Kinetic resolution of racemic 6-substituted 1,2,3,4-tetrahydroquinaldines with chiral acyl chlorides. Experiment and quantum chemical simulation

Article abstract of DOI:10.1007/s11172-021-3164-9

A comparative study of the kinetic resolution (KR) of racemic 6-substituted 2-methyl-1,2,3,4-tetrahydroquinolines with acyl chlorides of (S)-naproxen, N-phthaloyl-(S)-leucine, and (R)-O-phenyllactic acid was carried out. The selectivity factors in the KR of racemic amines with acyl chlorides of (S)-naproxen and (R)-O-phenyllactic acid were shown to be approximately the same and higher than those for the KR of N-phthaloyl-(S)-leucyl chloride. The reasons for the stereodifferentiation in the KR of racemic tetrahydroquinaldines containing groups of different electronic properties by acyl chlorides of three different chiral acids were explained using the DFT method. The conditions for stabilizing π—π interactions of aromatic fragments of the reagents, which do not occur in the same form in the transition state and lead to the minor diastereoisomeric product, are created in the transition state of the faster acylation reaction with (S)-naproxen and (R)-O-phenyllactic acyl chlorides. In the case of the KR of 2-methyl-1,2,3,4-tetrahydroquinoline and 2-methyl-6-methoxy-1,2,3,4-tetrahydroquinoline with N-phthaloyl-(S)-leucyl chloride, the acylation diastereoselectivity is determined, most likely, by conformational factors. The individual (S)-enantiomer of 2-methyl-6-methoxy-1,2,3,4-tetrahydroquinoline of high optical purity was synthesized using the KR of the racemate with (S)-naproxen acyl chloride.

Full text of DOI:10.1007/s11172-021-3164-9

Russian Chemical Bulletin, International Edition, Vol. 70, No. 5, pp. 890—899, May, 2021
890
Kinetic resolution of racemic 6-substituted 1,2,3,4-tetrahydroquinaldines
with chiral acyl chlorides. Experiment and quantum chemical simulation*
E. N. Chulakov, M. A. Korolyova, L. Sh. Sadretdinova, A. A. Tumashov, M. I. Kodess, G. L. Levit, and V. P. Krasnov
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi, 620108 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 1189. E-mail: ca@ios.uran.ru
A comparative study of the kinetic resolution (KR) of racemic 6-substituted 2-methyl-
1,2,3,4-tetrahydroquinolines with acyl chlorides of (S)-naproxen, N-phthaloyl-(S)-leucine,
and (R)-O-phenyllactic acid was carried out. The selectivity factors in the KR of racemic amines
with acyl chlorides of (S)-naproxen and (R)-O-phenyllactic acid were shown to be approxi-
mately the same and higher than those for the KR of N-phthaloyl-(S)-leucyl chloride. The
reasons for the stereodifferentiation in the KR of racemic tetrahydroquinaldines containing
groups of different electronic properties by acyl chlorides of three different chiral acids were
explained using the DFT method. The conditions for stabilizing — interactions of aromatic
fragments of the reagents, which do not occur in the same form in the transition state and lead
to the minor diastereoisomeric product, are created in the transition state of the faster acylation
reaction with (S)-naproxen and (R)-O-phenyllactic acyl chlorides. In the case of the KR of
2-methyl-1,2,3,4-tetrahydroquinoline and 2-methyl-6-methoxy-1,2,3,4-tetrahydroquinoline
with N-phthaloyl-(S)-leucyl chloride, the acylation diastereoselectivity is determined, most
likely, by conformational factors. The individual (S)-enantiomer of 2-methyl-6-methoxy-
1,2,3,4-tetrahydroquinoline of high optical purity was synthesized using the KR of the racemate
with (S)-naproxen acyl chloride.
Key words: kinetic resolution, racemic amines, acyl chlorides, acylation, selectivity, transi-
tion state, density functional theory.
Kinetic resolution (KR) of racemates is a chemical
process in which one of the enantiomers forms the prod-
uct more rapidly than another enantiomer under the action
of the chiral non-racemic agent.1 The KR method is among
the efficient modern methods for the synthesis of enan-
tiomerically pure amines and their derivatives. Stereo-
selective acylation under the action of chiral resolving
agents (CRAs) or in the presence of chiral catalysts is
often used for the KR of racemic amines.2—5 If the chiral
center is in the acyl fragment of the CRA, then the KR
products are diastereomerically enriched amides and
enantiomerically enriched unreacted substrate.
In this work, we performed for the first time the com-
parative study of the KR of racemic 6-methoxy- and
6-nitro-2-methyl-1,2,3,4-tetrahydroquinolines (com-
pounds 2 and 3) by representatives of three different groups
of resolving agents: acyl chlorides of (S)-naproxen (4),
N-phthaloyl-(S)-leucine (5), and (R)-О-phenyllactic acid
(6) under the conditions identical to the earlier studied
KR of racemic amine 1.10,13,16
We studied the KR of racemic heterocyclic amines,
including 2-methyl-1,2,3,4-tetrahydroquinoline (1), as
a result of diastereoselective acylation with chiral acyl
chlorides.6—18 The major advantage of this approach is
caused by a broad accessibility of chiral acids and simplic-
ity of the process. We have previously found that the efficient
KR of racemic amines is achieved by using 2-arylpropio-
nyl chlorides,6,8,11,13 N-protected amino acyl chlor-
ides,6,7,9,10,12–15,17 and 2-aryloxy acyl chlorides16,18 as CRAs.
* Dedicated to Academician of the Russian Academy of Sciences
V. N. Charushin on the occasion of his 70th birthday.
X = H (1), MeO (2), NO2 (3)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 890—899, May, 2021.
1066-5285/21/7005-0890 © 2021 Springer Science+Business Media LLC

Acylative kinetic resolution
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
891
Results and Discussion
were isolated by preparative HPLC after the treatment of
the reaction mixture.
As can be seen from the data presented in Table 1, the
stereoselectivity of acylation with (S)-naproxen acyl chlor-
ide (4) in dichloromethane at 20 C increased in the
series 3 (X = NO2) > 1 (X = H) > 2 (X = OMe), and the
selectivity factor s is 23, 15, and 8, respectively. In all
cases, the acylation selectivity increased with decreasing
temperature at a similar regularity. It should be mentioned
that the electron-withdrawing nitro group in position 6 of
amine strongly decreases its nucleophilicity leading to
a low conversion (see Table 1). Similar regularities
were observed for acylation with (R)-phenoxypropionyl
chloride (6): the selectivity factor s in the acylation of
amines 3, 1, and 2 at 20 С was 27, 13, and 8, respectively.
The stereoselectivity of acylation of amines 1 and 2
with N-phthaloyl-(S)-leucyl chloride (5) was approxi-
mately the same (s = 13 and 11 at 20 C; s = 19 at –20 C)
(see Table 1) and lower than that in the case of acyl chlor-
ides 4 and 6. It should specially be mentioned that the
acylation of amine 3 containing the electron-withdrawing
nitro group with acyl chloride 5 did not occur: no formation
of amides 12 was observed in the reaction mixture, and un-
reacted racemic amide 3 (ee 0) was isolated quantitatively.
Thus, the stereoselectivity in KR of amines 1—3 with
acyl chlorides 4—6 depends on the nature of the substitu-
ent in position 6 of amine. Therefore, it is of interest to
study the structures of the diastereomeric transition states
by quantum chemical methods.
The kinetic resolution of racemic amines 2 and 3 was
carried out in dichloromethane at an amine—acyl chloride
molar ratio of 2 : 1 at 20 and –20 С for 6 h, and the ini-
tial concentration of racemic amine was 0.1 mol L–1
(Scheme 1).
