Novel C2-symmetric phenylglycine derivatives as organocatalysts of the Michael reaction between nitroalkenes and ketones

Article abstract of DOI:10.1007/s11172-021-3163-x

A comprehensive study of the activity of the amide-type organocatalysts based on (R)- and (S)-phenylglycine and 1,2-di(2-pyridyl)-1,2-diaminoethane in the asymmetric Michael reaction between various nitroalkenes and ketones was carried out. The products o

Full text of DOI:10.1007/s11172-021-3163-x

Russian Chemical Bulletin, International Edition, Vol. 70, No. 5, pp. 885—889, May, 2021
885
Novel C2-symmetric phenylglycine derivatives as organocatalysts
of the Michael reaction between nitroalkenes and ketones*
A. A. Kostenko, O. Yu. Kuznetsova, A. S. Kucherenko, and S. G. Zlotin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
E-mail: alexkucherenko@yandex.ru
A comprehensive study of the activity of the amide-type organocatalysts based on (R)- and
(S)-phenylglycine and 1,2-di(2-pyridyl)-1,2-diaminoethane in the asymmetric Michael reaction
between various nitroalkenes and ketones was carried out. The products of the studied reactions
were formed in up to 99% yield, with syn diastereoselectivity (dr) >20 : 1 and enantiomeric
excess of up to 93% ee for syn-isomer. The organocatalysts can be regenerated and reused in at
least seven reaction cycles.
Key words: asymmetric catalysis, organocatalysis, phenylglycine, Michael reaction, green
chemistry, biologically active compounds.
In recent years, asymmetric organocatalysis has been
increasingly used to design complex chiral compounds.1—7
An important direction in this field of chemistry is the
development of new catalysts based on small organic
molecules.8—10 The Michael reaction is one of the most
efficient and powerful synthetic tools for the stereoselec-
tive formation of new carbon—carbon bonds.11—13 Nitro
olefins are widely used as Michael acceptors in the reac-
tions with CH acids, since the resulting chiral γ-nitro
carbonyl compounds can serve as universal precursors for
the construction of more complex chiral biologically active
compounds.14 Earlier,15,16 we have synthesized organo-
catalysts based on proline and its derivatives (substituted
pyrrolidines, etc.), which have proved to be efficient in the
asymmetric Michael reaction between nitro olefins and
various aldehydes and ketones. Amino acids and their
derivatives containing a primary amino group, which form
the basis for enzymatic catalysis in living systems, are very
attractive as catalysts.17—19 Chiral derivatives of primary
amino acids, and especially C2-symmetric ones, have
been poorly studied as organocatalysts of asymmetric
Michael reactions, meanwhile, they can serve as effi-
cient "donors of chirality" in some other asymmetric
processes.20—23 The introduction of fragments of chiral
pyridine-containing diamines into amino acids often
increases the activity and selectivity of catalysts, as
well as prolongs their active period.23 The present study
is aimed at discovering the potential of catalysts typified
by primary amines in the reactions between nitrostyrenes
and ketones.
Results and Discussion
As the sources of chirality, we chose a sterically hin-
dered amino acid phenylglycine in both enantiomeric
forms. Diastereoisomeric organocatalysts I and II were
synthesized in two steps from commercially available
N-benzyloxycarbonyl-2-phenylglycines 1 and heterocyclic
(S,S)-1,2-di(2-pyridyl)-1,2-diaminoethane 2 we obtained
earlier.23 In the first step, diaminoethane 2 was acylated
with N-benzyloxycarbonyl-2-phenylglycines 1 using ethyl
chloroformate in THF. In the second step, the protective
groups were removed by catalytic hydrogenation in the
presence of 5% Pd/C, which gave the corresponding amido
amines I and II as white powders in high overall yields
(81—85%) (Scheme 1).
The catalytic efficiency of the thus obtained C2-sym-
metric primary amido amines I and II was tested in a model
Michael reaction between nitrostyrene 3a and cyclohex-
anone 4a (Scheme 2, Table 1).
