Kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and its structural analogs by using 2-arylpropionyl chlorides

Article abstract of DOI:10.1007/s10593-012-1051-x

Acylation of 2-methyl-1,2,3,4-tetrahydroquinoline and 2-methylindoline with the acyl chlorides of naproxen, ibuprofen, and 2-phenylpropionic acid has been found to lead to efficient kinetic resolution with predominant formation of the (S,S)-(R,R)-diastere

Full text of DOI:10.1007/s10593-012-1051-x

Chemistry of Heterocyclic Compounds, Vol. 48, No. 5, August, 2012 (Russian Original Vol. 48, No. 5, May, 2012)
KINETIC RESOLUTION OF RACEMIC 2-METHYL-
1,2,3,4-TETRAHYDROQUINOLINE AND ITS STRUCTURAL
ANALOGS BY USING 2-ARYLPROPIONYL CHLORIDES
E. N. Chulakov1, G. L. Levit1, A. A. Tumashov1,
L. Sh. Sadretdinova1, and V. P. Krasnov1*
Acylation of 2-methyl-1,2,3,4-tetrahydroquinoline and 2-methylindoline with the acyl chlorides of
naproxen, ibuprofen, and 2-phenylpropionic acid has been found to lead to efficient kinetic resolution
with predominant formation of the (S,S)-(R,R)-diastereoisomers. The highest acylation stereoselectivity
was found in toluene at -20°C. No significant kinetic resolution of N-(sec-butyl)aniline and
2-methylpiperidine was achieved by using 2-arylpropionyl chlorides.
Keywords: 2-arylpropionic acids, 2-methylindoline, 2-methyl-1,2,3,4-tetrahydroquinoline, acyl
chlorides, acylation, kinetic resolution.
Kinetic resolution (KR) [1], based on the difference in conversion rates of racemate enantiomers in
reactions with asymmetric reagents or catalysts, has been used successfully to prepare optically pure
biologically active compounds and synthetic intermediates [2-4]. Pure enantiomers of chiral amines are
frequently isolated by KR as a result of an acylation reaction in the presence of either acylation enzymes [5,6] or
synthetic catalysts of chiral acyl transfer [7-9]. In recent years, KR methods have also been intensively
developed for the resolution of racemic amines through the action of chiral acylating agents [10-14].
We have proposed the use of chiral acyl chlorides, namely, 2-arylpropionyl chlorides and N-protected
amino acyl chlorides, as resolving acylating agents for the KS of heterocyclic aromatic amines [15-22]. Of
special interest among 2-arylpropionic acids is (S)-naproxen ((S)-2-(6-methoxynaphth-2-yl)propionic acid),
since this acid is a nonsteroidal anti-inflammatory drug commonly used in clinical practice and available
commercially as a pure enantiomer. Naproxen has a characteristic UV absorption maximum at 230 nm with a
high molar extinction coefficient. This makes naproxen and its derivatives very convenient chiral derivatizing
Me
Me
N
N
Me
N
H
Me
N
Me
H
H
H
1c
1a
1b
1d
_______
*To whom correspondence should be addressed, e-mail: ca@ios.uran.ru.
1I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, 22 S Kovalevskoi
St./20 Akademicheskaya St., Yekaterinburg 620990, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 779-788, May, 2012. Original
article submitted February 29, 2012.
724
0009-3122/12/4805-0724©2012 Springer Science+Business Media, Inc.

agents for determining the stereoisomeric purity of various optically active compounds by HPLC [23] and other
methods [24]. The (S)-naproxen acyl chloride ((S)-2a) was first used in our laboratory for the preparative
resolution of racemic amines, including 2-methyl-1,2,3,4-tetrahydroquinoline (1a) and 2-methylindoline (1b)
[15, 16].
A serious problem hindering the common use of KR for obtaining optically pure compounds remains
the impossibility of predicting the stereochemical result of the reaction from the structures of the amine and the
resolving agent. Thus, it is quite important to obtain information on the results of KR using the broadest
possible range of resolving agents and substrates. A possible approach to finding efficient resolving agents
involves carrying out the reaction between a racemic amine and a racemic acylating agent. Such a reaction gives
two racemic amides, namely, (S,S)(R,R) and (R,S)(S,R), whose ratio (dr) is equal to the selectivity factor
s = kfast/kslow [1, 25, 26]. In this case, the ratio of the concentrations of the diastereoisomeric products is
independent of both the starting reagent ratio and the reaction time. We previously used this approach for
evaluating the selectivity of acylating 3-methyl-2,3-dihydro-4H-[1,4]benzoxazines with 2-arylpropionyl
chlorides [22].
In the present work, we studied kinetic resolution diastereoselectivity in the acylation of racemic amines
1a-d with 2-arylpropionyl chlorides, derived from: naproxen 2a, ibuprofen (2-(4-isobutyl-phenyl)propionic
acid) 2b and 2-phenylpropionic acid 2c.
