Synthesis of enantiomers of 6-nitro-and 6-amino-2-methyl-1,2,3,4- tetrahydroquinolines

Article abstract of DOI:10.1007/s10593-012-1053-8

Enantiomers of 2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline have been obtained by kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline in acylation with acyl chlorides of N-protected amino acids followed by regioselective nitration of the di

Full text of DOI:10.1007/s10593-012-1053-8

Chemistry of Heterocyclic Compounds, Vol. 48, No. 5, August, 2012 (Russian Original Vol. 48, No. 5, May, 2012)
SYNTHESIS OF ENANTIOMERS OF 6-NITRO- AND
6-AMINO-2-METHYL-1,2,3,4-TETRAHYDROQUINOLINES
D. A. Gruzdev1, G. L. Levit1, M. I. Kodess1, and V. P. Krasnov1*
Enantiomers of 2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline have been obtained by kinetic resolution
of racemic 2-methyl-1,2,3,4-tetrahydroquinoline in acylation with acyl chlorides of N-protected amino
acids followed by regioselective nitration of the diastereoisomeric amides and acidic hydrolysis. The
introduction of a trifluoroacetyl protecting group into the position 1 of the enantio pure nitro compound
followed by the reduction led to (S)-6-amino-2-methyl-1-trifluoroacetyl-1,2,3,4-tetra-hydroquinoline in
a high yield.
Keywords: amides, diastereoisomers, enantiomers, kinetic resolution, nitration, reduction.
The enantiomers of 2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline (1) and 6-amino-2-methyl-1,2,3,4-tet-
rahydroquinoline (2) are of interest as structural fragments of biologically active compounds [1-4].
O2N
H2N
N
N
Me
Me
H
H
1
2
There are literature precedents for the preparation of racemic 2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline
(1) in the course of a tandem reductive amination and nucleophilic aromatic substitution of 4-(2-fluoro-
5-nitrophenyl)-2-butanone [5] and also its (-)-enantiomer ((-)1) as a result of enantioselective catalytic
hydrogenation of 2-methyl-6-nitroquinoline [6]. It is known that the regioselective introduction of a nitro group
into the aromatic fragment of 1,2,3,4-tetrahydroquinolines is a complex problem, and previous investigations in
this area have led to contradictory results [7-10]. Systematic study of the nitration of 1,2,3,4-tetrahydroquinoline
and its derivatives has shown that in the presence of N-acyl substituents, the reaction proceeds selectively at the
position 6 of the aromatic ring (the para position relative to the nitrogen atom) [11-16], while in the case of a
bulky group (such as Fmoc) the regiodirected formation of the 6-nitro derivative was observed in 99% yield
[16].
_______
*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. 805-815, May, 2012. Original
article submitted February 29, 2012.
748
0009-3122/12/4805-0748©2012 Springer Science+Business Media, Inc.

