Diastereoselective acylation of racemic heterocyclic amines with N-tosyl-(s)-prolyl chloride and its structural analogs

Article abstract of DOI:10.1007/s10593-014-1538-8

A comparative study on the kinetic resolution of racemic amines (2,3-dihydro-4H-1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline derivatives) via diastereoselective acylation with N-tosyl-(S)-prolyl chloride and its structural analogs was performed. The effect of resolving agent structure on the stereoselectivity of heterocyclic amine acylation was examined. The highest stereoselectivity was achieved in the case of acylation with acyl chlorides bearing a conformationally restricted pyrrolidine ring and an aromatic substituent in the protecting group at the nitrogen atom.

Full text of DOI:10.1007/s10593-014-1538-8

Chemistry of Heterocyclic Compounds, Vol. 50, No. 6, September, 2014 (Russian Original Vol. 50, No. 6, June, 2014)
DIASTEREOSELECTIVE ACYLATION OF RACEMIC
HETEROCYCLIC AMINES WITH N-TOSYL-(S)-PROLYL
CHLORIDE AND ITS STRUCTURAL ANALOGS
1
1
1
1
*
S. A. Vakarov , D. A. Gruzdev , E. N. Chulakov , L. Sh. Sadretdinova ,
M. A. Ezhikova1, M. I. Kodess1, G. L. Levit1, and V. P. Krasnov1
A comparative study on the kinetic resolution of racemic amines (2,3-dihydro-4H-1,4-benzoxazine and
1,2,3,4-tetrahydroquinoline derivatives) via diastereoselective acylation with N-tosyl-(S)-prolyl chloride
and its structural analogs was performed. The effect of resolving agent structure on the stereoselectivity
of heterocyclic amine acylation was examined. The highest stereoselectivity was achieved in the case of
acylation with acyl chlorides bearing a conformationally restricted pyrrolidine ring and an aromatic
substituent in the protecting group at the nitrogen atom.
Keywords: acyl chlorides, proline, racemic amines, acylation, diastereoselectivity, kinetic resolution.
Kinetic resolution (KR) of racemic mixtures [1] is currently one of the most important methods for the
preparation of enantiomerically pure amines and their derivatives. Acylation reactions are frequently used for
KR of racemic amines [2-4]. In this case, one of the amide isomers is formed faster, while the unreacted amine
becomes enriched with another enantiomer.
Recently, enantiomerically pure heterocyclic amines have been frequently prepared by enantioselective
acylation in the presence of enzymes [5-7] or synthetic catalysts [8-12], as well as by diastereoselective
acylation with chiral acylating agents [13-15].
We have performed systematic studies of KR of racemic heterocyclic amines via diastereoselective
acylation with N-protected aminо acyl chlorides [16-20] and 2-arylpropionyl chlorides [20-24]. This approach
allows to study the factors affecting stereoselectivity and also to obtain amine enantiomers with optical purity
more than 99%. The use of natural amino acids as readily available enantiopure resolving agents provides a
significant structural diversity of these agents.
We have previously studied KR of a series of heterocyclic amines via acylation with N-tosyl-(S)-prolyl
chloride and established that the reactions of this compound with racemic aromatic heterocyclic amines occur
with remarkable diastereoselectivity [25, 26].
_______
*To whom correspondence should be addressed, e-mail: gruzdev-da@ios.uran.ru.
1I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, 22 S. Kovalevskoi
St. / 20 Akademicheskaya St., Yekaterinburg 620137, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 908-927, June, 2014. Original
article submitted March 12, 2014.
838
0009-3122/14/5006-0838©2014 Springer Science+Business Media New York

In the current work, we continued the study of reagent structure effect on the stereochemical outcome of
acylation. For this purpose, we performed acylation of racemic heterocyclic amines with N-tosyl-(S)-prolyl
chloride (2a) and its structural analogs 2b-h obtained from the corresponding acids 1a-h. (S)-Proline derivatives
2a-c have different aryl fragments in the protecting group. Reagents 2d,e contain aliphatic sulfamide groups of
different volume. N-Tosyl-(S)-indoline-2-carbonyl chloride (2f) has an additional annelated fragment, while
compound 2g is an acyclic analog of acyl chloride 2f. Acyl chloride 2h may be considered as an oxygen-
containing analog of proline derivatives.
ArSO2Cl, Et3N, NaOH
H2O, Me2CO
O
O
O
0°C – room temp., 12 h
N
N
H
N
OH
OH
OH
SO2
Ts
1a
Ar
1b (Ar = 2-naphthyl)
1c (Ar = 1-naphthyl)
(for 1d)
1) MeSO2Cl, Et3N, CH2Cl2; 0°C, 30 min; room temp., 24 h;
2) NaOH, H2O, Me2CO; –5°C, 2 h; room temp., 24 h
O
O
(for 1e)
N
H
N
1) t-BuSOCl, Et3N, CH2Cl2, 0°C, 2 h;
2) MCPBA, CH2Cl2; 0°C, 2 h; room temp., 1 h;
3) NaOH, H2O, Me2CO, 5°C, 18 h
OMe
OH
SO2
· HCl
R
1d (R = Me)
1e (R = t-Bu)
TsCl, Py
O
O
O
room temp., 1 h
N
N
H
OH
OH
OH
N
Ts
Me
1g
1f
Ts
O
O
(COCl)2
DMF (cat.)
OH
1h
O
O
benzene, room temp.
6 h
(COCl)2
room temp., 20 h
N
N
O
1h
OH
Cl
2a–g
SO2
SO2
O
R
R
Cl
2h
1a–g
We have previously prepared acyl chloride 2a using the reaction of acid 1a with oxalyl chloride in the
presence of DMF [25, 26]. New acylating agents 2b-h were obtained from acids 1b-h by analogous procedure
and were used without further purification. N-Protected amino acids 1b,c,e,f were obtained from (S)-proline or
(S)-indoline-2-carboxylic acid and the respective sulfonyl chlorides by analogy with published methods [27-29].
N-Mesyl-(S)-proline (1d) was synthesized from (S)-proline methyl ester by mesylation and subsequent
hydrolysis of the ester group.
Acyl chlorides 2a-d,f,g were air-stable crystalline compounds, the derivatives of tert-butylsulfonyl-(S)-
proline 2е and (S)-tetrahydrofuran-2-carboxylic acid 2h were unstable upon storage and were used freshly
prepared (purity not less than 96% according to 1H NMR spectroscopy data).
Acylation of the racemic amines 3a-c was performed for 6 h at amine–acyl chloride 2:1 molar ratio and
0.1 М initial concentration of amine. Previously, we have established that the solvent of choice for KR of amine
3a with acyl chloride 2a is dichloromethane, and that for KR of amines 3b,c is toluene [26]; therefore the
stereoselectivity of acylation with reagents 2b-h was investigated in the solvents most suitable for each amine
(Table 1).
839

Y
Y
Y
Y
Y
Y
O
0.5 equiv. 2a–h
CH2Cl2 or toluene
20°C, 6 h
+
NH
Me
N
R*
NH
Me
X
X
X
Me
(RS)-3a–c
(R,S)-4–11 a, (R,S)-4–10 b
(R,S)-4–7,9–10 c
(major)
(S)-3a–c
(major)
3a, 4-11 a X = O, Y = F; 3b, 4-10 b X = O, Y = H; 3c, 4-10 c X = CH2, Y = H
The diastereomeric excess (de, %) of formed amides 5-11 was determined by HPLC on silica gel and by
1H NMR spectroscopy. The enantiomeric excess (ee, %) of unreacted amines 3a-c was determined by HPLC on
chiral stationary phase (Chiralcel OD-H). Based on the values of de and ee the racemate conversion (C, %) and
selectivity factor (s) were calculated [1]:
C = [eeamine / (eeamine + deamide)]×100,
s = ln[(1 - C)×(1 - eeamine)]/ln[(1 - C)×(1 + eeamine)].
The results of diastereoselective acylation of racemic amines 3а-с with acyl chlorides 2a-h are
presented in Table 1.
TABLE 1. Results of Diastereoselective Acylation of Amines 3a-c with
Acyl Chlorides 2a-h*
Resolving
agent
(R,S)-amide ee of (S)-amine, Conversion,
Selectivity
factor, s
Amine
Solvent
CH2Cl2
(de, %)*2
%*3
C, %
67
69
52
54
39
68
30
16
34
75
79
61
45
50
76
48
59
51
37
19
57
26
45
47
40
43
33
46
42
43
32
47
50
46
45
40
47
45
46
48
46
42
46
42
21*4
16
14
9.7
14
18
3.1
1.8
9.0
28*4
22
12
5.2
11
3a
2a
2b
2c
2d
2e
2f
2g
2h
2g
2a
2b
2c
2d
2e
2f
4a (83)
5a (78)
6a (79)
7a (70)
8a (81)
9a (80)
10a (41)
11a (21)
10a (73)
4b (85)
5b (80)
6b (72)
7b (54)
8b (74)
9b (86)
10b (59)
4c (70)
5c (54)
6c (45)
7c (26)
9c (67)
10c (36)
toluene
toluene
3b
28
6.2
10*4
5.5
3.7
2.0
8.9
2.7
2g
2a
2b
2c
2d
2f
toluene
3c
2g
_______
*The average values for 2-4 parallel experiments.
*2HPLC data (ReproSil 100 Si).
*3HPLC data (Chiralcel OD-H).
*4Previously reported data [26].
840

As in the case of using acyl chloride 2a as a resolving agent [26], the products of acylation of amines
3a-c with its structural analogs 2b-h contained predominantly (R,S)-amides 5-11, while the unreacted amines
were enriched in (S)-enantiomers. Individual (R,S)-diastereoisomers of amides 5-9, 11 were isolated from the
KR products by recrystallization or flash chromatography. The absolute configuration of (R,S)-amides 5a,c, 7b
was established by X-ray structural analysis, based on the known configuration of the acyl fragment (Figs. 1, 2).
Major (R,S)-diastereoisomers of amides 10b,c could not be isolated as individual compounds from the KR
products. In the case of amides 5a,c, 6a, 7b,c, 11a, chromatographic separation also provided minor
(S,S)-diastereoisomers. In order to unambiguously assign the HPLC peaks and NMR signals, (S,S)-amides 5b,
9a,c, 10b,c were synthesized starting from enantiomerically pure amines (S)-1a-c.
Fig. 1. The structures of (R,S)-amides 5a (a) and 5c (b) with atoms represented by thermal
vibration ellipsoids of 50% probability.
Fig. 2. The structure of amide (R,S)-7b with atoms represented by thermal
vibration ellipsoids of 50% probability.
The KR of amines 3a-c with N-arylsulfonyl-(S)-prolyl chlorides 2a-c demonstrated that increased
volume of aromatic substituent in the protecting group of resolving agent did not improve the stereoselectivity.
Thus, the stereoselectivity of acylation with naphthylsulfonyl-(S)-prolyl chlorides 2b,c in all cases was lower
than in the case of acylation with the tosyl derivative 2a. Acylation of 2-methyl-1,2,3,4-tetrahydroquinoline (3c)
with acyl chlorides 2b,c occurred with lower stereoselectivity than acylation of 2,3-dihydrobenzoxazine
derivatives 3a,b. At the same time, the KR of racemic amine 3b with acyl chloride 2b occurred with higher
efficiency than the KR with isomeric acyl chloride 2c (in toluene at 20°C, selectivity factor s was 22 and 12,
respectively).
The KR of racemic amines 3a-c with N-mesyl-(S)-prolyl chloride (2d), which did not contain aromatic
groups in its structure, occurred less selectively compared to the KR with acyl chlorides 2a-c. Thus, the KR of
racemate 3a in dichloromethane at 20°C led to amide (R,S)-7a with de 70% (s 9.7); while in the case of amines
3b,c in toluene the selectivity factor s was 5.2 and 2.0, respectively.
By the example of KR of racemic dihydrobenzoxazines 3a,b with acyl chlorides 2d,e, it was shown that
an increased volume of alkyl substituent in the protecting group of resolving agent led to a substantial increase
of acylation stereoselectivity, accompanied by decreased conversion of racemate. Nevertheless, the selectivity
factor s did not exceed 14 in the case of acylation with the acyl chloride 2e and was lower than in the case of
using arylsulfonyl-(S)-prolyl chlorides.
841