The highest activity and enantioselectivity in the model
reaction between compounds 3a and 4a was exhibited by
amide organocatalyst I based on (1S,2S)-1,2-di(2-pyridyl)-
ethane-1,2-diamine and (S)-phenylglycine. The highest
yield (85%) and enantiomeric excess (up to 92% ee) of
product 5a were achieved when the solvent-free reaction
was carried out at 0 °C in the presence of 15 mol.% of the
catalyst (Table 1, entry 9). The use of organic solvents
proved to be inefficient. A decrease in the amount of
catalyst I to 5 mol.% (entries 10 and 11) had an insignifi-
cant effect on the reaction enantioselectivity, with the
yield of product 5a markedly decreasing.
Organocatalyst I (15 mol.%, neat, 0 °C) showing the
highest yield and enantioselectivity was used further to
* Dedicated to Academician of the Russian Academy of Sciences
V. N. Charushin on the occasion of his 70th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 885—889, May, 2021.
1066-5285/21/7005-0885 © 2021 Springer Science+Business Media LLC

Kostenko et al.
886
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
Scheme 1
Table 1. Optimization of the conditions of the model reaction
between nitrostyrene 3a and cyclohexanone 4aа
Entry
T/°C
Catalyst
(mol.%)
Solvent
Yieldb,c
of 5a (%)
eed
(%)
e
1
2
3
4
5
6
7
8
~20
~20
~20
~20
~20
~20
~20
~20
0
I (15)
II (15)
I (15)
I (15)
I (15)
I (15)
I (15)
I (15)
I (15)
I (10)
I (5)
—
85
76
69
88
80
84
90
87
82
70
55
84
62f
60
67
59
60
63
67
92
91
88
e
—
PhMe
CH2Cl2
EtOAc
ТГФ
EtOH
PriOH
e
9
10
11
—
e
0
—
e
0
—
а Reaction conditions: catalyst I or II (5—15 mol.%), nitrostyrene
3a (7.5 mg, 0.05 mmol), cyclohexanone 4a (9.8 mg, 0.1 mmol),
solvent (0.1 mL) or neat, 24 h, ~20 °C.
Reagents and conditions: i. ClCO2Et, Et3N, THF, ~20 °C, 24 h;
ii. H2 (1 atm.), 5% Pd/C, MeOH, 5 h.
b The yield of syn-5a after flash chromatography on silica gel.
c Diastereomeric ratio of syn : anti > 20 : 1 (1Н NMR spectral data).
d Enantiomeric excess was determined by HPLC on a Chiralpak
AD-H chiral phase, the (1R,2S)-configuration of product 5a was
confirmed by comparing the rotation angle with the literature data.11
e Solvent-free.
Scheme 2
f (1S,2R)-5a was obtained.
Scheme 3
4a (2 equiv.)
Reagents and conditions: catalyst I or II, solvent, 24 h.
carry out reactions between various nitrostyrenes and
cyclic and linear ketones (Scheme 3, Table 2). The reac-
tion between cyclopentanone 4b and nitrostyrene 3a gave
product 5b (dr syn : anti = 7 : 1) in high yield (99%) and
syn-enantioselectivity (90% ee) (see Table 2, entry 2). The
reaction of nitrostyrene 3a with methyl ethyl ketone 4c
proceeded regioselectively at the methylene group to give
branched product 5c in moderate yield (55%) and enantio-
meric excess (78% ee) (entry 3). Acetone (4d) readily
reacts with nitro olefin 3b to form adduct 5d in moderate yield
(61%) and high enantioselectivity (89% ee) (see Table 2, entry 4).
Aromatic nitro olefins 3 containing halogen atoms (entries
4—6) or a nitro group in the aromatic ring (entry 8) can also
be involved into the reaction (66—79% yields, 80—87% ее).