Me
Me
Me
Cl
Cl
Cl
Me
O
O
O
Me
MeO
2b
2c
2a
Acyl chlorides 2a-c were obtained by treating the corresponding 2-arylpropionic acids with oxalyl
chloride in benzene at room temperature. The products were obtained in 95-97% yield and optical purity >98%,
1
as indicated by H NMR spectroscopy. The freshly prepared acyl chlorides were used in acylation reactions
without further purification.
Acylation of racemic heterocyclic amines 1a,b with the racemic acyl chlorides 2a-c was carried out at a
2:1 reagent ratio in toluene, dichloromethane and acetonitrile at 20 and -20°C over 6 h. The initial concentration
of the racemic amine was 0.1 mol/l.
1
The resulting mixture of diastereoisomeric amides was analyzed by HPLC and H NMR spectroscopy.
The (S,S)-amides 3c-f were obtained by counter synthesis, starting from (S)-amines 1a,b and (S)-acyl chlorides
2b,c, in order to assign the configuration of the products. These (S,S)-amides correspond in their HPLC
retention time and NMR spectra to the (S,S)- or (R,R)-diastereoisomers.
725

TABLE 1. Ratio of (S,S)(R,R)- and (R,S)(S,R)-Diastereoisomers 3a-f in
the Acylation Products
Acylation
agent
dr*
Amine
Solvent
Product
20°C
-20°C
PhMe
97:3
98:2
1a
2a
2b
2c
2a
2b
2c
3a
CH2Cl2
MeCN
PhMe
92:8
94:6
86:14
97:3
85:15
98:2
3c
3e
3b
3d
3f
CH2Cl2
MeCN
PhMe
92:8
94:6
87:13
96:4
89:11
98:2
CH2Cl2
MeCN
PhMe
89:11
82:18
94:6
90:10
83:17
95:5
1b
CH2Cl2
MeCN
PhMe
92:8
93:7
76:24
95:5
80:20
96:4
CH2Cl2
MeCN
PhCH3
CH2Cl2
MeCN
92:8
92:8
81:19
94:6
84:16
95:5
89:10
80:20
91:9
80:20
_______
*dr = (S,S),(R,R) / (R,S),(S,R) from HPLC data.
As in the acylation of racemic amines 1a,b with the acyl chloride (S)-2a [21], the resulting amides 3c-f,
obtained by using the racemic acyl chlorides 2b,c, were enriched in the (S,S),(R,R)-diastereoisomers, but
contained a small amount (~10%) of (R,S),(S,R)-diastereoisomers. For an unequivocal assignment of the NMR
signals and HPLC retention times, we synthesized mixtures of (S,S)- and (S,R)-amides 3c-f containing up to
50% of the (S,R)-diastereoisomer, starting from (S)-amines 1a,b and racemic acyl chlorides 2b,c taken in a 2:1
ratio.
The diastereoisomeric ratio of the resulting amides 3a-f was determined by HPLC, using the area ratio
of the (S,S),(R,R)- and (R,S),(S,R)-amide peaks. Table 1 gives the mean values from two to four parallel
determinations.
The highest acylation selectivity for all the investigated acyl chlorides was observed in toluene. Lower
selectivity was found in the more polar solvents (Table 1). All the investigated acyl chlorides 2a-c displayed
high stereoselectivity in the acylation of heterocyclic amines 1a,b. However, the selectivity in the acylation of
amine 1b was somewhat lower than in the acylation of amine 1a. For example, the diastereoisomeric ratio of the
amides formed in the acylation of amines 1a,b with the acyl chloride 2a in toluene at 20°C was 97:3 and 94:6,
respectively. We should note that, in contrast to KR with N-protected amino acyl chlorides [20, 21], the reaction
temperature in all cases had only a slight effect on the stereochemical result of the reaction.
Acylation of racemic N-(sec-butyl)aniline (1c) and 2-methylpiperidine (1d), which may be considered
structural analogs of 2-methyl-1,2,3,4-tetrahydroquinoline (1a), using the acyl chlorides of naproxen (2a) and
ibuprofen (2b), was carried out with a 2:1 reagent ratio in toluene at 20 and -20°C over 6 h; the initial
concentration of the racemic amine was 0.1 mol/l. The resulting mixture of diastereoisomeric amides 4a,b and
5a,b was analyzed by HPLC and 1H NMR spectroscopy (Table 2).
The stereoselectivity in the acylation of amines 1c,d was considerably lower (the maximum dr was
66:34 in the amine 1d acylation with acyl chloride 2b) than for amines 1a,b. Thus, we did not carry out
assignment of the configuration of resulting amides 4a,b and 5a,b.
726

Me
N
Ar
O
Me
N
Ar
O
+
Me
Me
Me
Me
(R,R)-4a,b
(S,S)-4a,b
PhMe
1c
2 equiv.