Acylation of amine 3a with (S)-tetrahydrofuran-2-ylcarbonyl chloride (2h) was significantly less selective
than acylation with N-sulfonylprolyl chlorides: the amide (R,S)-11a was isolated with de 21% (s 1.8).
The presence of an annelated aromatic fragment in the structure of N-tosyl-(S)-indoline-2-ylcarbonyl
chloride (2f) did not result in improved acylation stereoselectivity of amines 3a-c. For example, the KR with
acyl chlorides 2а,f occurred with a similar selectivity (Table 1).
The KR of racemic amines 3a-c via acylation with acyl chloride 2g having an аcyclic structure occurred
much less selectively than the KR using reagents 2a,f. However, the diastereoselectivity of acylation of racemic
7,8-difluoro-3-methylbenzoxazine 3a with acyl chloride 2g in toluene was higher than that in dichloromethane (s 9.0
and 3.1, respectively). It may be explained by the peculiarities of solvation of the reagents. Stereoselectivity of
acylation of heterocyclic amines with N-sulfonyl-(S)-prolyl chlorides is likely due to the presence of a rigid five-
membered ring in the resolving agent molecule, which determines the arrangement of chlorocarbonyl and sulfamide
groups during the interaction with the chiral amine molecule.
The higher efficiency of the KR of heterocyclic amines with acyl chlorides 2a-c,f having aromatic
substituents at the sulfonyl group, compared to alkylsulfonylprolyl chlorides 2d,e, provides an evidence for the
significant role of aromatic interactions in the process of stereodiscrimination [16, 17].
The differences in the stereoselectivity of acylation of non-fluorinated amines 3b,c with N-tosyl- (2a)
and N-naphthylsulfonyl-(S)-prolyl chlorides 2b,c was in agreement with our previously proposed model [26],
according to which the relative orientation of the reagent molecules is dictated by π-stacking between the
aromatic rings of amine (δ-) and the arylsulfonyl group of the resolving agent (δ+). Due to the higher electron
density in naphthyl system (reagents 2b,c) compared to phenyl ring (reagent 2a) the parallel arrangement with the
electron-rich aromatic ring of the amine in the transition state produced energetically less favored π-stacking
interactions.
Apparently, the aromatic interactions between the amine molecule and the indoline ring of reagent 2f
are also less favored than the stacking interaction with the electron-deficient phenyl fragment of tosyl group.
The significant stereoselectivity of acylation of benzoxazine derivatives 3a,b with acyl chloride 2e
containing a tert-butyl group could likely be explained by the steric hindrances created by the N-protecting
group (Fig. 3а,b). Besides that, the reaction of acyl chloride 2e with (R)-amines may be facilitated by the nonpolar
CH–π interactions between the amine molecule and the pyrrolidine fragment of acylating agent (Fig. 3c). The
methyl group of N-mesyl-(S)-prolyl chloride (2d) probably causes no significant steric hindrances, resulting in
low stereoselectivity.
а)
F
b)
c)
F
F
F
Me
O
O
H
HN
Cl
HN
O
O
H O
O
Me
Cl
NH
Cl
N
H
Me
F
N
N
O
Bu-t
S
S
S
Bu-t
Bu-t
O
O
O
F
O
O
CH-
(R)-3a – 2e
Without steric hindrance
(S)-3a – 2e
Steric hindrance
Fig. 3. The proposed stereodifferentiation mechanism during the acylation of amine 1a
with acyl chloride 2e.
842

Thus, we have studied the diastereoselective acylation of racemic heterocyclic amines (2,3-dihydro-4H-
1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline derivatives) with N-tosyl-(S)-prolyl chloride and its structural
analogs and demonstrated that the reaction proceeds highly stereoselectively in the cases of acylating agents
containing a conformationally rigid pyrrolidine fragment and aromatic substituents in the N-sulfonyl group.
EXPERIMENTAL
1
The H NMR spectra of compounds 1d, 2h and amides 5-11 were recorded on a Bruker Avance 500
instrument (500 MHz), those of the other compounds were recorded on a Bruker DRX-400 instrument (400 MHz)
in DMSO-d6 (amides 5-11) or CDCl3 (the rest of compounds). 19F NMR spectra were recorded on a Bruker
1
Avance 500 instrument (470 MHz) in DMSO-d6. The internal references were TMS (for H nuclei) and
hexafluorobenzene (for 19F nuclei). The NMR spectra of amides 5-11 were recorded at 100°C, the spectra of the
rest of compounds – at room temperature. High-resolution mass spectra were obtained on an 1200 Infinity
instrument (Agilent Technologies) with a 6540 Accurate-Mass Q-TOF (Agilent Technologies) detector, using
electrospray ionization in positive ion mode; drying with N2 (350°C, 10 l/min, 2.7 atm); capillary voltage
3.5 kV. Elemental analysis was performed on a Perkin Elmer 2400 II analyzer. Melting points were determined
on SMP3 apparatus (Barloworld Scientific). Specific rotation was determined on a Perkin Elmer 341
polarimeter. HPLC analysis was performed on a Knauer Smartline-1100 chromatograph using a ReproSil 100 Si
column (250  4.6 mm, 5 µm, for amides 5-11), a Chiralcel OD-H column (Daicel Corp., Japan, 250  4.6 mm,
for amines 3a-с); with detection at 220 nm, eluent flow rate 1 ml/min. Flash chromatography was performed on
230-400 mesh silica gel from Alfa Aesar, UK. TLC analysis was performed on Sorbfil plates (Imid, Russia).
(S)-Proline methyl ester hydrochloride [30], N-tosyl-(S)-prolyl chloride (2a) [26], N-methyl-N-tosyl-
(S)-phenylalanyl chloride (2g) [31], (RS)-7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazine (3a) [32],
(S)-7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazine ((S)-3a) [21], (RS)-3-methyl-2,3-dihydro-4H-1,4-benz-
oxazine (3b) [32], (S)-3-methyl-2,3-dihydro-4H-1,4-benzoxazine ((S)-3b) [19], (RS)-2-methyl-1,2,3,4-tetra-
hydroquinoline (3c) [33], and (S)-2-methyl-1,2,3,4-tetrahydroquinoline ((S)-3c) [19] were obtained according to
published methods. The other reagents were commercially available. Amides 4a-с were described previously
[25, 26].
N-Naphthylsulfonyl-(S)-prolines 1b,c (General Method). A solution of (S)-proline (0.58 g,
5.00 mmol) in 0.5 N NaOH solution (10 ml) at 0°С was stirred and treated with Et3N (0.77 ml, 5.50 mmol) and
then with the corresponding naphthylsulfonyl chloride (1.19 g, 5.25 mmol) in acetone (5 ml). The reaction
mixture was stirred for 12 h at room temperature, then acidified with 1 N HCl to pH 1-2 and left for 24 h at
10°C. The precipitate was filtered off and recrystallized from EtOH–H2O mixture (compound 1b) or hexane–
CHCl3 (compound 1c).
N-(2-Naphthylsulfonyl)-(S)-proline (1b). Yield 1.37 g (90%). White powder. Mp 136-137°С
20
1
(mp 133-135°С [34], mp 138°С [35]). [α]D -88.3° (с 1.0, CHCl3). H NMR spectrum, δ, ppm (J, Hz):
1.72-1.81 (1H, m, 4-CHB); 1.91-2.02 (2H, m, 3-CHB, 4-CHA); 2.10-2.18 (1H, m, 3-CHA); 3.35 (1H, dt, J = 9.7,
J = 7.4) and 3.58 (1H, ddd, J = 9.9, J = 6.5, J = 3.7, 5-CH2); 4.38 (1H, dd, J = 8.2, J = 3.5, 2-СН); 4.50-6.00
(1H, br. s, COOH); 7.62-7.69 (2H, m, H-6,7 naphthyl); 7.87 (1H, dd, J = 8.7, J = 1.6, H-5 naphthyl); 7.92-7.95
(1H, m, H-8 naphthyl); 7.99-8.01 (2H, m, H-3,4 naphthyl); 8.46 (1H, d, J = 1.6, H-1 naphthyl). Found, %:
C 58.71; H 4.87; N 4.46; S 10.62. C15H15NO4S. Calculated, %: C 59.00; H 4.95; N 4.59; S 10.50.
N-(1-Naphthylsulfonyl)-(S)-proline (1c). Yield 1.36 g (89%). White powder. Mp 125-126°С
20
20
1
(mp 126°С [36], mp 80°С [37]). [α]D -51.7° (с 1.1, MeOH) ([α]D -53.2° (с 1.0, MeOH) [36]). H NMR
spectrum was identical to that described previously [37]. Found, %: C 58.83; H 4.79; N 4.58; S 10.19.
C15H15NO4S. Calculated, %: C 59.00; H 4.95; N 4.59; S 10.50.
N-Methylsulfonyl-(S)-proline (1d). A solution of (S)-proline methyl ester hydrochloride (16.56 g,
0.1 mol) and Et3N (56 ml, 0.4 mol) in CH2Cl2 (100 ml) was cooled to 0°C, and mesyl chloride (7.74 ml,
843

0.1 mol) was added dropwise. The reaction mixture was stirred for 30 min at 0°C and for 24 h at room
temperature, then washed with 1 N HCl (2×15 ml), saturated NaCl solution (4×20 ml), 5% NaHCO3 solution
(2×20 ml), and H2O (2×20 ml). The organic layer was dried over MgSO4, evaporated under vacuum, the residue
was recrystallized from hexane–EtOAc mixture, and N-methylsulfonyl-(S)-proline methyl ester was obtained.
Yield 9.12 g (44%). Colorless powder. Mp 60-63°С. [α]D20 -83.6° (с 1.1, CHCl3). 1H NMR spectrum, δ, ppm (J,
Hz): 1.96-2.11 (3H, m, 3-CHB, 4-CH2); 2.29 (1H, dtd, J = 12.4, J = 8.6, J = 7.3, 3-CHA); 3.02 (3H, s, CH3SO2);
3.45 (1H, ddd, J = 9.1, J = 6.8, J = 5.6) and 3.56 (1H, dt, J = 9.1, J = 7.2, 5-CH2); 3.76 (3H, s, COOCH3); 4.51
(1H, dd, J = 8.6, J = 3.7, 2-СН). Found, %: C 40.81; H 6.59; N 6.87; S 15.70. C7H13NO4S. Calculated, %:
C 40.57; H 6.32; N 6.76; S 15.47.
A solution of N-methylsulfonyl-(S)-proline methyl ester (2.07 g, 10 mmol) in acetone (100 ml) was
treated at -5°C with 2 N NaOH (12 ml, 24 mmol). The reaction mixture was stirred for 2 h at -5°C and for 24 h
at room temperature, then acidified with 1 N HCl to pH 4-5 and evaporated under vacuum. The residue was
treated with CH2Cl2 (20 ml) and H2O (20 ml), stirred, the organic layer was separated, washed with H2O (4×20 ml),
and dried over MgSO4. The solution was evaporated, the residue was recrystallized from hexane–EtOAc
20
1
mixture. Yield 1.04 g (54%). Colorless powder. Mp 76-78°С. [α]D -73.3° (c 1.0, MeOH). H NMR spectrum,
δ, ppm (J, Hz): 2.01-2.08 (2H, m, 4-CH2); 2.20 (1H, dtd, J = 12.8, J = 5.8, J = 3.9) and 2.33 (1H, dq, J = 12.8,
J = 8.6, 3-CH2); 3.01 (3H, s, СH3); 3.47 (1H, dt, J = 9.2, J = 6.2) and 3.54 (1H, dt, J = 9.2, J = 7.4, 5-CH2);
4.53 (1H, dd, J = 8.7, J = 3.9, 2-СН); 5.0-7.0 (1H, br. s, COOH). Found, %: C 37.54; H 6.00; N 7.28; S 16.82.
C6H11NO4S. Calculated, %: C 37.30; H 5.74; N 7.25; S 16.59.
N-(tert-Butylsulfonyl)-(S)-proline (1e). А. A solution of (S)-proline methyl ester hydrochloride
(3.15 g, 19 mmol) in CH2Cl2 (200 ml) was treated with Et3N (26.5 ml, 190 mmol) at 0°С, followed by dropwise
addition of tert-butylsulfinyl chloride (5.34 g, 38 mmol) solution in CH2Cl2 (70 ml). The reaction mixture was
stirred for 2 h at 0°С, washed with 1 N HCl (2×100 ml), saturated NaCl solution (2×100 ml), and 5% NaHCO3
solution (2×100 ml). The organic layer was dried over MgSO4, evaporated, the residue was purified by flash
chromatography (eluent benzene–EtOAc), giving N-tert-butylsulfinyl-(S)-proline methyl ester as a mixture of
diastereomers. Yield 3.28 g (74%), colorless oil.
B. A solution of N-tert-butylsulfinyl-(S)-proline methyl ester (3.27 g, 14 mmol) in CH2Cl2 (500 ml) was
cooled to 0°С, and MCPBA (4.83 g, 28 mmol) was added. The reaction mixture was stirred for 2 h at 0°С and
for 1 h at room temperature, then washed with 5% NaHCO3 solution (2×100 ml) and with saturated Na2SO3
solution (2×100 ml). The organic layer was dried over MgSO4 and evaporated. The obtained oil (2.96 g) was
dissolved in acetone (125 ml), the solution was cooled to -5°С and treated with 1 N NaOH (30 ml). The reaction
mixture was stirred for 2 h and left overnight at 5°С, then washed with Et2O (2×50 ml), acidified with 1 N HCl
to pH 1, and extracted with CH2Cl2 (3×50 ml). The organic layer was dried over MgSO4 and evaporated, hexane
(40 ml) was added to the residue, the precipitate was filtered off. Yield 2.01 g (45%, calculated from (S)-proline
20
1
methyl ester). White powder. Mp 133-135°C (hexane). [α]D -66.6° (c 1.0, CHCl3). H NMR spectrum, δ, ppm
(J, Hz): 1.41 (9H, s, C(СH3)3); 1.92-2.16 (3H, m, 3-CHB, 4-CH2); 2.28 (1H, dq, J = 12.5, J = 8.3, 3-CHA); 3.43-3.55
(1H, m) and 3.73 (1H, dt, J = 9.5, 7.0, 5-CH2); 4.53 (1H, dd, J = 8.4, J = 3.8, 2-СН); 5.0-8.0 (1H, br. s, COOH).
Found, %: C 46.02; H 7.25; N 5.78; S 13.61. C9H17NO4S. Calculated, %: C 45.94; H 7.28; N 5.95; S 13.63.
N-Tosyl-(S)-indoline-2-carboxylic acid (1f). A solution of (S)-indoline-2-carboxylic acid (0.49 g,
3.0 mmol) in pyridine (12 ml) was cooled to 0°C, TsCl (0.69 g, 3.6 mmol) was added. The reaction mixture was
stirred for 1 h at room temperature. The obtained solution was poured into H2O (120 ml), washed with CHCl3
(2×20 ml), then acidified with 4 N HCl to pH 2-3, and extracted with EtOAc (3×40 ml). The organic layer was
washed with saturated aqueous NaCl solution (3×40 ml), dried over MgSO4, treated with activated carbon, and
evaporated. The precipitate was recrystallized from H2O–MeOH mixture (7.0 : 5.5 ml). Yield 0.68 g (71%).
1
Colorless powder. Mp 159-162°С (H2O–MeOH). [α]D20 +120° (с 1.0, MeOH). H NMR spectrum, δ, ppm (J,
Hz): 2.38 (3H, s, CH3); 3.11 (1H, dd, J = 16.5, J = 10.7) and 3.24 (1H, dd, J = 16.5, J = 4.2, 3-CH2); 4.77 (1H,
dd, J = 10.7, J = 4.2, 2-СН); 7.03-7.08 (2H, m, Н indoline); 7.22-7.26 (3H, m, Н indoline, H Ts); 7.62-7.64 (3H,
844