We have developed a procedure for the regeneration
of organocatalyst I (Table 3). Thus, trifluoroacetic acid
was added to the solution after the reaction completion,
the mixture was stirred for 30 min and concentrated,
product 5a and unreacted starting compounds were ex-
tracted with diethyl ether. The organic layer was decanted,
the trifluoroacetate salt of catalyst I was treated with Et3N,
washed with water, and vacuum dried. The regenerated
3a—c: Ar = Ph (a), 3-ClC6H4 (b), 2-BrC6H4 (c), 4-MeOC6H4 (d),
4-O2NC6H4 (e)
4a—d: R1 + R2 = (CH3)2 (a), (CH2)2 (b); R1 = H, R2 = Me (c), H (d)
Compounds 5
Ar
Ph
Ph
R1
—(CH2)3—
—(CH2)2—
Me
R2
a
b
c
d
e
f
Ph
H
H
3-ClC6H4
3-ClC6H4
2-BrC6H4
4-MeOC6H4
4-O2NC6H4
H
—(CH2)3—
—(CH2)3—
—(CH2)3—
—(CH2)3—
g
h
Reagents and conditions: catalyst I (15 mol.%), neat, 0 °C, 24 h.
catalyst was used in the following cycles. After seven
regenerations of catalyst I, its structure did not change
(1H NMR data). An increase in the reaction time during
the seventh cycle is apparently associated with mechanical
losses of the catalyst in the regeneration process (about
30% by weight after the seventh cycle).

Chiral nitro ketones
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
887
Table 2. Scope of application of organocatalyst Ia
Experimental
Entry Nitro-
Ketone 4 Product
Yieldb,c eed (syn)
We used commercially available reagents (Sigma-Aldrich
Co.). Solvents were purified according to standard procedures.
The starting nitroolefins 3 were synthesized according to the
known procedures.25 Column chromatography was performed
on silica gel (Aldrich, 0.060—0.200 μm), the eluent was hexane—
styrene 3
of 5 (%)
5 (%)
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3b
3c
3d
3e
4a
4b
4с
4d
4a
4a
4a
4a
5a
5b
5с
5d
5e
5f
85
99e
55
61
75
79
66
70
84
90
78
89
88
85
82
93
1
ethyl acetate (2 : 1 or 1 : 1). Н and 13C NMR spectra were re-
corded at 25 °С on a Bruker AM-300 spectrometer (300 MHz
(1H) and 75 MHz (13C). High-resolution mass spectra were
obtained on a Bruker microTOF II instrument. The enantio-
meric composition of compounds 5a—h was analyzed on a Styer
high performance liquid chromatograph with a UV detector
(220—254 nm) on stationary chiral phases (Chiralpak AD-H,
AS-H, and OD-H, a 25-cm column). The rotation angles were
determined on a Jasco P-2000 polarimeter.
Synthesis of catalysts I and II (general procedure). Tri-
ethylamine (0.66 mL) was added to a solution of (R)- or (S)-N-
benzyloxycarbonyl-2-phenylglycine 1 (1.2 g, 4.68 mmol) in
anhydrous THF (10 mL). Then, ethyl chloroformate (446.0 μL,
0.508 g, 4.68 mmol) was added slowly dropwise to the mixture,
which was stirred for 30 min, followed by the addition of diamine
2 (0.5 g, 2.34 mmol). The reaction mixture was stirred for 24 h.
The formed precipitate was filtered off, the filtrate was dried with
MgSO4, the solvent was evaporated on a rotary evaporator. The
residue was dissolved in methanol (10 mL), 5% Pd/C (100 mg)
was added, and the mixture was stirred for 5 h in an H2 atmosphere
(1 atm.). The reaction mixture was filtered, the filtrate was con-
centrated to obtain products I and II as white high-melting
powders.
5g
5h
а Reaction conditions: catalyst I (3.6 mg, 0.0075 mmol, 15 mol.%),
nitrostyrene 3 (0.05 mmol), ketone 4 (0.1 mmol), 0 °C, 24 h.
b The yield of syn-5 after flash chromatography on silica gel.
c Diastereomeric ratio of syn : anti > 20 : 1 (1Н NMR spectral data).
d
Enantiomeric excess was determined by HPLC on Chiralpak
AD-H, AS-H, and OD-H chiral phases.
e The ratio of syn : anti = 7 : 1.