In the present work, we propose a new approach to the directed synthesis of the enantiomers of amines 1
and 2, based on a kinetic resolution of racemic amines by acylation with acyl chlorides of chiral acids. Kinetic
resolution (KR) is a method of resolution of optical isomers based on a difference in the conversion rate of the
substrate enantiomers with a chiral reagent, or in the presence of a chiral catalyst [17, 18]. The effectiveness of
KR is assessed according to the ratio of the rate constants for reactions of the substrate enantiomers, known as
the selectivity factor (s). The value of s may be calculated from optical purity data for the reaction product and
the unreacted substrate (de or ee) and the conversion (C) [17, 18].
ln[(1C)(1 eeunreact)]
ln[(1C)(1 eeunreact.)]
eeunreact
;
[17].
s 
С 
eeunreact  deproduct
The KR process is considered to be adequate from a preparative point of view if s > 10 [19].
KR in acylation reactions is one of the most important methods for obtaining enantiomers of
heterocyclic amines [18-22]. In our laboratory, a study on the KR of 2-methyl-1,2,3,4-tetrahydroquinoline (3)
and other racemic heterocyclic amines on acylation with acyl chlorides of N-protected amino acids [23-26] and
2-arylpropionic acids [27-30] has been carried out. We have demonstrated that N-phthaloyl-(S)-amino acyl
chlorides 4a,b are efficient separating agents and may be used for obtaining (S)-enantiomers of heterocyclic
amines [24, 25]. In particular, diastereoisomerically pure (S,S)-amides of N-phthaloyl-(S)-alanine (5a) and
N-phthaloyl-(S)-phenylalanine (5b) with 2-methyl-1,2,3,4-tetrahydroquinoline were obtained in 54% and 53%
yield, relative to racemic amine 3 [24, 25].
In the present work, we showed that N-phthaloyl-(S)-leucyl chloride (4c) is a more efficient resolving
agent for amine 3, compared to the reagents 4a and 4b studied previously (selectivity factor s was 6.6, 12 and
19 for the amine 3 reaction with acyl chlorides 4a-c in CH2Cl2 at -20oC). The amide (S,S)-5c (de > 99.8%) was
obtained after a single recrystallization of the KR product in 28% yield relative to racemic amine 3. The
absolute configuration of compound (S,S)-5c was determined on the basis of X-ray structural analysis data (Fig.
1) taking into account the known configuration of the acyl fragment.
In the acyl fragment of amide (S,S)-5c, there are no groups subject to nitration under mild conditions.
Consequently this compound is of interest as an intermediate for obtaining optically pure nitro- and amino-
substituted derivatives of 2-methyl-1,2,3,4-tetrahydroquinoline.
According to the known procedure [16], we carried out the nitration of amide (S,S)-5c with an
equimolar mixture of KNO3 and H2SO4 in CH2Cl2 at room temperature. After column flash chromatography,
amide (S,S)-6 was isolated in 77% yield. The composition, structure and purity of compound (S,S)-6 were
confirmed by NMR spectroscopy, HPLC, and elemental analysis. In the NMR spectra of amides containing a
749

residue of amine 1 or 3, broadened signals for the majority of protons were observed at room temperature. On
1
recording the H NMR spectra at 100oC in DMSO-d6, the signals became narrow and well resolved. A similar
phenomenon was previously observed by us during investigation of structurally related amides [23-30].
Fig. 1. Molecular structures of amides (S,S)-5c (a) and (R,S)-8 (b), according to X-ray structural analysis data.
750

The hydrolysis of amide (S,S)-6 under the conditions previously used by us for hydrolysis of other
amides of N-phthaloyl-(S)-amino acids (heating in a mixture of conc. HCl and AcOH) [24, 25], was not
successful. The (S)-enantiomer of 2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline ((S)-1) was obtained by acidic
hydrolysis of amide (S,S)-6 on refluxing in 2 N H2SO4 in dioxane, in 56% overall yield, relative to amide
(S,S)-5c.
Nitration of the diastereoisomeric mixture 5c led to a mixture of amides 6, from which diastereoisomer
(R,S)-6 was isolated chromatographically. Hydrolysis of amide (R,S)-6 (H2SO4 in dioxane) gave amine (R)-1.
The optical purities of the enantiomers (S)-1 and (R)-1 were not less than 96% and 98%, respectively (according
to chiral HPLC data).
We attempted to nitrate (R,S)-amide 7 (de > 99% according to HPLC data), obtained by KR of racemic
amine 3 with N-tosyl-(S)-prolyl chloride according to a previously described procedure [23]. Nitration of amide
(R,S)-7 proceeded slower and led to the formation of a complex mixture with the predominant product due to
nitration at the position 6 of the amine fragment. Amide (R,S)-8 (purity 97% according to data of HPLC and 1H
NMR spectroscopy) was isolated by column flash chromatography in 37% yield, relative to amide (R,S)-7. The
structure of (R,S)-amide 8 was confirmed by X-ray structural analysis (Fig. 1). Hydrolysis of amide (R,S)-8 on
refluxing in dioxane in the presence of conc. H2SO4 required more extended heating in comparison with the
hydrolysis of amides of N-phthaloyl-(S)-amino acids. As a result, enantiomer (R)-1 was obtained in 85% yield
and ee 98% (according to chiral HPLC data).
Reduction of the nitro group of compound 1 was also studied. The reduction of amine (S)-1 by the
action of Sn in HCl led to amine 2 in 73% yield. However, compound 2 contained 20% of impurities (according
1
to H NMR spectroscopy data), and the purity was unaffected by recrystallization or chromatography. This is
likely due to the readily oxidation of p-diaminobenzene system by the air oxygen. Consequently, to obtain
derivatives of (S)-6-amino-2-methyl-1,2,3,4-tetrahydroquinoline we proposed an alternative route, involving
introduction of a protecting group. It is known that trifluoroacetamides are readily hydrolyzed under mild
alkaline conditions; therefore the use of a trifluoroacetyl group is a convenient method of temporarily blocking
an amino group. Trifluoroacetamides are stable under conditions of catalytic hydrogenation [31].
Trifluoroacetylation of compounds (S)-1 and (R)-1 by the standard procedure led to amides (S)-9 and (R)-9.
Amine (S)-10 was formed upon reduction of the nitro derivative (S)-9 with hydrogen in the presence of Pd/C.
751

