
[M+H–H2O]+.
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(R
)-(4-Methoxyphenyl)(phenyl)methanol:39 123 mg, 72% yield; White solid; [α]D +2.1 (c
20
1.65, CHCl3, 9% ee); lit.:39 [α]D +1.5 (c 1.08, CHCl3, 5% ee); enantiomeric excess
determined by HPLC analysis on Daicel Chiralpak IA column (0.46 x 25 cm), hexane/iꢀPrOH
90:10, 0.8 mL/min, λ = 254 nm, tR: 13.37 min (R), 14.37 min (S). MS (DCI/NH3): m/z = 197
[M+H–H2O]+.
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(S
)-Phenyl(o-tolyl)methanol:40 103 mg, 65% yield; White solid; [α]D +8.2 (c 2.0, CHCl3,
20
99% ee); lit.:40 [α]D +7.3 (c 0.735, CHCl3, 98% ee); enantiomeric excess determined by
HPLC analysis on Daicel Chiralpak IC column (0.46 x 25 cm), hexane/iꢀPrOH = 98:2, 0.6
mL/min, λ = 254 nm, tR: 28.8 min (S), 32.6 min (R). MS (DCI/NH3): m/z = 181 [M+H–H2O]+.
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(1R,4R
)-1,4-Diphenylbutan-1,4-diol:41 186 mg, 96% yield; White solid. [α]D +51 (c 1.1,
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CHCl3, >99% ee), lit.:41 [α]D25 +58 (c 1.02, CHCl3, 99% ee); enantiomeric excess determined
by SFC analysis on Daicel Chiralcel ODꢀH column (0.46 x 25 cm), scCO2/MeOH 95:5, 4
mL/min, P = 150 bar, λ = 215 nm, tR: 22.13 min (R,R), 25.69 min (meso), 28.08 min (S,S). MS
(DCI/NH3): m/z = 242 [M+H–H2O]+.
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Acknowledgements
This work was supported by CNRS (Centre National de la Recherche Scientifique) and
MENESR (Ministère de l'Education nationale, de l'Enseignement supérieur et de la
Recherche). We gratefully acknowledge China Scholarship Council for a grant to L. Z. We
also thank PCAS for a grant to Q. L. We would like to thank Dr Céline Fosse for mass
spectrometry analyses and Dr LiseꢀMarie Chamoreau for the Xꢀray analyses.
1
Supporting Information Available. Copies of H and 13C NMR spectra of all compounds,
HPLC or SFC chromatograms of the ATH products.
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CCDCꢀ1517930, CCDCꢀ1517928 and CCDCꢀ1517929 contain the supplementary
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