Table 3. Regeneration of catalyst I in the reac-
tion between compounds 3а and 4аа
Cycle
Yield of 5a (%)
eе of 5a (%)
1
82
80
79
78
75
71
65
92
92
91
90
87
83
75
2
3
4
(2S,2´S)-N,N´-[(1S,2S)-1,2-Di(2-pyridyl)ethane-1,2-diyl]-
bis(2-amino-2-phenylacetamide) (I). The yield was 0.95 g (85%),
a white powder. M.p. >230 °С. 1H NMR (DMSO-d6), δ: 4.87
(s, 2 H); 5.11 (br.s, 4 H); 5.85 (s, 2 H); 7.21—7.35 (m, 12 H);
7.50 (m, 2 H); 7.77 (m, 2 H); 8.01 (s, 2 H); 8.50 (m, 2 H).
5
6
7b
а
Reaction conditions: catalyst I (36.0 mg,
0.075 mmol, 15 mol.%), nitrostyrene 3a (74.5 mg,
0.5 mmol), cyclohexanone 4a (98.0 mg,
1.0 mmol), 0 °C, 24 h.
13
C NMR (DMSO-d6), δ: 57.3, 58.0, 121.1, 127.6, 129.1, 129.3
134.0, 144.3, 157.2, 170.1. Found: m/z 481.5685 [M + H]+.
Calculated for C28H29N6O2: 481.5683.
b Reaction time 30 h.
(2R,2´R)-N,N´-[(1S,2S)-1,2-Di(2-pyridyl)ethane-1,2-diyl]-
bis(2-amino-2-phenylacetamide) (II). The yield was 0.91 g (81%),
a white powder. M.p. >230 °С. 1H NMR (DMSO-d6), δ: 4.84
(s, 2 H); 5.13 (br.s, 4 H); 5.86 (s, 2 H); 7.22—7.36 (m, 12 H);
7.49 (m, 2 H); 7.75 (m, 2 H); 8.03 (s, 2 H); 8.51 (m, 2 H).
The products of Michael reactions 5 between ketones
4 and β-nitrostyrene derivatives 3 can be used in the syn-
thesis of enantiomerically enriched drugs. For example,
product 5g can be converted in several steps into the anti-
depressant (–)-venlafaxine (trade name Effexor).24
In conclusion, we have obtained a new efficient
C2-symmetric organocatalyst based on the amino acid
(S)-phenylglycine and (S,S)-1,2-di(2-pyridyl)-1,2-di-
aminoethane. It was found to be efficient in the solvent-free
Michael reaction between nitroalkenes and various cyclic
and acyclic ketones. The products were formed in high
yields (up to 99%), diastereo- (>20 : 1) and enantioselec-
tivity for the syn-isomer (up to 93% ee). The compounds
obtained can find application in the synthesis of chiral
enantiomerically pure drugs. A procedure for the regen-
eration of organocatalysts based on primary amines has
been developed, which ensures their multiple (at least
seven cycles) use.
13
C NMR (DMSO-d6), δ: 57.3, 58.1, 121.0, 127.8, 129.3, 129.5
134.1, 144.3, 157.1, 170.0. Found: m/z 481.5687 [M + H]+.
Calculated for C28H29N6O2: 481.5683.
Catalytic Michael reaction between compounds 3 and 4 (gen-
eral procedure). A corresponding ketone 4 (2 equiv., 0.1 mmol)
was added to a mixture of organocatalyst I or II (3.6 mg,
0.0075 mmol, 15 mol.%) and nitrostyrene 3 (0.05 mmol), and
the mixture was stirred for 24 h at the temperature indicated in
Table 1 (optimization of conditions) or at 0 °С (synthesis of
compounds 5b—h). The solvent was evaporated, the residue was
extracted with diethyl ether (3×4 mL) and purified by flash
chromatography on silica gel (eluent hexane—ethyl acetate, 2 : 1
or 1 : 1). The spectral data for compounds 5b—h correspond to
those published earlier.26
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone (5a). The
yield was 10.1 mg (82%), a white powder. M.p. 124—126 °С,
20
[α]D –29.6 (c 0.1, CHCl3), 92% ee. 1H NMR (CDCl3), δ:
1.10—1.22 (m, 1 H); 1.47—1.73 (m, 4 H); 1.98—2.04 (m, 1 H);

Kostenko et al.