2a,b
1 equiv.
+
Me
Ar
O
Me
Ar
O
+
N
N
Me
Me
Me
Me
(R,S)-4a,b
(S,R)-
,
4a b
Me
Ar
Me
N
Ar
O
N
+
O
Me
Me
(R,R)-5a,b
(S,S)-5a,b
PhMe
1d
2 equiv.
2a,b
1 equiv.
+
Me
Ar
O
Me
Ar
O
+
N
N
Me
Me
(S,R)-5a,b
(R,S)-5a,b
4, 5 a Ar = 6-MeO-naphthalen-2-yl; b Ar = 4-(i-Bu)C6H4
The achievement of efficient KS apparently requires the amine to contain a heterocyclic fragment,
whose conformational mobility is additionally limited by the condensed aromatic system.
Thus, we have shown that all the investigated 2-arylpropionic acid derivatives are capable of providing
efficient kinetic resolution of racemic cyclic amines. At the same time, kinetic resolution of their acyclic
structural analogs using 2-arylpropionyl chlorides proved impossible.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker DRX-400 spectrometer (400 MHz) in CDCl3 at room
temperature (acyl chlorides 2a-c) and in DMSO-d6 at 100°C (amides 3-5) with TMS as internal standard. The
TABLE 2. Ratio of (S,S)(R,R)- and (R,S)(S,R)-Diastereoisomers 4a,b and
5a,b in the Acylation Products
Acylation
agent
dr
Amine
Product
20 °C
-20 °C
58:42*
60:40*
60:40*
65:35*2
60:40*
62:38*
62:38*
66:34*2
1c
2a
2b
2a
2b
4a
4b
5a
5b
1d
_______
*From HPLC data.
*2From 1H NMR spectral data.
727

hydrogen atoms at the common carbon atom are designated as A and B. The high-resolution mass spectra were
recorded on a Bruker Daltonics MicroOTOF-Q II mass spectrometer using electrospray ionization and direct
sample inlet with flow rate 180 l/h and positive ion mode in the mass range 50-800 Da at 250°C capillary
temperature. The elemental analysis was carried out on a Perkin Elmer PE 2400 II analyzer. The HPLC analysis
of the diastereoisomeric composition of amides 3d, 4a,b, and 5a,b was carried out on a Knauer Smartline-1000
chromatograph using a 4.6250-mm column packed with ReproSil 100 Si (5 m). The elution rate was 1
ml/min with detection at 220 nm. The mobile phase was 80:1 hexane–2-propanol for amide 4a, 160:1 hexane–
2-propanol for amide 5a, 250:1 hexane–2-propanol for amide 3d, and 200:1 hexane–2-propanol for amide 4b.
The HPLC analysis of the diastereoisomeric content of amides 3c,e,f was carried out on an Agilent-1100
chromatograph using a 4.6250-mm Phenomenex Luna C18 column (5 m). The elution rate was 0.8 ml/min
with detection at 220 nm. The mobile phase was 90:10 acetonitrile–water for products 3c,e and 65:35
acetonitrile–water for amide 3f. Flash column chromatography was carried out on silica gel 60 (230-400 mesh)
with benzene as the eluent. The melting points were determined on a Barloworld Scientific SMP3 instrument.
The specific rotation was determined on a Perkin Elmer 341 polarimeter and given in (deg.·ml)/(g·dm); the
solution concentration is given in g/100 ml.
(RS)-2-Methyl-1,2,3,4-tetrahydroquinoline (1a) [27], N-(sec-butyl)aniline (1c) [28], and (RS)-naproxen [29]
were obtained by reported methods. (S)-2-Methyl-1,2,3,4-tetrahydroquinoline and (S)-2-methylindoline (1b) were
obtained as described in our previous work [16]. Commercial samples of (RS)-2-methylindoline, (RS)-2-methyl-
piperidine (1d), (S)-naproxen, ibuprofen, (S)-ibuprofen, (RS)-2-phenylpropionic acid and (S)-2-phenylpropionic
acid were used. All the solvents were purified by standard procedures immediately before use.
2-Arylpropionyl Chlorides 2a-c (General Method). Oxalyl chloride (175 l, 2.0 mmol) was added to
a stirred suspension of acid (1.0 mmol) in benzene (5 ml). The reaction mixture was stirred for 6 h at room
temperature, evaporated in vacuum and dried over P2O5. Acyl chlorides 2a-c were characterized in our previous
work [22].