Scheme 1
X = H (1, 7, 10, 13), OMe (2, 8, 11, 14), NO2 (3, 9, 12, 15)
R =
(4, 7—9),
(5, 10—12),
There were earlier attempts to explain reasons for the
stereoselectivity in the acylative KR of racemic amines.20
However, it has only recently been found on the basis of
the calculations in terms of the density functional theory
(DFT) that the acylation of heterocyclic amines with
chiral acyl chlorides proceeds via the SN2-like concerted
mechanism; i.e., the nucleophile is added simultaneously
with the elimination of the HCl molecule via the four-
center transition state.21 It was shown for the KR of race-
mic benzoxazines with acyl chlorides of 2-aryloxy acids
that aromatic interactions between the reactants played
a significant role in stereodifferentiation and determined
a high selectivity of the process. In this work, the geo-
metries of the diastereomeric transition states (TSs) and
the corresponding free Gibbs energies for the reactions of
amines 1—3 with acyl chlorides 4—6 were determined
using the DFT method at the CPCMC-CH2Cl2-B3LYP-
D3-gCP/def2-TZVP//B3LYP-D3-gCP/def2-SVP level
of theory, which (as shown previously) described well the
quantitative dependence of the acylation selectivity on the
reactant structure.21,22
(6, 13—15)
Reagents and conditions: 4—6 (0.5 equiv.), CH2Cl2, 6 h, 20 С
(–20 С).
The diastereomeric excess (de, %) of the amides formed
in the reaction mixture was determined by reversed-phase
HPLC (RP-HPLC), and the enantiomeric excess (ee, %)
of unreacted amines 2 and 3 was determined by HPLC on
a Chiralcel OD-H chiral stationary phase. When com-
paring the retention times of unreacted amines on the
HPLC chromatograms with the published data,12,19 it has
been found that the (R)-enantiomer prevails in unreacted
amines in all cases and, hence, the (S)-enantiomers more
rapidly enter into acylation with all studied acyl chlorides
(see Scheme 1). In each case, based on the experimentally
determined de values of amides and ee values of unreacted
amines (R)-2 and (R)-3, we calculated the conversion (C)
and selectivity factor (s), being the ratio of the rate constants
of the fast and slow reacting enantiomers: s = kfast/kslow
The stereochemical results of the KR of amines 2, 3, and
1 (for comparison) are given in Table 1. Individual (S,S)-
and (S,R)-diastereomers of amides 8, 9, 11, 14, and 15
The structures of the diastereomeric TSs in the reaction
of amine 1 with acyl chloride 4 are shown in Fig. 1. The
four-center TS is schematically shown in Fig. 1, а. For
the reactions of acyl chlorides with amines, the formed
C—N bond and cleaved C—Cl bond are orthogonal
1
.

Chulakov et al.
892
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
Table 1. Results of the KR of amines 1—3 with acyl chlorides 4—6 in dichloromethanea
Amine
X
Acyl chloride
T/С
Amide
deb
(R)-amine eec
Cd
se
%
1
2
3
1
2
3
1
2
3
1
2
1
2
3
2
3
H
4
4
4
4
4
4
5
5
5
5
5
6
6
6
6
6
20
20
(S,S)-7
(S,S)-8
77.0
62.9
89.1
72.8
68.7
94.0
76.0
74.0
—
80.2
83.2
74.0
62.9
88.1
71.2
93.3
66.0
62.3
28.0
61.6
63.7
2.9
60.4
54.3
0
64.7
55.0
66.7
62.3
52.3
65.2
19.4
46
50
24
46
49
13
44
42
—
44
40
47
50
37
48
17
1513
18
OMe
NO2
H
20
(S,S)-9
23
–20
–20
–20
20
20
20
–20
–20
20
20
20
(S,S)-7
1213
11
OMe
NO2
H
OMe
NO2
H
OMe
H
OMe
NO2
OMe
NO2
(S,S)-8
(S,S)-9
33
(S,S)-10
(S,S)-11
(S,S)-12
(S,S)-10
(S,S)-11
(S,R)-13
(S,R)-14
(S,R)-15
(S,R)-14
(S,R)-15
1310
11
—
1910
19
1316
18
27
–20
–20
12
35
a The average values of two to four parallel experiments are presented.
b According to RP-HPLC (see Experimental).
c According to HPCL on Chiralcel OD-H (see Experimental).
d Conversion, C = [eeamine/(eeamine + deamide)]•100%.1
e Selectivity factor, s = ln[(1 – C)(1 – eeamine)]/ln[(1 – C)(1 + eeamine)].1
(the N—C—Cl angle is 85.4—91.9). The O=C—Cl and
N—C=O angles lie in a range of 105.5—114.5, which
corresponds to the Bürgi—Dunitz trajectory typical of the
nucleophilic addition to the carbonyl group.23 The distance
between the Cl atom and H atom of amine ranges from
2.2 to 2.5 Å, which is consistent with the assumption about
the Coulomb interactions between them.
In the acylation of amines 1—3 with acyl chloride 4,
aromatic interactions of the corresponding fragments of
the reactants by the –-stacking type with a non-strictly
parallel arrangement of the aromatic rings (see Fig. 1, а)
occur in all cases of the TSs of the reactions leading to the
predominant (S,S)-diastereomer ((S,S)-TS). In the en-
ergetically unfavorable (R,S)-TS, the 6-methoxynaphthyl
group of acyl chloride 4 passes from a gauche-conform-
ation to trans-conformation with respect to the nitrogen
atom due to the van der Waals and Coulomb repulsion
interactions with the benzene ring of amine. As a result,
dispersion interactions of the aromatic fragments of the
reactants in the (R,S)-TS become impossible (see Fig. 1, b).
A lower energy of the (S,R)-TSs compared to that of
(R,R)-TSs in the reactions of amines 1—3 with acyl chlor-
ide 6 is also determined by stacking stabilizing interactions,
which do not occur for steric reasons in the energetically
b
a
Fig. 1. Geometry of the diastereomeric TSs in the reaction of amine 1 with acyl chloride 4 in dichloromethane: TS leading to pre-
dominant amide (S,S)-7 (a) and TS leading to minor amide (R,S)-7 (b). The four-centered TS is designated by dash lines.

Acylative kinetic resolution
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
a
893
b
Fig. 2. Geometries of energetically more favorable (S,S)-TS (a) and less favorable (R,S)-TS (b) in the reaction of amine 1 with
acyl chloride 5.
unfavorable (R,R)-TS because of strongly approached
benzene rings, which results in the Coulomb and van der
Waals repulsion interactions, and synclinal position of the
Cl atom and phenoxy group.
energy of the TS and reagent complex (RC), are presented
in Table 2. The RC structure was determined from the
geometry of the TS by the optimization with the fixation
of the Cl–C(O) bond length equal to that in the molecule
of the corresponding initial acyl chloride. The geometries
of the reactant complexes according to the presence or
absence of aromatic interactions predominantly corre-
sponded to the TS structure.
The free Gibbs activation energies (see Table 2) cor-
responds, on the whole, to the experimental values deter-
mined from the selectivity factor s and, in the case of
acylation with acyl chlorides 4 and 6, depend on the
substituent in position 6 of tetrahydroquinaldine. It has
been shown that the (S,S)-TSs are preferable compared
to the (R,S)-TSs, and (S,S)-amides are predominantly
For the acylation of amines 1 and 2 with acyl chloride 5,
the conformation relative to the bond between the carbonyl
carbon atom and chiral carbon atom of the acylating agent
in the TSs required an additional analysis. It was found by
the conformational search for the TS that in the ener-
getically favorable (S,S)-TS the N-phthaloyl group existed
in the trans-conformation to the nitrogen atom of amine
(Fig. 2, a), whereas the isobutyl group occupies this posi-
tion in the energetically less favorable (R,S)-TS (Fig. 2, b).