888
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
2.26—2.44 (m, 2 H); 2.61 (m, 1 H); 3.69 (dt, 1 H, J1 = 9.9 Hz,
J2 = 4.5 Hz); 4.56 (dd, 1 H, J1 = 12.6 Hz, J2 = 9.9 Hz); 4.87 (dd,
1 H, J1 = 12.6 Hz, J2 = 4.5 Hz); 7.08—7.11 (m, 2 H); 7.19—7.27
(m, 3 H). Found: m/z 248.1284 [M + H]+. Calculated for
C14H18NO3: 248.1281. The enantiomeric excess was determined
on a Diacel Chiralpak AD-H stationary chiral phase at 254 nm
(hexane—propan-2-ol (85 : 15), 1.0 mL min–1; t(R) = 8.69 min
(minor), 10.54 min (major)).
326.0388 [M + H]+. Calculated for C14H17BrNO3: 326.0386.
The enantiomeric excess was determined on a Diacel Chiralpak
AS-H stationary chiral phase at 220 nm (hexane—propan-2-ol
(90 : 10), 1.0 mL min–1; t(R) = 16.65 min (minor), 22.48 min
(major)).
(S)-2-[(R)-1-(4-Methoxyphenyl)-2-nitroethyl]cyclohexanone
(5g). The yield was 9.1 mg (66%), a white powder. M.p.
78—80 °С, [α]D –21.3 (c 0.1, CHCl3), 82% ee. 1H NMR
20
(S)-2-((R)-2-Nitro-1-phenylethyl)cyclopentanone (5b).
A 7 : 1 mixture of syn- and anti-diastereomers. The yield was
11.7 mg (99%), a white powder. syn-Isomer 90% ee. 1H NMR
(CDCl3), δ: 1.43—1.52 (m, 1 H); 1.68—1.75 (m, 1 H); 1.85—1.96
(m, 2 H); 2.08—2.18 (m, 1 H); 2.32—2.43 (m, 1.73 H, syn);
2.49—2.55 (m, 0.27 H, anti); 3.66—3.72 (m, 0.89 H, syn);
3.82—3.85 (m, 0.17 H, anti); 4.71 (dd, 1 Н, J1 = 12.8 Hz,
J2 = 10.0 Hz); 5.02 (d, 1 Н, J = 7.62 Hz); 5.34 (dd, 1 Н,
J1 = 12.8 Hz, J2 = 5.6 Hz); 7.15—7.19 (m, 2 Н); 7.28—7.34
(m, 3 H). Found: m/z 234.1124 [M + H]+. Calculated for
(CDCl3), δ: 1.15—1.32 (m, 1 H); 1.43—1.83 (m, 4 H); 1.97—2.17
(m, 1 Н); 2.25—2.47 (m, 2 H); 2.54—2.72 (m, 1 H); 3.62—3.79
(m, 4 H); 4.56 (dd, 1 Н, J1 = 12.3 Hz, J2 = 10.1 Hz); 4.90 (dd,
1 H, J1 = 12.3 Hz, J2 = 4.6 Hz); 6.83 (d, 2 H, J = 8.8 Hz); 7.06
(d, 2 H, J = 8.6 Hz). Found: m/z 278.1389 [M + H]+. Calculated
for C15H20NO4: 278.1387. The enantiomeric excess was de-
termined on a Diacel Chiralpak AD-H stationary chiral phase
at 220 nm (hexane—propan-2-ol (95 : 5), 1.0 mL min–1
t(R) = 24.68 min (minor), 31.42 min (major)).
;
(S)-2-[(R)-2-Nitro-1-(4-nitrophenyl)ethyl]cyclohexanone
(5h). The yield was 10.2 mg (70%), a pale yellow oil. M.p.