Kinetic Resolution (General Method). A solution of acyl chloride 2a-c (0.15 mmol) in a solvent
(toluene, methylene dichloride, or acetonitrile) (1.5 ml) was added in a single portion to a solution of amine
1a-d (0.3 mmol) in the indicated solvent (1.5 ml). The reaction mixture was kept at constant temperature for 5 h
and washed with 1 N hydrochloric acid (2×3 ml). (In the case of the reaction in acetonitrile, 1 N hydrochloric
acid (5 ml) was added, and the amide was extracted with benzene). The organic layer was washed with saturated
aqueous NaCl solution (4×3 ml), 5% aqueous sodium bicarbonate solution (2×3 ml), and water (2×3 ml), dried
over magnesium sulfate, and evaporated to dryness in vacuum. The diastereoisomeric composition of amides
3c-f, 4a,b and 5a,b was determined by HPLC or 1H NMR spectroscopy.
The mixtures of amides and pure (S,S)-diastereoisomers 3a,b were described in our previous work [16].
Preparation of the (S,S)-Amides 3c-f. A solution of (S)-acyl chloride 2b or 2c (1 mmol) in toluene
(10 ml) was added to a solution of (S)-amine 1a,b (2 mmol) in toluene (10 ml). The reaction mixture was kept at
constant 20°C temperature for 6 h, washed with 1 N hydrochloric acid (2×3 ml), saturated aqueous NaCl
solution (4×3 ml), 5% aqueous sodium bicarbonate solution (2×3 ml) and water (2×3 ml), dried over
magnesium sulfate and evaporated to dryness in vacuum. The (S,S)-amides 3c-e were separated by flash
chromatography. The (S,S)-amide 3f was separated by recrystallization from ethanol–water.
N-[(2S)-2-(4-Isobutylphenyl)propionyl]-(2S)-2-methyl-1,2,3,4-tetrahydroquinoline ((S,S)-3c). Yield
20
1
0.242 g (72%). Colorless oil. []D +129.7° (с 1.02, CHCl3). dr  99.9% (HPLC: τ 12.2 min). H NMR
spectrum, , ppm (J, Hz): 0.81 (6Н, d, J = 6.6, СН2СН(CH3)2); 0.91 (3Н, d, J = 6.5, 2-CH3); 1.16 (1Н, dddd,
J = 13.0, J = 10.1, J = 6.7, J = 5.3, Н-3A); 1.36 (3Н, d, J = 6.9, 2'-CH3); 1.69-1.81 (1Н, m, СН2СНMe2); 1.86 (1Н,
ddd, J = 15.0, J = 10.1, J = 5.3, H-4A); 2.13 (1Н, dddd, J = 13.0, J = 7.5, J = 5.3, J = 5.3, H-3B); 2.33 (1Н, ddd,
J = 15.0, J = 5.3, J = 5.3, H-4B); 2.34 (2Н, d, J = 7.0, СН2СНMe2); 4.24 (1Н, q, J = 6.9, H-2'); 4.63 (1Н, ddq,
J = 7.5, J = 6.7, J = 6.5, H-2); 6.66-6.73 (2Н, m, H Ar); 6.83-6.90 (2Н, m, H Ar); 6.97-7.02 (1Н, m, H-5); 7.10
(1Н, ddd, J = 7.4, J = 7.4, J = 1.1, H-6); 7.18-7.26 (1Н, m, H-7); 7.28-7.32 (1Н, m, H-8). Found, m/z: 336.2322
[M+Н]+. С23H30NO. Calculated, m/z: 336.2327.
728

N-[(2S)-2-(4-Isobutylphenyl)propionyl]-(2S)-2-methylindoline ((S,S)-3d). Yield 0.257 g (80%).
Colorless oil. []D20 +63.7° (с 1.07, CHCl3). dr  99.9% (HPLC: τ 4.9 min). 1H NMR spectrum, , ppm (J, Hz):
0.85 (6Н, d, J = 6.6, СН2СН(CH3)2); 0.92 (3Н, d, J = 6.3, 2-CH3); 1.43 (3Н, d, J = 6.8, 2'-CH3); 1.78-1.88 (1Н,
m, СН2СНMe2); 2.43 (2Н, d, J = 7.0, СН2СНMe2); 2.55-2.60 (1Н, m, H-3A); 3.36 (1Н, dd, J = 15.7, J = 8.6,
H-3B); 4.18 (1Н, q, J = 6.8, H-2'); 4.75-4.84 (1Н, m, H-2); 6.95-7.00 (1Н, m, H-5); 7.06-7.11 (2Н, m, H Ar);
7.11-7.16 (1Н, m, H-6); 7.21 (1Н, dd, J = 13.7, J = 7.7, H-4); 7.27-7.31 (2Н, m, H Ar); 7.93-7.97 (1Н, m, H-7).
Found, %: С 81.95; Н 8.57; N 4.08. С22H27NO. Calculated, %: С 82.20; Н 8.47; N 4.36.