O2N
(CF3CO)2O
H2N
O
O
H2
10% Pd/C
(S)-1
N
CF3
N
CF3
CH2Cl2
, 30 min
78%
EtOH
20°C, 3 h
88%
Me
Me
(S)-9
(S)-10
In the 1H, 13C, and 19F NMR spectra of compound (S)-10, recorded at room temperature, double sets of
signals were observed for the protons in positions 2, 3, 4, and 8, and also for the fluorine atoms of the CF3
group. The ratio of conformers was 74:26. This is apparently associated to the hindered rotation about the amide
bond. On heating to 100oC, merging of the conformer signals was observed in the NMR spectra, but even at this
temperature some signals remained significantly broadened, in particular the signals of the CH2 group protons
and of H-8, and of the carbons of the methylene groups, and the nodal carbon C-8a.
Thus, we have proposed a new route for obtaining the enantiomers of 2-methyl-6-nitro-1,2,3,4-
tetrahydroquinoline, reduction of which, after introducing the trifluoroacetyl protecting group, led to the
enantiomers of 6-amino-1-trifluoroacetyl-2-methyl-1,2,3,4-tetrahydroquinoline.
EXPERIMENTAL
1
The H, 19F, and 13C NMR spectra were recorded on a Bruker DRX-500 spectrometer (500, 470, and
125 MHz respectively) using TMS and hexafluorobenzene as internal standards. The NMR spectra of amides 5,
6, 8-10 were recorded at 100oC, and of amines 1-3 at room temperature. The complete assignment of signals of
1
1
compound (R,S)-8 in H and 13C NMR spectra was carried out with the aid of two-dimensional NMR H-1H
COSY, H-13C HSQC, and HMBC. The high-resolution mass spectra were obtained on a Bruker Daltonics
1
series MicrOTOF-Q II mass spectrometer, electrospray ionization with direct sample inlet (flow rate 180 μl/h).
The mass spectrometer was operated in the positive ionization mode in the mass range of 50-800 Da, at a
capillary temperature of 250oC. Elemental analysis was carried out on Perkin Elmer 2400 II or Euro Vector
EA3000 analyzers. Melting points were determined on a SMP3 instrument (Barloworld Scientific). Specific
rotation was determined on a Perkin Elmer 341 polarimeter. HPLC analysis was performed on a Knauer
Smartline-1100 chromatograph using ReproSil 100 Si column (2504.6 mm, 5 μm for amides 5-8) and
Chiralcel OD-H column (2504.6 mm, for amine 1 and amide 10), detection at 220 nm, flow rate of 1 ml/min.
(R,S)-2-Methyl-1,2,3,4-tetrahydroquinoline (3) [32] and amide (R,S)-7 [23] were obtained by known
procedures. Compounds 4a,b and 5a,b were described previously [24, 25]. The remaining reactants were
commercially available. Solvents were purified by traditional procedures.
N-Phthaloyl-(S)-leucyl Chloride (4c). Oxalyl chloride (0.7 ml, 8.04 mmol) and DMF (5 μl) were
added to a suspension of N-phthaloyl-(S)-leucine (1.00 g, 3.83 mmol) in a benzene–hexane 1:1 mixture (80 ml).
The reaction mixture was stirred for 5 h and evaporated. The residue was dried in vacuum over P2O5. Yield 1.06
g (99%). Colorless oil. [α]D20 -53.7o (c 1.4, C6H6). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.95 (3H, d, J =
6.6) and 0.97 (3H, d, J = 6.6, CH(CH3)2); 1.47-1.57 (1H, m, CHMe2); 2.05 (1H, ddd, J = 14.3, J = 10.0, J = 4.3)
and 2.37 (1H, ddd, J = 14.3, J = 11.1, J = 4.3, CH2CHMe2); 5.13 (1H, dd, J = 11.1, J = 4.3, CHCO); 7.77-7.82
(2H, m, H NPhth); 7.90-7.94 (2H, m, H NPhth). Found, %: C 60.29; H 5.04; N 4.94; Cl 12.15. C14H14ClNO3.
Calculated, %: C 60.11; H 5.04; N 5.01; Cl 12.67.
(S)-2-Methyl-1-[N'-phthaloyl-(S)-leucyl]-1,2,3,4-tetrahydroquinoline ((S,S)-5c). A solution of acyl
chloride 4c (4.20 g, 15 mmol) in CH2Cl2 (150 ml) was added to a solution of amine 3 (4.42 g, 30 mmol) in
CH2Cl2 (150 ml) at -20oC under stirring. After 6 h the reaction mixture was washed with 1 N HCl (2100 ml),
NaCl solution (3100 ml), 5% NaHCO3 solution (2100 ml), and water (2100 ml). The organic layer was
dried over MgSO4 and evaporated. The residue was recrystallized from a hexane–EtOAc mixture, 2.5:1. Yield
752