C
13H16NO3: 234.1125. The enantiomeric excess was determined
80—82 °С, [α]D –30.3 (c 1.0, CHCl3), 93% ee. 1H NMR
20
on a Diacel Chiralpak AD-H stationary chiral phase at 220 nm
(hexane—propan-2-ol (95 : 5), 1.0 mL min–1; t(R) = 12.29 min
(major, anti), 14.20 min (minor, anti), 15.87 min (minor, syn),
87.00 min (major, syn)).
(CDCl3), δ: 1.28—1.37 (m, 1 H); 1.43—1.88 (m, 4 H; 2.09—2.18
(m, 1 Н); 2.25—2.52 (m, 2 H); 2.58—2.80 (m, 1 H); 3.91 (td, 1 H,
J1 = 9.8 Hz, J2 = 4.5 Hz); 4.67 (dd, 1 H, J1 = 13.0 Hz,
J2 = 10.2 Hz); 4.98 (dd, 1 H, J1 = 13.0 Hz, J2 = 4.5 Hz); 7.38
(d, 2 H, J = 8.8 Hz); 8.18 (d, 2 H, J = 8.8 Hz). Found: m/z
293.1136 [M + H]+. Calculated for C14H17N2O5: 293.1132. The
enantiomeric excess was determined on a Diacel Chiralpak
AD-H stationary chiral phase at 220 nm (hexane—propan-2-ol
(80 : 20), 0.5 mL min–1; t(R) = 39.66 min (minor), 69.34 min
(major)).
Regeneration of organocatalyst I (general procedure). After
the reaction was completed, trifluoroacetic acid (22.0 μL,
0.3 mmol) was added to the reaction mixture, the solution was
stirred for 30 min and concentrated. Product 5a and unreacted
starting compounds were extracted with diethyl ether (5×4 mL).
The organic layer was decanted, Et3N (43.0 μL, 0.31 mmol) was
added to the remaining catalyst, the resulting mixture was washed
with water (5×2 mL) and vacuum dried (1.0 Torr, 70 °С, 1 h).
New portions of the starting compounds 3a (74.5 mg, 0.5 mmol)
and 4a (103.0 μL, 1.0 mmol) were added to the regenerated
catalyst I and the process was repeated.
(3S,4R)-3-Methyl-5-nitro-4-phenylpentan-2-one (5c). The
20
yield was 6.1 mg (55%), a colorless oil, [α]D –34.1 (c 0.1,
CHCl3), 78% ee. 1H NMR (CDCl3), δ: 0.93 (d, 3 Н, J = 7.2 Hz);
2.15 (s, 3 H); 2.89—2.94 (m, 1 H); 3.59 (dt, 1 Н, J1 = 9.3 Hz,
J2 = 4.8 Hz); 4.48—4.61 (m, 2 H); 7.05—7.08 (m, 2 H); 7.18—7.27
(m, 3 H). Found: m/z 222.1121 [M + H]+. Calculated for
C12H16NO3: 222.1125. The enantiomeric excess was determined
on a Diacel Chiralpak AS-H stationary chiral phase at 220 nm
(hexane—propan-2-ol (90 : 10), 0.5 mL min–1; t(R) = 14.90 min
(minor), 16.20 min (major)).
(R)-4-(3-Chlorophenyl)-5-nitropentan-2-one (5d). The yield
20
was 7.4 mg (61%), a colorless oil, [α]D –5.1 (c 0.1, CHCl3),
89% ee. 1H NMR (CDCl3), δ: 2.05 (s, 3 H); 2.84 (d, 2 H,
J = 6.9 Hz); 4.00 (d, 1 H, J = 5.6 Hz); 4.60 (dd, 1 H, J1 = 9.0 Hz,
J2 = 5.7 Hz); 4.68 (dd, 1 H, J1 = 7.0 Hz, J2 = 5.0 Hz); 7.22—7.34
(m, 5 H). Found: m/z 242.0575 [M + H]+. Calculated for
C11H13ClNO3: 242.0578. The enantiomeric excess was deter-
mined on a Diacel Chiralpak AS-H stationary chiral phase
at 220 nm (hexane—propan-2-ol (85 : 15), 1.0 mL min–1
t(R) = 21.76 min (minor), 29.79 min (major)).