m, Н indoline, H Ts); 3.0-9.0 (1H, br. s, COOH). Found, %: C 60.57; H 4.89; N 4.72; S 10.03. C16H15NO4S.
Calculated, %: C 60.55; H 4.76; N 4.41; S 10.10.
Acyl chlorides 2b-f (General Method). A suspension of N-sulfonylproline 1b-e (5.0 mmol) or the acid
1f in benzene (20 ml) was treated with oxalyl chloride (0.92 ml, 10.5 mmol) and DMF (5 µl). The reaction
mixture was stirred at room temperature for 6 h and evaporated. Hexane (20 ml) was added to the residue, and
the mixture was left overnight at low temperature. The precipitate was filtered off and dried under vacuum over
P2O5.
N-(2-Naphthylsulfonyl)-(S)-prolyl Chloride (2b). Yield 1.55 g (96%). Colorless powder. Mp 109-110°С
20
20
1
(mp 107-109°С [34]). [α]D -80.4° (с 1.0, CHCl3) ([α]D -81.6° (с 1.0, CHCl3) [34]). H NMR spectrum, δ,
ppm (J, Hz): 1.79-1.88 (1H, m) and 1.93-2.04 (1H, m, 4-CH2); 2.17-2.26 (2H, m, 3-CH2); 3.43 (1H, dt, J = 9.6,
J = 7.4) and 3.55 (1H, ddd, J = 9.6, J = 7.4, J = 4.8, 5-CH2); 4.72 (1H, dd, J = 7.6, J = 5.3, 2-СН); 7.62-7.70
(2H, m, H-6,7 naphthyl); 7.85 (1H, dd, J = 8.7, J = 1.8, H-8 naphthyl); 7.92-7.94 (1H, m, H-5 naphthyl);
7.99-8.01 (2H, m, H-3,4 naphthyl); 8.45 (1H, d, J = 1.8, H-1 naphthyl). Found, %: C 55.24; H 4.26; N 4.46.
C15H14ClNO3S. Calculated, %: C 55.64; H 4.36; N 4.33.
N-(1-Naphthylsulfonyl)-(S)-prolyl Chloride (2c). Yield 1.42 g (88%). Colorless powder. Mp 59-62°С
1
(hexane–CH2Cl2). H NMR spectrum, δ, ppm (J, Hz): 1.87-2.05 (2H, m, 4-CH2); 2.20-2.33 (2H, m, 3-CH2);
3.48-3.54 (2H, m, 5-CH2); 4.84 (1H, dd, J = 8.5, J = 4.2, 2-СН); 7.54-7.71 (3H, m, H-3,6,7 naphthyl); 7.94 (1H,
d, J = 8.2, H-4 naphthyl); 8.10 (1H, d, J = 8.2, H-2 naphthyl); 8.27 (1H, dd, J = 7.3, J = 1.0, H-5 naphthyl); 8.79
(1H, d, J = 8.7, H-8 naphthyl). Found, %: C 55.94; H 4.24; N 4.37; S 10.04. C15H14ClNO3S. Calculated, %:
C 55.64; H 4.36; N 4.33; S 9.90.
N-Methylsulfonyl-(S)-prolyl Chloride (2d). Yield 0.97 g (92%). Colorless powder. Mp 59-62°С
(hexane–CH2Cl2). [α]D20 -67.4° (c 1.0, benzene). 1H NMR spectrum, δ, ppm (J, Hz): 2.00-2.12 (2H, m, 4-CH2);
2.27-2.34 (1H, m) and 2.44 (1H, dtd, J = 13.3, J = 9.1, J = 7.2, 3-CH2); 3.02 (3H, s, CH3); 3.48 (1H, ddd,
J = 9.3, J = 7.4, J = 5.1) and 3.61 (1H, dt, J = 9.3, J = 7.4, 5-CH2); 4.83 (1H, dd, J = 9.0, J = 4.0, 2-СН). Found,
%: C 34.20; H 4.79; N 6.68. C6H10ClNO3S. Calculated, %: C 34.05; H 4.76; N 6.62.
N-tert-Butylsulfonyl-(S)-prolyl Chloride (2e). Yield 1.21 g (95%). Colorless amorphous powder.
1H NMR spectrum, δ, ppm (J, Hz): 1.41 (9H, s, C(СH3)3); 1.97-2.07 (2H, m, 4-CH2); 2.23 (1H, ddt, J = 13.2,
J = 6.4, J = 3.8) and 2.39 (1H, dq, J = 13.2, J = 8.4, 3-CH2); 3.44-3.49 (1H, m) and 3.79 (1H, dt, J = 9.7,
J = 7.0, 5-CH2); 4.98 (1H, dd, J = 8.4, J = 3.8, 2-СН).
N-Tosyl-(S)-indoline-2-carbonyl Chloride (2f). Yield 1.61
g
(96%). Colorless powder.
Mp 123-125°С. [α]D20 +71.1° (с 0.94, benzene). 1H NMR spectrum, δ, ppm (J, Hz): 2.39 (3H, s, CH3); 3.24 (1H,
dd, J = 16.7, J = 4.9) and 3.34 (1H, dd, J = 16.7, J = 10.8, 3-CH2); 5.05 (1H, dd, J = 10.8, J = 4.9, 2-СН);
7.02-7.11 (2H, m, H indoline); 7.23-7.26 (3H, m, Н indoline, H Ts); 7.57-7.59 (1H, m, H indoline); 7.69 (2H, d,
J = 8.2, H Ts). Found, %: C 57.15; H 4.37; N 4.48. C16H14ClNO3S. Calculated: C 57.23; H 4.20; N 4.17.
(S)-Tetrahydrofuran-2-carbonyl Chloride (2h). A solution of (S)-tetrahydrofuran-2-carboxylic acid
(1h) (0.20 g, 1.72 mmol) in oxalyl chloride (1.5 ml, 17.20 mmol) was stirred for 20 h under argon atmosphere,
1
evaporated, dried under vacuum. Yield 0.16 g (70%). Colorless oil. H NMR spectrum, δ, ppm (J, Hz):
1.94-2.03 (2H, m, 4-CH2); 2.24 (1H, dddd, J = 13.1, J = 7.5, J = 6.7, J = 5.1) and 2.39 (1H, dtd, J = 13.1,
J = 8.6, J = 7.0, 3-CH2); 4.00-4.07 (2H, m, 5-CH2); 4.73 (1H, dd, J = 8.6, J = 5.1, 2-СН).
KR of Racemic Amines 3а-с. Preparation of Amides 5-11 (General Method). A solution of amine
3a (1.0 mmol) in a chosen solvent (5 ml) (CH2Cl2 in the case of amides 5-9a, 11a, toluene in the case of the amide
10a), or amine 3b,c in toluene (5 mL) at 20°C was treated with a solution of acyl chloride 2a-h (0.5 mmol) in
the same solvent (5 ml). (The study of KR was performed with 0.3 mmol of amine 3a-c in 1.5 ml of solvent and
0.15 mmol of the acyl chloride 2a-h in 1.5 ml of the same solvent). The reaction mixture was stirred for 6 h at
20°С, washed with HCl (4 N in the case of amine 3a, 1 N in the case of amines 3b,c; 2×4 ml), thus separating
unreacted amines enriched in the (S)-isomers. The organic layer containing amides 5-11 was washed with
saturated NaCl solution (4×5 ml), 5% NaHCO3 solution (2×5 ml), H2O (2×5 ml), dried over MgSO4, and
845

evaporated. The amide diastereomers were separated by recrystallization or flash chromatography (eluent
benzene–EtOAc).
The acidic aqueous solutions of unreacted amines 3а-с were neutralized with Na2CO3 and extracted
with CHCl3 (2×5 ml). The organic layer was washed with H2O (2×5 ml), dried over MgSO4, and evaporated.
(3R,2'S)-7,8-Difluoro-3-methyl-N-[N'-(2-naphthylsulfonyl)prolyl]-2,3-dihydro-4H-1,4-benzoxazine
((R,S)-5a). Yield 116 mg (49%) after flash chromatography (slow-eluting diastereomer). Colorless powder. Mp
20
1
203-204°С. [α]D -242° (c 1.0, CHCl3). HPLC (hexane–2-PrOH, 10:1): de > 99%, τR 9.9 min. H NMR
spectrum, δ, ppm (J, Hz): 1.18 (3H, d, J = 6.9, CH3); 1.64-1.73 (1H, m, 4-CHB proline); 1.98-2.05 (2H, m,
3-CHB proline, 4-CHA proline); 2.11-2.20 (1H, m, 3-CHA proline); 3.42-3.55 (2H, m, 5-CH2 proline); 4.25 (1H,
dd, J = 10.8, J = 2.9) and 4.36 (1H, dd, J = 10.8, J = 1.4, 2-CH2); 4.68 (1H, dd, J = 8.3, J = 4.0, 2-СН proline);
4.80-4.87 (1H, m, 3-СН); 6.79 (1H, td, J = 9.7, J = 8.2, H-6); 7.15-7.22 (1H, m, H-5); 7.59-7.71 (3H, m,
19
H naphthyl); 7.96-8.04 (3H, m, H naphthyl); 8.15 (1H, s, H-1 naphthyl). F NMR spectrum, δ, ppm: 2.5-2.6
(1F, m, F-8); 21.3-21.8 (1F, m, F-7). Found, m/z: 473.1348 [M+H]+. C24H23F2N2O4S. Calculated, m/z: 473.1341.
(3S,2'S)-7,8-Difluoro-3-methyl-N-[N'-(2-naphthylsulfonyl)prolyl]-2,3-dihydro-4H-1,4-benzoxazine
((S,S)-5a). Yield 12 mg (5%) after flash chromatography (fast-eluting diastereomer). Colorless powder.
20
1
Mp 161-162°С. [α]D +90.0° (c 0.6, CHCl3). HPLC (hexane–2-PrOH, 10:1): de 98.6%, τR 5.7 min. H NMR
spectrum, δ, ppm (J, Hz): 1.17 (3H, d, J = 6.9, CH3); 1.64-1.73 (1H, m) and 1.79-1.86 (1H, m, 4-CH2 proline);
1.93-2.04 (2H, m, 3-CH2 proline); 3.42 (1H, ddd, J = 13.1, J = 9.7, J = 6.2) and 3.44 (1H, ddd, J = 13.1, J = 9.8,
J = 6.5, 5-CH2 proline); 4.18 (1H, dd, J = 11.0, J = 2.9) and 4.41 (1H, dd, J = 11.0, J = 1.5, 2-CH2); 4.89 (1H, qdd,
J = 6.9, J = 3.0, J = 1.6, 3-СН); 5.07 (1H, dd, J = 8.1, J = 4.3, 2-СН proline); 6.93 (1H, td, J = 9.8, J = 8.2,
H-6); 7.56 (1H, ddd, J = 9.5, J = 5.3, J = 2.5, H-5); 7.63-7.71 (2H, m, H-6,7 naphthyl); 7.85 (1H, dd, J = 8.7,
J = 1.8, H-3 naphthyl); 8.01 (1H, d, J = 8.1, H naphthyl); 8.09 (1H, d, J = 8.7, H-4 naphthyl); 8.12 (1H, d, J = 8.0,
19
H naphthyl); 8.45 (1H, d, J = 1.8, H-1 naphthyl). F NMR spectrum, δ, ppm: 2.3-2.4 (1F, m, F-8); 21.1-21.3
(1F, m, F-7). Found, %: C 60.85; H 4.40; F 7.80; N 5.96; S 7.01. C24H22F2N2O4S. Calculated, %: C 61.01; H 4.69;
F 8.04; N 5.93; S 6.79.
(3R,2'S)-3-Methyl-N-[N'-(2-naphthylsulfonyl)prolyl]-2,3-dihydro-4H-1,4-benzoxazine
((R,S)-5b).
Yield 70 mg (32%) after recrystallization from a mixture of hexane–EtOAc. Colorless powder. Mp 178-179°С.
[α]D -324° (c 1.1, CHCl3). HPLC (hexane–2-PrOH, 20:1): de > 99%, τR 11.1 min. 1H NMR spectrum, δ, ppm
20
(J, Hz): 1.15 (3H, d, J = 6.9, CH3); 1.59-1.68 (1H, m, 4-CHB proline); 1.96-2.18 (3H, m, 3-CH2 and 4-CHA
proline); 3.42 (1H, ddd, J = 9.7, J = 7.1, J = 6.0) and 3.52 (1H, dt, J = 9.7, J = 6.6, 5-CH2 proline); 4.19 (1H, dd,
J = 10.9, J = 1.8) and 4.23 (1H, dd, J = 10.9, J = 2.8, 2-CH2); 4.71 (1H, dd, J = 8.1, J = 4.3, 2-СН proline);
4.79-4.87 (1H, m, 3-СН); 6.82 (1H, ddd, J = 8.2, J = 7.1, J = 1.3, H-7); 6.98 (1H, dd, J = 8.2, J = 1.3, H-8); 7.16
(1H, ddd, J = 8.2, J = 7.1, J = 1.2, H-6); 7.21-7.26 (1H, m, H-5); 7.48-7.53 (1H, m, H naphthyl); 7.61-7.70 (2H,
m, H naphthyl); 7.93-8.01 (3H, m, H naphthyl); 8.06 (1H, s, H naphthyl). Found, %: C 66.32; H 5.48; N 6.39; S
7.56. C24H24N2O4S. Calculated, %: C 66.04; H 5.54; N 6.42; S 7.35.
(2R,2'S)-2-Methyl-N-[N'-(2-naphthylsulfonyl)prolyl]-1,2,3,4-tetrahydroquinoline ((R,S)-5c). Yield
87 mg (40%) after recrystallization from a mixture of hexane–EtOAc. Colorless powder. Mp 215-216°С.
[α]D -358° (c 1.0, CHCl3). HPLC (hexane–2-PrOH, 20:1): de > 99%, τR 10.1 min. 1H NMR spectrum, δ, ppm
20
(J, Hz): 1.04 (3H, d, J = 6.5, CH3); 1.28-1.35 (1H, m, 3-CHB); 1.50-1.58 (1H, m, 4-CHB proline); 1.95-2.08 (3H,
m, 4-CHB, 3-CHB proline, 4-CHA proline); 2.38 (1H, ddt, J = 13.0, J = 7.7, J = 5.3, 3-CHA); 2.66-2.70 (2H, m,
4-CHA, 3-CHA proline); 3.33-3.39 (1H, m) and 3.46-3.53 (1H, m, 5-CH2 proline); 4.38 (1H, dd, J = 8.0, J = 4.4,
2-СН proline); 4.73 (1H, sextet, J = 6.8, 2-СН); 6.98 (1H, d, J = 7.8, H-5); 7.17 (1H, td, J = 7.7, J = 1.6, H-6);
7.28 (1H, td, J = 7.5, J = 1.2, H-7); 7.32 (1H, dd, J = 8.5, J = 1.8, H naphthyl); 7.35-7.37 (1H, m, H-8);
7.60-7.68 (2H, m, H naphthyl); 7.87-7.93 (3H, m, H naphthyl); 7.95-7.98 (1H, m, H naphthyl). Found, %:
C 69.26; H 6.13; N 6.62; S 7.38. C25H26N2O3S. Calculated, %: C 69.10; H 6.03; N 6.45; S 7.38.
(2S,2'S)-2-Methyl-N-[N'-(2-naphthylsulfonyl)prolyl]-1,2,3,4-tetrahydroquinoline ((S,S)-5c). Yield
24 mg (11%) after flash chromatography (fast-eluting diastereomer). Colorless powder. Mp 144-146°С.
[α]D20 +192° (c 0.4, CHCl3). HPLC (hexane–2-PrOH, 10:1): de > 99%, τR 7.1 min. 1H NMR spectrum, δ, ppm (J,
Hz): 1.02 (3H, d, J = 6.6, CH3); 1.23-1.30 (1H, m, 3-CHB); 1.48-1.57 (3H, m, 3-CHB proline, 4-CH2 proline);
846