The values of the free activation energies of the TSs,
which were calculated as the difference between the Gibbs
Table 2. Calculated difference in the activation Gibbs energies (ΔΔG#) of the competitive TSs and the factor s at the
CPCMC-CH2Cl2-B3LYP-D3-gCP/def2-TZVP//B3LYP-D3-gCP/def2-SVP level of theory compared to the experi-
mental factor s values and the ΔΔG# values calculated on the basis of factor s
Amine
Acyl
Predominant
T/K
Calculation
Experiment
chloride
amide diastereomer
ΔΔG#/ kJ mol–1
scalc
ΔΔG# b/kJ mol–1
sexp
a
1
2
3
1
2
4
4
4
4
4
4
5
5
5
5
6
6
6
6
6
(S,S)-7
(S,S)-7
293
253
293
253
293
253
293
253
293
253
293
293
253
293
253
6.63
6.65
5.49
5.99
8.07
7.14
6.09
5.40
5.92
6.60
6.09
5.57
5.83
7.94
8.32
15
23.6
9.5
17.3
24.5
29.8
12.2
13.1
11.4
23
6.59
5.23
5.07
5.04
7.64
7.35
6.25
6.19
5.84
6.19
6.25
5.07
5.23
8.03
7.48
1513
1213
18
(S,S)-8
(S,S)-8
11
(S,S)-9
23
(S,S)-9
33
(S,S)-10
(S,S)-10
(S,S)-11
(S,S)-11
(S,R)-13
(S,R)-14
(S,R)-14
(S,R)-15
(S,R)-15
1310
1910
11
19
1
2
12.2
9.8
1316
18
16
12
3
26
27
52
35
#
/(RT)
a scalc = e–ΔΔG
.
b ΔΔG# = –RTlns.

Chulakov et al.
894
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
formed, as in experiment, in the reactions of amines 1—3
with acyl chlorides 4 and 5. In the reactions of amines
1—3 with acyl chloride 6, the (S,R)-TSs are energetically
preferable compared to the (R,R)-TSs.
The DFT calculations also showed that the reactions
of acyl chloride 5 with amines 1 and 2 involved no explicit
interactions between the aromatic fragments of the reac-
tants according to the —-stacking type. The N-phthaloyl
group is located in the trans-conformation to the nitrogen
atom of amine in the (S,S)-TS leading to the predominant
diastereomer, whereas it is the isobutyl group in the
(R,S)-TS (see Fig. 2). Stereoselectivity is caused by the
difference in steric hindrances that are created by this group.
It is most likely that the conformational factors (rather than
those associated with nonvalent interactions of aromatic
fragments) cause the situation that the selectivity factor
values s are nearly the same for amines 1 and 2 in experi-
ment and calculation (see Table 2) and are independent
of the electronic effect of substituent X (see Scheme 1).
It has been found that the KR of amine 2 with acyl
chlorides 4 and 6 is characterized by close values of selectiv-
ity factor, but acyl chloride 4 is somewhat more accessible
in large amounts. In addition, the possibility of separating
a mixture of the formed (S,S)- and (R,S)-diasteremeric
amides by recrystallization is an important advantage of
(S)-naproxen acyl chloride (4) compared to other acyl
chlorides studied. Therefore, acyl chloride 4 was chosen
as the resolving agent for the preparative isolation of
(S)-2-methyl-6-methoxy-1,2,3,4-tetrahydroquinoline
((S)-2). Acylation was carried out in dichloromethane at
–20 С (Scheme 2). Amide (S,S)-8 (de 68%) was isolated
in a yield of 85% (relative to acyl chloride 4). The single
recrystallization from a hexane–PriOH mixture made
According to the calculated Gibbs activation energies
ΔG#, 6-methoxytetrahydroquinaldine (2) is the most
nucleophilic amine in the studied series. The acylation
stereoselectivity of amines 1—3 with acyl chlorides 4 and
6 increased in the series 2 ≤ 1 < 3 in both experiment and
calculation, which is consistent with the concept about an
increase in steric hindrances with decreasing N—CO bond
length as the nucleophilicity of amine decreases.20 The
lower the nucleophilicity of amine, the closer its approach
to the reaction center needed for TS formation and the
stronger repulsive interactions of amine with the atoms
lying near the reaction center.
The calculations show that the N—CO bond in the TS
in the case of amine 3 is shorter than those for amines 1
and 2 and the van der Waals repulsions of the fragments
and aromatic systems close to the reaction center in the
TSs leading to the minor diastereomer are maximal. In
addition, it has previously been found that the stabilizing
energy of stacking interactions of the nitrosubstituted
aromatic compounds is higher than that of the unsubsti-
tuted ones24 due to a lower Coulomb repulsion of the
π-systems when the electron density is shifted toward the
nitro group, which can be observed in our case as well in
the energetically favorable TS with 6-nitrosubstituted
amine 3 as compared to tetrahydroquinaldines 1 and 2.
Scheme 2
Reagents and conditions: i. 4 (0.5 equiv.), CH2Cl2, –20 C, 6 h; ii. hexane—PriOH, recrystallization; iii. HCl—AcOH, 92—95 C.

Acylative kinetic resolution
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
895
signal (C 39.5) for 13C. The full assignment of 1H and 13C signals
was performed using 2D 1H—13C HSQC and HMBC experi-
ments. The 1D and 2D NMR experiments for amides (S,S)-8
and (R,S)-8 were carried out at 120 C, and those for other
compounds were conducted at room temperature.
it possible to obtain diastereomerically pure (S,S)-8
(de >99%) in an overall yield of 53% (see Scheme 2). The
unreacted (R)-enantiomer of amine 2 (ее 62%) was iso-
lated in a yield of 48%.
The standard procedure of acidic hydrolysis (under
reflux in a mixture of concentrated HCl and AcOH) of
diastereomerically pure amide (S,S)-8 resulted in the
(S)-enantiomer of amine 2 (ee > 99%) in a yield of 85%
(see Scheme 2). The total yield of amine (S)-2 (based on
the starting racemate) was 23%. The acidic hydrolysis of
amide (S,S)-8 was not accompanied by the racemization
of the chiral center in the amine residue and led to enan-
tiomerically pure amine.
Melting points were determined on a Stuart SMP3 instrument
(Barloworld Scientific, Great Britain). Elemental analysis was
carried out on a CHNS/O Perkin—Elmer 2400 II automated
analyzer. Optical rotations were measured on a Perkin—Elmer
M341 polarimeter (Perkin—Elmer Instruments, USA). Specific
rotation is expressed in (deg mL) (g dm)–1, and the solution
concentration is given in g (100 mL)–1
.
Diastereomeric excess of amides 8, 9, 11, 14, and 15 was
determined on an Agilent 1100 chromatograph (Phenomenex
Luna C18(2) column, 250×4.6 mm, elution rate 0.8 mL min–1
detection at 230 nm, eluent MeCN—H2O).
,
It should be mentioned that the methods for synthesis
of (S)-enantiomer of amine 2 described in the literature
and based on catalytic hydrogenation in the presence of
the chiral catalysts make it possible to obtain the target
product with ee 78—81%.18,25
Enantiomeric excess of amines 2 and 3 was determined on
a Knauer Smartline-1100 chromatograph (Chiralcel OD-H
column, 2504.6 mm, elution rate 1 mL min–1, detection at
220 nm, hexane—PriOH (40 : 1) eluent for 2 ((R) 10.1 min,
(S) 12.2 min); hexane—PriOH—MeOH (95 : 4 : 1) for 3
((R) 20.5 min, (S) 22.8 min)).
Thus, we comparatively studied the kinetic resolution
of racemic amines 1—3 with acyl chlorides of (S)-na-
proxen, N-phthaloyl-(S)-leucine, and (R)-О-phenyllactic
acid. The selectivity factors in the KR of racemic amines
1—3 with acyl chlorides 4 and 6 were shown to be ap-
proximately the same and higher than those for acyl
chloride 5. The reasons for stereodifferentiation in the KR
of racemic amines 1—3 containing the groups different in
electronic properties with acyl chlorides of three different
chiral acids were explained using the DFT method at the
CPCMC-CH2Cl2-B3LYP-D3-gCP/def2-TZVP//B3LYP-
D3-gCP/def2-SVP level of theory. The competitive ac-
ylation reactions proceed via the concerted mechanism.
