Biphenyl-Based Bis(thiourea) Organocatalyst for Asymmetric and syn -Selective Henry Reaction

Article abstract of DOI:10.1055/s-0036-1588594

A scalable, efficient and chromatography-free synthesis of a new enantiopure C ₂-symmetric bis(thiourea) catalyst was accomplished from a readily available starting material. The developed strategy could be conducted on a multi-gram scale. Both the prepared enantiomers of the bis(thiourea) organocatalyst have been tested in the asymmetric Henry reaction under thoroughly optimized conditions during which an unusual solvent effect on enantioselectivity was found. The corresponding adducts were obtained in excellent yields with good to excellent enantioselectivities. The achieved high reactivity and enantioselectivity in the nitroaldol reaction of nitroalkanes with aromatic aldehydes suggests promising potential for this catalyst. Moreover, a significant syn-diastereoselectivity was observed.

Full text of DOI:10.1055/s-0036-1588594

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–K
paper
A
J. Otevrel, P. Bobal
Paper
Synthesis
Biphenyl-Based Bis(thiourea) Organocatalyst for Asymmetric and
syn-Selective Henry Reaction
Jan Otevrel
Pavel Bobal*
Department of Chemical Drugs, Faculty of Pharmacy, University
of Veterinary and Pharmaceutical Sciences Brno, Palackeho
1946/1, 612 42 Brno, Czech Republic
bobalp@vfu.cz
Received: 21.07.2016
Accepted after revision: 25.08.2016
Published online: 21.09.2016
antioenriched aromatic nitroaldol adducts, however, only
moderate enantioselectivities were achieved.5 The major
advance came after Ito showed atropisomeric 4,4′-biin-
danyl-based bis(thiourea) and Kitagaki reported [2.2]para-
cyclophane-based bis(thiourea) catalysts that both reached
the excellent levels of enantiocontrol (>90% ee), and
demonstrated that bis(thiourea) catalysts are one of the
best currently known organocatalysts for the asymmetric
Henry reaction (Figure 1).6
DOI: 10.1055/s-0036-1588594; Art ID: ss-2016-e0514-op
Abstract A scalable, efficient and chromatography-free synthesis of a
new enantiopure C2-symmetric bis(thiourea) catalyst was accomplished
from a readily available starting material. The developed strategy could
be conducted on a multi-gram scale. Both the prepared enantiomers of
the bis(thiourea) organocatalyst have been tested in the asymmetric
Henry reaction under thoroughly optimized conditions during which an
unusual solvent effect on enantioselectivity was found. The corre-
sponding adducts were obtained in excellent yields with good to excel-
lent enantioselectivities. The achieved high reactivity and enantioselec-
tivity in the nitroaldol reaction of nitroalkanes with aromatic aldehydes
suggests promising potential for this catalyst. Moreover, a significant
syn-diastereoselectivity was observed.
R
S
R'
R''
N
X
Ar
Ar
H
N
H
N
H
H
N
N
H
N
N
H
Ar
Ar
N
N
H
Ar
H
H
N
H
N
S
R
R
S
Nagasawa 2005–2012
R
S
Key words organocatalysis, asymmetric Henry reaction, chiral
bis(thiourea), chiral Brønsted acid catalysis, syn-diastereoselectivity
Shi 2007
H
N
CF3
S
S
Ar
NH
S
HN
NH
Among an enormous number of organocatalysts, the
chiral thioureas have developed a dominant place in asym-
metric H-bond catalysis due to their synthetic availability
and ability to catalyze a broad range of organic reactions.1
The Henry reaction as a key C–C forming process is not an
exception either.2 Since the pioneering work of Najera with
chiral guanidine organocatalysts, a number of organocata-
lyzed variants exists nowadays.3 Nagasawa and co-workers,
in a series of reports that started in 2005, fused the guani-
dine moiety with the bis(thiourea) motif in one conforma-
tionally flexible and catalytically active molecule and ob-
tained good to very good enantioselectivities and excellent
diastereoselectivities.4 The scope of their work was, never-
theless, limited only to aliphatic or alicyclic substrates and
unsuitable for aromatic aldehydes. The paper of Shi et al.
dealing with BINAM-based and related bis(thiourea) cata-
lysts demonstrated that the bis(thiourea) structural ele-
ment may reach promising results also in syntheses of en-
N
H
H
N
N
H
H
N
CF3
CF3
NH
NH
S
S
NH
Ar
Kitagaki 2013
Ar
S
N
CF3
H
(Ra)-1 & (Sa)-1
Ito 2013
Figure 1 Structures of bis(thiourea) derivatives applied for the asym-
metric Henry reaction
The Kitagaki catalysts, probably because of the low ste-
ric shielding planar nature of the cyclophane backbone, ex-
hibited only very poor diastereoselectivities with higher ni-
troalkanes. In the case of the Ito catalysts, the reaction with
nitroethane did not proceed at all. The major drawbacks of
Ito and Kitagaki catalysts are the relative difficulties of tun-
ing the properties of their skeletons and the use of homoge-
neous catalysts based on precious transition-metal com-
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B
J. Otevrel, P. Bobal
Paper
Synthesis
plexes during their syntheses, which implies the necessity
for chromatographic purification steps. Moreover, the pos-
sible presence of N-(trimethylsilyl)trifluoroacetamide and
trifluoroacetamide side products arising from the N,O-
bis(trimethylsilyl)trifluoroacetamide–K2CO3 system used as
an imidate base precursor by Ito et al. can make purification
of the final nitroaldol products cumbersome.7
In our work, we focused on the atropisomeric biphenyl
skeleton because we believe that biphenyls are closer to the
development of ideal organocatalysts for the enantioselec-
tive Henry reaction in comparison with the aforementioned
chiral scaffolds due to their lower molecular weight, good
synthetic accessibility, easily convertible steric and elec-
tronic properties of substituent, and dihedral angles. In or-
der to prove our concept, we chose 6,6′-dimethylbiphenyl-
2,2′-diamine (MAB) as a model chiral auxiliary. MAB and its
derivatives have shown their potency in many metal-cata-
lyzed and several organocatalyzed reactions.8,9 In 2013 Xu
and Wang applied MAB also in cooperative enamine–metal
Lewis acid catalysis and Peters in 2015 documented its ef-
fectiveness in a hydrogen donor site of a cooperative poly-
functional Ni–azolium catalyst.10 The almost orthogonal
torsion angle between two nitrogens and a possible alter-
ation of the 6,6′-substituents can provide an excellent and
tunable asymmetric environment for the organocatalyzed
Henry reaction.11
Herein, we report the first example of the new enantio-
pure biphenyl-based C2-symmetric bis(thiourea) 1 as a
highly effective organocatalyst for the asymmetric Henry
reaction (Scheme 1). Racemic MAB and both its enantio-
mers are commercially available or can be prepared and re-
solved from a readily available inexpensive starting materi-
al via a relatively straightforward fashion. An additional ad-
vantage is chromatography-free purification of the final
catalyst and the possibility to conduct the synthesis on a
multi-gram scale.12a
Figure 2 Single-crystal X-ray structure ORTEP diagram of the
bis(thiourea) catalyst (Ra)-112b
With both the enantiomers of bis(thiourea) catalyst 1 in
hand, we explored its feasibility for the enantioselective
variant of the Henry reaction between nitromethane and 4-
nitrobenzaldehyde (10k) as a model, highly reactive sub-
strate. Optimization experiments shown in Table 1 were
carried out mainly at ambient temperature.12a
Initial reaction conditions (Table 1, entries 1 and 2)
were adopted from literature protocols.5,6 According to our
assumption, the reaction catalyzed by (Ra)-1 led to the for-
mation of (S)-nitro alcohol, whereas (Sa)-1 provided the op-
posite enantiomer with the same enantiopurity (entries 1
and 2). In contrast to some literature reports, the prolonged
reaction time did not lead, in our hands, to an appreciable
loss of enantiomeric excess (entry 2).6b
We found no significant influence of higher (20 mol%)
or lower (5 mol%) catalyst loading on the ee values, but the
reduced catalyst loading resulted in slower reaction rates
(entries 3 and 4).
