Nitroalkenes in the Ni(II) Catalyzed Asymmetric Michael Addition. Convenient Route to the Key Intermediate of Brivaracetam

Article abstract of DOI:10.1002/hlca.201800170

A series of Ni(II) complexes with novel chiral ligands derived from (1R,2R)-1,2-diphenylethane-1,2-diamine was synthesized. The catalytic activity of these complexes in the asymmetric Michael reaction is demonstrated. Asymmetric addition of diethyl malonate to ω-nitrostyrene and 1-nitropent-1-ene in the presence of these complexes leads to the enantiomerically enriched diethyl (S)-2-(2-nitro-1-phenylethyl)malonate (up to 96 % ee) and (R)-diethyl 2-(1-nitropenthan-2-yl)malonate (up to 91 % ee). (4R)-4-Propylpyrrolidin-2-one, the key intermediate of antiepileptic drug brivaracetam, was obtained from the corresponding nitroester.

Full text of DOI:10.1002/hlca.201800170

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chimica acta
Accepted Article
Title: Nitroalkenes in the Ni(II) catalyzed asymmetric Michael addition.
Convenient route to the key intermediate of brivaracetam.
Authors: Alexander Reznikov, Leonid Kapranov, Valentina Ivankina,
Anastasiya Sibiryakova, Victor Rybakov, and Yuri Klimochkin
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10.1002/hlca.201800170
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Nitroalkenes in the Ni(II) catalyzed asymmetric Michael addition.
Convenient route to the key intermediate of brivaracetam
Alexander N. Reznikov, *,a Leonid E. Kapranov,a Valentina V. Ivankina,a
Anastasiya E. Sibiryakova,a Victor B. Rybakov,b Yuri N. Klimochkina
a Department of Organic Chemistry, Samara State Technical University, 443100, Samara, Russia
orgphosphorus@yandex.ru
b Department of Chemistry, Moscow State University, 119991, Mosсow, Russia
A series of Ni(II) complexes with novel chiral ligands derived from (1R,2R)-1,2-diphenylethane-1,2-diamine were synthesized. The catalytic
activity of these complexes in the asymmetric Michael reaction is demonstrated. Asymmetric addition of diethyl malonate to ω-nitrostyrene
and 1-nitropent-1-ene in the presence of these complexes leads to the enantiomerically enriched diethyl (S)-2-(2-nitro-1-phenylethyl)malonate
(up to 96 % ee) and (R)-diethyl 2-(1-nitropenthan-2-yl)malonate (up to 91 % ee). (4R)-4-Propylpyrrolidin-2-one, the key intermediate of
antiepileptic drug brivaracetam, was obtained from corresponding nitroester.
Keywords: Michael addition • Asymmetric catalysis • Neurological agents • N Ligands • Nickel
Introduction
[1]
Metal catalyzed asymmetric Michael addition is an effective strategy for the total synthesis of natural compounds and is used as the initial
stage of a series of cascade transformations [2-5]. The reaction of 1,3-dicarbonyl compounds with nitroalkenes attracts the greatest attention,
since the resulting adducts suggest a wide range of possible further applications, the most important of which is the reductive cyclization аs
the way to pyrrolidine-2-ones and gamma-amino acids [6, 7]. A number of these compounds are used as drugs for the treatment of CNS
disorders ((R)-baclofen 1 [8-10], (R)-rolipram 2 [11, 12], (S)-pregabalin 3 [13-18] (Figure 1)).
Figure 1. Pyrrolidine-2-ones and gamma-amino acids for the treatment of CNS disorders.
The strategy for the synthesis of chiral Michael adducts [19-26], based on the use of nickel complexes with chiral ligands, was applied to obtain
non-racemic GABA derivatives [27], polysubstituted cyclohexanes [28], piperidin-2-ones [29]. We have also shown that Ni(II) complexes with chiral
diamines are active catalysts in asymmetric conjugate addition of other Michael donors, such as β-oxo phosphonates [30] and β-oxo sulfoxides
[31]. However, enantioselectivity strongly depends on the nature of the unsaturated substrate. Therefore, research in this area remains relevant.
Brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide) 4 (Figure 2) is a novel high-affinity ligand of synaptic vesicle protein 2A
(SV2A) [32, 33], that is marketed by UCB and used to treat partial-onset seizures with or without secondary generalisation [34]
.
1
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Figure 2. Brivaracetam 4
The known procedures for the preparation of brivaracetam usually include generation of two or more stereoisomers of synthetic intermediates
and thus one or more separation steps of these stereoisomers are required in order to obtain the desired compound. These separation steps
may lower the overall yield and are generally time- and cost-consuming. The existing methods of the synthesis of brivaracetam are multistage
and involves using of chromatography with a chiral stationary phase and the chiral starting reagents (Scheme 1) [35-38]
.
Scheme 1. Тhe existing methods of the synthesis of brivaracetam 4.
In the present work we report on the synthesis of a number of Ni(II) complexes with N,N´-disubstituted derivatives of (R,R)-1,2-diphenylethane-
1,2-diamine (DPEN), (R,R)-cyclohexane-1,2-diamine (DACH) and (S,S)-bicyclo[2.2.2]octane-2,3-diamine, screening of their catalytic activity in the
reactions of asymmetric addition of diethyl malonate (5) to ω-nitrostyrene and 1-nitropent-1-ene (6) as a key step in the synthesis of
neurotropic drugs - GABA analogues and synthesis of the key intermediate (R)-(8) of brivaracetam (Scheme 2).
Scheme 2. Synthesis of the key intermediate of brivaracetam (R)-8
The advantage of the proposed method consists in asymmetric Michael addition as a key step. This allows to create the asymmetric center of
desired configuration which remains unchanged in the later steps of the synthesis. Thus, the main objective is to ensure a high enantiomeric
excess of the (R)-isomer by searching for effective chiral catalysts of the Michael addition.
2
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Results and Discussion
As shown by the authors [19], asymmetric induction in the reaction of 1,3-dicarbonyl compounds with nitroalkenes is caused by steric hindrance
of substituents at the nitrogen atoms of the chiral ligands (Scheme 3). Therefore the use of a Ni(II) complex with unsubstituted DACH as a
catalyst leads to a product with a low yield and enantioselectivity (6 %) [20]
.
Scheme 3. Proposed transition state for the Ni-catalyzed Michael addition of 1,3-dicarbonyl compounds to nitroalkenes [19]
.
However, the reaction catalyzed by a complex of similar structure but with a ligand containing tertiary amino groups (N, N'-dibenzyl-N, N'-
dimethylcyclohexane-1,2-diamine) also leads to a decrease in the rate and enantioselectivity of the reaction [19]. This fact shows that the
possible formation of hydrogen bond between secondary amino group of the ligand and the nitro group of the substrate in the favored
transition state can also make a certain contribution to the difference in the energies of favored and disfavored transition states. Consequently,
it can be assumed that the condition for achieving high enantioselectivity of Michael addition is a combination of the secondary amino group
and the bulky substituent at the nitrogen atom in the ligand structure.
Therefore we should expect that the nature of the substituents in the chiral diamines will significantly affect the enantioselectivity of the
reaction. To achieve an asymmetric induction in the reaction of diethyl malonate with 1-nitropent-1-ene we used ligands that provide the
conformational rigidity of resulting chelate with varied aromatic and heteroaromatic substituents.