N-[(2S)-2-Phenylpropionyl]-(2S)-2-methyl-1,2,3,4-tetrahydroquinoline ((S,S)-3e). Yield 0.218 g
(75%). Colorless oil. []D20 +190.2° (с 1.0, CHCl3). dr  99.9% (HPLC: τ 6.2 min). 1H NMR spectrum, , ppm
(J, Hz): 0.92 (3Н, d, J = 6.5, 2-CH3); 1.16 (1Н, dddd, J = 13.1, J = 10.0, J = 6.7, J = 5.1, H-3A); 1.39 (3Н, d,
J = 6.9, 2'-CH3); 1.88 (1Н, ddd, J = 15.0, J = 10.0, J = 5.6, H-4A); 2.14 (1Н, dddd, J = 13.1, J = 7.0, J = 5.6,
J = 5.4, H-3B); 2.37 (1Н, ddd, J = 15.0, J = 5.4, J = 5.1, H-4B); 4.29 (1Н, q, J = 6.9, H-2'); 4.63 (1Н, ddq,
J = 7.0, J = 6.7, J = 6.5, H-2); 6.79-6.84 (2Н, m, H Ph); 7.02-7.06 (1Н, m, H-5); 7.06-7.10 (3Н, m, H Ph);
7.09-7.14 (1Н, m, H-6); 7.20-7.25 (1Н, m, H-7); 7.29-7.33 (1Н, m, H-8). Found, m/z: 280.1696 [M+Н]+.
С19H22NO. Calculated, m/z: 280.1701.
N-[(2S)-2-Phenylpropionyl]-(2S)-2-methylindoline ((S,S)-3f). Yield 0.207 g (78%). Colorless
20
1
crystals, mp 115ºC (EtOH–H2O). []D +95.0° (с 1.0, CHCl3). dr 99.9% (HPLC: τ 13.0 min). H NMR
spectrum, , ppm (J, Hz): 0.94 (3Н, d, J = 6.4, 2-CH3); 1.46 (3Н, d, J = 6.9, 2'-CH3); 2.56-2.62 (1Н, m, H-3A);
3.36 (1Н, dd, J = 15.8, J = 8.6, H-3B); 4.23 (1Н, q, J = 6.9, H-2'); 4.77-4.86 (1Н, m, H-2); 6.96-7.00 (1Н, m,
H-5); 7.11-7.16 (1Н, m, H-6); 7.18-7.22 (1Н, m, H-4); 7.22-7.42 (5Н, m, H Ph); 7.93-7.97 (1Н, m, H-7). Found,
%: С 81.54; Н 7.30; N 5.25. С18H19NO. Calculated, %: С 81.48; Н 7.22; N 5.28.
Preparation of Amides 3c-f (Diastereoisomeric Mixture). A solution of the (RS)-acyl chloride 2b or
2c (1 mmol) in toluene (10 ml) was added to a solution of the (S)-amine 1a or 1b (2 mmol) in toluene (10 ml) at
20°C. The reaction mixture was kept at 20°C temperature for 6 h, washed with 1 N hydrochloric acid (2×3 ml),
saturated aqueous NaCl solution (4×3 ml), 5% sodium bicarbonate solution (2×3 ml) and water (2×3 ml), dried
over magnesium sulfate and evaporated to dryness in vacuum. Amides 3c-f were purified by flash
chromatography.
N-[(2RS)-2-(4-Isobutylphenyl)propionyl]-(2S)-2-methyl-1,2,3,4-tetrahydroquinoline (3c). Yield
0.195 g (58%). Colorless oil. dr 0% (S,S/R,S 50:50) (HPLC: τ(S,S) 12.2 min, τ(R,S) 13.6 min). 1H NMR spectrum,
, ppm (J, Hz): 0.81 (3Н, d, J = 6.6, СН2СН(CH3)2 (S,S)); 0.88 (3Н, d, J = 6.6, СН2СН(CH3)2 (R,S)); 0.91
(1.5Н, d, J = 6.5, 2-CH3 (S,S)); 1.00 (1.5Н, d, J = 6.7, 2-CH3 (R,S)); 1.16 (1Н, dddd, J = 13.0, J = 10.1, J = 6.7,
J = 5.3, H-3A); 1.27 (1.5Н, d, J = 6.7, 2'-CH3 (R,S)); 1.36 (1.5Н, d, J = 6.9, 2'-CH3 (S,S)); 1.70-1.81 (1Н, m,
СН2СНMe2); 1.86 (0.5Н, ddd, J = 15.0, J = 10.1, J = 5.3, H-4A (S,S)); 2.13 (1Н, dddd, J = 13.0, J = 7.5,
J = 5.3, J = 5.3, H-3B); 2.33 (0.5Н, ddd, J =15.0, J = 5.3, J = 5.3, H-4B (S,S)); 2.34 (1Н, d, J = 7.0, СН2СНMe2
(S,S)); 2.42-2.45 (0.5Н, m, H-4A (R,S)); 2.45 (1Н, d, J = 7.0, СН2СНMe2 (R,S)); 2.62 (0.5Н, ddd, J = 15.0, J = 5.3,
J = 5.3, H-4B (R,S)); 3.70 (0.5Н, q, J = 6.7, H-2' (R,S)); 4.24 (0.5Н, q, J = 6.9, H-2' (S,S)); 4.63 (0.5Н, ddq, J = 7.5,
J = 6.7, J = 6.5, H-2 (S,S)); 4.72 (0.5Н, ddq, J = 6.7, J = 6.7, J = 6.5, H-2 (R,S)); 6.67-6.72 (1Н, m, С6Н4 (S,S)); 6.85-
6.90 (1Н, m, С6Н4 (S,S)); 6.98-7.02 (0.5Н, m, H-5 (S,S)); 7.03-7.14 (3H, m, H-5 (R,S) + H-6 (S,S) + С6Н4 (R,S));
7.16-7.26 (2Н, m, H-6 (R,S) + H-7 + H-8 (R,S)); 7.28-7.32 (0.5Н, m, H-8 (S,S)). Found, %: С 82.50; Н 8.99; N 4.15.