CF3
The larger improvement of ee was reached with a lower
loading of a base with the optimum of 5 mol% (entries 5
and 6). In entries 6–14 we examined the type of a base.
With stronger bases like DBU and TMG, the reaction yielded
very low enantioselectivity and did not lead to complete
conversions (entries 10 and 11). Although the use of DABCO
in the Henry reaction has been reported, we obtained only
traces of nitroaldol product with a loading of 5 mol% (entry
12).5,6 Secondary and tertiary amines like DIPA and NEP re-
sulted in moderate enantioselectivities (entries 13 and 14).
In the case of BDMA, the reaction rate was sluggish (entry
8) and the higher loading led to a decrease of enantioselec-
tivity (entry 9). The best results were obtained with tertiary
amines DIPEA and TMEDA (entries 6 and 7).
S
N
H
H
N
N
H
H
N
CF3
CF3
3,5-(CF3)2C6H3NCS
NH2
NH2
THF
25 °C, 48 h
(y. 93%, > 99% ee)
S
CF3
(Ra)-(–)-1 or (Sa)-(+)-1
(Ra)-(+)-9 or (Sa)-(–)-9
Scheme 1 Synthesis of the bis(thiourea) (Ra)-1 and (Sa)-112a
X-ray data obtained from (Ra)-1 clearly show an almost
orthogonal arrangement of the biphenyl system and the
syn–anti conformation of the thiourea defined by the S–C–
N–H torsion angle (Figure 2).12b
We further studied the role of the solvent as shown in
Table 1, entries 15–21. It is well known that many thiourea
catalysts exhibited high levels of enantiocontrol in THF and
therefore we concentrated mainly on ethereal solvents. In
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

C
J. Otevrel, P. Bobal
Paper
Synthesis
accordance with the literature, we confirmed that THF gave
the highest ee values from all of the tested solvents.5,6b DMF
in combination with the TMEDA base may also be advanta-
geous due to slightly higher reaction rates in comparison
with THF but with respect to the ee values and the purity of
the final products, THF represented the preferred variant. It
Table 1 Optimization Steps of the Reaction Conditionsa
O
OH
MeNO2
(Sa)- or (Ra)-1
NO2
H
solvent
base
O2N
O2N
10k
11k
Entry
Catalyst (mol%)
Base (mol%)
MeNO2 (equiv)
Solvent
Time (h)
Conv. (%)b
ee (%)c
1
2
(Ra)-1 (10)
(Sa)-1 (10)
(Ra)-1 (5)
DIPEA (20)
DIPEA (20)
DIPEA (20)
DIPEA (20)
DIPEA (10)
DIPEA (5)
TMEDA (5)
BDMA (5)
BDMA (20)
DBU (5)
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
28d
20
20
40
20
20
20
20
20
THF
0.5
24
>99
>99
>99
>99
>99
>99
95
49 (S)
49 (R)
50 (S)
49 (S)
52 (S)
53 (S)
55 (S)
56 (S)
47 (S)
1 (R)
THF
3
THF
1.0
1.0
2.0
2.0
2.0
2.0
12
4
(Ra)-1 (20)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Ra)-1 (10)
(Sa)-1 (10)
(Ra)-1 (10)
(Sa)-1 (10)
(Sa)-1 (10)
(Sa)-1 (10)
(Ra)-1 (10)
(Sa)-1 (10)
THF
5
THF
6
THF
7
THF
8
THF
60
9
THF
>99
90
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29h
30h
THF
2.0
2.0
2.0
0.5
2.0
4.0
2.0
1.0
2.0
2.0
2.0
2.0
0.5
2.0
2.0
3.0
3.0
3.0
3.0
24
TMG (5)
THF
90
1 (R)
DABCO (5)
DIPA (5)
THF
<5
–
THF
98
41 (S)
44 (S)
53 (S)
49 (S)
0 (±)
NEP (5)
THF
98
DIPEA (5)
TMEDA (5)
DIPEA (5)
DIPEA (5)
DIPEA (5)
DIPEA (5)
DIPEA (5)
DIPEA (5)
DIPEA (5)
TMEDA (5)
TMEDA (5)
TMEDA (5)
TMEDA (5)
TMEDA (5)
TMEDA (5)
TMEDA (5)
DMF
DMF
CH2Cl2
PhMe
Et2O
diglyme
dioxane
MeNO2
THF
98
98
98
98
5 (S)
98
23 (S)
49 (S)
28 (S)
11 (S)
56 (S)
67 (R)
66 (S)
70 (R)
68 (R)
55 (R)
80 (S)
86 (R)
98
98
98
98
THF
>99
>99
>99
>99
>99
>99
>99
THF
THFe
THFf
THFg
THF
THFe
24
a For the complete table, see the Supporting Information. Unless otherwise noted, reactions were performed at 25 °C on 0.1 mmol scale at 1 M concentration;
BDMA = N,N-dimethylbenzylamine, DIPA = N,N-diisopropylamine, NEP = N-ethylpiperidine.
b Determined from HPLC analyses (Hypersil silica column, Hp–iPrOH, λ = 230 nm).
c Determined from chiral HPLC analyses of crude reaction mixtures filtered through a silica plug (for details, see the experimental section).
d MeNO2 was used as both the solvent and reactant.
e Twofold dilution.
f Fourfold dilution.
g THF with 5% of water.
h Performed at –30 °C.
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D
J. Otevrel, P. Bobal
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Synthesis
is remarkable that the use of non-polar solvents like CH2Cl2
(entry 17) or toluene (entry 18) resulted in a dramatic de-
crease of enantioselectivity. In diethyl ether (entry 19) and
toluene also the solubility issues were observed. The pres-
ence of water (entry 28) in the reaction medium negatively
affected the ee values probably due to interference with the
hydrogen-bonding properties of the catalyst; a similar ef-
fect was reported with methanol.5,14 Despite the fast con-
version, nitromethane itself (entry 22) was also found to be
an inappropriate solvent, which is in agreement with the
previous work of Hiemstra.14 This solvent effect was also
discussed in Baerends computational study.15 Similarly to
the work of Hiemstra and Himo,14b we found a significant
correlation between the Lewis basicity of the solvents and
the enantioselective outcome of the asymmetric Henry re-
action (Figure 3).13 Although the origin of this effect is still
unclear, it indicates an important role of the solvent in the
asymmetric induction and suggests the formation of
thiourea–solvent hydrogen-bonded complexes, which may
shift the equilibrium between the active form and the rest-
ing state of the catalyst. Alternatively, the chiral catalytical-
ly active thiourea–solvent H-bonded complexes may also be
directly involved in the enantiodiscrimination processes.
crease in the enantioselectivity. This effect likely cannot be
explained only by its role as a reactant. It may be caused by
the participation of the nitromethane in a solvation shell
and/or by affecting the possible self-aggregation properties
of the catalyst.
We also investigated the influence of dilution of the re-
action mixture on ee (entries 26 and 27) and we were
pleasantly surprised that the twofold dilution of the reac-
tion medium resulted in a noticeable effect on the enantio-
meric excess and maintained reasonable reaction rates
proven even at a diminished temperature (entries 29 and
30). This phenomenon will be an impetus for our further
investigations. More or less similar solvent effects were de-
scribed in amine–thiourea catalysis and were explained in
terms of monomer–oligomer equilibration of bifunctional
catalysts.16
With the thoroughly optimized reaction conditions, we
explored the substrate scope of the asymmetric Henry reac-
tion mediated by (Ra)-1 and (Sa)-1, and the results are sum-
marized in Table 2. Accordingly, several nitroaldol transfor-
mations of nitromethane with wide series of aromatic and
heteroaromatic aldehydes 10a–p,u producing nitro alcohols
11a–p,u were performed. It is mentionable that enantio-
meric excesses were measured directly from the crude re-
action mixture without any further purification steps.