Initially, we obtained N,N´-dibenzylated (1R,2R)-DPEN derivatives L1-L6 through successive treatment of diamine 9 with acetone to form
imidazolidine 10 and following reaction with substituted benzyl chlorides in the presence of K2CO3. Acid hydrolysis of imidazolidines 11a-f
leads to DPEN derivatives (1R,2R)-L1-L6 (Scheme 4).
Scheme 4. Synthesis of N,N´-disubstituted derivatives of (1R,2R)-1,2-diphenylethane-1,2-diamine L1-L6.
3
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Other previously described chiral ligands - derivatives of (1R,2R)-DACH L7-L12 [39-43] and (2R,3R)-bycyclo[2.2.2]octane-2,3-diamine L13 [44] were
synthesized to compare the catalytic properties of their complexes (Scheme 5).
Scheme 5. Synthesis of N,N´-disubstituted derivatives of (1R,2R)-cyclohexane-1,2-diamine L7-L12 and (2R,3R)-bycyclo[2.2.2]octane-2,3-diamine L13
Ni(II) complexes with chiral ligands (1R,2R)-L1-L11 and (2R,3R)-L13 were obtained by the reaction of anhydrous nickel(II) bromide 17 with
chiral vicinal diamines in acetonitrile (Scheme 6).
Scheme 6. Synthesis of Ni(II) complexes 18a-n
According to the elemental analysis, the composition of complexes 18a-n corresponds to formula [NiBr2L2] (L = L1-L11, L13). In the IR spectra
of 18a-n the v(NH) is shifted towards lower wave numbers by 40-100 cm-1 in comparison with v(NH) for the free ligand. Other absorption
bands basically correspond to those in the IR spectra of free ligands.
The single crystal X-ray diffraction study of compound 18b (L = L2) proved trans-configuration of octahedral Ni(II) complex (Figure 3).
4
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Figure 3. General view of compound 18b molecule in the crystal.
In the case of a ligand with adamantylmethyl substituent L12, the complex 19 containing only one coordinated diamine is formed (Scheme 7):
Scheme 7. Synthesis of Ni(II) complexes with ligand L12.
To study the catalytic activity of the complexes 18a-n, 19 and the enantioselectivity of Michael addition, we have performed a screening of this
complexes in the reaction of diethylmalonate with ω-nitrostyrene and 1-nitropent-1-ene.
Initially, we screened the obtained complexes in the model reaction of diethyl malonate 5 with ω-nitrostyrene 20 (Scheme 8, Table 1). Toluene
was chosen as a solvent, because previously we found the best results in the reactions of nitrostyrene with Michael donors [30]
.
Scheme 8. Asymmetric addition of diethyl malonate 5 to ω-nitrostyrene 20.
Table 1. Asymmetric addition of diethyl malonate 5 to ω-nitrostyrene 20 in the presence of complexes 18a-n and 19.
Entrya
Catalyst
Additive
Conversion, %b
Yield, %c
ee, %d
1
[NiBr2(L1)2]
18a
-
>99
87
95
2
[NiBr2(L2)2]
18b
-
>99
85
95
5
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3
4
5
6
[NiBr2(L3)2]
-
-
-
-
>99
>99
>99
>99
83
89
86
87
96
96
95
94
18c
[NiBr2(L4)2]
18d
[NiBr2(L5)2]
18e
[NiBr2(L6)2]
18f
7
[NiBr2(L7)2]
-
>99
>99
>99
>99
>99
>99
50
87
85
87
86
86
85
32
81
95
94
97
93
93
93
10
42
18g
8
[NiBr2(L8)2]
-
18h
9
[NiBr2(L9)2]
-
18j
10
11
12
13
14
[NiBr2(L10)2]
-
18k
[NiBr2(L11)2]
-
18m
[NiBr2(L13)2]
-
18n
[NiBr2(L12)2]
-
19
[NiBr2(L12)2]
Et3N
>99
19
a Reaction conditions: 1.10 mmol of ω-nitrostyrene, 1.00 mmol of diethyl malonate, 0.02 mmol (2 mol. %) of Ni(II) catalyst in toluene (1 ml),
25 oC, 72 h. b Determined by NMR. c Isolated yield after flash chromatography. dEnantiomeric excess was determined by chiral HPLC analysis
using a Chiralcel AD column; the absolute configuration of 21 was determined by comparison with the literature data [19]
.
As seen from the data given in the table, all the studied octahedral complexes showed high catalytic activity in this reaction. The
enantioselectivity of the reaction is 94-97% and depends weakly on the presence of substituents in the aromatic ring. Similar enantiomeric
excesses of the (S)-isomer of nitroester 21 (entries 1 and 7) are achieved in the presence of complexes with N,N'-dibenzylated derivatives of
DPEN and DACH. The highest enantioselectivity (97%) was achieved with the complex 18j (entry 9), in which the chlorine atom is in the para
position. On the oppose, ortho-fluorobenzyl substituents at the nitrogen atom of the ligand lead to a certain decrease in enantioselectivity
(entry 8). The complex 19 with one diamine containing adamantyl substituent showed low activity in the studied reaction (entry 13). Addition
of one equivalent of triethylamine leads to an increase in catalytic activity. However, even in this case, the enantiomeric excess of the (S)-isomer
is only 42% (entry 14).
The use of the less electrophilic 1-nitropent-1-ene as an unsaturated substrate (Scheme 9, Table 2) leads to a significant decrease in the
reaction rate. Reaction at room temperature is slow (entry 1). Therefore, further reaction was carried out at 50 oC (entries 2-9).
Optimization of the reaction conditions in the presence of complexes 18a, 18m, 18n and 19 (Table 2) showed that highest reaction rates are
achieved in the absence of solvent, however, the enantioselectivity of the reaction is lower in this case (entries 2, 4, 6).
6
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Scheme 9. Asymmetric addition of diethyl malonate 5 to 1-nitroреnt-1-ene 6.
Table 2. Optimization of reaction condition for asymmetric addition of diethyl malonate 5 to 1-nitropent-1-ene 6 a.
Entrya
Catalyst
Solvent
t, o
C
Time, h
Conversion, %b
Yield, %c
ee, %d
1
[NiBr2(L1)2]
18a
-
25
72
16
ND
ND
2
3
4
5
6
[NiBr2(L1)2]
18a
-
50
50
50
50
50
12
72
12
72
12
76
62
86
91
84
86
82
[NiBr2(L1)2]
CCl4
-
33
24
68
82
81
18a
[NiBr2(L11)2]
83
18m
[NiBr2(L11)2]
CCl4
-
>99
>99
18m
[NiBr2(L12)2]
18n
7
8
9
[NiBr2(L12)2]
EtOAc
toluene
CCl4
50
50
50
12
12
12
>99
>99
>99
83
83
82
83
85
87
18n
[NiBr2(L12)2]
18n
[NiBr2(L12)2]
18n
a
Reaction conditions: 1.10 mmol of 1-nitropent-1-ene, 1.00 mmol of diethyl malonate, 0.02 mmol (2 mol. %) of Ni(II)
catalyst. b Determined by NMR. c Isolated yield after flash chromatography d Enantiomeric excess was determined by chiral
HPLC analysis using a Chiralcel AD column; the absolute configuration of 7 assigned by analogy to the known product 21.