;
This work was financially supported by the Russian
Science Foundation (Project No. 16-13-10470P).
This work does not involve human participants and
animal models.
(S)-2-[(R)-1-(3-Chlorophenyl)-2-nitroethyl]cyclohexanone
(5e). The yield was 10.5 mg (75%), a brownish oil, 88% ee.
1H NMR (CDCl3), δ: 1.08—1.24 (m, 1 H); 1.45—1.72 (m, 4 H);
1.93—1.96 (m, 1 H); 2.19—2.36 (m, 2 H); 2.52—2.65 (m, 1 H);
3.67 (dt, 1 H, J1 = 9.9 Hz, J2 = 4.5 Hz); 4.52 (dd, 1 Н, J1 = 12.6 Hz,
J2 = 9.9 Hz); 4.83 (dd, 1 Н, J1 = 12.6 Hz, J2 = 4.5 Hz); 6.96—7.01
(m, 1 H); 7.08 (s, 1 H); 7.12—7.20 (m, 2 H). Found: m/z 282.0889
[M + H]+. Calculated for C14H17ClNO3: 282.0891. The enan-
tiomeric excess was determined on a Diacel Chiralpak AS-H
stationary chiral phase at 220 nm (hexane—propan-2-ol (90 : 10),
0.5 mL min–1; t(R) = 20.70 min (minor), 23.00 min (major)).
(S)-2-[(R)-1-(2-Bromophenyl)-2-nitroethyl]cyclohexanone
(5f). The yield was 12.2 mg (79%), a pale yellow powder. M.p.
The authors declare no competing interest.
References
1. G. Zhan, W. Du, Y. C. Chen, Chem. Soc. Rev., 2017, 46,
1675—1692; DOI: 10.1039/C6CS00247A.
2. J. Alemán, S. Cabrera, Chem. Soc. Rev., 2013, 42, 774—793;
DOI: 10.1039/C2CS35380F.
3. T. James, M. Van Gemmeren, B. List, Chem. Rev., 2015, 115,
9388—9409; DOI: 10.1021/acs.chemrev.5b00128.
4. J. Y. Du, Y. H. Ma, F. X. Meng, R. R. Zhang, R. N. Wang,
H. L. Shi, Q. Wang, Y. X. Fan, H. L. Huang, J. C. Cui,
C. L. Ma, Org. Lett., 2019, 21, 465—468; DOI: 10.1021/acs.
orglett.8b03709.
80—82 °С, [α]D –43.2 (c 0.1, CHCl3), 85% ee. 1H NMR
20
(CDCl3), δ: 1.26—1.35 (m, 1 H); 1.51—1.76 (m, 4 H); 2.01—2.04
(m, 1 H); 2.27—2.47 (m, 2 H); 2.83 (br.s, 1 H); 4.24 (br.s, 1 H);
4.82 (s, 2 H); 7.05 (t, 1 Н, J = 7.6 Hz); 7.14 (d, 1 Н, J = 7.6 Hz);
7.22—7.24 (m, 1 Н); 7.50 (d, 1 Н, J = 8.0 Hz). Found: m/z

Chiral nitro ketones
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
889
5. D. S. Ji, Y. C. Luo, X. Q. Hu, P. F. Xu, Org. Lett., 2020, 22,
1028—1033; DOI: 10.1021/acs.orglett.9b04571.
17. K. M. Koeller, C. H. Wong, Nature, 2001, 409, 232—240;
DOI:10.1038/35051706.
6. K. N. Gavrilov, I. V. Chuchelkin, V. K. Gavrilov, S. V.
Zheglov, I. D. Firsin, V. M. Trunina, A. V. Maximychev,
A. M. Perepukhov, Russ. Chem. Bull., 2021, 70, 336.
7. K. N. Gavrilov, S. V. Zheglov, V. K. Gavrilov, I. D. Firsin,
M. G. Maksimova, Russ. Chem. Bull., 2019, 68, 1376; DOI:
10.1007/s11172-019-2564-6.