The best results both in terms of reactivity and enantio-
selectivity were generally achieved with electron-deficient
substrates, especially with ortho-substituted benzalde-
hydes, 3- and 4-nitrobenzaldehydes and nicotinaldehyde
(entries 3, 4, 7, 11, and 14). Sufficiently high rates but
slightly lower ee values were obtained with benzaldehydes
bearing halogen or halogen-containing groups in meta- or
para-positions (entries 6, 9, 10, and 12). The reactions of
electron-richer 10a, 10b, and 10e proceeded somewhat
more slowly (120 h). Lower conversion of 10m (88%) even
after 120 h at –30 °C (see the Supporting Information)
forced us to repeat the experiment also at 0 °C and it was
observed that the reaction carried out at the higher tem-
perature gave the nitroaldol product in a shorter time with
only a slight decrease in enantioselectivity (entry 13). The
reactions of benzaldehydes possessing electron-donating
groups and conjugated 10p provided 68–71% ee but re-
quired prolonged reaction time even at 0 °C and were not
completed in 120 h (entries 8, 15, and 16). On the other
hand, the reaction of aliphatic 10u proceeded smoothly;
however, the enantioselectivity was only moderate (entry
17).
Figure 3 Enantiomeric excess dependence on the Lewis basicity of the
aprotic solvents [nitroaldol reaction conditions: 10k, 1 (10 mol%),
DIPEA (5 mol%), 25 °C; Lewis basicity scale uses BF3 as the reference
Lewis acid, the experimental value for diglyme is not available]13
During our experiments with the different nitrometh-
ane concentrations (entries 23–25), we found interesting
evidence of a certain optimal concentration of nitrometh-
ane in the reaction mixture, which ensured the optimum
enantioselectivity. Doubling the nitromethane excess to 20
equivalents led in all studied cases to improved reaction
rates and somewhat better ee values, but in the case of
TMEDA as a base (entry 24), we observed a dramatic in-
Diastereoselective transformations were examined us-
ing nitroethane or 1-nitropropane under established condi-
tions with four model benzaldehyde derivatives. Although
the substrate scope of the experiment was limited, it was
clearly revealed that syn-adducts were in all cases obtained
in high to excellent enantiomeric excesses and moderate to
high diastereomeric ratios (Table 3). To the best of our
knowledge, this represents the first known example of a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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J. Otevrel, P. Bobal
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Synthesis
Table 2 Substrate Scope of the Catalytic Enantioselective Henry Reactiona
MeNO2 (20 equiv)
(Sa)- or (Ra)-1 (10 mol%)
O
OH
NO2
TMEDA (5 mol%), THF (–30 or 0 °C)
R1
10a–p,u
H
R1
11a–p,u
Entry
Aldehyde 10 (R1)
Catalyst
Temp (°C)
Time (h)
Product
Conv. (%)b
ee (%)c
1
2
10a (Ph)
(Ra)-1
(Ra)-1
(Sa)-1
(Sa)-1
(Ra)-1
(Ra)-1
(Ra)-1
(Ra)-1
(Ra)-1
(Ra)-1
(Sa)-1
(Ra)-1
(Sa)-1
(Ra)-1
(Sa)-1
(Sa)-1
(Ra)-1
–30
–30
–30
–30
–30
–30
–30
0
120
120
12
12
72
24
12
36
48
48
12
48
36
12
96
96
24
11a
11b
11c
11d
11e
11f
98
98
78 (S)
78 (S)
92 (R)
94 (R)
78 (S)
85 (S)
87 (S)
69 (S)
82 (S)
81 (S)
86 (R)
82 (S)
60 (R)
87 (S)
71 (R)
68 (R)
43 (S)
10b (1-naphthyl)
10c (2-O2NC6H4)
10d (2-ClC6H4)
10e (3-MeC6H4)
10f (3-FC6H4)
3
>99
>99
95
4
5
6
97
7
10g (3-O2NC6H4)
10h (4-MeOC6H4)
10i (4-ClC6H4)
10j (4-BrC6H4)
10k (4-O2NC6H4)
10l (4-F3CC6H4)
10m (2-thienyl)
10n (3-pyridyl)
10od
11g
11h
11i
>99
90
8
9
–30
–30
–30
–30
0
92
10
11
12
13
14
15
16
17
11j
95
11k
11l
>99
>99
94
11m
11n
11o
11p
11u
–30
0
>99
95
10p (PhCH=CH)e
10u (PhCH2CH2)
0
90
–30
>99
a Reactions were performed on 0.1 mmol scale at 0.5 M concentration.
b Determined from HPLC analyses (Hypersil silica column, Hp–iPrOH, λ = 230 nm); isolated yields are reported in the experimental section.
c Determined from chiral HPLC analyses of the crude reaction mixtures filtered through a silica plug (for details, see the experimental section).
d R1 = 1,3-benzodioxol-5-yl.
e trans-Cinnamaldehyde.
Table 3 Substrate Scope of the Catalytic Enantio- and Diastereoselective Henry Reactiona
R2CH2NO2 (20 equiv)
OH
O
(Sa)- or (Ra)-1 (10 mol%)
R2
R1
TMEDA (5 mol%), THF (–30 °C)
R1
H
NO2
11q–t
10d,f,i,j
Entry
Aldehyde 10
Nitroalkane
(R2)
Product
Catalyst
Time (h)b
dr (%)
(ratio syn/anti)
ee (%)
(R1)
(syn/anti)c
1
2
3
4
10d
(2-ClC6H4)
Me
Me
Me
Et
11q
11r
11s
11t
(Sa)-1
(Ra)-1
(Sa)-1
(Ra)-1
12
24
48
48
91:9d (90:10)c
75:25d (71:29)c
74:26d (76:24)c
79:21d (82:18)c
97:18 (R,R)/(R,S)
10f
(3-FC6H4)
90:35 (S,S)/(S,R)
92:36 (R,R)/(R,S)
89:53 (S,S)/(S,R)
10i
(4-ClC6H4)
10j
(4-BrC6H4)
a Unless otherwise noted, reactions were performed at –30 °C on 0.4 mmol scale at 0.5 M concentration.
b Quenched after >99% conversion determined by HPLC analyses (Hypersil silica column, Hp–iPrOH, λ = 230 nm); isolated yields are reported in the experimental
section.
c Determined from chiral HPLC analyses of the crude reaction mixtures filtered through a silica plug (for details, see the experimental section).
d Determined from 1H NMR measurements of the crude reaction mixtures.
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J. Otevrel, P. Bobal
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TS-I:
TS-II:
F3C
H3C
H3C
N
CH3
N
CH3
N
S
S
S
N
S
N
CF3
CF3
CF3
CF3
F3C
F3C
N
H
H
H
H
N
N
H
H
H
H
O
O
O
N
O
O
N
H
O
F3C
H
H
H
R2
CH3
N
R2
R1
R1
H3C
H3C
CH3
TS-III:
F3C
TS-IV:
F3C
S
S
S
N
S
CF3
CF3
CF3
CF3
N
N
N
H
H
H
H
N
N
N
H
H
H
H
O
O
O
N
O
O
N
O
F3C
F3C
R2
R1
H
R1
R2
H
H
H
Figure 4 Plausible transition-state model of the (Ra)-1 catalyzed nitroaldol reaction describing the preference for the formation of (S,S)-adduct
significantly syn-selective organocatalyst for the asymmet-
ric nitroaldol reaction of aromatic aldehydes.4b,17 Analo-
gously to our previous observations, ortho-substituted sub-
strate (entry 1) provided the best outcome in terms of en-
antio- and diastereocontrol.