The conditions for the stabilizing π—π-interactions of the
reactants are created in the transition state of the faster
acylation reactions involving acyl chlorides 4 and 6, while
they are not created in the same form for steric reasons in
the transition state leading to the minor diastereoisomer
of the product. In the case of the KR of amines 1 and 2
with acyl chloride 5, the acylation diastereoselectivity is
determined, most likely, by conformational factors. The
individual (S)-enantiomer of amine 2 of high optical
purity was obtained using the KR of the racemate with
(S)-naproxen acyl chloride.
Preparative resolution of diastereomeric amides 8, 9, 11, 14,
and 15 was conducted on a Shimadzu LC-20 Prominence chrom-
atograph (Phenomenex Luna C18(2) column, 250×21.6 mm,
detection at 254 nm, eluent flow rate 10 mL min–1; MeCN—H2O
(70 : 30) eluent for 8, 9, and 11 and MeCN—H2O (65 : 35) eluent
for 14 and 15). The volume of the injected sample was 1 mL.
Kinetic resolution of amine 2 with acyl chlorides 4—6 (gen-
eral procedure). A solution of acyl chloride 4 (5 or 6) (0.28 mmol)
in CH2Cl2 (2.8 mL) was added as one portion at a specified
temperature to a solution of amine 2 (100.0 mg, 0.56 mmol) in
CH2Cl2 (2.8 mL). The reaction mixture was kept at a specified
temperature for 6 h and subsequently washed with 1 М HCl
(2×5 mL) (acidic washing solutions were collected separately),
a saturated solution of NaCl (3×5 mL), a 5% solution of NaHCO3
(10 mL), and water (2×5 mL). The organic layer was dried over
MgSO4 and evaporated to dryness. The obtained mixture of
diastereomers of the corresponding amide was analyzed by HPLC
(Phenomenex Luna C18(2)). The acidic water layer was neutral-
ized by Na2CO3 and extracted with CHCl3 (2×3 mL), and the
organic layer was washed with water (2×3 mL), dried with
MgSO4, and evaporated to dryness. The obtained unreacted
amine was analyzed by chiral HPLC (Chiralcel OD-H).
Kinetic resolution of amine 3 with acyl chlorides 4—6 (gen-
eral procedure). A solution of acyl chloride 4 (5 or 6) (0.26 mmol)
in CH2Cl2 (2.6 mL) was added as one portion at a specified
temperature to a solution of amine 3 (100.0 mg, 0.52 mmol) in
CH2Cl2 (2.6 mL). The reaction mixture was kept at a specified
temperature for 6 h and consequently washed with a 3% solution
of NH4OH (2×5 mL) (to neutralize unreacted acyl chloride),
a saturated solution of NaCl (3×5 mL), and water (2×5 mL).
The organic layer was dried over MgSO4 and evaporated to dry-
ness. The diastereomeric composition of amides was determined
in a mixture with unreacted amine by HPLC (Phenomenex Luna
C18(2)). Unreacted amine was isolated from the mixture by flash
chromatography on silica gel (benzene—ethyl acetate (9 : 1)
eluent), and the enantiomeric composition was determined by
chiral HPLC (Chiralcel OD-H).
Experimental
Racemic 2-methyl-6-methoxy-1,2,3,4-tetrahydroquinoline
(2)26 and 2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline (3)27
were synthesized by the earlier described methods. (S)-2-(6-
Methoxynaphth-2-yl)propionyl (4),13 N-phthaloyl-(S)-leucyl
(5),10 and (R)-2-phenoxypropionyl (6)16 chlorides were synthe-
sized using known procedures. Other reagents were commer-
cially available. The solvents were purified by standard methods.
1H and 13C NMR spectra were recorded on a Bruker
AVANCE-500 spectrometer (500 and 126 MHz, respectively) in
a solution of DMSO-d6. Chemical shifts were measured relative
to SiMe4 as the internal standard for 1H and relative to the solvent
Preparative resolution of diastereomers of amides 8, 9, 11, 14,
and 15 (general procedure). After KR, a weighed sample (300 mg)
of each mixture of diastereomers 8, 9, 11, 14, and 15 (de 63—89%)

Chulakov et al.
896
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
was dissolved in MeCN (10 mL). The obtained solutions were
injected by portions into a preparative chromatograph (the volume
of the injected sample was 1 mL). The fractions with individual
diastereomers were combined, evaporated, and dried to obtain
individual diastereomers in 90—95% yield (based on their content
in the mixture).
J = 6.7 Hz); 4.63 (sextet, 1 H, C(2)H, J = 6.6 Hz); 7.06 (br.s,
1 H, C(3ʺ)H); 7.09 (dd, 1 H, C(7ʺ)H, J = 8.9 Hz, J = 2.4 Hz);
7.22 (d, 1 H, C(5ʺ)H, J = 2.4 Hz); 7.30 (br.s, 1 H, C(1ʺ)H);
7.62—7.65 (m, 2 H, C(4ʺ)H, C(8ʺ)H); 7.82 (d, 1 H, C(8)H,
J = 8.8 Hz); 7.87 (d, 1 H, C(5)H, J = 2.5 Hz); 8.11 (dd, 1 H,
C(7)H, J = 8.8 Hz, J = 2.5 Hz). 13C NMR, : 19.34 (br.s,
C(2)Me); 19.56 (C(3´)); 24.03 (C(4)); 30.44 (br.s, C(3)); 42.80
(C(2´)); 48.95 (C(2)); 55.07 (OMe); 105.62 (C(5ʺ)); 118.65
(C(7ʺ)); 121.50 (C(7)); 122.66 (C(5)); 125.39 (C(1ʺ)); 125.65
(C(3ʺ)); 126.89 (C(4ʺ)); 126.97 (C(8)); 128.26 (C(8ʺa)); 128.86
(C(8ʺ)); 132.92 (C(4ʺa)); 135.22 (br.s, C(4a)); 136.25 (C(2ʺ));
143.50 (C(8a)); 143.78 (C(6)); 157.03 (C(6ʺ)); 173.30 (C(1´)).
Found (%): С, 71.17; Н, 5.81; N, 6.96. C24H24N2O4. Calculat-
ed (%): С, 71.27; Н, 5.98; N, 6.93.
(2S,2´S)-2-Methyl-6-methoxy-N-[2´-(6ʺ-methoxynaphth-
2ʺ-yl)propionyl]-1,2,3,4-tetrahydroquinoline [(S,S)-8]. The yield
was 219.9 mg (90%), colorless crystals, m.p. 143—144 С.