С23H29NO. Calculated, %: С 82.34; Н 8.71; N 4.17.
N-[(2RS)-2-(4-Isobutylphenyl)propionyl]-(2S)-2-methylindoline (3d). Yield 0.241 g (75%). Colorless
oil. dr 10% (S,S/R,S 55:45) (HPLC: τ(R,S) 4.1 min, τ(S,S) 4.9 min). 1H NMR spectrum, , ppm (J, Hz): 0.85 (6Н, d,
J = 6.6, СН2СН(CH3)2); 0.92 (1.65Н, d, J = 6.3, 2-CH3 (S,S)); 1.28 (1.35Н, d, J = 6.3, 2-CH3 (R,S)); 1.42
(1.35Н, d, J = 6.8, 2'-CH3 (R,S)); 1.43 (1.65Н, d, J = 6.8, 2'-CH3 (S,S)); 1.78-1.88 (1Н, m, СН2СНMe2); 2.41
(0.9Н, d, J = 7.0, СН2СНMe2 (R,S)); 2.43 (1.1Н, d, J = 7.0, СН2СНMe2 (S,S)); 2.55-2.61 (1Н, m, H-3A); 3.11
(0.45Н, dd, J = 16.0, J = 8.9, H-3B (R,S)); 3.36 (0.55Н, dd, J = 15.7, J = 8.6, H-3B (S,S)); 4.03 (0.45Н, q,
J = 6.8, H-2' (R,S)); 4.18 (0.55Н, q, J = 6.8, H-2' (S,S)); 4.55-4.62 (0.45Н, m, H-2 (R,S)); 4.76-4.82 (0.55Н, m,
H-2 (S,S)); 6.95-7.00 (1Н, m, H-5); 7.07-7.11 (2Н, m, H Ar); 7.10-7.15 (1Н, m, H-6); 7.21 (1Н, dd, J = 13.7,
729

J = 7.7, H-4); 7.25-7.32 (2Н, m, H Ar); 7.91-8.00 (1Н, m, H-7). Found, %: С 81.91; Н 8.54; N 4.07. С22H27NO.
Calculated, %: С 82.20; Н 8.47; N 4.36.
N-[(2RS)-2-Phenylpropionyl]-(2S)-2-methyl-1,2,3,4-tetrahydroquinoline (3e). Yield 0.182 g (65%).
Colorless oil. dr 50% (S,S/R,S 75:25) (HPLC: τ(S,S) 6.2 min, τ(R,S) 6.5 min). 1H NMR spectrum, , ppm (J, Hz): 0.92
(2.25Н, d, J = 6.5, 2-CH3 (S,S)); 1.01 (0.75Н, d, J = 6.5, 2-CH3 (R,S)); 1.16 (0.75Н, dddd, J = 13.1, J = 10.0, J = 6.7,
J = 5.1, H-3A (S,S)); 1.28 (0.75Н, d, J = 6.9, 2'-CH3 (R,S)); 1.27-1.35 (0.25Н, m, H-3A (S,S)); 1.39 (2.25Н, d,
J = 6.9, 2'-CH3 (S,S)); 1.88 (0.75Н, ddd, J = 15.0, J = 10.0, J = 5.6, H-4A (S,S)); 2.14 (1Н, dddd, J = 13.1,
J = 7.0, J = 5.6, J = 5.4, H-3A); 2.37 (0.75Н, ddd, J = 15.0, J = 5.4, J = 5.1, H-4B (S,S)); 2.42-2.50 (0.25Н, m, H-4B
(R,S)); 2.62 (0.75Н, ddd, J = 15.0, J = 5.8, J = 5.7, H-4B (R,S)); 4.01 (0.25Н, q, J = 6.9, H-2' (R,S)); 4.29 (0.75Н, q,
J = 6.9, H-2' (S,S)); 4.63 (0.75Н, ddq, J = 7.0, J = 6.7, J = 6.5, H-2 (S,S)); 4.73 (0.25Н, ddq, J = 6.9, J = 6.8, J = 6.7,
H-2 (R,S)); 6.79-6.84 (2Н, m, H Ph); 7.02-7.04 (1Н, m, H-5); 7.06-7.10 (3Н, m, H Ph); 7.09-7.14 (1Н, m, H-6);
7.19-7.26 (1Н, m, H-7); 7.29-7.33 (1Н, m, H-8). Found, %: С 81.68; Н 7.64; N 4.95. С19H21NO. Calculated, %:
С 81.68; Н 7.58; N 5.01.