The stereochemical output of the reaction may be pre-
liminarily explained by the steric hindrance of the aldehyde
and nitronate substituents in the proposed simplified mod-
el of the transition state (TS-I, Figure 4) inspired by the
Nagasawa postulate of the dual activation mode.4 Further
kinetic and spectroscopic studies are subject to our ongoing
research.
In summary, we have developed a novel readily avail-
able bis(thiourea) organocatalyst for the asymmetric Henry
reaction. The highest levels of enantiocontrol documented
by the enantiomeric excesses 92–97% were generally ob-
served with electron-deficient ortho-substituted aromatic
aldehydes. Besides enantioselective nitromethane addi-
tions, catalyst 1 promoted also syn-selective formation of
nitroaldol adducts with higher nitroalkanes in the diaste-
reomeric ratio range of 3:1 to 10:1.
HRMS spectra were measured by a LTQ Orbitrap Hybrid Mass spec-
trometer (Thermo Electron Corp.) with a direct injection into an APCI
source (400 °C) in the positive or negative mode.
The diffraction data of (Ra)-(–)-1 were collected at 120 K on a Rigaku
MicroMax-007 HF rotating anode four-circle diffractometer using
Mo-Kα radiation. The structure was solved using the SHELXS program
and refined (full matrix least-squares refinement on F2) using the
SHELXL program.18 All non-hydrogen atoms were refined anisotropi-
cally. HPLC spectra were recorded on a Dionex UltiMate 3000 LC Sys-
tem (Thermo Fisher Scientific Inc.). IR spectra were collected on a
SmartMIRacle ATR Zn/Se for Nicolet Impact 410 FT-IR (Thermo Scien-
tific Corp.).
Specific rotation was determined by an automatic polarimeter AA-10
(Optical Activity Ltd.) using a cell with a path length of 1 dm with the
concentration in g/100 mL. Melting points were measured by a Böetius
apparatus (Franz Küstner Nachf. KG) and are uncorrected.
Routine monitoring of the reaction progress and purity of intermedi-
ates was done using TLC plates with a normal phase silica gel 60 F254
(Merck). Preparative separations were performed with a Büchi Se-
pacore flash system X10 (BÜCHI Labortechnik AG). Low temperature
experiments were done in a custom-made aluminum heat-transfer
block immersed in a cooling bath of a Bath Circulator CoolTech 320
(Thermo Electron Corp.). Hx = n-hexane, Hp = n-heptane.
Solvents and reagents were purchased from commercial suppliers
and if not stated otherwise, used as received. All starting aldehydes
were checked by TLC for the presence of acidic impurities and then
either used as is or distilled, recrystallized, or filtered through a plug
of silica gel before their use. Piperonal and hydrocinnamaldehyde
were prepared from the corresponding alcohols by known proce-
dures.19 Racemic MAB and its enantiomers were synthesized from o-
toluidine according to the literature.12a,20 Moisture and air-sensitive
reactions were performed with thoroughly dried glassware under an
inert atmosphere of argon in dry solvents using standard Schlenk
techniques. Dry CH2Cl2 was distilled from CaH2 and dry THF from po-
tassium benzophenone–ketyl.
For full experimental details, see the Supporting Information.
Routine NMR spectra were measured by a Varian Inova VXR-300 MHz
(Agilent Technologies). High resolution NMR spectra were obtained
from a Bruker Avance III HD 700 MHz NMR spectrometer (Bruker
Corp.) and a Bruker Avance III HD 850 MHz NMR spectrometer
(Bruker Corp.). All NMR measurements were performed at 25 °C. The
signal of TMS or the residual solvent signals of CDCl3 or DMSO-d6
were used as an internal reference.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

G
J. Otevrel, P. Bobal
Paper
Synthesis
1,1′-(6,6′-Dimethylbiphenyl-2,2′-diyl)bis{3-[3,5-bis(trifluoro-
which was connected via a standard blue PEEK capillary tubing
(length: 200 mm; i.d. 0.01 in; o.d. 1/16 in) to the Phenomenex Lux
Cellulose-1 column (3 μm, 250 × 4.6 mm).
methyl)phenyl]thiourea} (1)12a
To a soln of 9 (106 mg, 500 μmol) in dry THF (2 mL), 3,5-bis(trifluoro-
methyl)phenyl isothiocyanate (187 μL, 1.02 mmol) was added drop-
wise at rt under an argon atmosphere. The reaction mass was stirred
for 2 d at rt. After TLC analysis (silica gel, Hp–EtOAc, 75:25) showed
complete conversion, the mixture was evaporated to dryness and the
resulting glassy solid was triturated (n-heptane) and sonicated. The
white fluffy precipitate was filtered off, washed with several portions
of fresh n-heptane and dried in vacuo to give a white powder; yield:
350 mg (93%); Rf = 0.22 (Hp–EtOAc, 75:25).
Absolute and relative configuration of the target adducts 11a–s and
11u was determined by comparison of 1H NMR spectra and the rela-
tive elution order of resolved peaks with authentic samples and liter-
ature data.6b,21–27 Absolute and relative configuration of 11t was as-
signed (S,S) by analogy with other β-nitro alcohols.
(S)-2-Nitro-1-phenylethanol (11a)21
Prepared with (Ra)-(–)-1 at –30 °C (120 h) according to the GP as a
colorless oil; yield: 15.4 mg (92%); 78% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 26.96 (minor, R), 32.77 min (ma-
jor, S)].
IR (neat): 3151, 2968, 1520, 1466, 1377, 1344, 1274, 1170, 1127, 995,
889, 700, 681 cm–1
.
1H NMR (700 MHz, CDCl3): δ = 2.05 (s, 6 H), 7.32 (d, JHH = 7.5 Hz, 2 H),
7.44 (dt, 1JHH = 15.6 Hz, 2JHH = 7.8 Hz, 4 H), 7.57 (br s, 2 H), 7.61 (s, 2 H),
7.91 (s, 4 H), 8.22 (br s, 2 H).
13C NMR (700 MHz, CDCl3): δ = 19.8, 119.6, 122.8 (q, 1JCF = 271.2 Hz),
123.6, 125.0, 129.7, 129.8, 131.6, 131.9 (q, 2JCF = 33.5 Hz), 134.8, 138.9,
139.1, 179.7.
1
2
1H NMR (300 MHz, DMSO-d6): δ = 4.57 (dd, JHH = 12.5 Hz, JHH = 9.9
Hz, 1 H), 4.85 (dd, 1JHH = 12.3 Hz, 2JHH = 3.3 Hz, 1 H), 5.29 (m, 1 H), 6.11
(dd, 1JHH = 5.0 Hz, 2JHH = 0.6 Hz, 1 H), 7.29–7.47 (m, 5 H).
13C NMR (75 MHz, DMSO-d6): δ = 70.1, 81.9, 126.2, 128.0, 128.4,
140.5.
19F NMR (800 MHz, CDCl3): δ = –63.01.
HRMS (ESI): m/z [M – H]– calcd for C32H22F12N4S2: 753.1021; found:
(S)-1-(Naphthalen-1-yl)-2-nitroethanol (11b)21
753.1025.
Prepared with (Ra)-(–)-1 at –30 °C (120 h) according to the GP as a
colorless oil; yield: 19.5 mg (90%); 78% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 34.57 (minor, R), 56.72 min (ma-
jor, S)].
rac-1
Mp 152–153 °C.