20
[]D –16.7 (с 1.0, CHCl3). HPLC (MeCN—H2O, 70 : 30):
τ 14.0 min; de 99.2%. 1H NMR, : 0.92 (d, 3 H, C(2)Me,
J = 6.5 Hz); 1.10—1.15 (m, 1 H, C(3)HB); 1.46 (d, 3 H, C(2´)Me,
J = 6.8 Hz); 1.70—1.78 (m, 1 H, C(4)HB); 2.07—2.13 (m, 1 H,
C(3)HA); 2.24 (dt, 1 H, C(4)HA, J = 14.8 Hz, J = 4.9 Hz); 3.74
(s, 3 H, C(6)OMe); 3.84 (s, 3 H, C(6ʺ)OMe); 4.37 (q, 1 H,
С(2´)H, J = 6.8 Hz); 4.66 (sextet, 1 H, C(2)H, J = 6.7 Hz); 6.56
(d, 1 H, C(5)H, J = 2.6 Hz); 6.84 (dd, 1 H, C(7)H, J = 8.6 Hz,
J = 2.7 Hz); 6.99 (br.d, 1 H, C(3ʺ)H, J = 8.2 Hz); 7.07 (dd,
1 H, C(7ʺ)H, J = 8.9 Hz, J = 1.5 Hz); 7.13–7.19 (m, 2 H, C(1ʺ)H,
C(5ʺ)H); 7.25 (d, 1 H, C(8)H, J = 8.6 Hz); 7.54−7.56 (m, 2 H,
C(8ʺ)H, C(4ʺ)H). 13C NMR, : 18.24 (C(3´)); 19.29 (C(2)Me);
24.50 (C(4)); 31.23 (C(3)); 41.43 (C(2´)); 47.24 (C(2)); 54.67
(C(6)OMe); 54.86 (C(6´)OMe); 105.90 (C(5ʺ)); 111.40 (C(7));
112.14 (C(5)); 117.52 (C(7ʺ)); 124.54 (C(1ʺ)); 125.10 (C(3ʺ));
125.76 (C(4ʺ)); 126.48 (C(8)); 127.88 (C(8ʺa)); 128.14 (C(8ʺ));
129.77 (C(8a)); 132.44 (C(4ʺa)); 136.26 (C(2ʺ)); 136.46 (br.s,
C(4a)); 156.63 (C(6ʺ)); 156.82 (C(6)); 172.15 (C(1´)). Found (%):
С, 77.02; Н, 6.87; N, 3.49. C25H27NO3. Calculated (%): С, 77.09;
Н, 6.99; N, 3.60.
(2R,2´S)-2-Methyl-N-[2´-(6ʺ-methoxynaphth-2ʺ-yl)prop-
ionyl]-6-nitro-1,2,3,4-tetrahydroquinoline [(R,S)-9]. The yield
was 15.5 mg (95%), light yellow oil. []D20 –389.4 (с 1.0, CHCl3).
HPLC (MeCN—H2O, 70 : 30): τ 18.1 min; de > 99.9%.
1H NMR, : 1.09 (d, 3 H, C(2)Me, J = 6.6 Hz); 1.33—1.41 (m,
1 H, C(3)HB); 1.44 (d, 3 H, C(2´)Me, J = 6.6 Hz); 1.64 (br.s,
1 H, C(3)HA); 2.61 (dt, 1 H, C(4)HB, J = 16.5 Hz, J = 6.1 Hz);
2.80 (ddd, 1 H, C(4)HA, J = 16.5 Hz, J = 9.1 Hz, J = 6.8 Hz);
3.88 (s, 3 H, C(6ʺ)OMe); 4.29 (q, 1 H, C(2´)H, J = 6.6 Hz);
4.67 (sextet, 1 H, C(2)H, J = 6.2 Hz); 7.16 (dd, 1 H, C(7ʺ)H,
J = 8.9 Hz, J = 2.6 Hz); 7.31 (d, 1 H, C(5ʺ)H, J = 2.6 Hz); 7.48
(dd, 1 H, C(3ʺ)H, J = 8.4 Hz, J = 1.8 Hz); 7.68 (br.s, 1 H,
C(8)H); 7.77 (br.d, 1 H, C(1ʺ)H, J = 1.5 Hz); 7.82 (d, 1 H,
C(8ʺ)H, J = 8.4 Hz); 7.83 (d, 1 H, C(4ʺ)H, J = 8.4 Hz); 8.05
(dd, 1 H, C(7)H, J = 9.0 Hz, J = 2.7 Hz); 8.10 (d, 1 H, C(5)H,
J = 2.7 Hz). 13C NMR, : 18.70 (C(2)Me); 21.74 (C(3´)); 23.47
(C(4)); 28.69 (br.s, C(3)); 43.21 (C(2´)); 48.26 (C(2)); 55.14
(OMe); 105.74 (C(5ʺ)); 118.77 (C(7ʺ)); 121.02 (C(7)); 123.59
(C(5)); 125.11 (C(1ʺ)); 126.04 (C(3ʺ)); 126.29 (C(8)); 127.42
(C(4ʺ)); 128.52 (C(8ʺa)); 129.19 (C(8ʺ)); 132.98 (br.s, C(4a));
133.18 (C(4ʺa)); 136.51 (C(2ʺ)); 142.83 (C(8a)); 143.35 (C(6));
157.20 (C(6ʺ)); 172.74 (C(1´)). Found (%): С, 71.16; Н, 6.08;
N, 7.04. C24H24N2O4. Calculated (%): С, 71.27; Н, 5.98; N, 6.93.
(2S,2´S)-2-Methyl-6-methoxy-N-[N-phthaloyl-(S)-leucyl]-
1,2,3,4-tetrahydroquinoline [(S,S)-11]. The yield was 245.3 mg
(2R,2´S)-2-Methyl-6-methoxy-N-[2´-(6ʺ-methoxynaphth-
2ʺ-yl)propionyl]-1,2,3,4-tetrahydroquinoline [(R,S)-8]. The yield
was 52.9 mg (95%), light yellow oil. []D20 –322 (с 1.0, CHCl3).
HPLC (MeCN—H2O, 70 : 30): τ 17.4 min; de > 99.9%. 1H NMR,
δ: 1.04 (d, 3 H, C(2)Me, J = 6.6 Hz); 1.25—1.30 (m, 1 H,
C(3)HB); 1.38 (d, 3 H, C(2´)Me, J = 6.8 Hz); 2.11—2.18 (m, 1 H,
C(3)HA); 2.45 (ddd, 1 H, C(4)HB, J = 15.2 Hz, J = 9.4 Hz,
J = 5.9 Hz); 2.62 (dt, 1 H, C(4)HA, J = 15.2 Hz, J = 5.5 Hz);
3.79 (s, 3 H, C(6)OMe); 3.91 (s, 3 H, C(6ʺ)OMe); 4.15 (q, 1 H,
C(2´)H, J = 6.8 Hz); 4.81 (sextet, 1 H, C(2)H, J = 6.6 Hz); 6.73
(dd, 1 H, C(7)H, J = 8.7 Hz, J = 2.4 Hz); 6.82 (d, 1 H, C(5)H,
J = 2.4 Hz); 7.02 (d, 1 H, C(8)H, J = 8.7 Hz); 7.18 (dd, 1 H,
C(7ʺ)H, J = 8.9 Hz, J = 2.1 Hz); 7.30 (br.d, 1 H, C(5ʺ)H,
J = 2.0 Hz); 7.49 (dd, 1 H, C(3ʺ)H, J = 8.3 Hz, J = 1.4 Hz);
7.76—7.80 (m, 3 H, C(4ʺ)H, C(8ʺ)H, C(1ʺ)H). 13C NMR, :
19.14 (С(2)Me); 20.41 (C(3´)); 24.66 (C(4)); 30.88 (C(3)); 41.80
(C(2´)); 47.03 (C(2)); 54.74 (C(6´)OMe); 54.79 (C(6)OMe);
106.03 (C(5ʺ)); 111.04 (C(7)); 112.44 (C(5)); 117.69 (C(7ʺ));
124.68 (C(1ʺ)); 125.73 (C(3ʺ)); 126.15 (C(8)); 126.23 (C(4ʺ));
128.17 (C(8ʺa)); 128.40 (C(8ʺ)); 129.61 (C(8a)); 132.60 (C(4ʺa));
135.30 (br.s, C(4a)); 137.14 (C(2ʺ)); 156.61 (C(6)); 156.80
(C(6ʺ)); 171.85 (C(1´)). Found (%): С, 76.98; Н, 6.85; N, 3.85.
C25H27NO3. Calculated (%): С, 77.09; Н, 6.99; N, 3.60.
(2S,2´S)-2-Methyl-N-[2´-(6ʺ-methoxynaphth-2ʺ-yl)prop-
ionyl]-6-nitro-1,2,3,4-tetrahydroquinoline [(S,S)-9]. The yield
was 260.9 mg (92%), light yellow powder, m.p. 118—121 С.