N-[(2RS)-2-Phenylpropionyl]-(2S)-2-methylindoline (3f). Yield 0.167 g (63%). Colorless oil. dr 20%
1
(S,S/R,S 60:40) (HPLC: τ(S,S) 13.0 min, τ(R,S) 13.7 min). H NMR spectrum, , ppm (J, Hz): 0.92 (1.8Н, d,
J = 6.3, 2-CH3 (S,S)); 1.28 (1.2Н, d, J = 6.3, 2-CH3 (R,S)); 1.45 (1.2Н, d, J = 6.8, 2'-CH3 (R,S)); 1.46 (1.8Н, d,
J = 6.9, 2'-CH3 (S,S)); 2.56-2.62 (1Н, m, H-3A); 3.12 (0.4Н, dd, J = 15.9, J = 8.9, H-3B (R,S)); 3.36 (0.6Н, dd,
J = 15.8, J = 8.6, H-3B (S,S)); 4.08 (0.4Н, q, J = 6.8, H-2' (R,S)); 4.23 (0.6Н, q, J = 6.9, H-2' (S,S)); 4.55-4.62
(0.4Н, m, H-2 (R,S)); 4.78-4.85 (0.6Н, m, H-2 (S,S)); 6.95-7.00 (1Н, m, H-5); 7.10-7.16 (1Н, m, H-6); 7.18-7.22
(1Н, m, H-4); 7.22-7.42 (5Н, m, H Ph); 7.93-7.97 (1Н, m, H-7). Found, %: С 81.30; Н 7.33; N 4.99. С18H19NO.
Calculated, %: С 81.48; Н 7.22; N 5.28.
Preparation of Amides 4a,b and 5a,b (Diastereoisomeric Mixtures). A solution of (R,S)-acyl
chloride 2a or 2b (1 mmol) in toluene (10 ml) was added to a solution of (R,S)-amine 1c or 1d (2 mmol) in
toluene (10 ml). The reaction mixture was kept at 20°C temperature for 6 h, washed with 1 N hydrochloric acid
(2×3 ml), saturated aqueous NaCl solution (4×3 ml), 5% sodium bicarbonate solution (2×3 ml), and water (2×3 ml),
dried over magnesium sulfate, and evaporated to dryness in vacuum. Diastereoisomers 4a,b and 5a,b were
separated by flash chromatography.
(2RS)-N-(sec-Butyl)-N-[(2RS)-2-(6-methoxynaphthalen-2-yl)propionyl]aniline (4a). Yield 0.289 g
(80%). Colorless oil. major/minor 60:40 (HPLC: τma.j 4.2 min, τmin. 4.5 min). 1H NMR spectrum, , ppm (J, Hz):
0.83 (1.2H, dd, J = 7.4, J = 7.4, CH2CH3 (min.)); 0.93 (1.8H, d, J = 6.8, CHCH3 (maj.)); 0.96 (1.8H, dd, J = 7.4,
J = 7.4, CH2CH3 (maj.)); 0.98 (1.2H, d, J = 6.8, CHCH3 (min.)); 1.13-1.30 (1H, m, NCH(Me)CHA (min.)); 1.35
(0.6H, dqd, J = 13.6, J = 7.4, J = 6.1, NCH(Me)CHB (maj.)); 1.41 (1.2H, d, J = 6.9, 2'-Me (min.)) and 1.42
(1.8H, d, J = 6.9, 2'-Me (maj.)); 1.51 (0.4H, dqd, J = 13.6, J = 7.4, J = 6.1, NCH(Me)CHB (min.)); 3.55 (1H, q,
J = 6.9, H-2'); 3.90 (3H, c, OCH3); 4.75-4.90 (1H, m, NCH(Me)Et); 7.00-7.62 (11H, m, H Ar + H Ph). Found,
%: С 79.58; Н 7.81; N 3.61. С24H27NO2. Calculated, %: С 79.74; Н 7.53; N 3.87.
(2RS)-N-(sec-Butyl)-N-[(2RS)-2-(4-isobutylphenyl)propionyl]aniline (4b). Yield 0.243 g (72%).