1.81-1.90 (1H, m, 3-CHA proline); 2.31 (1H, ddt, J = 13.0, J = 7.7, J = 5.2, 3-CHA); 2.42 (1H, ddd, J = 15.0,
J = 10.0, J = 5.2) and 2.62 (1H, dt, J = 15.0, J = 5.2, 4-CH2); 3.38-3.47 (2H, m, 5-CH2 proline); 4.64 (1H,
sextet, J = 6.8, 2-СН); 4.97 (1H, dd, J = 7.7, J = 4.5, 2-СН proline); 7.18 (1H, td, J = 7.5, J = 1.0, H-6); 7.23
(1H, d, J = 7.7, H-5); 7.33 (1H, t, J = 7.5, H-7); 7.52 (1H, d, J = 7.8, H-8); 7.64-7.71 (2H, m, H-6,7 naphthyl);
7.82 (1H, dd, J = 8.7, J = 1.8, H-3 naphthyl); 8.01 (1H, d, J = 8.0, H naphthyl); 8.08 (1H, d, J = 8.7, H-4
naphthyl); 8.13 (1H, d, J = 7.8, H naphthyl); 8.46 (1H, d, J = 1.8, H-1 naphthyl). Found, %: C 69.25; H 6.01;
N 6.44; S 7.64. C25H26N2O3S. Calculated, %: C 69.10; H 6.03; N 6.45; S 7.38.
(3R,2'S)-7,8-Difluoro-3-methyl-N-[N'-(1-naphthylsulfonyl)prolyl]-2,3-dihydro-4H-1,4-benzoxazine
((R,S)-6a). Yield 102 mg (43%) after flash chromatography (slow-eluting diastereomer). Colorless powder. Mp
20
1
146-149°С. [α]D -203° (c 1.0, CHCl3). HPLC (hexane–2-PrOH, 20:1): de > 99%, τR 12.8 min. H NMR
spectrum, δ, ppm (J, Hz): 1.13 (3H, d, J = 6.9, CH3); 1.74-1.84 (1H, m, 4-CHB proline); 1.99-2.09 (2H, m,
3 CHB proline, 4-CHA proline); 2.17-2.25 (1H, m, 3-CHA proline); 3.48-3.57 (2H, m, 5-CH2 proline); 4.08 (1H,
dd, J = 10.9, J = 2.8) and 4.36 (1H, dd, J = 10.9, J = 1.4, 2-CH2); 4.72-4.77 (1H, m, 3-СН); 4.80 (1H, dd, J = 8.4,
J = 3.5, 2-СН proline); 6.82 (1H, ddd, J = 9.8, J = 9.6, J = 8.2, H-6); 7.05-7.11 (1H, m, H-5); 7.52 (1H, t, J = 7.8,
H naphthyl); 7.57-7.64 (2H, m, H naphthyl); 7.96 (1H, d, J = 7.7, H naphthyl); 8.03-8.05 (1H, m, H naphthyl);
8.18 (1H, dm, J = 8.2, H naphthyl); 8.59 (1H, d, J = 8.4, H naphthyl). 19F NMR spectrum, δ, ppm: 2.4-2.6 (1F,
m, F-8); 21.2-21.5 (1F, m, F-7). Found, %: C 61.09; H 4.79; F 7.74; N 5.81; S 6.95. C24H22F2N2O4S. Calculated,
%: C 61.01; H 4.69; F 8.04; N 5.93; S 6.79.
(3S,2'S)-7,8-Difluoro-3-methyl-N-[N'-(1-naphthylsulfonyl)prolyl]-2,3-dihydro-4H-1,4-benzoxazine
((S,S)-6a). Yield 14 mg (6%) after flash chromatography (fast-eluting diastereomer). Yellowish powder. Mp 66-
69°С. [α]D20 +39.1° (c 0.6, CHCl3). HPLC (hexane–2-PrOH, 20:1): de 98.4%, τR 7.4 min. 1H NMR spectrum, δ,
ppm (J, Hz): 1.14 (3H, d, J = 6.9, CH3); 1.75-1.83 (1H, m) and 1.84-1.89 (1H, m, 4-CH2 proline); 1.97-2.04
(1H, m) and 2.07-2.14 (1H, m, 3-CH2 proline); 3.44-3.49 (2H, m, 5-CH2 proline); 4.11 (1H, dd, J = 11.0,
J = 2.9) and 4.38 (1H, dd, J = 11.0, J = 1.5, 2-CH2); 4.83 (1H, qdd, J = 6.9, J = 2.9, J = 1.5, 3-СН); 5.18 (1H,
dd, J = 8.3, J = 4.0, 2-СН proline); 6.89 (1H, td, J = 9.8, J = 8.3, H-6); 7.50 (1H, ddd, J = 9.5, J = 5.4, J = 2.4,
H-5); 7.61-7.68 (3H, m, H naphthyl); 8.03-8.05 (1H, m, H naphthyl); 8.18-8.21 (2H, m, H naphthyl); 8.71 (1H,
dm, J = 8.6, H naphthyl). 19F NMR spectrum, δ, ppm: 2.36-2.48 (1F, m, F-8); 21.15-21.25 (1F, m, F-7). Found,%:
C 60.82; H 4.95; N 5.59. C24H22F2N2O4S. Calculated, %: C 61.01; H 4.69; N 5.93.
(3R,2'S)-3-Methyl-N-[N'-(1-naphthylsulfonyl)prolyl]-2,3-dihydro-4H-1,4-benzoxazine ((R,S)-6b).
Yield 68 mg (31%) after flash chromatography (slow-eluting diastereomer). Colorless powder. Mp 114-117°С.
20
1
[α]D -278° (c 1.0, CHCl3). HPLC (hexane–2-PrOH, 20:1): de 99%, τR 7.7 min. H NMR spectrum, δ, ppm (J,
Hz): 1.10 (3H, d, J = 6.9, CH3); 1.70-1.79 (1H, m, 4-CHB proline); 2.01-2.12 (2H, m, 3-CHB proline, 4-CHA
proline); 2.15-2.22 (1H, m, 3-CHA proline); 3.44-3.58 (2H, m, 5-CH2 proline); 4.07 (1H, dd, J = 10.9, J = 2.8)
and 4.15 (1H, dd, J = 10.9, J = 1.5, 2-CH2); 4.71-4.78 (1H, m, 3-СН); 4.83 (1H, dd, J = 8.3, J = 3.6, 2-СН
proline); 6.83 (1H, ddd, J = 8.0, J = 7.4, J = 1.4, H-6); 6.92 (1H, dd, J = 8.2, J = 1.4, H-8); 7.11 (1H, ddd,
J = 8.2, J = 7.4, J = 1.4, H-7); 7.14-7.18 (1H, m, H-5); 7.47 (1H, t, J = 7.8, H naphthyl); 7.53-7.62 (2H, m,
H naphthyl); 7.86-7.88 (1H, m, H naphthyl); 8.00-8.03 (1H, m, H naphthyl); 8.15 (1H, dm, J = 8.2, H naphthyl);
8.57 (1H, dm, J = 8.5, H naphthyl). Found, %: C 66.36; H 5.54; N 6.18; S 7.55. C24H24N2O4S. Calculated, %:
C 66.04; H 5.54; N 6.42; S 7.35.
3-Methyl-N-[N'-(1-naphthylsulfonyl)prolyl]-2,3-dihydro-4H-1,4-benzoxazine (6b) (mixture of
diastereoisomers). Yield 70 mg (32%) after flash chromatography. Colorless amorphous powder. HPLC
1
(hexane–2-PrOH, 20:1): (R,S)/(S,S) = 64:36; τR (S,S)-6b 5.7 min, τR (R,S)-6b 7.7 min. H NMR spectrum, δ,
ppm (J, Hz): 1.10 (1.92H, d, J = 6.9, CH3 (R,S)); 1.11 (1.08H, d, J = 6.9, CH3 (S,S)); 1.70-1.85 (1.36H, m,
4-CHB proline (R,S), 4-CH2 proline (S,S)); 1.96-2.12 (2H, m, 3-CHB proline (R,S), 3-CH2 proline (S,S), 4-CHA
proline (R,S)); 2.15-2.22 (0.64H, m, 3-CHA proline (R,S)); 3.45-3.58 (2H, m, 5-CH2 proline); 4.03-4.08 (1H, m,
2-CHB); 4.15 (0.64H, dd, J = 10.9, J = 1.5, 2-CHA (R,S)); 4.19 (0.36H, dd, J = 11.0, J = 1.5, 2-CHA (S,S));
4.71-4.80 (1H, m, 3-СН); 4.83 (0.64H, dd, J = 8.4, J = 3.5, 2-СН proline (R,S)); 5.23 (0.36H, dd, J = 7.8,
J = 4.0, 2-СН proline (S,S)); 6.83 (0.64H, ddd, J = 8.0, J = 7.5, J = 1.4, H-6 (R,S)); 6.85-6.94 (1.36H, m, H-6
847