1
2
1H NMR (300 MHz, DMSO-d6): δ = 4.72 (dd, JHH = 12.6 Hz, JHH = 9.7
Hz, 1 H), 5.01 (dd, 1JHH = 12.5 Hz, 2JHH = 2.9 Hz, 1 H), 6.13 (d, JHH = 9.2
Hz, 1 H), 6.40 (br s, 1 H), 7.55–7.68 (m, 3 H), 7.81 (d, JHH = 7.0 Hz, 1 H),
(Ra)-(–)-1
25
Mp 112–114 °C; [α]D –136 (c 1.00, acetone); >99% ee [HPLC (Phe-
1
2
7.93 (d, JHH = 8.2 Hz, 1 H), 8.00 (dd, JHH = 8.2 Hz, JHH = 1.1 Hz, 1 H),
8.22 (d, JHH = 8.6 Hz, 1 H).
nomenex Chirex (S)-ICA & (R)-NEA column, 5 μm, 250 × 4.0 mm;
iPrOH–Hx, 20:80; 20 °C; 1 mL/min; λ = 230 nm): tR = 13.52 min (R)].
13C NMR (75 MHz, DMSO-d6): δ = 67.5, 81.7, 122.6, 124.2, 125.5,
125.9, 126.8, 128.6, 129.0, 129.6, 133.3, 135.8.
(Sa)-(+)-1
25
Mp 114–116 °C; [α]D +137 (c 1.00, acetone); >99% ee [HPLC (Phe-
(R)-2-Nitro-1-(2-nitrophenyl)ethanol (11c)21
nomenex Chirex (S)-ICA & (R)-NEA column, 5 μm, 250 × 4.0 mm;
iPrOH–Hx, 20:80; 20 °C; 1 mL/min; λ = 230 nm): tR = 9.57 min (S)].
Prepared with (Sa)-(+)-1 at –30 °C (12 h) according to the GP as an or-
ange oil; yield: 20.2 mg (95%); 92% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 28.02 (major, R), 32.01 min (mi-
nor, S)].
Catalytic Enantio- and Diastereoselective Henry Reaction; General
Procedure (GP)
1
2
1H NMR (300 MHz, DMSO-d6): δ = 4.61 (dd, JHH = 12.8 Hz, JHH = 9.5
Hz, 1 H), 4.97 (dd, 1JHH = 12.9 Hz, 2JHH = 2.8 Hz, 1 H), 5.81 (d, JHH = 9.3
Hz, 1 H), 6.41 (d, JHH = 3.5 Hz, 1 H), 7.61 (ddd, 1JHH = 8.3 Hz, 2JHH = 7.2
Hz, 3JHH = 1.6 Hz, 1 H), 7.81 (td, 1JHH = 7.6 Hz, 2JHH = 1.1 Hz, 1 H), 7.92
(dd, 1JHH = 7.8 Hz, 2JHH = 1.7 Hz, 1 H), 8.05 (dd, 1JHH = 8.1 Hz, 2JHH = 1.0
Hz, 1 H).
Catalyst (Ra)-1 or (Sa)-1 (7.5 mg; 10 μmol) and an appropriate alde-
hyde (100 μmol) were dissolved in dry THF (200 μL) at rt under atmo-
sphere of argon and then left to cool to –30 °C (or 0 °C). After 15 min,
TMEDA (0.75 μL, 5 μmol) was added in one portion. After another
15 min the nitroalkane (2 mmol) was added dropwise and the mix-
ture was stirred for 12–120 h at the aforementioned temperature.
13C NMR (75 MHz, DMSO-d6): δ = 66.2, 81.0, 124.4, 129.2, 129.4,
134.0, 135.6, 147.2.
When the complete disappearance of the starting material was com-
plete by TLC (silica gel, Hp–CH2Cl2, 50:50), the reaction mass was
quenched with sat. aq NH4Cl solution and the mixture was extracted
with EtOAc (3 × 2 mL). The organic extracts were collected and dried
(anhyd Na2SO4). The supernatant was filtered through a short pad of
silica gel in a Pasteur pipette and washed thoroughly with several
portions of fresh EtOAc. The filtrate was evaporated in vacuo and the
residue was dissolved in 1 mL of mobile phase and directly subjected
to HPLC analysis. Samples for NMR experiments were isolated by
flash chromatography (silica gel, EtOAc–Hp 10–100%).
(R)-1-(2-Chlorophenyl)-2-nitroethanol (11d)21
Prepared with (Sa)-(+)-1 at –30 °C (12 h) according to the GP as a col-
orless oil; yield: 19.2 mg (97%); 94% ee [HPLC (iPrOH–Hp, 5:95;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 56.99 (major, R), 61.00 min (mi-
nor, S)].
1
2
1H NMR (300 MHz, DMSO-d6): δ = 4.50 (dd, JHH = 12.5 Hz, JHH = 9.7
Hz, 1 H), 4.82 (dd, 1JHH = 12.5 Hz, 2JHH = 2.8 Hz, 1 H), 5.64 (dd, 1JHH = 9.7
2
Enantiomeric excesses and diastereomeric ratios were determined
from the crude reaction mixtures without further purification steps.
Hypersil silica column (3 μm, 100 × 4.6 mm was used as a precolumn,
Hz, JHH = 2.6 Hz, 1 H), 6.34 (br s, 1 H), 7.33–7.48 (m, 3 H), 7.69 (dd,
1JHH = 7.3 Hz, 2JHH = 2.0 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 67.2, 80.4, 127.6, 128.3, 129.3,
129.8, 130.9, 137.6.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

H
J. Otevrel, P. Bobal
Paper
Synthesis
1
2
(S)-2-Nitro-1-(m-tolyl)ethanol (11e)21b
1H NMR (300 MHz, DMSO-d6): δ = 4.58 (dd, JHH = 12.6 Hz, JHH = 9.7
Hz, 1 H), 4.85 (dd, 1JHH = 12.5 Hz, 2JHH = 3.4 Hz, 1 H), 5.30 (m, 1 H); 6.20
(d, JHH = 4.8 Hz, 1 H), 7.45 (dd, 1JHH = 15.6 Hz, 2JHH = 8.7 Hz, 4 H).
Prepared with (Ra)-(–)-1 at –30 °C (72 h) according to the GP as a col-
orless oil; yield: 16.2 mg (89%); 78% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 23.39 (minor, R), 27.24 min (ma-
jor, S)]
13C NMR (75 MHz, DMSO-d6): δ = 69.3, 81.6, 128.2, 128.4, 132.5,
139.5.
1H NMR (300 MHz, DMSO-d6): δ = 2.32 (s, 3 H), 4.55 (dd, JHH = 12.4
1
Hz, 2JHH = 10.0 Hz, 1 H), 4.82 (dd, 1JHH = 12.5 Hz, 2JHH = 3.3 Hz, 1 H), 5.24
(S)-1-(4-Bromophenyl)-2-nitroethan-1-ol (11j)21b
(dd, 1JHH = 9.9 Hz, 2JHH = 3.3 Hz, 1 H), 6.06 (br s, 1 H), 7.11–7.29 (m, 4
H).
13C NMR (75 MHz, DMSO-d6): δ = 21.0, 70.1, 82.0, 123.3, 126.8, 128.3,
128.5, 137.6, 140.4.
Prepared with (Ra)-(–)-1 at –30 °C (48 h) according to the GP as a col-
orless waxy solid oil; yield: 20.9 mg (85%); 81% ee [HPLC (iPrOH–Hp,
20:80; 0.5 mL/min; 5 °C; λ = 230 nm): tR = 27.37 (minor, R), 35.99 min
(major, S)].