The enantioselectivity of the addition of diethyl malonate 5 to 1-nitropent-1-ene 6 is also lower than the reaction with ω-nitrostyrene. This fact
can be explained by conformational flexibility of the propyl substituent, which reduces the difference in the energy of the transition states in
accordance with the adopted stereochemical model for catalysis by chiral Lewis acids [19]
.
The highest enantioselectivity in the reaction of diethyl malonate with 1-nitropent-1-ene was achieved for the complexes 18a and 18b with the
ligands L1 and L2 - diphenylethanediamine derivatives (Table 3, entries 1, 2). However, the reaction rate in this case was lower than for
complexes based on ligands - cyclohexane-1,2-diamine derivatives L7 - L12 (entries 7-12). Complex 19 is the least active in the catalysis of the
Michael reaction (entry 13), as in the case with nitrostyrene (see Table 1). The enantiomeric excess in the presence of 19 is 16 %, but it increases
to 63 % when 19 is used in combination with triethylamine.
Table 3. Asymmetric addition of diethyl malonate 5 to 1-nitropent-1-ene 6 a.
Entrya
1
Catalyst
Additive
Time, h
72
Conversion, %b
33
Yield, %c
24
ee, %d
[NiBr2(L1)2]
-
91
18a
7
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2
3
4
5
6
[NiBr2(L2)2]
-
-
-
-
-
72
72
72
72
72
40
50
43
50
50
29
41
32
40
39
91
89
87
90
86
18b
[NiBr2(L3)2]
18c
[NiBr2(L4)2]
18d
[NiBr2(L5)2]
18e
[NiBr2(L6)2]
18f
7
[NiBr2(L7)2]
-
72
72
72
12
72
12
72
72
>99
88
87
65
86
64
82
82
42
62
87
84
85
81
86
87
16
63
18g
8
[NiBr2(L8)2]
-
18h
9
[NiBr2(L9)2]
-
>99
85
18j
10
11
12
13
14
[NiBr2(L10)2]
-
18k
[NiBr2(L11)2]
-
>99
>99
53
18m
[NiBr2(L12)2]
-
18n
[NiBr2(L13)2]
-
19
[NiBr2(L13)2]
Et3N
87
19
a Reaction conditions: 1.10 mmol of 1-nitropent-1-ene, 1.00 mmol of diethyl malonate, 0.02 mmol (2 mol. %) of Ni(II) catalyst in CCl4 (1ml), 50 oC. b Determined by
NMR. c Isolated yield after flash chromatography. dEnantiomeric excess was determined by chiral HPLC analysis using a Chiralcel AD column.
The resulting Michael adduct was used to synthesize the key intermediate of brivaracetam. Hydrogenation of nitroester 7 in isopropanol in the
presence of Ra-Ni leads to the (4R)-4-propylpyrrolidine-2-one-3-carboxylic acid ester 22 as a mixture of trans- and cis-isomers (9 : 1 according
NMR 1H) (Scheme 10).
Scheme 10. Synthesis of 4-propylpyrrolidine-2-one-3-carboxylic acid ester 22.
The NOESY experiment showed no interaction between H3 and H4 of the pyrrolidine moiety of 22a (see Supporting information). Based on
these data, it can be concluded that major stereoisomer of 22 is a trans isomer.
Subsequent hydrolysis of this ester in the presence of a base in an aqueous organic medium gave (3R,4R)- and (3S,4S)-4-propylpyrrolidine-2-
one-3-carboxylic acid 23. Decarboxylation of the acid 23 by refluxing in toluene gives (4R)-4-propyl pyrrolidin-2-one 8 (Scheme 11).
8
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Scheme 11. Synthesis of (4R)-4-propylpyrrolidine-2-one 8.
Optical rotatory power of 8 corresponds to sign and absolute value of known data for (4R)-4-propyl pyrrolidin-2-one [35]
.
Conclusions
In conclusion, new Ni(II) complexes, effective for Michael addition catalysis, were synthesized and described. The enantioselectivity of addition
of diethyl malonate to ω-nitrostyrene in the presence of these complexes is 94 - 97 % and to 1-nitropent-1-ene is 82 - 91 %. We have shown
that nickel complexes with 1,2-diphenylethane-1,2-diamine derivatives provide the greatest enantioselectivity in the reaction of diethyl
malonate with 1-nitropent-1-ene, but have less catalytic activity compared to analogous complexes with cyclohexane-1,2-diamine.
An effective approach to the key intermediate of the antiepileptic drug brivaracetam is proposed.
Experimental Section
General information
1H, 13C NMR spectra were recorded on JEOL JNM-ECX400 (1H NMR - 399.78 MHz, 13C NMR 100.53 MHz). All signals were expressed as ppm
using residual solvent peak as an internal standard. FTIR spectra were recorded on a Shimadzu IRAffinity-1 spectrophotometer with Specac®
Quest ATR. Melting points were determined on an electrothermal melting point apparatus OptiMelt and are uncorrected. Elemental analysis
was performed on EuroVector EA-3000 analyzer. Optical rotatory power was measured on Rudolph Research Analytical (Autopol V Plus
Automatic Polarimeter) at 589 nm. The enantiomeric purity of the products was determined by HPLC analysis on Waters LC equipped with a
chiral stationary phase column Chiralcel AD-3 with hexane/2-propanol 82:18 as eluent, 1.2 ml/min, λ = 210 nm. Column chromatography was
performed on Silica gel 60, Merck (230 – 400 mesh). X-Ray crystallographic data was collected using a Stoe STADI-VARI Pilatus-100K
diffractometer. CCDC-1841633 contains the supplementary crystallographic data for this work. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc. cam.ac.uk/data_request/cif. Ligands L1 [43], L7-L12 [38-42], L13 [43] and complexes 18a
[43], 18g [19], 18k-n [43] were obtained in accordance with previously described procedures.
General procedure for the synthesis of imidazolidines 11b-f.
To (1R,2R)-1.2-diphenylethane-1,2-diamine 9 (4.87 mmol) acetone (45 ml) and TsOH (25 mg) were added, and the resulting mixture was
refluxed for 3 h. Then, to resulting solution of 10 anhydrous K2CO3 (14.6 mmol), KI (0.983 mmol) and substituted benzyl chloride (9.83 mmol)
were added and the mixture was refluxed with vigorous stirring for 12 h. Reaction mixture was filtered, the precipitate washed with boiling
acetone, filtrate was evaporated. The residue was recrystallized from acetone.
o
20
(4R,5R)-2,2-Dimethyl-1,3-Bis(4-methylbenzyl)-4,5-diphenylimidazolidine (11b). Yield: 0.42 g (32 %). M.p. 113 – 115 C. [α]D = +88.0 (c
0.5, acetone). IR (neat/cm-1): 3026 (w), 2974 (w), 2922 (w), 2843 (w), 2793 (w), 1603 (w), 1514 (m), 1489 (w), 1452(w), 1371 (m), 1356 (m), 1315
(m)., 1252 (m), 1207 (m), 1179 (m), 1082 (w), 1070 (w), 1020 (w), 961 (w), 831 (w), 799 (s), 752 (s), 696 (vs), 617 (w), 559 (w), 509 (w), 490 (s), 478
(m). 1H NMR (400 MHz, C6D6) δ: 1.19 (s, 6H, CH3), 2.05 (s, 6H, CH3), 3.56 (s, 4H, CH2), 3.82 (s, 2H, CH), 6.89-6.91 (m, 4H), 6.97-7.01 (m, 2H), 7.02-
7.07 (m, 4H), 7.17-7.19 (m, 4H), 7.24-7.27 (m, 4H). 13C NMR (100.5 MHz, C6D6) δ: 20.81 (CH3), 26.04 (CH3), 51.53 (CH2), 75.89 (CH), 79.59 (C(CH3)2),
127.38 (CH), 128.01 (CH), 128.57 (CH), 128.62 (CH), 128.95 (CH), 135.70 (C), 138.04 (C), 140.65 (C). Anal. calc. for C33H36N2 (460.66): C 86.04, H
7.88, N 6.08; found: C 86.14, H 7.81, N 6.01.