(S,S), H-8 (S,S), H-8 (R,S)); 7.04-7.18 (1.64H, m, H-5 (R,S), H-7 (R,S), H-7 (S,S)); 7.45-7.69 (3.36H, m, H-5
(S,S), H naphthyl); 7.87 (0.64H, d, J = 7.5, H naphthyl (R,S)); 8.00-8.06 (1H, m, H naphthyl); 8.14-8.23 (1.36H,
m, H naphthyl); 8.57 (0.64H, d, J = 8.4, H naphthyl (R,S)); 8.73 (0.36H, d, J = 8.5, H naphthyl (S,S)). Found, %:
C 68.32; H 5.54; N 5.77. C24H24N2O4S·0.5C6H6. Calculated, %: C 68.19; H 5.72; N 5.89.
(2R,2'S)-2-Methyl-N-[N'-(1-naphthylsulfonyl)prolyl]-1,2,3,4-tetrahydroquinoline ((R,S)-6c). Yield
80 mg (37%) after flash chromatography (slow-eluting diastereomer). Colorless powder. Mp 146-150°С.
[α]D20 -271° (c 0.6, CHCl3). HPLC (hexane–2-PrOH, 20:1): de 98.2%, τR 7.7 min. 1H NMR spectrum, δ, ppm (J,
Hz): 1.02 (3H, d, J = 6.5, CH3); 1.25-1.32 (1H, m, 3-CHB); 1.58-1.65 (1H, m, 4-CHB proline); 2.00-2.11 (3H, m,
3-CH2 proline, 4-CHA proline); 2.30 (1H, ddt, J = 13.0, J = 7.6, J = 5.4, 3-CHA); 2.56 (1H, ddd, J = 15.0,
J = 9.8, J = 5.3) and 2.62 (1H, dt, J = 15.0, J = 5.4, 4-CH2); 3.36-3.42 (1H, m) and 3.49-3.54 (1H, m, 5-CH2
proline); 4.54 (1H, dd, J = 8.0, J = 3.6, 2-СН proline); 4.67 (1H, sextet, J = 6.9, 2-СН); 6.96 (1H, d, J = 7.7,
H naphthyl); 7.18 (1H, td, J = 7.5, J = 1.5, H-6); 7.23 (1H, td, J = 7.5, J = 1.3, H-7); 7.29 (1H, d, J = 7.5, H-5);
7.42 (1H, t, J = 7.8, H naphthyl); 7.51 (1H, ddd, J = 8.5, J = 7.0, J = 1.4, H naphthyl); 7.58 (1H, ddd, J = 8.1,
J = 7.0, J = 1.4, H naphthyl); 7.71 (1H, d, J = 7.5, H-8); 7.99 (1H, dm, J = 8.2, H-4 naphthyl); 8.12 (1H, dm,
J = 8.2, H naphthyl); 8.46 (1H, d, J = 8.6, H naphthyl). Found, %: C 68.93; H 5.94; N 6.36; S 7.54.
C25H26N2O3S. Calculated, %: C 69.10; H 6.03; N 6.45; S 7.38.
2-Methyl-N-[N'-(1-naphthylsulfonyl)prolyl]-1,2,3,4-tetrahydroquinoline (6c) (mixture of diastereo-
isomers). Yield 96 mg (44%) after flash chromatography. Colorless amorphous powder. HPLC (hexane–2-PrOH,
1
20:1): (R,S)/(S,S) = 52:48; τR (S,S)-6c 6.6 min, τR (R,S)-6c 7.7 min. H NMR spectrum, δ, ppm (J, Hz): 0.98
(1.44H, d, J = 6.5, CH3 (S,S)); 1.02 (1.56H, d, J = 6.5, CH3 (R,S)); 1.24-1.32 (1H, m, 3-CHB); 1.52-1.66 (1.96H,
m, 3-CHB proline (S,S), 4-CHB proline (R,S), 4-CH2 proline (S,S)); 1.85-1.92 (0.48H, m, 3-CHA proline (S,S));
2.00-2.11 (1.56H, m, 3-CH2 proline (R,S), 4-CHA proline (R,S)); 2.25-2.34 (1H, m, 3-CHA); 2.38-2.46 (0.48H,
m, 4-CHB (S,S)); 2.53-2.65 (1.52H, m, 4-CH2 (R,S), 4-CHA (S,S)); 3.37-3.54 (2H, m, 5-CH2 proline); 4.54
(0.52H, dd, J = 7.8, J = 3.6, 2-СН proline (R,S)); 4.58-4.71 (1H, m, 2-СН); 5.13 (0.48H, dd, J = 8.2, J = 3.9, 2-СН
proline (S,S)); 6.96 (0.52H, d, J = 8.0, H naphthyl (R,S)); 7.15-7.71 (7H, m, H Ar); 7.98-8.24 (2.48H, m,
H naphthyl); 8.46 (0.52H, d, J = 8.6, H naphthyl (R,S)); 8.76 (0.48H, d, J = 8.4, H naphthyl (S,S)). Found, %:
C 69.13; H 6.02; N 6.41; S 7.36. C25H26N2O3S. Calculated, %: C 69.10; H 6.03; N 6.45; S 7.38.
(3R,2'S)-7,8-Difluoro-3-methyl-N-(N'-methylsulfonylprolyl)-2,3-dihydro-4H-1,4-benzoxazine ((R,S)-7a).
Yield 69 mg (38%) after flash chromatography (slow-eluting diastereomer). Yellowish powder. Mp 73-77°С.
[α]D20 -178° (c 1.2, CHCl3). HPLC (hexane–2-PrOH, 5:1): de > 99%, τR 16.8 min. 1H NMR spectrum, δ, ppm (J,
Hz): 1.16 (3H, d, J = 6.8, 3-CH3); 1.92-2.09 (3H, m, 3-CHB proline, 4-CH2 proline); 2.31-2.40 (1H, m, 3-CHA
proline); 2.87 (3H, s, CH3SO2); 3.39-3.47 (2H, m, 5-CH2 proline); 4.21 (1H, dd, J = 11.0, J = 2.9) and 4.35 (1H,
dd, J = 11.0, J = 1.4, 2-CH2); 4.71-4.76 (2H, m, 2-СН proline, 3-СН); 6.88 (1H, ddd, J = 10.1, J = 9.6, J = 8.1,
19
H-6); 7.45-7.53 (1H, m, H-5). F NMR spectrum, δ, ppm: 2.2-2.3 (1F, m, F-8); 21.0-21.1 (1F, m, F-7). Found,
m/z: 361.1032 [M+H]+. C15H19F2N2O4S. Calculated, m/z: 361.1028.
7,8-Difluoro-3-methyl-N-[N'-methylsulfonyl-(S)-prolyl]-2,3-dihydro-4H-1,4-benzoxazine
(7a)
(mixture of diastereoisomers). Yield 54 mg (30%) after flash chromatography. Yellow amorphous powder.
HPLC (hexane–2-PrOH, 5:1): (R,S)/(S,S) = 68:32; τR (S,S)-7a 10.3 min, τR (R,S)-7a 16.8 min. H NMR
1
spectrum, δ, ppm (J, Hz): 1.14-1.18 (3H, m, 3-CH3); 1.85-2.09 (3H, m, 3-CHB proline, 4-CH2 proline);
2.15-2.24 (0.32H, m, 3-CHA proline (S,S)); 2.31-2.40 (0.68H, m, 3-CHA proline (R,S)); 2.87 (2.04H, s, CH3SO2
(R,S)); 2.94 (0.96H, s, CH3SO2 (S,S)); 3.39-3.47 (2H, m, 5-CH2 proline); 4.12 (0.32H, dd, J = 11.0, J = 2.9,
2-CHB (S,S)); 4.21 (0.68H, dd, J = 11.0, J = 2.9, 2-CHB (R,S)); 4.34-4.39 (1H, m, 2-CHA); 4.71-4.76 (1.36H, m,
2-CH proline (R,S), 3-CH (R,S)); 4.85 (0.32H, qdd, J = 6.8, J = 2.9, J = 1.4, 3-CH (S,S)); 4.99 (0.32H, dd, J = 8.3,
J = 4.4, 2-CH proline (S,S)); 6.85-6.92 (1H, m, H-6); 7.47-7.53 (1H, m, H-5). 19F NMR spectrum, δ, ppm:
2.2-2.3 (1F, m, F-8); 20.9-21.1 (1F, m, F-7). Found, %: C 50.00; H 5.17; F 10.37; N 7.73. C15H18F2N2O4S.
Calculated, %: C 49.99; H 5.03; F 10.54; N 7.77.
(3R,2'S)-3-Methyl-N-[N'-methylsulfonylprolyl]-2,3-dihydro-4H-1,4-benzoxazine ((R,S)-7b). Yield
71 mg (44%) after flash chromatography (slow-eluting diastereomer). Yellowish powder. Mp 105-108°С.
848

[α]D20 -240° (c 1.0, CHCl3). HPLC (hexane–2-PrOH–MeOH, 100:8:2): de > 99%, τR 14.4 min. 1H NMR spectrum,
δ, ppm (J, Hz): 1.13 (3H, d, J = 6.8, 3-CH3); 1.92-2.10 (3H, m, 3-CHB proline, 4-CH2 proline); 2.34-2.41 (1H,
m, 3-CHA proline); 2.93 (3H, s, CH3SO2); 3.39-3.47 (2H, m, 5-CH2 proline); 4.14 (1H, dd, J = 10.9, J = 2.8) and
4.19 (1H, dd, J = 10.9, J = 1.7, 2-CH2); 4.68-4.72 (1H, m, 3-СН); 4.75 (1H, dd, J = 8.4, J = 4.0, 2-СН proline);
6.85-6.90 (2H, m, H-7,8); 7.05 (1H, ddd, J = 8.2, J = 7.3, J = 1.5, H-6); 7.55-7.60 (1H, m, H-5). Found, %:
C 55.54; H 6.28; N 8.45; S 9.92. C15H20N2O4S. Calculated, %: C 55.54; H 6.21; N 8.64; S 9.88.
(3S,2'S)-3-Methyl-N-[N'-methylsulfonylprolyl]-2,3-dihydro-4H-1,4-benzoxazine ((S,S)-7b). Yield
21 mg (13%) after flash chromatography (fast-eluting diastereomer). Yellowish powder. Mp 48-54°С.
[α]D20 +95.9° (c 1.0, CHCl3). HPLC (hexane–2-PrOH–MeOH, 100:8:2): de > 99%, τR 9.0 min. 1H NMR spectrum, δ,
ppm (J, Hz): 1.12 (3H, d, J = 6.8, 3-CH3); 1.81-1.94 (2H, m, 4-CH2 proline); 1.98-2.06 (1H, m) and 2.11-2.18
(1H, m, 3-CHA proline); 2.95 (3H, s, CH3SO2); 3.43 (2H, t, J = 6.8, 5-CH2 proline); 4.07 (1H, dd, J = 10.9, J = 3.0)
and 4.20 (1H, dd, J = 10.9, J = 1.7, 2-CH2); 4.78 (1H, qdd, J = 6.8, J = 3.0, J = 1.7, 3-СН); 5.03 (1H, dd, J = 8.4,
J = 4.4, 2-СН proline); 6.85-6.91 (2H, m, H-7,8); 7.05 (1H, ddd, J = 8.2, J = 7.3, J = 1.5, H-6); 7.63-7.67 (1H,
m, H-5). Found, %: C 55.97; H 6.30; N 8.38; S 10.03. C15H20N2O4S. Calculated, %: C 55.54; H 6.21; N 8.64;
S 9.88.
(2R,2'S)-2-Methyl-N-[N'-methylsulfonylprolyl]-1,2,3,4-tetrahydroquinoline ((R,S)-7c). Yield 27 mg
(17%) after flash chromatography (fast-eluting diastereomer). Colorless powder. Mp 130-132°С. [α]D20 -334°
(c 0.5, CHCl3). HPLC (hexane–2-PrOH, 10:1): de > 99%, τR 11.2 min. 1H NMR spectrum, δ, ppm (J, Hz): 1.02
(3H, d, J = 6.5, 2-CH3); 1.26-1.34 (1H, m, 3-CHB); 1.86-1.93 (1H, m, 4-CHB proline); 2.07-2.15 (2H, m, 3-CHB
proline, 4-CHA proline); 2.27-2.35 (2H, m, 3-CHA, 3-CHA proline); 2.51-2.63 (2H, m, 4-CH2); 2.73 (3H, s,
CH3SO2); 3.36 (1H, ddd, J = 9.2, J = 7.3, J = 5.7) and 3.42 (1H, dt, J = 9.2, J = 6.7, 5-CH2 proline); 4.42 (1H,
dd, J = 8.3, J = 3.8, 2-СН proline); 4.69 (1H, sеxtеt, J = 6.8, 2-СН); 7.12-7.23 (4H, m, H-5,6,7,8). Found, %:
C 59.49; H 7.00; N 8.74; S 9.98. C16H22N2O3S. Calculated, %: C 59.60; H 6.88; N 8.69; S 9.94.
(2S,2'S)-2-Methyl-N-[N'-methylsulfonylprolyl]-1,2,3,4-tetrahydroquinoline ((S,S)-7c). Yield 13 mg
20
(8%) after flash chromatography (fast-eluting diastereomer). Pale-yellow oil. [α]D +198° (c 0.5, CHCl3).
HPLC (hexane–2-PrOH, 10:1): de 96.2 %, τR 8.3 min. 1H NMR spectrum, δ, ppm (J, Hz): 1.02 (3H, d, J = 6.6,
2-CH3); 1.26-1.34 (1H, m, 3-CHB); 1.57-1.63 (1H, m, 4-CHB proline); 1.76-1.96 (3H, m, 3-CH2 proline, 4-CHA
proline); 2.30 (1H, ddt, J = 13.1, J = 7.5, J = 5.5, 3-CHA); 2.42-2.50 (1H, m) and 2.64 (1H, dt, J = 15.0, J = 5.4,
4-CH2); 2.94 (3H, s, CH3SO2); 3.35-3.43 (2H, m, 5-CH2 proline); 4.68 (1H, dquin, J = 7.5, J = 6.6, 2-СН); 4.93
(1H, dd, J = 8.2, J = 4.2, 2-СН proline); 7.15 (1H, td, J = 7.4, J = 1.2, H-6); 7.20-7.24 (2H, m, H-5,7); 7.37-7.39
(1H, m, H-8). Found, %: C 59.84; H 7.07; N 8.42; S 9.83. C16H22N2O3S. Calculated, %: C 59.60; H 6.88;
N 8.69; S 9.95.
(3R,2'S)-N-[N'-tert-Butylsulfonylprolyl]-7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazine
((R,S)-8a). Yield 48 mg (24%) after recrystallization from EtOH. Colorless crystals. Mp 162-164°С.
1
[α]D20 -172° (c 1.0, CHCl3). HPLC (hexane–2-PrOH, 20:1): de 99.4%, τR 13.6 min. H NMR spectrum, δ, ppm
(J, Hz): 1.15 (3H, d, J = 6.8, 3-CH3); 1.26 (9H, s, С(CH3)3); 1.85-2.12 (3H, m, 3-CHB proline, 4-CH2 proline);
2.31-2.41 (1H, m, 3-CHA proline); 3.48-3.62 (2H, m, 5-CH2 proline); 4.20 (1H, dd, J = 10.9, J = 2.8) and 4.34
(1H, dd, J = 10.9, J = 1.4, 2-CH2); 4.72-4.78 (1H, m, 3-СН); 4.87 (1H, dd, J = 8.2, J = 3.6, 2-СН proline); 6.87
19
(1H, ddd, J = 10.1, J = 9.6, J = 8.2, H-6); 7.38-7.50 (1H, m, H-5). F NMR spectrum, δ, ppm (J, Hz): 2.3-2.4
(1F, m, F-8); 20.9-21.2 (1F, m, F-7). Found, %: C 53.66; H 6.10; F 9.54; N 6.69; S 7.83. C18H24F2N2O4S.
Calculated, %: C 53.72; H 6.01; F 9.44; N 6.96; S 7.97.
N-[N'-tert-Butylsulfonyl-(S)-prolyl]-7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazine
(8a)
(mixture of diastereoisomers). Yield 38 mg (19%) after flash chromatography. Colorless oil. HPLC (hexane–
1
2-PrOH, 20:1): (R,S)/(S,S) = 65:35; τR (S,S)-8a 7.0 min, τR (R,S)-8a 13.6 min. H NMR spectrum, δ, ppm (J,
Hz): 1.13-1.16 (3H, m, 3-CH3); 1.26 (5.85H, s, С(CH3)3 (R,S)); 1.32 (3.15H, s, С(CH3)3 (S,S)); 1.78-2.25
(3.35H, m, 3-CH2 proline (S,S), 3-CHB proline (R,S), 4-CH2 proline); 2.32-2.40 (0.65H, m, 3-CHA proline
(R,S)); 3.45-3.63 (2H, m, 5-CH2 proline); 4.11 (0.35H, dd, J = 11.1, J = 2.9, 2-CHB (S,S)); 4.20 (0.65H, dd,
J = 11.0, J = 2.8, 2-CHB (R,S)); 4.34 (0.65H, dd, J = 11.0, J = 1.4, 2-CHA (R,S)); 4.38 (0.35H, dd, J = 11.1,
849