1
2
1H NMR (300 MHz, DMSO-d6): δ = 4.57 (dd, JHH = 12.6 Hz, JHH = 9.7
(S)-1-(3-Fluorophenyl)-2-nitroethanol (11f)21b
Hz, 1 H), 4.85 (dd, 1JHH = 12.5 Hz, JHH = 3.5 Hz, 1 H), 5.28 (dd, 1JHH = 9.7
Hz, JHH = 3.3 Hz, 1 H), 6.20 (br s, 1 H), 7.40–7.43 (m, 2 H), 7.54–7.59
2
2
Prepared with (Ra)-(–)-1 at –30 °C (24 h) according to the GP as a col-
orless oil; yield: 17.6 mg (95%); 85% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 23.58 (minor, R), 27.56 min (ma-
jor, S)].
(m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 69.3, 81.6, 121.1, 128.5, 131.3,
139.9.
1H NMR (300 MHz, DMSO-d6): δ = 3.40 (br s, 1 H), 4.59 (dd, 1JHH = 12.6
Hz, 2JHH = 9.7 Hz, 1 H), 4.89 (dd, 1JHH = 12.6 Hz, 2JHH = 3.5 Hz, 1 H), 5.32
(d, JHH = 7.7 Hz, 1 H), 7.17–7.10 (m, 1 H), 7.27–7.31 (m, 2 H), 7.38–7.45
(m, 1 H).
(R)-2-Nitro-1-(4-nitrophenyl)ethanol (11k)21,22
Prepared with (Sa)-(+)-1 at –30 °C (12 h) according to the GP as an or-
ange oil; yield: 20.4 mg (96%); 86% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 40.32 (major, R), 51.53 min (mi-
nor, S)].
13C NMR (75 MHz, DMSO-d6): δ = 69.4, 81.6, 113.1 (d, 2JCF = 22.5 Hz),
2
3
3
114.7 (d, JCF = 21.0 Hz), 122.3, 130.4 (d, JCF = 8.3 Hz), 143.5 (d, JCF
=
6.8 Hz), 162.3 (d, 1JCF = 242.3 Hz).
1
2
1H NMR (300 MHz, DMSO-d6): δ = 4.64 (dd, JHH = 12.7 Hz, JHH = 9.4
Hz, 1 H), 4.95 (dd, 1JHH = 12.7 Hz, 2JHH = 3.4 Hz, 1 H), 8.23 (d, JHH = 8.8
19F NMR (282 MHz, DMSO-d6): δ = –112.97 to –112.88 (m).
(S)-2-Nitro-1-(3-nitrophenyl)ethan-1-ol (11g)21b
Hz, 2 H), 5.43–5.46 (m, 1 H), 6.43 (d, JHH = 4.4 Hz, 1 H), 7.74 (d, JHH
8.8 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 69.1, 81.2, 123.5, 127.6, 147.2,
148.0.
=
Prepared with (Ra)-(–)-1 at –30 °C (12 h) according to the GP as a yel-
low oil; yield: 20.4 mg (96%); 87% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 41.51 (minor, R), 46.79 min (ma-
jor, S)].
(S)-2-Nitro-1-[4-(trifluoromethyl)phenyl]ethan-1-ol (11l)23
1
2
1H NMR (300 MHz, DMSO-d6): δ = 4.67 (dd, JHH = 12.7 Hz, JHH = 9.4
Prepared with (Ra)-(–)-CAT at –30 °C (48 h) according to the GP as a
colorless oil; yield: 21.9 mg (93%); 82% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 20.20 (minor, R), 25.14 min (ma-
jor, S)].
Hz, 1 H), 4.96 (dd, 1JHH = 12.6 Hz, 2JHH = 3.5 Hz, 1 H), 5.48 (dd, 1JHH = 9.2
Hz, 2JHH = 2.7 Hz, 1 H), 6.46 (br s, 1 H), 7.64–7.69 (m, 1 H), 7.91 (d, JHH
=
7.7 Hz, 1 H), 8.16 (ddd, 1JHH = 8.2 Hz, 2JHH = 2.3 Hz, 3JHH = 0.8 Hz, 1 H),
8.33 (t, JHH = 2.0 Hz, 1 H).
1
2
1H NMR (300 MHz, DMSO-d6): δ = 4.63 (dd, JHH = 12.6 Hz, JHH = 9.5
Hz, 1 H), 4.93 (dd, 1JHH = 12.5 Hz, 2JHH = 3.4 Hz, 1 H), 5.43 (dd, 1JHH = 9.5
Hz, 2JHH = 2.9 Hz, 1 H), 6.35 (br s, 1 H), 7.68–7.75 (m, 4 H).
13C NMR (75 MHz, DMSO-d6): δ = 69.0, 81.4, 121.1, 122.8, 130.0,
133.0, 142.9, 147.9.
13C NMR (75 MHz, DMSO-d6): δ = 69.5, 81.6, 124.3 (q, 1JCF = 271.5 Hz),
125.2 (q, 3JCF = 3.8 Hz), 127.1, 128.7 (q, 2JCF = 31.7 Hz), 145.2.
(S)-1-(4-Methoxyphenyl)-2-nitroethanol (11h)21b
19F NMR (282 MHz, DMSO-d6): δ = –61.29.
Prepared with (Ra)-(–)-1 at 0 °C (36 h) according to the GP as a yel-
lowish oil; yield: 16.8 mg (85%); 69% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 35.82 (minor, R), 45.71 min (ma-
jor, S)].
(R)-2-Nitro-1-(thiophen-2-yl)ethanol (11m)21b
Prepared with (Sa)-(+)-1 at 0 °C (36 h) according to the GP as a yellow-
ish oil; yield: 15.0 mg (87%); 60% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 28.12 (major, R), 31.04 min (mi-
nor, S)].
1H NMR (300 MHz, DMSO-d6): δ = 4.64 (dd, JHH = 12.5 Hz, JHH = 3.7
Hz, 1 H), 4.95 (dd, 1JHH = 12.5 Hz, 2JHH = 3.7 Hz, 1 H), 5.53 (dd, 1JHH = 9.7
Hz, 2JHH = 3.5 Hz, 1 H), 6.51 (br s, 1 H), 7.02 (dd, 1JHH = 5.0 Hz, 2JHH = 3.6
Hz, 1 H), 7.11 (dt, 1JHH = 3.4 Hz, 2JHH = 0.9 Hz, 1 H), 7.49 (dd, 1JHH = 5.0
Hz, 2JHH = 1.2 Hz, 1 H).
1
1H NMR (300 MHz, DMSO-d6): δ = 3.75 (s, 3 H), 4.55 (dd, JHH = 12.3
Hz, 2JHH = 9.9 Hz, 1 H), 4.78 (dd, 1JHH = 12.4 Hz, 2JHH = 3.6 Hz, 1 H), 5.22
(dd, 1JHH = 9.5 Hz, 2JHH = 2.7 Hz, 1 H), 5.99 (br s, 1 H), 6.93 (d, JHH = 9.0
Hz, 2 H), 7.36 (d, JHH = 9.0 Hz, 2 H).
1
2
13C NMR (75 MHz, DMSO-d6): δ = 55.1, 69.7, 82.0, 113.8, 127.5, 132.4,
159.0.
(S)-1-(4-Chlorophenyl)-2-nitroethanol (11i)21
13C NMR (75 MHz, DMSO-d6): δ = 66.2, 81.7, 124.4, 125.6, 127.1,
144.3.