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(4R,5R)-1,3-Bis(4-fluorobenzyl)-2,2-dimethyl-4,5-diphenylimidazolidine (11c). Yield: 0.60 g (41 %). M.p. 119 – 121 оС. [α]D20 = +97.2 (c 0.5,
acetone). IR (neat/cm-1): 3028 (w), 2970 (w), 2795 (w), 1603 (m), 1506 (vs), 1454 (m), 1373 (m), 1360 (m), 1254 (m), 1217 (vs), 1152 (s), 1015 (m),
926 (w), 916 (w), 837 (s), 812 (vs), 754 (vs), 690 (vs), 631 (w), 617 (m), 561 (m). 1H NMR (400 MHz, С6D6) δ: 1.03 (s, 6H, CH3), 3.34 (d, 2Н, СН2, 2JHH
14.6 Hz), 3.42 (d, 2Н, СН2, 2JHH 14.6 Hz), 3.70 (s, 2H, CH), 6.67-6.73 (m, 4Н), 6.93-7.03 (m, 10Н), 7.09-7.14 (m, 4Н). 13С NMR (100.5 MHz, С6D6) δ:
25.80 (s, CH3), 51.12 (s, СН2), 75.82 (s, СН), 79.45 (s, С(СН3)2), 114.56 (d, СН, 2JCF 22.0 Гц), 127.51 (s, CH), 128.02 (s, СН), 128.50 (s, СН), 130.30 (d,
3
4
1
СН, JCF 7.7 Гц), 136.52 (d, С, JCF 2.9 Гц), 140.13 (s, С), 161.85 (d, С-F, JCF 244.4 Гц). Anal. calc. for C31H30F2N2 (468.59): C 79.46, H 6.45, N 5.98;
found: C 79.52, H 6.40, N 5.91.
о
20
(4R,5R)-1,3-Bis(4-chlorobenzyl)-2,2-dimethyl-4,5-diphenylimidazolidine (11d). Yield: 1.42 g (41 %). M.p. 166 – 167 С. [α]D = +109.2 (c
0.5, acetone). IR (neat/cm-1): 3030 (w), 2980 (w), 2845 (w), 2793 (w), 1601 (w), 1489 (s), 1452 (m), 1369 (m), 1315 (m), 1238 (w), 1256 (m), 1215
(m), 1186 (m), 1171 (m), 1088 (s), 1015 (s), 962 (w), 862 (w), 835 (m), 808 (m), 794 (vs), 758 (s), 698 (vs), 671 (m), 631 (m), 610 (m), 554 (m), 511
1
2
2
(s). H NMR (400 MHz, С6D6) δ: 0.98 (s, 6H, CH3), 3.29 (d, 2Н, СН2, JHH 14.6 Hz), 3.37 (d, 2Н, СН2, JHH 14.6 Hz), 3.68 (s, 2H, CH), 6.80-7.12 (m,
18Н). 13С NMR (100.5 MHz, С6D6) δ: 25.81 (CH3), 51.17 (СН2), 75.73 (СН), 79.46 (С(СН3)2), 127.55 (CH), 127.97 (СH), 128.03 (СН), 128.49 (СН),
130.17 (СH), 132.21 (С-Сl), 139.40 (C), 139.94 (C). Anal. calc. for C31H30Cl2N2 (501.50): C 74.25, H 6.03, N 5.59; found: C 74.31, H 5.96, N 5.52.
20
(4R,5R)-1,3-Bis(4-bromobenzyl)-2,2-dimethyl-4,5-diphenylimidazolidine (11e). Yield: 1.57 g (55 %). M.p. 179 – 181 оС. [α]D = +102.2 (c
0.5, acetone). IR (neat/cm-1): 3030 (w), 2980 (w), 2845 (w), 2793 (w), 1601 (w), 1485 (s), 1452 (m), 1369 (m), 1357 (m), 1315 (m), 1256 (m), 1213
(m), 1186 (m), 1171 (m), 1069 (s), 1011 (vs), 962 (w), 862 (w), 831 (s), 804 (m), 791 (vs), 758 (vs), 698 (vs), 658 (m), 635 (m), 602 (w), 552 (w). 1H
NMR (400 MHz, С6D6) δ: 0.96 (s, 6H, CH3), 3.26 (d, 2Н, СН2, 2JHH 14.6 Hz), 3.34 (d, 2Н, СН2, 2JHH 14.6 Hz), 3.67 (s, 2H, CH), 6.84 (d, 4Н, 3JНН 8.2 Hz),
3
6.98 (d, 4Н, JНН 8.2 Hz), 7.07-7.17 (m, 10Н). 13С NMR (100.5 MHz, С6D6) δ: 25.82 (CH3), 51.20 (СН2), 75.70 (СН), 79.46 (С(СН3)2), 120.31 (С-Br),
127.56 (CH), 128.04 (СH), 128.48 (СН), 130.53 (СН), 130.93 (СH), 139.89 (С). Anal. calc. for C31H30Br2N2 (590.40): C 63.07, H 5.12, N 4.74; found: C
63.14, H 5.07, N 4.69.
20
(4R,5R)-1,3-Bis(4-iodobenzyl)-2,2-dimethyl-4,5-diphenylimidazolidine (11f). Yield: 0.52 g (59 %). M.p. 189 – 191 оС. [α]D = +86.6 (c 0.5,
acetone). IR (neat/cm-1): 3030 (w), 2982 (w), 2791 (w), 1600 (w), 1585 (w), 1566 (w), 1481 (m), 1452 (m), 1398 (w), 1367 (m), 1315 (m), 1256 (s),
1213 (s), 1184 (s), 1070 (m), 1057 (m), 1026 (m), 1004 (vs), 962 (w), 947 (w), 914 (w), 831 (s), 787 (vs), 758 (vs), 698 (vs), 653 (m), 629 (m), 503 (m).
1H NMR (400 MHz, С6D6) δ: 0.95 (s, 6H, CH3), 3.25 (d, 2Н, СН2, 2JHH 14.7 Hz), 3.32 (d, 2Н, СН2, 2JHH 14.7 Hz), 3.66 (s, 2H, CH), 6.72 (d, 4Н, 3JНН 8.0
3
Hz), 6.98 (d, 4Н, JНН 8.0 Hz), 7.07-7.10 (m, 6Н), 7.34-7.37 (m, 4Н). 13С NMR (100.5 MHz, С6D6) δ: 25.84 (CH3), 51.27 (СН2), 75.68 (СН), 79.47
(С(СН3)2), 91.68 (С-I), 127.54 (CH), 128.04 (СH), 128.48 (СН), 130.81 (СН), 136.93 (СH), 139.89 (С), 140.56 (С). Anal. calc. for C31H30I2N2 (684.40): C
54.40, H 4.42, N 4.09; found: C 54.47, H 4.37, N 4.02.