J = 1.5, 2-CHA (S,S)); 4.72-4.78 (0.65H, m, 3-СН (R,S)); 4.80-4.89 (1H, m, 3-СН (S,S), 2-СН proline (R,S));
5.10 (0.35H, dd, J = 8.3, J = 3.7, 2-СН proline (S,S)); 6.84-6.93 (1H, m, H-6); 7.40-7.53 (1H, m, H-5). 19F NMR
spectrum, δ, ppm: 2.3-2.5 (1F, m, F-8); 20.9-21.3 (1F, m, F-7). Found, %: C 53.90; H 6.19; F 9.63; N 6.73;
S 8.21. C18H24F2N2O4S. Calculated, %: C 53.72; H 6.01; F 9.44; N 6.96; S 7.97.
(3R,2'S)-N-[N'-tert-Butylsulfonylprolyl]-3-methyl-2,3-dihydro-4H-1,4-benzoxazine
((R,S)-8b).
20
Yield 59 mg (32%) after recrystallization from EtOH. Colorless crystals. Mp 109-110°С. [α]D -190° (c 1.0,
CHCl3). HPLC (hexane–2-PrOH, 20:1): de 98.2%, τR 8.3 min. 1H NMR spectrum, δ, ppm (J, Hz): 1.12 (3H, d,
J = 6.8, 3-CH3); 1.24 (9H, s, С(CH3)3); 1.85-2.14 (3H, m, 3-CHB proline, 4-CH2 proline); 2.32-2.41 (1H, m,
3-CHA proline); 3.50-3.63 (2H, m, 5-CH2 proline); 4.13 (1H, dd, J = 11.0, J = 2.8) and 4.18 (1H, dd, J = 11.0,
J = 1.8, 2-CH2); 4.67-4.75 (1H, m, 3-СН); 4.92 (1H, dd, J = 8.4, J = 3.6, 2-СН proline); 6.83-6.90 (2H, m,
H-7,8); 7.02-7.07 (1H, m, H-6); 7.48-7.57 (1H, m, H-5). Found, %: C 58.87; H 7.06; N 7.39; S 8.47.
C18H26N2O4S. Calculated, %: C 58.99; H 7.15; N 7.64; S 8.75.
N-[N'-tert-Butylsulfonyl-(S)-prolyl]-3-methyl-2,3-dihydro-4H-1,4-benzoxazine (8b) (mixture of
diastereoisomers). Yield 35 mg (19%) after flash chromatography. Colorless oil. HPLC (hexane–2-PrOH, 20:1):
(R,S)/(S,S) = 70:30; τR (S,S)-8b 5.3 min, τR (R,S)-8b 8.3 min. 1H NMR spectrum, δ, ppm (J, Hz): 1.10-1.16 (3H,
m, 3-CH3); 1.24 (6.3H, s, С(CH3)3 (R,S)); 1.33 (2.7H, s, С(CH3)3 (S,S)); 1.73-2.15 (3.3H, m, 3-CH2 proline
(S,S), 3-CHB proline (R,S), 4-CH2 proline); 2.32-2.41 (0.7H, m, 3-CHA proline (R,S)); 3.45-3.64 (2H, m, 5-CH2
proline); 4.06 (0.3H, dd, J = 11.0, J = 3.2, 2-CHB (S,S)); 4.12-4.23 (1.7H, m, 2-CH2 (R,S), 2-CHA (S,S));
4.67-4.75 (0.7H, m, 3-СН (R,S)); 4.75-4.82 (0.3H, m, 3-СН (S,S)); 4.92 (0.7H, dd, J = 8.6, J = 3.6, 2-СН
proline (R,S)); 5.17 (0.3H, dd, J = 8.4, J = 3.6, 2-СН proline (S,S)); 6.83-6.90 (2H, m, H-7,8); 7.03-7.07 (1H, m,
H-6); 7.48-7.57 (0.7H, m, H-5 (R,S)); 7.61-7.64 (0.3H, m, H-5 (S,S)). Found, %: C 59.18; H 7.37; N 7.39;
S 9.01. C18H26N2O4S. Calculated, %: C 58.99; H 7.15; N 7.64; S 8.75.
(3R,2'S)-7,8-Difluoro-3-methyl-N-(N'-tosylindolin-2-ylcarbonyl)-2,3-dihydro-4H-1,4-benzoxazine
((R,S)-9a). Yield 61 mg (25%) after flash chromatography (slow-eluting diastereomer). Colorless powder.
20
1
Mp 169-170°С. [α]D -141° (c 0.82, CHCl3). HPLC (hexane–2-PrOH, 40:1): de > 99%, τR 7.8 min. H NMR
spectrum, δ, ppm (J, Hz): 1.22 (3H, d, J = 6.9, 3-CH3); 2.33 (3H, s, ArCH3); 3.14 (1H, dd, J = 16.3, J = 5.8) and
3.51 (1H, dd, J = 16.3, J = 10.5, 3-CH2 indoline); 4.33 (1H, dd, J = 10.9, J = 3.0) and 4.41 (1H, dd, J = 10.9,
J = 1.4, 2-CH2); 4.88-4.93 (1H, m, 3-СН); 5.25 (1H, dd, J = 10.5, J = 5.8, 2-СН indoline); 6.91 (1H, ddd,
J = 10.0, J = 9.5, J = 8.1, H-6); 6.98 (1H, td, J = 7.5, J = 1.0, H indoline); 7.13-7.19 (2H, m, H indoline); 7.26
(2H, d, J = 8.1, H Ts); 7.34-7.38 (2H, m, H-5, H indoline); 7.44 (2H, br. d, J = 8.1, H Ts). 19F NMR spectrum, δ,
ppm: 2.6-2.7 (1F, m, F-8); 21.7-22.0 (1F, m, F-7). Found, %: C 61.95; H 4.54; F 7.44; N 5.95; S 6.72.
C25H22F2N2O4S. Calculated, %: C 61.97; H 4.58; F 7.84; N 5.78; S 6.62.
(3R,2'S)-3-Methyl-N-(N'-tosylindolin-2-ylcarbonyl)-2,3-dihydro-4H-1,4-benzoxazine
((R,S)-9b).
Yield 90 mg (40%) after flash chromatography (slow-eluting diastereomer). Colorless powder. Mp 184-187°С.
[α]D20 -162° (c 1.1, CHCl3). HPLC (hexane–2-PrOH, 40:1): de 98.4%, τR 6.9 min. 1H NMR spectrum, δ, ppm (J,
Hz): 1.18 (3H, d, J = 6.7, 3-CH3); 2.30 (3H, s, ArCH3); 3.16 (1H, dd, J = 16.3, J = 6.3) and 3.52 (1H, dd, J = 16.3,
J = 10.4, 3-CH2 indoline); 4.24 (1H, dd, J = 10.8, J = 1.5) and 4.32 (1H, dd, J = 10.8, J = 3.0, 2-CH2); 4.88-4.95
(1H, m, 3-СН); 5.23 (1H, dd, J = 10.4, J = 6.3, 2-СН indoline); 6.91 (1H, ddd, J = 8.1, J = 7.4, J = 1.3,
H indoline); 6.96-7.00 (2H, m, H indoline); 7.12-7.38 (9H, m, H Ar). Found, %: C 66.83; H 5.30; N 6.33;
S 7.10. C25H24N2O4S. Calculated, %: C 66.95; H 5.39; N 6.25; S 7.15.
3-Methyl-N-(N'-tosyl-(S)-indolin-2-ylcarbonyl)-2,3-dihydro-4H-1,4-benzoxazine (9b) (mixture of
diastereoisomers). Yield 168 mg (12%) after flash chromatography. Colorless amorphous powder. HPLC
1
(hexane–2-PrOH, 40:1): (R,S)/(S,S) = 70:30; τR (S,S)-9b 5.9 min, τR (R,S)-9b 6.9 min. H NMR spectrum, δ,
ppm (J, Hz): 1.17-1.20 (3H, m, 3-CH3); 2.30 (2.1H, s, ArCH3 (R,S)); 2.34 (0.9H, s, ArCH3 (S,S)); 2.93-2.97
(0.3H, m, 3-CHB indoline (S,S)); 3.16 (0.7H, dd, J = 16.3, J = 6.3, 3-CHB indoline (R,S)); 3.28 (0.3H, dd,
J = 16.0, J = 10.8, 3-CHA indoline (S,S)); 3.52 (0.7H, dd, J = 16.3, J = 10.5, 3-CHA indoline (R,S)); 4.18 (0.3H,
dd, J = 10.9, J = 2.9, 2-CHB (S,S)); 4.22-4.27 (1H, m, 2-CHB (R,S), 2-CHA (S,S)); 4.32 (0.7H, dd, J = 10.8,
J = 3.0, 2-CHA (R,S)); 4.80-4.85 (0.3H, m, 3-CH (S,S)); 4.88-4.95 (0.7H, m, 3-CH (R,S)); 5.23 (0.7H, dd,
850