Prepared with (Ra)-(–)-1 at –30 °C (48 h) according to the GP as a yel-
lowish oil; yield: 17.5 mg (87%); 82% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 24.91 (minor, R), 30.98 min (ma-
jor, S)].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

I
J. Otevrel, P. Bobal
Paper
Synthesis
(S)-2-Nitro-1-(pyridin-3-yl)ethan-1-ol (11n)6b
(1S,2S)-1-(3-Fluorophenyl)-2-nitropropan-1-ol (11r)25
Prepared with (Ra)-(–)-1 at –30 °C (12 h) according to modified the
GP; the crude reaction mixture was diluted with brine instead of
quenching with sat. NH4Cl soln as a yellowish oil; yield: 14.6 mg
(87%); 87% ee [HPLC (iPrOH–Hp, 25:75; 0.6 mL/min; 5 °C; λ =
205 nm): tR = 43.96 (minor, R), 88.66 min (major, S)].
Prepared with (Ra)-(–)-1 at –30 °C (24 h) according to the GP as a col-
orless oil; yield: 18.5 mg (93%); mixture of diastereomers;
90:35% ee (S,S)/(S,R); dr 75:25 (71:29) syn/anti [HPLC (iPrOH–Hp,
20:80; 0.5 mL/min; 5 °C; λ = 230 nm): tR = 16.55 (minor, 1R,2S), 20.77
(major, 1S,2R), 17.92 (minor, 1R,2R), 21.11 min (major, 1S,2S)].
1
2
1H NMR (700 MHz, DMSO-d6): δ = 4.70 (dd, JHH = 12.7 Hz, JHH = 9.6
1H NMR (700 MHz, CDCl3): δ = 1.33 (d, JHH = 6.7 Hz, 3.00 H, syn), 1.48
1
2
3
Hz, 1 H), 4.93 (ddd, JHH = 12.7 Hz, JHH = 3.5 Hz, JHH = 0.9 Hz, 1 H),
(dd, 1JHH = 6.9 Hz, 2JHH = 1.4 Hz, 1.00 H, anti), 2.78 (br s, 0.99 H, syn+an-
5.36 (m, 1 H), 6.27 (d, JHH = 5.1 Hz, 1 H), 7.40 (ddd, 1JHH = 7.9 Hz, 2JHH
=
ti), 4.68 (qd, JHH = 6.8 Hz, JHH = 3.5 Hz, 0.33 H, anti), 4.72 (dq, JHH
=
1
2
1
4.8 Hz, 3JHH = 0.6 Hz, 1 H), 7.85–7.87 (m, 1 H), 8.52 (dd, 1JHH = 4.8 Hz,
2JHH = 1.8 Hz, 1 H), 8.66 (d, JHH = 2.4 Hz, 1 H).
8.8 Hz, JHH = 6.9 Hz, 1.00 H, syn), 5.02 (d, JHH = 9.0 Hz, 1.00 H, syn),
5.41 (d, JHH = 3.2 Hz, 0.33 H, anti), 7.02 (td, 1JHH = 8.7 Hz, 2JHH = 1.6 Hz,
0.33 H, anti), 7.05–7.10 (m, 2.00 H, syn), 7.12–7.14 (m, 1.66 H,
syn+anti), 7.34–7.39 (m, 1.33 H, syn+anti).
2
13C NMR (176 MHz, DMSO-d6): δ = 68.0, 81.3, 123.5, 134.2, 135.9,
148.0, 149.2.
13C NMR (176 MHz, CDCl3): δ = 11.8 (anti), 16.3 (syn), 73.1 (d, 4JCF = 2.5
4
(R)-1-(1,3-Benzodioxol-5-yl)-2-nitroethanol (11o)24
Hz, anti), 75.5 (d, JCF = 2.5 Hz, syn), 87.1 (anti), 88.1 (syn), 113.1 (d,
2
2
2JCF = 21.1 Hz, anti), 113.9 (d, JCF = 22.9 Hz, syn), 115.4 (d, JCF = 21.1
Prepared with (Sa)-(+)-1 at 0 °C (96 h) according to the GP as a yellow-
ish waxy solid; yield: 17.3 mg (82%); 71% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 44.04 (major, R), 55.59 (minor S)].
2
4
Hz, anti), 116.2 (d, JCF = 19.4 Hz, syn), 121.5 (d, JCF = 3.8 Hz, anti),
122.6 (d, 4JCF = 2.5 Hz, syn), 130.3 (d, 3JCF = 8.9 Hz, anti), 130.6 (d, 3JCF
=
3
3
8.9 Hz, syn), 140.7 (d, JCF = 7.0 Hz, syn), 141.0 (d, JCF = 7.0 Hz, anti),
1
2
1H NMR (300 MHz, DMSO-d6): δ = 4.56 (dd, JHH = 12.4 Hz, JHH = 9.8
162.9 (d, 1JCF = 248.3 Hz, syn+anti).
Hz, 1 H), 4.77 (dd, 1JHH = 12.4 Hz, 2JHH = 3.6 Hz, 1 H), 5.22 (dd, 1JHH = 9.9
2
Hz, JHH = 3.5 Hz, 1 H), 6.00 (q, JHH = 1.1 Hz, 3 H), 6.87–9.94 (m, 2 H),
(1R,2R)-1-(4-Chlorophenyl)-2-nitropropan-1-ol (11s)24,25
7.02 (d, JHH = 1.6 Hz, 1 H).
Prepared with (Sa)-(+)-1 at –30 °C (48 h) according to the GP as a col-
orless oil; yield: 19.6 mg (91%); mixture of diastereomers;
92:36% ee (R,R)/(R,S); dr 74:26 (76:24) syn/anti [HPLC (iPrOH–Hp,
20:80; 0.5 mL/min; 5 °C; λ = 230 nm): tR = 16.95 (major, 1R,2S), 20.20
(minor, 1S,2R), 19.35 (major, 1R,2R), 22.07 min (minor, 1S,2S)].
13C NMR (75 MHz, DMSO-d6): δ = 69.9, 82.0, 101.1, 106.8, 108.12,
119.7, 134.5, 147.0, 147.4.
(R,E)-1-Nitro-4-phenylbut-3-en-2-ol (11p)21b
Prepared with (Sa)-(+)-1 at 0 °C (96 h) according to the GP as a yellow
oil; yield: 13.9 mg (72%); 68% ee [HPLC (iPrOH–Hp, 20:80; 0.5 mL/min;
5 °C; λ = 230 nm): tR = 70.65 (minor, S), 77.07 min (major, R)].
1H NMR (700 MHz, CDCl3): δ = 1.31 (d, JHH = 6.9 Hz, 3.00 H, syn), 1.47
(d, JHH = 6.9 Hz, 1.05 H, anti), 2.84 (br s, 1.35 H, syn+anti), 4.63–4.67
(m, 0.35 H, anti), 4.69–4.73 (m, 1.00 H, syn), 4.99 (d, JHH = 8.9 Hz, 1.00
H, syn), 5.36 (d, JHH = 3.8 Hz, 0.35 H, anti), 7.29–7.32 (m, 2.70 H,
syn+anti), 7.35–7.38 (m, 2.70 H, syn+anti).
13C NMR (176 MHz, CDCl3): δ = 11.9 (anti), 16.3 (syn), 73.2 (anti), 75.5
(syn), 87.2 (anti), 88.2 (syn), 127.3 (anti), 128.2 (syn), 128.9 (anti),
129.1 (syn), 134.3 (anti), 135.0 (syn), 136.7 (syn), 136.9 (anti).
1
2
1H NMR (300 MHz, DMSO-d6): δ = 4.47 (dd, JHH = 12.3 Hz, JHH = 9.2
1
2
Hz, 1 H), 4.87–4.91 (m, 1 H), 4.79 (dd, JHH = 12.0 Hz, JHH = 3.0 Hz, 1
H), 5.86 (d, JHH = 5.3 Hz, 1 H), 6.32 (dd, 1JHH = 16.0 Hz, 2JHH = 5.8 Hz, 1
H), 6.72 (dd, 1JHH = 16.0 Hz, 2JHH = 1.2 Hz, 1 H), 7.24–7.45 (m, 5 H).