General procedure for synthesis of diamines L2-L6.
To imidazolidine 11b-f (2.65 mmol) 10% hydrochloric acid (13 ml) and acetic acid (26 ml) were added. The mixture was refluxed for 6 h.
Reaction mixture was cooled, filtered, and the precipitate of the diamine dihydrochloride was treated with saturated aqueous solution of NaOH.
Diamine was extracted with CH2Cl2 (3×25 ml). The extract was dried over K2CO3 and solvent was evaporated.
20
(1R,2R)-N,N´-Bis(4-methylbenzyl)-1,2-diphenylethane-1,2-diamine (L2). Yield: 0.24 g (89 %). M.p. 67 – 70 оС. [α]D = -29.4 (c 1.0, CHCl3).
IR (neat/cm-1): 3313 (w), 3024 (w), 2920 (w), 1514 (w), 1490 (w), 1452 (s), 1217 (w), 1199 (w), 1103 (m), 1072 (w), 1020 (w), 914 (w), 870 (w), 849
(w), 802 (m), 750 (vs), 696 (vs), 608 (m), 590 (m), 567 (m), 480 (s). 1H NMR (400 MHz, СDCl3) δ: 2.28 (broad s, 2Н, NH), 2.34 (s, 6H, CH3), 3.44 (d,
2H, CH2, 2JHH 13.1 Hz), 3.62 (d, 2H, CH2, 2JHH 13.1 Hz), 3.70 (s, 2H, CH), 7.03-7.06 (m, 4H), 7.09-7.18 (m, 14H). 13С NMR (100.5 MHz, СDCl3) δ: 21.21
(s, CH3), 51.14 (s, CH2), 68.41 (s, CH), 126.94 (s, CH), 128.02 (s, CH), 128.10 (s, CH), 128.14 (s, CH), 129.08 (s, CH), 136.37 (C), 137.67 (C), 141.37 (C).
Anal. calc. for C30H32N2 (420.60): C 85.67, H 7.67, N 6.66; found: C 85.75, H 7.61, N 6.61.
(1R,2R)-N,N´-Bis(4-fluorobenzyl)-1,2-diphenylethane-1,2-diamine (L3). Yield: 0.40 g (73 %). M.p. 65 – 67 оС. [α]D20 = -29.1 (c 1.0, CHCl3). IR
(neat/cm-1): 3345 (w), 3327 (w), 3028 (w), 2882 (w), 2828 (w), 2760 (w), 1601 (m), 1508 (vs), 1454 (m), 1433 (m), 1346 (w), 1308 (w), 1219 (vs),
1155 (m), 1113 (m), 1072 (m), 1063 (m), 1028 (w), 1016 (w), 978 (w), 916 (w), 856 (m), 841 (m), 833 (m), 820 (vs), 756 (vs), 694 (vs), 648 (m), 600
(vs), 554 (m), 544 (m). 1H NMR (400 MHz, СDCl3) δ: 2.47 (broad s, 2Н, NH), 3.46 (d, 2Н, СН2, 2JHH 13.3 Hz), 3.64 (d, 2Н, СН2, 2JHH 13.3 Hz), 3.70 (s,
2Н, СН), 6.93-6.99 (m, 4Н), 7.04-7.07 (m, 4Н), 7.14-7.20 (m, 10Н). 13С NMR (100.5 MHz, СDCl3) δ: 50.64 (s, СН2), 68.21 (s, СН), 115.19 (d, СН, 2JCF
10
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3
21.1 Hz), 127.18 (s, СН), 127.99 (s, СН), 128.17 (s, СН), 129.73 (d, СН, JCF 7.7 Hz), 136.11 (s, С), 140.85 (s, С), 161.95 (d, С-F, 1JCF 244.4 Hz). Anal.
calc. for C28H26F2N2 (428.52): C 78.48, H 6.12, N 6.54; found: C 78.54, H 6.08, N 6.49.
(1R,2R)-N,N´-Bis(4-chlorobenzyl)-1,2-diphenylethane-1,2-diamine (L4). Yield: 0.84 g (65 %), pale yelow oil. [α]D20 = -44.1 (c 1.0, CHCl3). IR
(neat/cm-1): 3312 (w), 3026 (w), 2974 (w), 2897 (w), 2826 (w), 1599 (w), 1489 (s), 1452 (s), 1406 (m), 1362 (w), 1263 (w), 1233 (w)., 1200 (m), 1088
(s), 1015 (s), 978 (w), 914 (w), 870 (w), 847 (m), 831 (m), 806 (s), 795 (s), 758 (s), 738 (m), 696 (vs), 673 (m), 633 (m), 609 (w), 578 (m), 551 (w), 521
(m). 1H NMR (400 MHz, СDCl3) δ: 2.36 (broad s, 2Н, NH), 3.45 (d, 2Н, СН2, 2JHH 13.7 Hz), 3.64 (d, 2Н, СН2, 2JHH 13.7 Hz), 3.68 (s, 2Н, СН), 7.02-7.06
(m, 4Н), 7.11-7.18 (m, 10Н), 7.23-7.27 (m, 4Н). 13С NMR (100.5 MHz, СDCl3) δ: 50.66 (СН2), 68.20 (СН), 127.20 (СН), 127.99 (СН), 128.19 (СН),
128.53 (СН), 129.53 (СН), 132.58 (С-Сl), 139.03 (С), 140.87 (С). Anal. calc. for C28H26Cl2N2 (461.43): C 72.88, H 5.68, N 6.07; found: C 72.93, H 5.62,
N 6.01.
(1R,2R)-N,N´-Bis(4-bromobenzyl)-1,2-diphenylethane-1,2-diamine (L5). Yield: 1.17 g (82 %), pale yelow oil. [α]D20 = -38.6 (c 1.0, CHCl3). IR
(neat/cm-1): 3312 (w), 3026 (w), 2918 (w), 2826 (w), 1591 (w), 1485 (s), 1452 (s), 1402 (m), 1346 (w), 1198 (w), 1103 (s), 1069 (s), 1011 (vs), 912 (w),
868 (w), 802 (m), 791 (m), 758 (m), 696 (vs), 656 (m), 625 (w), 573 (s), 542 (w), 515 (m). 1H NMR (400 MHz, СDCl3) δ: 2.46 (broad s, 2Н, NH), 3.43
2
2
3
3
(d, 2Н, СН2, JHH 13.5 Hz), 3.63 (d, 2Н, СН2, JHH 13.5 Hz), 3.68 (s, 2Н, СН), 7.03 (d, 4Н, JHH 8.2 Hz), 7.07 (d, 4Н, JHH 8.2 Hz), 7.14-7.19 (m, 6Н),
7.38-7.41 (m, 4Н). 13С NMR (100.5 MHz, СDCl3) δ: 50.63 (СН2), 68.07 (СН), 120.75 (С-Br), 127.27 (СН), 127.99 (СН), 128.22 (СН), 129.95 (СН),
131.50 (СH), 139.30 (С), 140.57 (C). Anal. calc. for C28H26Br2N2 (550.34): C 61.11, H 4.76, N 5.09; found: C 61.18, H 4.69, N 5.02.