J = 10.5, J = 6.3, 2-CH indoline (R,S)); 5.66 (0.3H, dd, J = 10.8, J = 4.8, 2-CH indoline (S,S)); 6.89-7.39
(11.1H, m, H Ar); 7.70-7.76 (0.9H, m, H Ar). Found, %: C 66.86; H 5.19; N 6.26; S 7.15. C25H24N2O4S.
Calculated, %: C 66.95; H 5.39; N 6.25; S 7.15.
(2R,2'S)-2-Methyl-N-(N'-tosylindolin-2-ylcarbonyl)-1,2,3,4-tetrahydroquinoline ((R,S)-9c). Yield
56 mg (25%) after flash chromatography (slow-eluting diastereomer). Colorless amorphous powder.
[α]D20 -184° (c 0.7, CHCl3). HPLC (hexane–2-PrOH, 40:1): de 95.6%, τR 10.6 min. 1H NMR spectrum, δ, ppm
(J, Hz): 1.09 (3H, d, J = 6.5, 2-CH3); 1.35 (1H, dddd, J = 13.0, J = 9.8, J = 7.3, J = 5.8) and 2.44 (1H, ddt,
J = 13.0, J = 7.6, J = 5.3, 3-CH2); 2.27 (3H, s, ArCH3); 2.63-2.78 (2H, m, 4-CH2); 3.19 (1H, dd, J = 16.2,
J = 6.6) and 3.38 (1H, dd, J = 16.2, J = 10.3, 3-CH2 indoline); 4.81 (1H, sextet, J = 6.9, 2-СН); 4.87 (1H, dd,
J = 10.3, J = 6.6, 2-СН indoline); 6.94-7.39 (12H, m, H Ar). Found, %: C 70.18; H 5.99; N 6.17; S 7.03.
C26H26N2O3S. Calculated, %: C 69.93; H 5.87; N 6.27; S 7.18.
(3R,2'S)-7,8-Difluoro-3-methyl-4-(N'-methyl-N'-tosylphenylalanyl)-2,3-dihydro-4H-1,4-benzoxazine
((R,S)-10a). Yield 135 mg (54%) after recrystallization from mixture hexane–EtOAc. Colorless powder.
Mp 150-151°C. [α]D -134° (c 1.0, CHCl3). HPLC (hexane–2-PrOH, 160:1): de > 99.5%, τR 10.7 min. 1H NMR
20
spectrum, δ, ppm (J, Hz): 1.12 (3H, d, J = 6.8, 3-CH3); 2.37 (3H, s, ArCH3); 2.74 (1H, dd, J = 13.8, J = 7.0) and
3.24 (1H, dd, J = 13.8, J = 8.0, CH2Ph); 2.95 (3H, s, NCH3); 3.71 (1H, dd, J = 10.9, J = 2.7) and 4.22 (1H, dd,
J = 10.9, J = 1.3, 2-CH2); 4.62-4.67 (1H, m, 3-СН); 5.20 (1H, dd, J = 8.0, J = 7.0, NCHCO); 6.80 (1H, td, J = 9.8,
J = 8.0, H-6); 6.87-6.95 (1H, m, H Ph); 7.12-7.14 (2H, m, H Ph); 7.20-7.29 (5H, m, H-5, H Ts, H Ph); 7.38 (2H, d,
J = 8.2, H Ts). 19F NMR spectrum, δ, ppm: 2.3-2.4 (1F, m, F-8); 21.5-21.7 (1F, m, F-7). Found, %: C 62.21; H 4.96;
N 5.60; F 7.19; S 6.56. C26H26F2N2O4S. Calculated, %: C 62.39; H 5.24; N 5.60; F 7.59; S 6.41.
7,8-Difluoro-3-methyl-4-(N'-methyl-N'-tosyl-(S)-phenylalanyl)-2,3-dihydro-4H-1,4-benzoxazine
(10a) (mixture of diastereoisomers). Yield 153 mg (61%) after flash chromatography. Colorless powder.
Mp 139-142°C. HPLC (hexane–2-PrOH, 160:1): (R,S)/(S,S) = 87:13; τR (S,S)-10a 8.1 min, τR (R,S)-10a
1
10.7 min. H NMR spectrum, δ, ppm (J, Hz): 0.88 (0.39H, d, J = 6.8, 3-CH3 (S,S)); 1.12 (2.61H, d, J = 6.8,
3-CH3 (R,S)); 2.37 (2.61H, s, ArCH3 (R,S)); 2.39 (0.39H, s, ArCH3 (S,S)); 2.60 (0.13H, dd, J = 13.4, J = 5.8,
3-CHB phenylalanine (S,S)); 2.74 (0.87H, dd, J = 13.7, J = 7.0, 3-CHB phenylаlanine (R,S)); 2.95 (2.61H, s,
NCH3 (R,S)); 3.00 (0.39H, s, NCH3 (S,S)); 3.08 (0.13H, dd, J = 13.4 J = 9.0, 3-CHA phenylаlanine (S,S)); 3.24
(0.87H, dd, J = 13.7, J = 8.0, 3-CHA phenylаlanine (R,S)); 3.72 (0.87H, dd, J = 11.0, J = 2.8, 2-CHB (R,S)); 3.87
(0.13H, br. d, J = 11.0, 2-CHB (S,S)); 4.22 (0.87H, dd, J = 11.0, J = 1.5, 2-CHA (R,S)); 4.25 (0.13H, dd,
J = 11.0, J = 1.5, 2-CHA (S,S)); 4.62-4.67 (0.87H, m, 3-CH (R,S)); 4.74-4.80 (0.13H, m, 3-CH (S,S)); 5.20
(0.87H, dd, J = 8.0, J = 7.0, NCHCO (R,S)); 5.24 (0.13H, dd, J = 9.0, J = 5.8, NCHCO (S,S)); 6.80 (0.87H, td,
J = 9.8, J = 8.0, H-6 (R,S)); 6.86-6.99 (1.13H, m, H-6 (S,S), H Ph); 7.12-7.40 (8.61H, m, H-5 (R,S), H Ph,
H Ts); 7.49-7.54 (0.13H, m, H-5 (S,S)); 7.63 (0.26H, d, J = 8.2, H Ts (S,S)). 19F NMR spectrum, δ, ppm: 2.3-2.4
(0.87F, m, F-8 (R,S)); 2.6-2.7 (0.13F, m, F-8 (S,S)); 21.5-21.8 (1F, m, F-7). Found, %: C 62.20; H 5.15; N 5.56;
S 6.53. C26H26F2N2O4S. Calculated, %: C 62.39; H 5.24; N 5.60; S 6.41.
3-Methyl-4-(N'-methyl-N'-tosyl-(S)-phenylanalyl)-2,3-dihydro-4H-1,4-benzoxazine (10b) (mixture
diastereoisomers). Yield 233 mg (80%) after flash chromatography. Colorless amorphous powder. HPLC
(hexane–2-PrOH, 80:1): (R,S)/(S,S) = 45:55; τR (S,S)-10b 5.6 min, τR (R,S)-10b 6.3 min. 1H NMR spectrum, δ,
ppm (J, Hz): 0.89 (1.65H, d, J = 6.8, 3-CH3 (S,S)); 1.10 (1.35H, d, J = 6.8, 3-CH3 (R,S)); 2.37 (1.35H, s, ArCH3
(R,S)); 2.38 (1.65H, s, ArCH3 (S,S)); 2.61 (0.55H, dd, J = 13.5, J = 6.6, 3-CHB phenylalanine (S,S)); 2.76
(0.45H, dd, J = 13.9, J = 7.1, 3-CHB phenylalanine (R,S)); 2.97 (1.35H, s, NCH3 (R,S)); 3.00 (1.65H, s, NCH3
(S,S)); 3.03 (0.55H, dd, J = 13.5, J = 8.5, 3-CHA phenylalanine (S,S)); 3.25 (0.45H, dd, J = 13.9, J = 7.8, 3-CHA
phenylаlanine (R,S)); 3.65 (0.45H, dd, J = 10.9, J = 2.4, 2-CHB (R,S)); 3.82 (0.55H, dd, J = 11.0, J = 3.0, 2-CHB
(S,S)); 4.04 (0.45H, dd, J = 10.9, J = 1.6, 2-CHA (R,S)); 4.10 (0.55H, dd, J = 11.0, J = 1.7, 2-CHA (S,S));
4.54-4.60 (0.45H, m, 3-CH (R,S)); 4.71 (0.55H, qdd, J = 6.8, J = 3.0, J = 1.7, 3-CH (S,S)); 5.25 (0.45H, t,
J = 7.6, NCHCO (R,S)); 5.30 (0.55H, br. t, J = 7.8, NCHCO (S,S)); 6.77-7.68 (13H, m, H Ar). Found, %:
C 67.18; H 6.25; N 5.81; S 6.98. C26H28N2O4S. Calculated, %: C 67.22; H 6.07; N 6.03; S 6.90.
851

2-Methyl-N-(N'-methyl-N'-tosyl-(S)-phenylalanyl)-1,2,3,4-tetrahydroquinoline (10c) (mixture of
diastereoisomers). Yield 104 mg (45%) after flash chromatography. Colorless amorphous powder. HPLC
1
(hexane–2-PrOH–MeOH, 1000:8:4): (R,S)/(S,S) = 50:50; τR (R,S)-10c 6.5 min, τR (S,S)-10c 7.0 min. H NMR
spectrum, δ, ppm (J, Hz): 0.93 (1.5H, d, J = 6.5, 2-CH3 (S,S)); 0.97 (1.5H, d, J = 6.5, 2-CH3 (R,S)); 1.17-1.27
(1H, m, 3-CHB); 2.08-2.21 (1.5H, m, 3-CHA, 3-CHB phenylalanine (S,S)); 2.34-2.40 (3.5H, m, 4-CHB (R,S),
ArCH3); 2.48-2.56 (1H, m, 4-CHA (R,S), 4-CHB (S,S)); 2.59-2.65 (1H, m, 4-CHA (S,S), 3-CHA phenylalanine
(S,S)); 2.71 (0.5H, dd, J = 13.7, J = 7.0, 3-CHB phenylalanine (R,S)); 2.90 (1.5H, s, NCH3 (R,S)); 3.03 (1.5H, s,
NCH3 (S,S)); 3.29 (0.5H, dd, J = 13.7, J = 7.9, 3-CHA phenylalanine (R,S)); 4.55-4.58 (1H, m, 2-CH); 5.05
(0.5H, t, J = 7.5, NCHCO (R,S)); 5.32 (0.5H, t, J = 7.5, NCHCO (S,S)); 6.47-7.49 (13H, m, H Ar). Found, %:
C 70.03; H 6.54; N 6.06; S 6.86. C27H30N2O3S. Calculated, %: C 70.10; H 6.54; N 6.06; S 6.93.
(3R,2'S)-7,8-Difluoro-3-methyl-N-[tetrahydrofuran-2-ylcarbonyl]-2,3-dihydro-4H-1,4-benzoxazine
((R,S)-11a). Yield 46.1 mg (31%) after flash chromatography (slow-eluting diastereomer). Yellowish powder.
20
1
Mp 69-72°С. [α]D -38.5° (c 1.3, CHCl3). HPLC (hexane–2-PrOH, 20:1): de > 99%, τR 11.7 min. H NMR
spectrum, δ, ppm (J, Hz): 1.18 (3H, d, J = 6.8, CH3); 1.82-1.96 (2H, m, 4-CH2 tetrahydrofuran); 2.04-2.11 (1H,
m) and 2.19-2.25 (1H, m, 3-CH2 tetrahydrofuran); 3.80 (1H, td, J = 7.7, J = 6.1) and 3.85 (1H, td, J = 7.7,
J = 6.7, 5-CH2 tetrahydrofuran); 4.20 (1H, dd, J = 11.0, J = 2.8) and 4.35 (1H, dd, J = 11.0, J = 1.6, 2-CH2);
4.74 (1H, qdd, J = 6.8, J = 2.8, J = 1.6, 3-СН); 4.83 (1H, dd, J = 7.7, J = 5.1, 2-СН tetrahydrofuran); 6.84 (1H,
ddd, J = 10.2, J = 9.6, J = 8.2, H-6); 7.59 (1H, ddd, J = 9.6, J = 5.5, J = 2.6, H-5). 19F NMR spectrum, δ, ppm
(J, Hz): 1.8 (1F, ddd, J = 21.0, J = 8.2, J = 2.6, F-8); 20.3 (1F, ddd, J = 21.0, J = 10.2, J = 5.5, F-7). Found, %:
C 59.38; H 5.48; F 13.27; N 4.99. C14H15F2N2O3. Calculated, %: C 59.36; H 5.34; F 13.41; N 4.94.
(3S,2'S)-7,8-Difluoro-3-methyl-N-[tetrahydrofuran-2-ylcarbonyl]-2,3-dihydro-4H-1,4-benzoxazine
((S,S)-11a). Yield 25.3 mg (17%) after flash chromatography (fast-eluting diastereomer). Yellowish powder.
Mp 82-85°С. [α]D20 +137° (c 0.5, CHCl3). HPLC (hexane–2-PrOH, 20:1): de 99.0%, τR 6.2 min. 1H NMR spectrum,
δ, ppm (J, Hz): 1.14 (3H, d, J = 6.9, CH3); 1.82-1.90 (1H, m, 4-CHB tetrahydrofuran); 1.94-2.01 (2H, m, 3-CHB
tetrahydrofuran, 4-CHA tetrahydrofuran); 2.13-2.21 (1H, m, 3-CHA tetrahydrofuran); 3.80 (1H, td, J = 7.8, J = 5.6)
and 3.84 (dt, J = 7.8, J = 6.7, 5-CH2 tetrahydrofuran); 4.17 (1H, dd, J = 10.9, J = 2.9) and 4.37 (1H, dd, J = 10.9,
J = 1.5, 2-CH2); 4.76 (1H, dd, J = 7.1, J = 5.7, 2-СН tetrahydrofuran); 4.87 (1H, qdd, J = 6.9, J = 2.9, J = 1.5,
19
3-СН); 6.87 (1H, ddd, J = 10.1, J = 9.6, J = 8.2, H-6); 7.63 (1H, ddd, J = 9.6, J = 5.3, J = 2.5, H-5). F NMR
spectrum, δ, ppm (J, Hz): 2.1 (1F, ddd, J = 21.0, J = 8.2, J = 2.5, F-8); 20.7 (1F, ddd, J = 21.0, J = 10.1, J = 5.3,
F-7). Found, %: C 59.64; H 5.47; F 13.30; N 4.96. C14H15F2NO3. Calculated, %: C 59.36; H 5.34; F 13.41;
N 4.94.
(3S,2'S)-3-Methyl-N-[N'-(2-naphthylsulfonyl)prolyl]-2,3-dihydro-4H-1,4-benzoxazine ((S,S)-5b). A
solution of acyl chloride 2b (324 mg, 1 mmol) in MeCN (10 ml) was added to a solution of amine (S)-3b (149
mg, 1 mmol) and N,N-diethylaniline (149 mg, 1 mmol) in MeCN (10 ml) at 20°C. Benzene (10 ml) was added
to the reaction mixture after 24 h, the solution was washed with 1 N HCl (2×10 ml), saturated NaCl solution
(3×15 ml), 5% NaHCO3 solution (2×15 ml), H2O (2×15 ml), dried over MgSO4, and evaporated. The residue
was recrystallized from a hexane–EtOAc mixture. Yield 275 mg (63%). Colorless powder. Mp 141-142°С.
20
1
[α]D +121° (c 1.2, CHCl3). HPLC (hexane–2-PrOH, 20:1): de 98.6%, τR 6.8 min. H NMR spectrum, δ, ppm
(J, Hz): 1.13 (3H, d, J = 6.8, CH3); 1.63-1.70 (1H, m) and 1.73-1.81 (1H, m, 4-CH2 proline); 1.87-2.00 (2H, m,
3-CH2 proline); 3.42-3.47 (2H, m, 5-CH2 proline); 4.11 (1H, dd, J = 11.1, J = 3.1) and 4.23 (1H, dd, J = 11.1,
J = 1.7, 2-CH2); 4.82 (1H, qdd, J = 6.8, J = 3.1, J = 1.7, 3-СН); 5.12 (1H, dd, J = 8.1, J = 4.2, 2-СН proline);
6.88-6.95 (2H, m, H-7,8); 7.07 (1H, ddd, J = 8.1, J = 7.3, J = 1.2, H-6); 7.63-7.71 (3H, m, H-5, H naphthyl);
7.85 (1H, dd, J = 8.6, J = 1.9, H naphthyl); 8.00-8.02 (1H, m, H naphthyl); 8.08-8.13 (2H, m, H naphthyl);
8.45-8.47 (1H, m, H naphthyl). Found, %: C 65.99; H 5.58; N 6.31. C24H24N2O4S. Calculated, %: C 66.04;
H 5.54; N 6.42.
(S,S)-Amides 9a,c, 10b,c (General Method). A solution of acyl chloride 2f or 2g (0.5 mmol) in toluene
(5 ml) was added to a solution of the amine (S)-3a, (S)-3b or (S)-3c (1.0 mmol) in toluene (5 ml) at 20°C. The
reaction mixture after 24 h was washed with HCl solution (4 N for amine (S)-3a; 1 N for amines (S)-3b and
852