13C NMR (75 MHz, DMSO-d6): δ = 68.9, 80.8, 126.5, 127.9, 128.3,
128.7, 130.8, 136.1.
(1S,2S)-1-(4-Bromophenyl)-2-nitrobutan-1-ol (11t)26
(1R,2R)-1-(2-Chlorophenyl)-2-nitropropan-1-ol (11q)25
Prepared with (Ra)-(–)-1 at –30 °C (48 h) according to the GP as a
milky oil; yield: 24.4 mg (89%); mixture of diastereomers;
89:53% ee (S,S)/(S,R); dr 79:21 (82:18) syn/anti [HPLC (iPrOH–Hp,
20:80; 0.5 mL/min; 5 °C; λ = 230 nm): tR = 15.59 (minor, 1R,2S), 17.12
(major, 1S,2R), 18.88 (minor, 1R,2R), 20.06 min (major, 1S,2S)].
1H NMR (700 MHz, CDCl3): δ = 0.88 (t, JHH = 7.4 Hz, 3.00 H, syn), 0.93
(t, JHH = 7.4 Hz, 0.81 H, anti), 1.39–1.45 (m, 1.00 H, syn), 1.81–1.89 (m,
1.27 H, syn+anti), 2.10–2.17 (m, 0.27 H, anti), 2.72 (br s, 1.10 H,
syn+anti), 4.51–4.57 (m, 1.27 H, syn+anti), 4.99 (d, JHH = 8.9 Hz, 1.00 H,
syn), 5.14 (d, J = 4.8 Hz, 0.27 H, anti), 7.24–7.26 (m, 2.54 H, syn+anti),
7.51 (d, J = 8.2 Hz, 0.54 H, anti), 7.53 (d, JHH = 8.2 Hz, 2.00 H, syn).
Prepared with (Sa)-(+)-1 at –30 °C (12 h) according to the GP as a col-
orless oil; yield: 19.8 mg (92%); mixture of diastereomers; 97:18% ee
(R,R)/(R,S); dr 91:9 (90:10) syn/anti [HPLC (iPrOH–Hp, 10:90;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 19.25 (major, 1R,2S), 22.56 (minor,
1S,2R), 25.82 (major, 1R,2R), 28.83 min (minor, 1S,2S)].
1H NMR (700 MHz, CDCl3): δ = 1.43–1.45 (m, 3.30 H, syn+anti), 2.85
(br s, 0.97 H, syn+anti), 4.84–4.88 (m, 1.10 H, syn+anti), 5.58 (d, JHH
8.3 Hz, 1.00 H, syn), 5.82 (d, JHH = 2.2 Hz, 0.10 H, anti), 7.29–7.31 (m,
1.10 H, syn+anti), 7.33–7.35 (m, 1.10 H, syn+anti), 7.38 (d, JHH = 8.0 Hz,
0.10 H, anti), 7.40 (d, JHH = 7.9 Hz, 1.00 H, syn), 7.49 (dd, 1JHH = 7.8 Hz,
2JHH = 1.4 Hz, 1.00 H, syn), 7.63 (dd, 1JHH = 7.7 Hz, 2JHH = 1.1 Hz, 0.10 H,
anti).
13C NMR (176 MHz, CDCl3): δ = 11.1 (anti), 15.9 (syn), 70.5 (anti), 71.8
(syn), 84.0 (anti), 88.0 (syn), 127.2 (anti), 127.6 (syn), 128.0 (anti),
128.2 (syn), 129.6 (syn+anti), 129.8 (syn), 130.0 (syn), 131.4 (anti),
132.7 (syn), 135.7 (anti), 136.0 (syn).
=
13C NMR (176 MHz, CDCl3): δ = 10.0 (syn), 10.3 (anti), 21.2 (anti), 23.8
(syn), 73.6 (anti), 74.8 (syn), 94.4 (anti), 94.9 (syn), 122.7 (anti), 123.2
(syn), 127.9 (anti), 128.5 (syn), 131.9 (anti), 132.2 (syn), 137.5 (anti),
137.6 (syn).
(S)-1-Nitro-4-phenylbutan-2-ol (11u)21a,27
Prepared with (Ra)-(–)-1 at –30 °C (24 h) according to the GP as a col-
orless oil; yield: 17.5 mg (90%); 43% ee [HPLC (iPrOH–Hp, 20:80;
0.5 mL/min; 5 °C; λ = 230 nm): tR = 44.22 (major, S), 47.83 (minor, R)]
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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J. Otevrel, P. Bobal
Paper
Synthesis
1H NMR (700 MHz, DMSO-d6): δ = 1.70–1.78 (m, 2 H), 2.67 (ddd, 1JHH
13.8 Hz, 2JHH = 9.5 Hz, 3JHH = 7.0 Hz, 1 H), 2.74–2.78 (m, 1 H), 4.14–4.19
=
(8) (a) Britovsek, G. J. P.; England, J.; White, A. J. P. Dalton Trans.
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1
2
1
(m, 1 H), 4.41 (dd, JHH = 12.2 Hz, JHH = 9.3 Hz, 1 H), 4.68 (dd, JHH
=
12.3 Hz, 2JHH = 3.3 Hz, 1 H), 5.51 (d, JHH = 6.4 Hz, 1 H), 7.20 (t, JHH = 7.4
Hz, 1 H), 7.24 (d, JHH = 7.4 Hz, 2 H), 7.30 (t, JHH= 7.8 Hz, 2 H).
13C NMR (176 MHz, DMSO-d6): δ = 31.0, 35.7, 67.6, 81.6, 125.9,
128.39, 128.41, 141.6.
Acknowledgement
Financial support for this work was provided by the projects IGA VFU
Brno 50/2014/FaF and 307/2015/FaF. Part of the work was carried out
with the support of core facilities of CEITEC (Central European Insti-
tute of Technology) under CEITEC open access project, ID No.
LM2011020, funded by the Ministry of Education, Youth and Sports
(MEYS) Czech Republic under the activity ‘Projects of major infra-
structures for research, development and innovations’. The X-ray part
of the work was realized in the X-ray Diffraction and Bio-SAXS Core
Facility of CEITEC within LQ1601 CEITEC 2020 project with financial
contribution made by MEYS Czech Republic within special support
paid from the National Programme for Sustainability II funds. The au-
thors wish to thank Radovan Fiala and Otakar Humpa (CEITEC) for as-
sistance with NMR measurements, Marek Necas (CEITEC) for X-ray
crystallography support, and Radim Hrdina (JLU Giessen) for helpful
discussion.
(9) Zhang, F.; Li, C.; Qi, C. Tetrahedron: Asymmetry 2013, 24, 380.
(10) (a) Deng, Y.; Liu, L.; Sarkisian, R. G.; Wheeler, K.; Wang, H.; Xu,
Z. Angew. Chem. Int. Ed. 2013, 52, 3663. (b) Mechler, M.; Peters,
R. Angew. Chem. Int. Ed. 2015, 54, 10303.
Supporting Information
Supporting information for this article is available online at
(11) Langhals, H.; Hofer, A.; Bernhard, S.; Siegel, J. S.; Mayer, P. J. Org.
Chem. 2011, 76, 990.
http://dx.doi.org/10.1055/s-0036-1588594.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(12) (a) For details of the synthesis of the catalyst, the additional
optimization data, full characterization of all compounds and
chiral analysis of compounds 1 and 11, see the Supporting
Information. (b) CCDC-1479754 contains the supplementary
crystallographic data for this paper. The data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via: www.ccdc.cam.ac.uk/getstructures.
(13) Laurence, C.; Gal, J. F. The BF3 Affinity Scale, In Lewis Basicity and
Affinity Scales: Data and Measurement, 1st ed.; John Wiley &
Sons Ltd: Chichester, 2010, 85.
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