20
(1R,2R)-N,N´-Bis(4-iodobenzyl)-1,2-diphenylethane-1,2-diamine (L6). Yield: 0.37 g (75 %). M.p. 47 – 49 оС. [α]D = -34.7 (c 1.0, CHCl3). IR
(neat/cm-1): 3304 (w), 3024 (w), 2918 (w), 2820 (w), 1601 (w), 1585 (w), 1481 (s), 1450 (s), 1398 (m), 1346 (w), 1196 (w), 1101 (s), 1072 (m), 1059
(m), 1026 (w), 1005 (vs), 912 (w), 868 (w), 802 (m), 787 (s), 758 (s), 696 (vs), 646 (w), 605 (w), 592 (w), 569 (s), 538 (w), 511 (m). 1H NMR (400 MHz,
СDCl3) δ: 2.49 (broad s, 2Н, NH), 3.42 (d, 2Н, СН2, 2JHH 13.5 Hz), 3.62 (d, 2Н, СН2, 2JHH 13.5 Hz), 3.68 (s, 2Н, СН), 6.95 (d, 4Н, 3JHH 8.2 Hz), 7.02 (d,
4Н, 3JHH 8.2 Hz), 7.13-7.18 (m, 6Н), 7.58-7.61 (m, 4Н). 13С NMR (100.5 MHz, СDCl3) δ: 50.69 (СН2), 68.07 (СН), 92.27 (С-I), 127.26 (СН), 127.99 (СН),
128.22 (СН), 130.25 (СН), 137.48 (СH), 139.99 (С), 140.56 (C). Found (%): C, 52.26; H, 4.02; N, 4.29. Calc. for C28H26I2N2 (%): C, 52.19; H 4.07; N,
4.35. Anal. calc. for C28H26I2N2 (644.34): C 52.19, H 4.07, N 4.35; found: C 52.26, H 4.02, N 4.29.
General procedure for the synthesis of complexes 18 and 19.
To a solution of diamine L1-L13 (0.910 mmol) in 5 ml of acetonitrile anhydrous NiBr2 17 (0.433 mmol) was added. The resulting mixture was
refluxed under argon for 12 h. The acetonitrile was evaporated in vacuo. The residue was dissolved in methyl tert-butyl ether (2 ml), and the
complex was precipitated by the addition of hexane (10 ml). The precipitate was filtered off and dried in vacuo.
о
Dibromobis[(1R,2R)-N,N´-bis(4-methylbenzyl)-1,2-diphenylethane-1,2-diamine]nickel(II) (18b). Yield: 0.22 g (72 %). M.p. 175 – 177 С
(decomp.). [α]D20 = +102.9 (c 1.0, CHCl3). IR (neat/cm-1): 3263 (w), 3022 (w), 2955 (w), 2918 (w), 1587 (w), 1516 (m), 1495 (m), 1439 (s), 1360 (w),
1315 (w), 1198 (w), 1123 (m), 1076 (m), 1059 (s), 1040 (s), 962 (s), 947 (s), 930 (s), 887 (vs), 816 (s), 797 (vs), 756 (s), 694 (vs), 650 (m), 640 (m),
600 (m), 583 (w), 554 (s), 544 (s), 521 (s). Anal. calc. for C60H64Br2N4Ni (1059.70): C 68.01, H 6.09, N 5.29; found: C 68.10, H 6.01, N 5.22.
Dibromobis[(1R,2R)-N,N´-bis(4-fluorobenzyl)-1,2-diphenylethane-1,2-diamine]nickel(II) (18c). Yield: 0.37 g (74 %). M.p. 178 - 180 оС
(decomp.). [α]D20 +133.9 (c 0.5, CHCl3). IR (neat/cm-1): 3260 (w), 3227 (w), 1603 (m), 1508 (vs), 1454 (m), 1439 (m), 1423 (w), 1300 (w), 1221 (vs),
1157 (m), 1103 (m), 1082 (m), 1057 (m), 1024 (w), 968 (m), 952 (s), 939 (m), 923 (w), 891 (s), 849 (m), 820 (s), 806 (s), 758 (vs), 696 (vs), 646 (m),
594 (m), 554 (m), 554 (m), 527 (m). Anal. calc. for C56H52Br2F4N4Ni (1075.56): C 62.54, H 4.87, N 5.21; found: C 62.61, H 4.82, N 5.16.
Dibromobis[(1R,2R)-N,N´-bis(4-chlorobenzyl)-1,2-diphenylethane-1,2-diamine]nickel(II) (18d). Yield: 0.86 g (83 %). M.p. 173 – 175оС
(decomp.). [α]D20 = +166.6 (c 0.5, CHCl3). IR (neat/cm-1): 3254 (w), 3238 (w), 3024 (w), 2937 (w), 1599 (w), 1493 (s), 1452 (m), 1435 (m), 1408 (w),
1302 (w), 1273 (w), 1157 (w), 1125 (m), 1090 (s), 1059 (s), 1014 (m), 945 (m), 932 (m), 885 (vs), 814 (s), 789 (vs), 760 (s), 698 (vs), 644 (m), 592 (m),
540 (s), 517 (s). Anal. calc. for C56H52Br2Cl4N4Ni (1141.37): C 58.93, H 4.59, N 4.91; found: C 59.01, H 4.52, N 4.85.
Dibromobis[(1R,2R)-N,N´-bis(4-bromobenzyl)-1,2-diphenylethane-1,2-diamine]nickel(II) (18e). Yield: 1.22 g (87 %). M.p. 165 – 167оС
(decomp.). [α]D20 = +102.3 (c 0.5, CHCl3). IR (neat/cm-1): 3258 (w), 3238 (w), 3040 (w), 2951 (w), 1591 (w), 1489 (s), 1452 (s), 1435 (s), 1404 (m),
1357 (w), 1304 (w), 1271 (w), 1186 (m), 1155 (w), 1124 (m), 1072 (s), 1059 (s), 1011 (s), 976 (m), 966 (s), 945 (s), 931 (m), 883 (vs), 821 (s), 812 (s),
783 (vs), 760 (s), 698 (vs), 656 (w), 626 (m), 619 (m), 584 (m), 540 (s), 517 (s). Anal. calc. for C56H52Br6N4Ni (1319.18): C 50.99, H 3.97, N 4.25;
found: C 51.07, H 3.91, N 4.19.
11
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10.1002/hlca.201800170
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Dibromobis[(1R,2R)-N,N´-bis(4-iodobenzyl)-1,2-diphenylethane-1,2-diamine]nickel(II) (18f). Yield: 0.30 g (69 %). M.p. 173 – 175оС
(decomp.). [α]D20 = +74.6 (c 0.5, CHCl3). IR (neat/cm-1): 3265 (w), 3256 (w), 1585 (w), 1493 (w), 1479 (m), 1454 (m), 1439 (m), 1396 (m), 1352 (w),
1300 (w), 1269 (w), 1182 (w), 1117 (m), 1080 (m), 1053 (s), 1003 (s), 966 (m), 945 (s), 885 (s), 820 (s), 783 (s), 758 (m), 696 (vs), 679 (vs), 650 (m),
621 (w), 611 (m), 592 (m), 530 (s), 513 (s). Anal. calc. for C56H52Br2I4N4Ni (1507.18): C 44.63, H 3.48, N 3.72; found: C 44.70, H 3.42, N 3.69.
Dibromobis[(1R,2R)-N,N´-bis(2-fluorobenzyl)cyclohexane-1,2-diamine]nickel(II) (18h). Yield: 0.12 g (79%). M.p. 198–200 оС (decomp.).