1
Colorless oil. major/minor 60:40 (HPLC: τmin. 4.4 min, τmaj. 5.1 min). H NMR spectrum, , ppm (J, Hz): 0.80
(1.2H, dd, J = 7.4, J = 7.4, CH2CH3 (min.)); 0.86 (6H, d, J = 7.1, СН2СН(CH3)2); 0.87 (1.8H, d, J = 6.8, CHCH3
(maj.)); 0.95 (1.8H, dd, J = 7.0, J = 7.0, CH2CH3 (maj.)); 0.96 (1.2H, d, J = 7.0, CHCH3 (min.)); 1.18-1.29
(1.4H, m) and 1.40-1.50 (0.6H, m, NCH(Me)CH2); 1.23 (1.2H, d, J = 6.9, 2'-CH3 (min.)); 1.24 (1.8H, d, J = 6.9,
2'-CH3 (maj.)); 1.77-1.87 (1H, m, СН2СНMe2); 2.40 (2Н, d, J = 7.0, СН2СНMe2); 3.41 (1H, q, J = 6.9, H-2');
4.45-4.58 (1H, m, NCH(Me)Et); 6.80-7.40 (9H, m, H Ar). Found, %: С 81.64; Н 9.51; N 3.93. С23H31NO.
Calculated, %: С 81.85; Н 9.26; N 4.15.
(2RS)-2-Methyl-N-[(2RS)-2-(6-methoxynaphthalen-2-yl)propionyl]piperidine (5a). Yield 0.243 g
1
(78%). Colorless oil. major/minor 60:40 (HPLC: τmin. 19.8 min, τmaj. 20.9 min). H NMR spectrum, , ppm (J,
Hz): 0.94 (1.8H, d, J = 6.9, 2-CH3 (maj.)); 1.09 (1.2H, d, J = 6.9, 2-CH3 (min.)); 1.39 (3H, d, J = 6.9, 2'-CH3);
1.22-1.60 (6H, m, 3,4,5-CH2); 2.68 (0.6H, ddd, J = 13.7, J = 12.7, J = 3.1, 6-CHA (maj.)); 2.86 (0.4H, ddd,
J = 13.3, J = 12.9, J = 3.0, 6-CHA (min.)); 3.87 (3H, c, OCH3); 3.96-4.07 (1H, m, 6-CHB); 4.11 (0.6H, q,
730

J = 6.9, H-2' (maj.)); 4.13 (0.4H, q, J = 6.9, H-2' (min.)); 4.48-4.57 (0.6H, m, H-2 (maj.)); 4.57-4.65 (0.4H, m, H-
2 (min.)); 7.12 (1H, dd, J = 8.9, J = 2.6, H-7''); 7.23 (1H, d, J = 2.7, H-5''); 7.35 (0.6H, dd, J = 8.5, J = 1.9, H-3''
(maj.)); 7.36 (0.4H, dd, J = 8.5; J = 1.9, H-3'' (min.)); 7.62 (0.6H, d, J = 1.7, H-1'' (maj.)); 7.64 (0.4H, d, J = 1.8,
H-1'' (min.)); 7.66-7.73 (2H, m, H-4'',8''). Found, %: С 76.92; Н 8.30; N 4.25. С20H25NO2. Calculated, %: С
77.14; Н 8.09; N 4.50.
N-[(2RS)-2-(4-Isobutylphenyl)propionyl]-(2RS)-2-methylpiperidine (5b). Yield 0.187 g (65%).
Colorless oil. major/minor 65:35 (according to 1H NMR spectroscopy). 1H NMR spectrum, , ppm (J, Hz): 0.86
(6H, d, J = 6.6, СН2СН(CH3)2); 0.89 (1.95H, d, J = 5.2, 2-CH3 (maj.)); 1.07 (1.05H, d, J = 5.4, 2-CH3 (min.));
1.28 (3H, d, J = 6.8, 2'-CH3); 1.20-1.60 (6H, m, 3,4,5-CH2); 1.78-1.88 (1Н, m, СН2СНMe2); 2.42 (2Н, d,
J = 7.1, СН2СНMe2); 2.68 (0.35H, ddd, J = 13.2, J = 13.2, J = 3.0, 6-CHA (min.)); 2.75-2.85 (0.65H, m, 6-CHA
(maj.)); 3.85-4.07 (1H, m, 6-CHB); 3.95 (1H, q, J = 6.8, H-2'); 4.35-4.50 (0.35H, m, H-2 (min.)); 4.50-4.60
(0.65H, m, H-2 (maj.)); 7.03-7.08 (2Н, m, H Ar); 7.09-7.16 (2Н, m, H Ar). Found, %: С 79.16; Н 10.19;
N 4.90. С19H29NO. Calculated, %: С 79.39; Н 10.17; N 4.87.
This work was financially supported by the Russian Foundation for Basic Research (grant 10-03-
00084), Ural Branch of the Russian Academy of Sciences (project 12-P-3-1030), and the Grants Council of the
Russian Federation President (grant NSh-5505.2012.3).
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