20
(94%), white powder, m.p. 111—115 С. []D +375 (с 1.0,
CHCl3). HPLC (MeCN—H2O, 70 : 30): τ 16.8 min; de > 99.9%.
1H NMR, : 0.32 (br.s, 3 H, C(6´)H); 0.63 (d, 3 H, C(5´)H,
J = 6.3 Hz); 0.70 (br.s, 1 H, C(3´)HB); 0.99 (d, 3 H, C(2)Me,
J = 6.4 Hz); 1.11 (br.s, 1 H, C(3)HB); 1.27 (br.s, 1 H, H(4´));
2.30—2.41 (br.m, 2 H, C(4)HB, C(3)HA); 2.56 (td, 1 H, C(3´)HA,
J = 13.0 Hz, J = 3.0 Hz); 2.65 (dт, 1 H, C(4)HA, J = 14.6 Hz,
J = 4.0 Hz); 3.79 (s, 3 H, C(6)OMe); 4.52 (sextet, 1 H, C(2)H,
J = 7.0 Hz); 5.52 (dd, 1 H, C(2´)H, J = 12.5 Hz, J = 3.1 Hz);
6.94–7.00 (m, 2 H, C(5)H, C(7)H); 7.38 (d, 1 H, C(8)H,
J = 8.4 Hz); 7.88—7.93 (m, 4 H, Phth). 13C NMR, : 19.96
(C(6´)); 20.53 (br.s, C(2)Me); 22.81 (C(5´)); 24.51 (C(4´));
26.34 (br.s, C(4)); 32.75 (br.s, C(3)); 33.84 (br.s, C(3´)); 49.39
(C(2)); 51.83 (C(2´)); 55.39 (OMe); 112.08 (C(7)); 112.96
(C(5)); 123.18 (C(4ʺ), C(7ʺ)); 126.03 (C(8)); 128.88 (C(4a));
131.20 (C(3ʺa), C(7ʺa)); 134.75 (C(5ʺ), C(6ʺ)); 138.60 (br.s,
C(8a)); 157.77 (C(1ʺ), C(3ʺ)); 168.45 (C(1´)). Found (%):
С, 71.51; Н, 6.76; N, 6.40. C25H28N2O4. Calculated (%):
С, 71.41; Н, 6.71; N, 6.66.
20
[]D +149.8 (с 1.0, CHCl3). HPLC (MeCN–H2O, 70 : 30):
τ 14.2 min; de > 99.9%. 1H NMR, : 0.82 (br.s, 3 H, C(2)Me);
1.30 (br.s, 1 H, C(3)HB); 1.44 (d, 3 H, C(2´)Me, J = 6.7 Hz);
1.98 (br.s, 1 H, C(4)HB); 2.13 (qd, 1 H, C(3)HA, J = 13.0 Hz,
J = 6.5 Hz); 2.51—2.57 (m, 1 H, C(4)HA, overlapped with signal
from DMSO); 3.84 (s, 3 H, C(6ʺ)OMe); 4.48 (q, 1 H, C(2´)H,
(2R,2´S)-2-Methyl-6-methoxy-N-[N-phthaloyl-(S)-leucyl]-
1,2,3,4-tetrahydroquinoline [(R,S)-11]. The yield was 36.7 mg
20
(94%), light yellow oil. []D –172 (с 1.0, CHCl3). HPLC

Acylative kinetic resolution
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
897
(MeCN—H2O, 70 : 30): τ 11.7 min; de > 99.9%. 1H NMR, :
0.84 (d, 3 H, C(6´)H, J = 6.5 Hz); 0.91 (br.s, 1 H, C(3)HB);
0.94 (d, 3 H, C(5´)H, J = 6.5 Hz); 0.99 (br.s, 3 H, C(2)Me);
1.36 (br.s, 1 H, C(4´)H); 1.78 (br.s, 1 H, C(3´)HB); 1.95—2.09
(br.m, 2 H, C(4)HB, C(3´)HA); 2.15—2.26 (br.m, 2 H, C(3)HA,
C(4)HA); 3.50 (s, 3 H, C(6)OMe); 4.48 (br.s, 1 H, C(2)H); 5.20
(dd, 1 H, C(2´)H, J = 10.0 Hz, J = 4.3 Hz); 6.18 (br.s, 1 H,
C(5)H); 6.57 (br.d, 1 H, C(7)H, J = 8.4 Hz); 7.20 (d, 1 H, C(8)H,
J = 8.4 Hz); 7.60—7.78 (m, 4 H, Phth). 13C NMR, : 20.61 (br.s,
C(2)Me); 21.66 (C(5´)); 23.42 (C(6´)); 24.02 (C(4´)); 25.62
(br.s, C(4)); 32.32 (br.s, C(3)); 38.91 (br.s, C(3´) (overlapped
with DMSO); 49.40 (C(2´)); 49.61 (br.s, C(2)); 55.04 (OMe);
11.78 (C(5)); 112.80 (C(7)); 122.54 (C(4ʺ), C(7ʺ)); 125.41 (br.s,
C(8)); 129.16 (C(4a)); 130.63 (C(3ʺa), C(7ʺa)); 134.33 (C(5ʺ),
C(6ʺ)); 136.69 (br.s, C(8a)); 156.68 (br.s, C(6)); 166.32 (C(1ʺ),
C(3ʺ)); 164.43 (C(1´)). Found (%): С, 71.48; Н, 6.73; N, 6.44.
C25H28N2O4. Calculated (%): С, 71.41; Н, 6.71; N, 6.66.
(2S,2´R)-2-Methyl-6-methoxy-N-(2´-phenoxypropionyl)-
1,2,3,4-tetrahydroquinoline [(S,R)-14]. The yield was 224.8 mg
J = 8.6 Hz); 8.10 (br.s, 1 H, C(5)H). 13C NMR, : 17.25 (C(3´));
19.05 (C(2)Me); 23.87 (C(4)); 29.54 (C(3)); 48.70 (C(2)); 70.65
(C(2´)); 114.59 (2×C(2ʺ)); 121.12 (C(4ʺ)); 121.48 (C(7)); 123.32
(C(5)); 125.78 (C(8)); 129.34 (2×C(3ʺ)); 134.19 (br.s, C(4a));
142.42 (C(8a)); 143.76 (C(6)); 156.61 (C(1ʺ)); 169.97 (C(1´)).
Found (%): С, 67.15; Н, 5.99; N, 8.40. C19H20N2O4. Calculat-
ed (%): С, 67.05; Н, 5.92; N, 8.23.
(2R,2´R)-2-Methyl-6-nitro-N-(2´-phenoxypropionyl)-1,2,3,4-
tetrahydroquinoline [(R,R)-15]. The yield was 19.6 mg (94%),
20
light yellow oil. []D –421 (с 1.0, CHCl3). HPLC (MeCN—
H2O, 65 : 35): τ 13.0 min; de > 99.9%. 1H NMR, : 1.05
(d, 3 H, C(2)Me, J = 6.6 Hz); 1.45 (d, 3 H, C(2´)Me, J = 6.5 Hz);
1.54—1.66 (m, 1 H, C(3)HB); 2.13—2.23 (m, 1 H, C(3)HA);
2.66 (dt, 1 H, C(4)HB, J1 = 16.4 Hz, J2 = 6.3 Hz); 2.87 (ddd,
1 H, C(4)HA, J = 16.4 Hz, J = 8.4 Hz, J = 6.8 Hz); 4.73 (sextet,
1 H, C(2)H, J = 6.2 Hz); 5.38 (q, 1 H, C(2´)H, J = 6.5 Hz);
6.88 (dd, 2 H, C(2ʺ)H, J = 8.7 Hz, J = 1.1 Hz); 6.96 (t, 1 H,
C(4ʺ)H, J = 7.4 Hz); 7.30 (dd, 2 H, C(3ʺ)H, J = 8.7 Hz,
J = 7.4 Hz); 7.66 (d, 1 H, C(8)H, J = 8.9 Hz); 8.01 (dd, 1 H,
C(7)H, J = 8.9 Hz, J = 2.8 Hz); 8.12 (d, 1 H, C(5)H, J = 2.8 Hz).