[α]D20 = -45.1 (c 1.0, CHCl3). IR (neat, ν/cm-1): 3279 (w), 2936 (m), 2855 (w), 1616 (w), 1585 (w), 1489 (s), 1450 (vs), 1229 (s), 1111 (m), 1090 (m),
1059 (m), 1038 (w), 972 (s), 932 (vs), 889 (s), 878 (vs), 837 (m), 820 (vs), 783 (m), 745 (vs), 696 (m), 434 (s), 419 (s). Anal. calc. for С40H48Br2F4N4Ni
(879.33): С, 54.64; Н, 5.50; N, 6.37; found: С, 54.69; Н, 5.46; N, 6.41.
Dibromobis[(1R,2R)-N,N´-bis(4-chlorobenzyl)cyclohexane-1,2-diamine]nickel(II) (18j). Yield: 0.15 g (62%). M.p. 158–160 оС (decomp.).
[α]D20 = -100.4 (c 1.0, CHCl3). IR (neat, ν/cm-1): 3264 (w), 2931 (m), 2860 (w), 1597 (w), 1575 (w), 1495 (s), 1450 (vs), 1408 (w), 1094 (vs), 1063 (m),
1013 (s), 976 (s), 937 (s), 895 (s), 880 (vs), 847 (m), 837 (m), 797 (vs), 658 (s), 478 (s), 422 (m), 407 (m), 401 (m). Anal. calc. for С40H48Br2Cl4N4Ni
(945.15): С, 50.83; Н, 5.12; N, 5.93; found: С, 50.89; Н, 5.09; N, 5.98.
o
Dibromo[(1R,2R)-N,N´-bis(adamantan-1-ylmethyl)cyclohexane-1,2-diamine]nickel(II) (19). Yield: 0.15 g (37%). M.p. >320 С (decomp.).
[α]D20 = -35.7 (c 1.0, CHCl3). IR (neat, ν/cm-1): 3264 (w), 3217 (w), 2899 (vs), 2845 (s), 1443 (vs), 1391 (w), 1368 (w), 1344 (w), 1317 (w), 1150 (w),
1092 (m), 1057 (m), 1040 (s), 1015 (s), 978 (s), 912 (m), 895 (m), 885 (m), 878 (m), 571 (w), 509 (w), 463 (w), 414 (s), 407 (m). Anal. calc. for
C28H46Br2N2Ni (629.18): C, 53.45; H, 7.37; N, 4.45; found: С, 53.52; Н, 7.31; N, 4.51.
General Procedure for Ni(II) Catalyzed Enantioselective Michael Addition of diethyl malonate 5 to ω-nitrostyrene 20.
Nickel(II) complex 18a-n or 19 (0.02 mmol) was added to a solution of 164 mg (1.10 mmol) ω-nitrostyrene 23 and 160 mg (1.00 mmol) diethyl
malonate 5 in 1 ml of toluene. The mixture was kept for 72 h at 20°C, the solvent was distilled off under reduced pressure, and the residue was
purified by chromatography on silica gel using CHCl3 as eluent.
Diethyl (S)-2-(2-nitro-1-phenylethyl)malonate (21). M.p. 45–46 оС. [α]D20 = +7.3 (c 1.5, CHCl3). IR (neat/cm-1): 2984 (w), 1728 (vs), 1553 (vs),
1497 (w), 1466 (w), 1456 (w), 1447 (w), 1369 (s), 1329 (m), 1300 (m), 1256 (m), 1231 (m), 1177 (s), 1152 (s), 1096 (m), 1026 (s), 988 (w), 860 (m),
768 (m), 700 (vs), 608 (m). 1H NMR (400 MHz, СDCl3) δ: 1.03 (t, 3H, CH3, 3JHH 7.1 Hz), 1.24 (t, 3H, CH3, 3JHH 7.1 Hz), 3.80 (d, 1H, CH(COOEt)2, 3JHH
9.2 Hz), 3.99 (q, 2H, CH2O, 3JHH 7.1 Hz), 4.15–4.30 (m, 3H, CH2O, CHPh), 4.80–4.95 (m, 2H, CH2NO2), 7.23–7.30 (m, 5H, Ph). 13С NMR (100.5 MHz,
СDCl3) δ: 13.79 (CH3), 14.02 (CH3), 43.06 (CHPh), 55.08 [CH(COOEt)2], 61.93 and 62.21 (CH2O), 78.68 (CH2NO2), 128.11 (CH), 128.41 (CH), 128.99
(CH), 136.36 (C), 166.90 and 167.53 (C=O). Anal. calc. for C15H19NO6 (309.32): C 58.25, H 6.19, N 4.53; found: C 58.29, H 6.14, N 4.49. HPLC
(Chiralcel AD, hexane/2-propanol = 82/18, 1.2 mL/min, λ = 210 nm, retention times: (R) (minor) 9.5 min, (S) (major) 23.9 min).
General Procedure for Ni(II) Catalyzed Enantioselective Michael Addition of diethyl malonate 5 to 1-Nitropent-1-ene 6.
To a mixture of diethyl malonate 5 (160 mg, 1.00 mmol) and 1-nitropent-1-ene 6 (127 mg, 1.10 mmol) the catalyst (0.02 mmol) was added and
the reaction mixture was stirred at 50 oC for 12 h. Conversion was determined by NMR analysis. The reaction product was isolated by flash
chromatography (CCl4 – 3 % ethyl acetate) to give the product as a pale yellow oil.
20
(R)-Diethyl 2-(1-nitropenthan-2-yl)malonate (7). Yield: 79 %. B.p. 105–110 C (1×10-3 torr). []D = +8.36 (с 1.0, CHCl3). IR (neat, ν/cm-1):
2967 (s), 2940 (s), 2877 (m), 1732 (s), 1551 (s), 1466 (s), 1446 (m), 1373 (m), 1304 (m), 1265 (m), 1219 (m), 1180 (m), 1157 (m), 1096 (w), 1026 (s),
1
3
3
864 (w), 810 (w), 737 (w), 698 (w). H NMR (400 MHz, CDCl3)  : 0.88 (t, 3H, JHH = 6.9 Hz), 1.23 (t, 6H, JHH = 7.1 Hz), 1.30 – 1.45 (m, 4H), 2.82 –
2.92 (m, 1H), 3.57 (d, 1H, 3JHH = 5.7 Hz), 4.17 (q, 1H, 3JHH = 8.0 Hz), 4.49 (dd, 1H, 3JHH 6.9 Hz, 2JHH 13.3 Hz), 4.66 (dd, 1H, 3JHH 5.0 Hz, 2JHH 13.3 Hz).
13C NMR (100.5 MHz, CDCl3)  : 13.79, 14.06, 19.87, 32.22, 36.73, 52.70, 61.80, 61.95, 76.75, 167.85, 168.05. Anal. calc. for C12H21NO6 (275.30): C,
52.35; H, 7.69; N, 5.09; found, %: C 52.29; H 7.73; N 5.07. HPLC analysis (Chiralсel AD column; hexane / 2-propanol, 98:2; flow rate 1.2 mL/min;
wavelength 210 nm); retention times: (R) (major) 8.82 min, (S) (minor) 10.15 min).