(S)-3c) (2×5 ml); with saturated NaCl solution (3×15 ml); 5% NaHCO3 solution (10 ml), and H2O (2×15 ml).
The organic layer was dried over MgSO4 and evaporated. The residue was purified by recrystallization or flash
chromatography.
(3S,2'S)-7,8-Difluoro-3-methyl-N-(N'-tosylindolin-2-ylcarbonyl)-2,3-dihydro-4H-1,4-benzoxazine
((S,S)-9a). Yield 180 mg (72%) after flash chromatography. Colorless amorphous powder. [α]D20 +112° (c 0.96,
CHCl3). HPLC (hexane–2-PrOH, 40:1): de > 99%, τR 6.4 min. 1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, d,
J = 6.8, 3-CH3); 2.35 (3H, s, ArCH3); 3.00 (1H, dd, J = 16.4, J = 5.0) and 3.36 (1H, dd, J = 16.4, J = 11.0,
3-CH2 indoline); 4.24 (1H, dd, J = 11.1, J = 2.8) and 4.43 (1H, dd, J = 11.1, J = 1.5, 2-CH2); 4.88 (1H, qdd,
J = 6.8, J = 2.8, J = 1.5, 3-СН); 5.62 (1H, dd, J = 11.0, J = 5.0, 2-СН indoline); 6.89-6.98 (2H, m, H-6, H Ar
indoline); 7.11-7.17 (2H, m, H indoline); 7.25-7.27 (1H, m, H indoline); 7.33-7.35 (2H, m, H Ts); 7.74-7.76
(2H, m, H Ts); 7.56 (1H, ddd, J = 9.5, J = 5.4, J = 2.5, H-5). 19F NMR spectrum, δ, ppm: 2.3-2.4 (1F, m, F-8);
21.3-21.4 (1F, m, F-7). Found, %: C 61.99; H 4.39; N 5.45; S 6.60. C25H22F2N2O4S. Calculated, %: C 61.97;
H 4.58; N 5.78; S 6.62.
(2S,2'S)-2-Methyl-N-(N'-tosylindolin-2-ylcarbonyl)-1,2,3,4-tetrahydroquinoline ((S,S)-9c). Yield
20
134 mg (60%) after flash chromatography. Colorless amorphous powder. [α]D +176° (c 0.63, CHCl3). HPLC
(hexane–2-PrOH, 40:1): de 97.8%, τR 9.5 min. 1H NMR spectrum, δ, ppm (J, Hz): 1.08 (3H, d, J = 6.6, 2-CH3);
1.29-1.38 (1H, m, 3-CHB); 2.30-2.38 (4H, m, ArCH3, 3-CHA); 2.54 (1H, ddd, J = 15.4, J = 10.0, J = 5.3,
4-CHB); 2.65-2.71 (2H, m, 4-CHA, 3-CHB indoline); 2.85-2.93 (1H, m, 3-CHA indoline); 4.68 (1H, sextet,
J = 6.8, 2-CH); 5.51 (1H, dd, J = 11.0, J = 4.7, 2-CH indoline); 6.92 (1H, td, J = 7.5, J = 1.2, H Ar); 7.03 (1H,
d, J = 7.6, H Ar); 7.13 (1H, t, J = 7.6, H Ar); 7.20 (1H, td, J = 7.5, J = 1.2, H Ar); 7.25-7.33 (5H, m, H Ar); 7.48
(1H, d, J = 7.8, H Ar); 7.68 (2H, d, J = 8.3, H Ts). Found, %: C 69.64; H 5.86; N 6.13; S 7.04. C26H26N2O3S.
Calculated, %: C 69.93; H 5.87; N 6.27; S 7.18.
(3S,2'S)-3-Methyl-4-(N'-methyl-N'-tosylphenylalanyl)-2,3-dihydro-4H-1,4-benzoxazine ((S,S)-10b).
Yield 167 mg (72%) after recrystallization from hexane–EtOAc mixture. Colorless powder. Mp 118-119°C.
[α]D20 -6.4° (c 1.1, CHCl3). HPLC (hexane–2-PrOH, 80:1): de > 99%, τR 5.6 min. 1H NMR spectrum, δ, ppm (J,
Hz): 0.89 (3H, d, J = 6.8, 3-CH3); 2.38 (3H, s, ArCH3); 2.61 (1H, dd, J = 13.5, J = 6.6) and 3.03 (1H, dd,
J = 13.5, J = 9.1, CH2Ph); 3.00 (3H, s, NCH3); 3.82 (1H, dd, J =11.0, J =2.9) and 4.10 (1H, dd, J = 11.0,
J = 1.7, 2-CH2); 4.71 (1H, qdd, J = 6.8, J = 2.9, J = 1.7, 3-СН); 5.30 (1H, br. t, J = 7.3, NСНCO); 6.83 (1H, dd,
J = 8.2, J = 1.4, H-8); 6.90 (1H, ddd, J = 8.2, J = 7.2, J = 1.3, H-7); 6.92-6.97 (2H, m, H Ph); 7.07 (1H, ddd,
J = 8.2, J = 7.2, J = 1.4, H-6); 7.11-7.18 (3H, m, H Ph); 7.35 (2H, d, J = 8.1, H Ts); 7.60 (2H, d, J = 8.1, H Ts);
7.66-7.69 (1H, dd, J = 8.2, J = 1.3, H-5). Found, %: C 67.03; H 6.40; N 5.70; S 6.89. C26H28N2O4S. Calculated,
%: C 67.22; H 6.07; N 6.03; S 6.90.
(2S,2'S)-2-Methyl-N-(N'-methyl-N'-tosylphenylalanyl)-1,2,3,4-tetrahydroquinoline
((S,S)-10c).
20
Yield 134 mg (58%) after flash chromatography. Colorless powder. Mp 105-107°C. [α]D +119° (c 1.0,
CHCl3). HPLC (hexane–2-PrOH–MeOH, 1000:8:4): de > 99.6%, τR 7.0 min. 1H NMR spectrum, δ, ppm (J, Hz):
0.93 (3H, d, J = 6.5, 2-CH3); 1.17-1.25 (1H, m, 3-CHB); 2.09-2.20 (2H, m, 3-CHA, 3-CHB phenylalanine); 2.35
(3H, s, ArCH3); 2.48-2.54 (1H, m, 4-CHB); 2.59-2.65 (2H, m, 4-CHA, 3-CHA phenylalanine); 3.03 (3H, s,
NCH3); 4.59 (1H, sextet, J = 6.8, 2-CH); 5.32 (1H, t, J = 7.5, NCHCO); 6.66 (2H, d, J = 7.3, H Ph); 7.03-7.31
(8H, m, H-5,6,7, H Ph, H Ts); 7.43 (1H, d, J = 7.9, H-8); 7.49 (2H, d, J = 8.2, H Ts). Found, m/z: 463.2054
[M+H]+. C27H31N2O3S. Calculated, m/z: 463.2050.
X-ray diffraction study of amides (R,S)-5a, (R,S)-5c, and (R,S)-7b was performed on an Xcalibur-3
X-ray diffractometer with a CCD detector according to the standard procedure (MoK radiation, graphite
monochromator, -scanning). The crystals for analysis were obtained by room temperature evaporation of
MeOH or 2-PrOH solutions. The data were acquired and processed with the CrysAlis software package [38].
The structures of compounds were solved by direct method, using the SHELXS-97 software and refined with
SHELXL-97 [39] in anisotropic approximation (isotropically for hydrogen atoms). The hydrogen atom
positions were partially solved and refined independently, and partially included in the refinement according to
the "rider" model with dependent thermal parameters. The X-ray structural analysis data were deposited at the
853

Cambridge Crystallographic Data Center (deposits CCDC 987552, CCDC 987553, CCDC 987554,
respectively).
Compound (R,S)-5a (C24H22F2N2O4S, M 472.50). Crystal dimensions 0.25×0.20×0.15 mm, a colorless
prism. Triclinic syngony, a 6.8959(14), b 7.831(2), c 11.565(3) Å; α 103.74(4), β 96.90(3), γ 115.09(2)°;
V 531.8(2) Å3; space group P1; Z 1; dcalc 1.475 g/cm3; μ 0.206 mm-1; 3.01 < θ < 28.28. The completeness for
θ  25.50° 96.8%. A total of 4075 reflections were collected (2487 independent, Rint 0.0229), 1512 reflections
with I > 2σ(I). S by F2 1.002. The final refinement parameters: R1(I > 2σ(I)) 0.0336, wR2(I > 2σ(I)) 0.0609.
R1 0.0698 (all data), wR2 0.0647 (all data).
Compound (R,S)-5с (C25H26N2O3S, M 434.54). Crystal dimensions 0.25×0.20×0.15 mm, a colorless prism.
Trigonal syngony, a 10.2248(4), b 10.2248(4), c 18.2595(15) Å; α 90.00, β 90.00, γ 120.00°; V 1653.21(16) Å3;
space group P31; Z 3; dcalc 1.309 g/cm3; μ 0.176 mm-1; 3.20 < θ < 28.29. The completeness for θ  28.29°
99.9%. A total of 10798 reflections were collected (5109 independent, Rint 0.0230), 3647 reflections with
I > 2σ(I). S by F2 1.000. The final refinement parameters: R1(I > 2σ(I)) 0.0313, wR2(I > 2σ(I)) 0.0524. R1 0.0524
(all data), wR2 0.053 (all data).
Compound (R,S)-7b (C15H20N2O4S, M 324.39). Crystal dimensions 0.24×0.19×0.12 mm, a colorless prism.
Orthorhombic syngony, a 8.1623(4), b 9.5289(8), c 20.660(2) Å; α 90.00, β 90.90, γ 90.00°; V 1606.9(2) Å3; space
group P212121; Z 4; dcalc 1.341 g/cm3; μ 0.221 mm-1; 2.68 < θ < 27.10. The completeness for θ  26.00° 98.1%.
A total of 5837 reflections were collected (3320 independent, Rint 0.0290), 1800 reflections with I > 2σ(I). S by
F2 1.000. The final refinement parameters: R1(I > 2σ(I)) 0.0341, wR2(I > 2σ(I)) 0.0564. R1 0.0753 (all data), wR2
0.0591 (all data).
The work was performed with financial support from the Russian Foundation for Basic Research (grants
13-03-00674, 13-03-12188), Ural Branch of the Russian Academy of Sciences (project 12-P-3-1030), and the
Grants Council of the President of the Russian Federation (grant NSh-3656.2014.3).
The authors would like to express their gratitude to Candidate of Chemical Sciences P. A. Slepukhin for
performing the X-ray diffraction.
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