13C NMR, : 17.68 (C(3´)); 18.59 (C(2)Me); 23.47 (C(4)); 29.29
(C(3)); 48.57 (C(2)); 71.69 (C(2´)); 114.96 (2×C(2ʺ)); 121.19
(C(4ʺ)); 121.20 (C(7)); 123.60 (C(5)); 126.26 (C(8)); 129.60
(2×C(3ʺ)); 133.69 (br.s, C(4a)); 142.19 (C(8a)); 143.82 (C(6));
156.69 (C(1ʺ)); 170.07 (C(1´)). Found (%): С, 67.21; Н, 6.03;
N, 8.24. C19H20N2O4. Calculated (%): С, 67.05; Н, 5.92; N, 8.23.
(S)-2-Methyl-6-methoxy-1,2,3,4-tetrahydroquinoline [(S)-2].
A solution of acyl chloride 4 (0.35 g, 1.41 mmol) in CH2Cl2
(14 mL) was added to a solution of amine 2 (0.5 g, 2.82 mmol)
in CH2Cl2 (14 mL) under stirring at –20 C. The reaction mix-
ture was stirred at –20 C for 6 h and then consecutively washed
with 1 М HCl (2×15 mL) (acidic washing solutions were collec-
ted separately), a saturated solution of NaCl (3×15 mL), a 5%
solution of NaHCO3 (2×15 mL), and water (2×15 mL). The
organic layer was dried over MgSO4 and evaporated to dryness.
The obtained amide (S,S)-8 (0.47 g, de 68%) was recrystallized
from a hexane—PriOH (20 : 1) mixture (20 mL). Amide (S,S)-8
was obtained as colorless crystals in a yield of 0.294 g (de 99.5%,
overall yield based on acyl chloride was 53%). A weighed sample
of amide (S,S)-8 (0.294 g, 0.75 mmol) was dissolved in glacial
AcOH (5 mL), concentrated HCl (5 mL) was added to the ob-
tained solution, and the resulting mixture was heated at 92—95 C
for 6 h. The reaction mixture was poured to water (100 mL). The
formed precipitate was filtered off. The filtrate was neutralized
by Na2CO3 to pH 8—9. The formed oil was extracted with benz-
ene (3×10 mL). The organic layer was washed with a saturated
solution of NaCl (2×15 mL), dried over MgSO4, and evapo-
rated to dryness. The product was purified by flash chromato-
graphy on silica gel (benzene—ethyl acetate (95 : 5) as eluent).
20
(92%), white crystals, m.p. 71—75 С. []D +184 (с 1.0,
CHCl3). HPLC (MeCN—H2O, 70 : 30): τ 10.6 min; de > 99.9%.
1H NMR, : 1.00 (br.s, 3 H, C(2)Me); 1.06—1.22 (br.m, 1 H,
C(3)HB); 1.59 (br.s, 3 H, C(2´)Me); 2.02—2.38 (br.m, 2 H,
C(4)HB, C(3)HA); 2.54—2.76 (br.m, 1 H, C(4)HA); 3.75 (s, 3 H,
C(6)OMe); 4.61 (br.s, 1 H, C(2)H); 4.92—5.54 (br.m, 1 H,
C(2´)H); 7.30–7.50 (br.m, 8 H, Ar). 13C NMR, : 18.63 (C(3´));
20.06 (C(2)Me); 25.91 (C(4)); 31.92 (C(3)); 47.94 (C(2)); 55.19
(OMe); 69.21 (C(2´)); 111.66 (C(5)); 113.07 (C(7)); 114.59
(2×C(2ʺ)); 120.96 (C(4ʺ)); 126.32 (C(8)); 128.68 (C(4a)); 129.23
(2×C(3ʺ)); 137.69 (C(8a)); 156.88 (C(6)); 157.48 (C(1ʺ)); 169.18
(C(1´)). Found (%): С, 73.68; Н, 7.25; N, 4.36. C20H23NO3.
Calculated (%): С, 73.82; Н, 7.12; N, 4.30.
(2R,2´R)-2-Methyl-6-methoxy-N-(2´-phenoxypropionyl)-
1,2,3,4-tetrahydroquinoline [(R,R)-14]. The yield was 52.3 mg
20
(94%), light yellow oil. []D –308 (с 1.0, CHCl3). HPLC
(MeCN—H2O, 65 : 35): τ 12.0 min; de > 99.9%. 1H NMR, :
1.00 (d, 3 H, C(2)Me, J = 6.4 Hz); 1.11 (br.s, 3 H, C(2´)Me);
1.36—1.86 (br.m, 1 H, C(3)HB); 1.99—2.38 (br.m, 2 H, C(4)HB,
C(3)HA); 2.52—2.85 (br.m, 1 H, C(4)HA); 3.74 (s, 3 H,
C(6)OMe); 4.67 (sextet, 1 H, C(2)H, J = 6.7 Hz); 5.04—5.48
(br.m, 1 H, C(2´)H); 6.73 (dd, 1 H, C(7)H, J = 8.6 Hz,
J = 2.3 Hz); 6.78—6.92 (br.m, 3 H, C(2ʺ)H, C(5)H); 6.95 (t, 1 H,
C(4ʺ)H, J = 7.5 Hz); 7.12—7.25 (br.s, 1 H, C(8)H); 7.30 (dd,
2 H, C(3ʺ)H, J = 8.5 Hz, J = 7.5 Hz). 13C NMR, : 16.84 (C(3´));
20.44 (C(2)Me); 26.13 (C(4)); 32.40 (C(3)); 48.37 (C(2)); 55.17
(OMe); 70.53 (C(2´)); 111.86 (C(7)); 112.75 (C(5)); 115.18 (br.s,
2×C(2ʺ)); 120.90 (C(4ʺ)); 126.20 (C(8)); 128.85 (C(4a)); 129.52
(2×C(3ʺ)); 138.08 (br.s, C(8a)); 156.96 (C(6)); 157.44 (br.s,
C(1ʺ)); 169.09 (C(1´)). Found (%): С, 73.73; Н, 7.17; N, 4.36.
C20H23NO3. Calculated (%): С, 73.82; Н, 7.12; N, 4.30.
20
The yield was 113 mg (85%), light yellow oil. []D –84.6
(2S,2´R)-2-Methyl-6-nitro-N-(2´-phenoxypropionyl)-1,2,3,4-
tetrahydroquinoline [(S,R)-15]. The yield was 251.2 mg (90%),
(с 2.2, CHCl3) (cf. Ref. 19: []D20 –65.3 (с 3.1, CHCl3); ee 78%).
HPLC (hexane—PriOH (40 : 1)): τ 12.2 min; ee 99.2%. The 1H
and 13C NMR spectra were identical to those described in the
literature.25 Found (%): C, 74.79; H, 8.64; N, 8.15. C11H15NO.
Calculated (%): C, 74.54; H, 8.53; N, 7.90.
20
light yellow powder, m.p. 109—113 С. []D +310 (с 1.0,
CHCl3). HPLC (MeCN—H2O, 65 : 35): τ 11.8 min; de > 99.9%.