Ethyl 2-oxo-4-propylpyrrolidine-3-carboxylate (mixture of (3R,4R)- and (3S,4R)-isomers) (22). The solution of 7 (9.4 g, 34.1 mmol) in 30
o
ml of i-PrOH is transferred to an autoclave and about 1 g of Raney nickel is added. The reaction mixture is allowed to react at 70 C under 50
bars of hydrogen pressure for 36 h. The catalyst is filtered off and washed with i-PrOH. The filtrate was concentrated in vacuo. The residue was
20
purified by silica column chromatography (CHCl3) to give the product as a pale yellow oil. Yield: 5.0 g (74 %). dr 9 : 1. []D = +31.4(с 1.0,
CHCl3). IR (neat, ν/cm-1): 3198 (w), 3098 (w), 2955 (w), 2930 (w), 2864 (w), 1732 (s), 1697 (vs), 1491 (w), 1456 (m), 1379 (m), 1337 (m), 1298 (m),
12
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1265 (m), 1204 (m), 1175 (s), 1155 (s), 1123 (m), 1092 (m), 1016 (m), 935 (w), 845 (w), 787 (m), 766 (m), 746 (m), 704 (m), 637 (m), 523 (s). H
3
NMR (400 MHz, CDCl3)  : 0.86 (t, 3H, 3JНН = 7.1 Hz), 1.20–1.30 (m, 5H), 1.36–1.48 (m, 2H), 2.74–2.84 (m, 1H), 2.93 (dd, 1H, JHH = 7.6 Hz, 2JHH
=
9.6 Hz), 3.02 (d, 1H, 3JHH = 8.9 Hz), 3.49 (t, 1H, J = 8.70 Hz), 4.10 – 4.25 (m, 2H, CH2O), 7.46 (bs, 1H, NH) (for (3R,4R)-isomer); 0.86 (t, 3H, 3JНН
=
7.1 Hz), 1.20 – 1.30 (m, 5H), 1.36 – 1.48 (m, 2H), 2.58 – 2.69 (m, 1H), 3.18 (t, 1H, J = 9.40 Hz), 3.26 (d, 1H, 3JHH = 9.15 Hz), 3.38 (t, 1H, J = 8.47 Hz),
7.35 (bs, 1H, NH) (for (3S,4R)-isomer). 13C NMR (100.5 MHz, CDCl3)  : 14.00, 14.21, 20.42, 36.01, 39.30, 46.79, 54.81, 61.60, 170.16, 174.00 (for
(3R,4R)-isomer); 14.06, 14.27, 20.82, 31.42, 39.10, 47.41, 52.53, 61.21, 169.07, 174.75 (for (3S,4R)-isomer). Anal. calc. for C10H17NO3 (199.25): C,
60.28; H, 8.60; N, 7.03; found, %: C 60.21; H 8.65; N 7.08.
2-Oxo-4-propylpyrrolidine-3-carboxylic acid (mixture of (3R,4R)- and (3S,4R)-isomers) (23). To a solution of 22 (5.22 g, 26.2 mmol) in
110 ml of ethanol 25 ml of the 15 % aqueous solution of KOH was added at 0 oC. The reaction mixture was stirred for 2 h at 0 oC and 30 min at
room temperature. Then 50 ml of water was added and the resulting solution was extracted with toluene. The organic layer was separated and
the aqueous phase was acidified with hydrochloric acid to pH 2 and extracted with chloroform. The extract was dried over sodium sulfate and
evaporated in vacuo to give the product as a pale yellow oil. Yield: 3.63 g (81 %). dr 9 : 1. []D20 = +52.5(с 1.0, CHCl3). IR (neat, ν/cm-1): 3287 (w),
2957 (w), 2930 (w), 2872 (w), 1682 (vs), 1659 (vs), 1649 (vs), 1489 (w), 1447 (w), 1377 (w), 1281 (m), 1206 (m), 1177 (m), 1121 (w), 1049 (w), 748
1
3
(m), 691 (m), 665 (m), 515 (m). H NMR (400 MHz, CDCl3)  : 0.90 (t, JHH = 7.3 Hz, 3H), 1.27 – 1.36 (m, 2H), 1.39 – 1.48 (m, 1H), 1.58 – 1.67 (m,
1H), 2.75 – 2.84 (m, 1H), 3.01 (dd, 3JHH = 7.8 Hz, 2JHH = 9.6 Hz, 1H), 3.08 (d, 3JHH = 8.9 Hz, 1H), 3.55 (t, 1H, J = 9.0 Hz), 7.61 (bs, 1H), 10.23 (bs, 1H)
(for (3R,4R)-isomer); 0.90 (t, 3H, 3JHH = 7.3 Hz), 1.27–1.36 (m, 2H), 1.39–1.48 (m, 1H), 1.58–1.67 (m, 1H), 2.65–2.74 (m, 1H), 3.24 (t, 1H, J = 8.9 Hz),
3.35 (d, 1H, 3JHH = 8.7 Нz), 3.40–3.48 (m, 1H), 7.61 (bs, 1H), 10.23 (bs, 1H) (for (3S,4R)-isomer). 13C NMR (100.5 MHz, CDCl3)  : 14.03, 20.41, 36.09,
38.75, 47.10, 53.77, 172.38, 175.38 (for (3R,4R)-isomer); 14.03, 20.75, 31.12, 38.66, 47.38, 52.32, 172.05, 176.11 (for (3S,4R)-isomer). Anal. calc. for
C8H13NO3 (171.19): C, 56.13; H, 7.65; N, 8.18; found, %: C 56.03; H 7.69; N 8.22.
(4R)-4-Propylpyrrolidin-2-one (8). Acid 23 (3.63 g, 21.2 mmol) was dissolved in 40 ml of toluene and refluxed for 6 hours. Then the reaction
mixture was evaporated in vacuo. The residue was purified by silica column chromatography (CHCl3) to give the product as a pale yellow oil.
20
Yield: 2.13 g (64 %); pale yellow oil; []D = +2.3(с 1.0, MeОН); IR (neat, ν/cm-1): 3229 (w), 2957 (w), 2926 (w), 2872 (w), 1686 (vs), 1489 (w),
1456 (w), 1425 (w), 1377 (w), 1285 (m), 1263 (w), 1244 (w), 1065 (w), 742 (w), 690 (w), 673 (w), 500 (m); 1H NMR (CDCl3) : 0.90 (t, 3 H, 3JHH = 7.0
Hz), 1.30 – 1.45 (m, 4H), 1.85–2.00 (m, 1H), 2.30–2.48 (m, 2H), 2.99 (dd, 1H, J = 15.13, 10.74 Hz), 3.38–3.48 (m, 1H), 6.90–7.10 (m, 1H); 13C NMR
(CDCl3) : 14.07, 20.71, 34.72, 36.86, 48.28, 178.34. Anal. calcd. for C7H13NO, (127.18): C, 66.11; H, 10.30; N, 11.01; Found, %: C 66.04; H 10.36; N
11.07.
Supplementary Material
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/MS-number.
Acknowledgements
This work was supported by the Russian Science Foundation (grant no. 18-13-00447) and using a STOE STADI VARI PILATUS-100K
diffractometer purchased by MSU Development Program.
Author Contribution Statement
The research was conceived by AR. AS, LK and VI carried out the experiments under the supervision of AR and YK. The discussion of the results
and the redaction of the manuscript were made by AR and YK. Experimental data were described by AS and AR. The crystallographic structures
were elucidated by VR.
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