8. U. Scheffler, R. Mahrwald, Chem. — Eur. J., 2013, 19,
14346—14396; DOI: 10.1002/chem.201301996.
9. V. Kozma, F. Fülöp, G. Szőllősi, Adv. Synth. Catal., 2020,
362, 2444—2458; DOI: 10.1002/adsc.202000335.
10. T. L. da Silva, R. S. Rambo, C. G. Jacoby, P. H. Schneider,
Tetrahedron, 2020, 76, 130874; DOI: 10.1016/j.tet.2019.130874.
11. A. Y. Sukhorukov, A. A. Sukhanova, S. G. Zlotin, Tetrahedron,
2016, 72, 6191—6281; DOI: 10.1016/j.tet.2016.07.067.
12. K. O. Eyong, H. L. Ketsemen, Z. Zhao, L. Du, A. Ingels,
V. Mathieu, A. Kornienko, K. G. Hull, G. N. Folefoc,
S. Baskaran, D. Romo, Med. Chem. Res., 2020, 29, 1058—1066;
DOI: 10.1007/s00044-020-02545-0.
18. G. Carrea, S. Riva, Angew. Chem., Int. Ed., 2000, 39,
2226—2254; DOI: 10.1002/1521-3773(20000703)39:13%
3C2226::AID-ANIE2226%3E3.0.CO;2-L.
19. P. J. Um, D. G. Drueckhammer, J. Am. Chem. Soc., 1998,
120, 5605—5610; DOI: 10.1021/ja980445b.
20. K. Sakthivel, W. Notz, T. Bui, C. F. Barbas, J. Am. Chem.
Soc., 2001, 123, 5260—5267; DOI: 10.1021/ja010037z.
21. L. W. Xu, J. Luo, Y. Lu, Chem. Commun., 2009, 1807—1821;
DOI: 10.1039/B821070E.
22. O. V. Serdyuk, C. M. Heckel, S. B. Tsogoeva, Org. Biomol.
Chem., 2013, 11, 7051—7071; DOI: 10.1039/C3OB41403E.
23. V. G. Lisnyak, A. S. Kucherenko, E. F. Valeev, S. G. Zlotin,
J. Org. Chem., 2015, 80, 9570—9577; DOI: 10.1021/
acs.joc.5b01555.
24. S. P. Chavan, S. Garai, K. P. Pawar, Tetrahedron Lett., 2013,
54, 2137—2139; DOI: 10.1016/j.tetlet.2013.02.029.
25. C. Xu, J. Du, L. Ma, G. Li, M. Tao, W. Zhang, Tetrahedron,
2013, 69, 4749—4757; DOI: 10.1016/j.tet.2013.02.084.
26. H. Huang, E. N. Jacobsen, J. Am. Chem. Soc., 2006, 128,
7170—7171; DOI: 10.1021/ja0620890.
13. Y. Wang, D. M. Du, Org. Chem. Front., 2020, 7, 3266—3283;
DOI: 10.1039/D0QO00631A.
14. D. Roca-Lopez, D. Sadaba, I. Delso, R. P. Herrera, T. Tejero,
P. Merino, Tetrahedron: Asymmetry, 2010, 21, 2561—2601;
DOI: 10.1016/j.tetasy.2010.11.001.
15. K. A. Bykova, A. A. Kostenko, A. S. Kucherenko, S. G. Zlotin, Russ.
Chem. Bull., 2019, 68, 1402; DOI: 10.1007/s11172-019-2568-2.
16. A. S. Kucherenko, V. G. Lisnyak, A. A. Kostenko, S. V.
Kochetkov, S. G. Zlotin, Org. Biomol. Chem., 2016, 14,
9751—9759; DOI: 10.1039/C6OB01606E.
Received November 14, 2020;
in revised form January 14, 2021;
accepted February 2, 2021