1H NMR, : 1.00 (br.d, 3 H, C(2)Me, J = 6.1 Hz); 1.45—1.60
(br.m, 4 H, C(3)HB, C(2´)Me); 2.14—2.21 (br.m, 1 H, C(3)HA);
2.56—2.62 (br.m, 1 H, C(4)HB); 2.84—2.90 (br.m, 1 H, C(4)HA);
4.58 (br.sextet, 1 H, C(2)H, J = 6.0 Hz); 5.42 (br.q, 1 H, C(2´)H,
J = 6.3 Hz); 6.66 (br.d, 2 H, C(2ʺ)H, J = 7.2 Hz); 6.89 (br.t,
1 H, C(4ʺ)H, J = 7.0 Hz); 7.19 (br.t, 2 H, C(3ʺ)H, J = 7.2 Hz);
7.64 (br.d, 1 H, C(8)H, J = 8.6 Hz); 7.94 (br.d, 1 H, C(7)H,
Quantum chemical calculations. Graphical simulation and
primary optimization of the transition state geometry were per-
formed by molecular mechanics and molecular dynamics meth-
ods (Ammp software package) and in the framework of the VEGA
ZZ program.28,29 As a result, the model structures of all dia-
stereomers of the transition states were obtained. The DFT

Chulakov et al.
898
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
calculations based on the model structures were performed using
the ORCA 4.2.1 program.30,31 The solvent (CH2Cl2) effect was
taken into account using the CPCMC implicit solvatation
model implemented in ORCA 4.2.1. Dispersion effects were
corrected using the Grimme semiempirical pairwise dispersion
correction scheme (D3).32—36 The entropy contributions to the
free Gibbs energies were calculated using the Quasi-RRHO ap-
proach for the calculation of corrections for vibrational motions.37
The geometric parameters and total electronic energies of single-
point calculations (EFSP) of the reactants, reagent complexes,
and TSs were calculated using the hybrid meta-GGA Becke—
Lee—Yang—Parr (B3LYP) functional38,39 and def2-SVP and
def2-TZVP Ahlrich´s basis sets.40 The search for transition states
at the first stage and primary calculation of the Hessian in the
gas phase were performed at the B3LYP-D3/def2-SVP level of
theory with a change in the length of the N—CO key bond. Every
iteration during geometry optimization was accompanied by the
determination of the energy of single-point calculations as a sum
of the total energy and dispersion correction D3 along with the
correction of the basis superposition error by the type of "geo-
metric counterbalance" gCP.41 The subsequent geometry opti-
mization of the ground and transition states (using the OptTS
function for TS), numerical calculations of the vibration frequencies,
and calculations of the energy parameters of the solvated struc-
tures were performed using the def2-TZVP basis set in CH2Cl2.
The value of the entropy component corresponding to the sym-
metry number n = 1 (since all reagents are chiral compounds)
were chosen for the calculation of the free Gibbs energy.42
4. V. P. Krasnov, D. A. Gruzdev, G. L. Levit, Eur. J. Org. Chem.,
2012, 1471; DOI: 10.1002/ejoc.201101489.
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2018, 12, 151; DOI: 10.2174/9781681086804118120006.
6. V. P. Krasnov, G. L. Levit, M. A. Korolyova, I. M. Bukrina,
L. Sh. Sadretdinova, I. N. Andreeva, V. N. Charushin,
O. N. Chupakhin, Russ. Chem. Bull., 2004, 53, 1253; DOI:
10.1023/B:RUCB.0000042282.29765.2f.
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dinova, V. P. Krasnov, V. N. Charushin, Russ. Chem. Bull.,
2011, 60, 948; DOI: 10.1007/s11172-011-0149-0.
9. G. L. Levit, D. A. Gruzdev, V. P. Krasnov, E. N. Chulakov,
L. Sh. Sadretdinova, M. A. Ezhikova, M. I. Kodess, V. N.
Charushin, Tetrahedron: Asymmetry, 2011, 22, 185; DOI:
10.1016/j.tetasy.2010.12.017.
10. D. A. Gruzdev, G. L. Levit, V. P. Krasnov, Tetrahedron:
Asymmetry, 2012, 23, 1640; DOI: 10.1016/j.tetasy.2012.11.001.
11. E. N. Chulakov, G. L. Levit, A. A. Tumashov, L. Sh. Sadret-
dinova, V. P. Krasnov, Chem. Heterocycl. Compd., 2012, 48,
724; DOI: 10.1007/s10593-012-1051-x.
12. D. A. Gruzdev, G. L. Levit, M. I. Kodess, V. P. Krasnov,
Chem. Heterocycl. Compd., 2012, 48, 748; DOI: 10.1007/
s10593-012-1053-8.
13. D. A. Gruzdev, E. N. Chulakov, G. L. Levit, M. A. Ezhikova,
M. I. Kodess, V. P. Krasnov, Tetrahedron: Asymmetry, 2013,
24, 1240; DOI: 10.1016/j.tetasy.2013.07.024.
14. D. A. Gruzdev, S. A. Vakarov G. L. Levit, V. P. Krasnov,
Chem. Heterocycl. Compd., 2014, 49, 1795; DOI: 10.1007/
s10593-014-1432-4.
15. S. A. Vakarov, D. A. Gruzdev, E. N. Chulakov, L. Sh.
Sadretdinova, M. A. Ezhikova, M. I. Kodess, G. L. Levit,
V. P. Krasnov, Chem. Heterocycl. Compd., 2014, 50, 838; DOI:
10.1007/s10593-014-1538-8.
16. S. A. Vakarov, D. A. Gruzdev, E. N. Chulakov, L. Sh. Sadret-
dinova, A. A. Tumashov, M. G. Pervova, M. A. Ezhikova,
M. I. Kodess, G. L. Levit, V. P. Krasnov, V. N. Charushin,
Tetrahedron: Asymmetry, 2016, 27, 1231; DOI: 10.1016/
j.tetasy.2016.10.004.
17. D. A. Gruzdev, E. N. Chulakov, L. Sh. Sadretdinova, G. L.
Levit, V. P. Krasnov, V. N. Charushin, Dokl. Chem., 2018,
483, 293; DOI: 10.1134/S0012500818120017.
18. S. A. Vakarov, D. A. Gruzdev, G. L. Levit, V. P. Krasnov,
V. N. Charushin, O. N. Chupakhin, Russ. Chem. Rev., 2019,
88, 1063; DOI: 10.1070/RCR4893.
This study was performed with the use of the equipment
of the Center for Joint Use "Spectroscopy and Analysis of
Organic Compounds" of the I. Ya. Postovsky Institute of
Organic Synthesis (Ural Branch of the Russian Academy
of Sciences, UB RAS).
The quantum chemical computations were carried out
using the equipment of the Center for Joint Use "Super-
computer Center of IMM UB RAS" of the N. N. Krasovsky
Institute of Mathematics and Mechanics of UB RAS. The
authors are grateful to S. V. Sharf (staff member of the
Center for Joint Use) for technical support in organization
of parallel computations.
This work was carried out within the framework of
the state assignment of the I. Ya. Postovsky Institute
of Organic Synthesis of UB RAS (theme No. AAAA-
A19-119011790134-1).
This paper does not contain description of studies on
animals or humans.
19. Sh.-M. Lu, C. Bolm, Adv. Synth. Catal., 2008, 350, 1101;
DOI: 10.1002/adsc.200800068.
The authors declare no competing of interests.
20. V. A. Potemkin, V. P. Krasnov, G. L. Levit, E. V. Bartoshevich,
I. N. Andreeva, M. B. Kuzminsky, N. A. Anikin, V. N.
Charushin, O. N. Chupakhin, Mendeleev Commun., 2004,
14, 69; DOI: 10.1070/MC2004v014n02ABEH001887.
21. M. A. Korolyova, S. A. Vakarov, D. N. Kozhevnikov, D. A.
Gruzdev, G. L. Levit, V. P. Krasnov, Eur. J. Org. Chem., 2018,
4577; DOI: 10.1002/ejoc.201800656.
22. S. A. Vakarov, M. A. Korolyova, D. A. Gruzdev, M. G.
Pervova, G. L. Levit, V. P. Krasnov, Russ. Chem. Bull., 2019,
68, 1257; DOI: 10.1007/s11172-019-2550-z.
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Received February 12, 2021;
accepted March 15, 2021