3.28 g (56%). Colorless crystals, mp 168-169oC. [α]D +447o (c 0.6, CHCl3), de 99.8% (HPLC: hexane–
20
1
2-PrOH, 80:1, τ 8.17 min). H NMR spectrum (DMSO-d6, 100oC), δ, ppm (J, Hz): 0.37 (3H, d, J = 6.6) and
0.63 (3H, d, J = 6.7, CH(CH3)2); 0.89 (1H, ddd, J = 13.8, J = 9.7, J = 3.7) and 2.56 (1H, ddd, J = 13.8, J = 12.1,
J = 3.9, CH2CHMe2); 1.02 (3H, d, J = 6.6, 2-CH3); 1.22-1.34 (2H, m, 3-CHA, CHMe2); 2.36 (1H, dddd,
J = 13.0, J = 7.9, J = 5.2, J = 4.6, 3-CHB); 2.45 (1H, ddd, J = 14.9, J = 10.7, J = 5.1) and 2.69 (1H, ddd,
J = 14.9, J = 4.8, J = 4.8, 4-CH2); 4.59 (1H, ddq, J = 7.7, J = 6.9, J = 6.6, H-2); 5.55 (1H, dd, J = 12.1, J = 3.7,
CHCO); 7.25 (1H, ddd, J = 7.5, J = 7.4, J = 1.2, H-6); 7.30-7.32 (1H, m, H-5); 7.33 (1H, ddd, J = 7.6, J = 7.4,
J = 1.4, H-7); 7.48 (1H, dd, J = 7.6, J = 1.2, H-8); 7.83-7.88 (4H, m, H NPhth). 13C NMR spectrum (DMSO-d6,
100oC), δ, ppm: 19.5; 19.6; 21.9; 24.2; 25.0; 31.8; 34.1; 48.7; 51.9; 122.5; 124.7; 125.7; 126.2; 127.2; 131.0;
134.0; 135.6; 136.0; 167.8; 168.2. Found, %: C 73.82; H 6.94; N 7.18. C24H26N2O3. Calculated, %: C 73.82;
H 6.71; N 7.17.
2-Methyl-1-[N'-phthaloyl-(S)-leucyl]-1,2,3,4-tetrahydroquinoline (5c) (Mixture of Diastereo-
isomers). The mother liquor after recrystallization of amide (S,S)-5c was evaporated. The mixture of amides
was purified by column flash chromatography on silica gel (eluent benzene → benzene–EtOAc, 95:5). Yield
1.87 g (32%). Amorphous powder, dr (S,S)/(R,S) 73:27 (HPLC: hexane–2-PrOH, 80:1, τ(R,S) 6.1 min, τ(S,S) 8.2
1
min). H NMR spectrum (DMSO-d6, 100oC), δ, ppm (J, Hz): 0.37 (2.19H, d, J = 6.6) and 0.63 (2.19H, d,
J = 6.7), CH(CH3)2 (S,S)); 0.87 (0.81H, d, J = 6.7) and 0.93 (0.81H, d, J = 6.5, CH(CH3)2 (R,S)); 0.89 (0.73H,
ddd, J = 13.8, J = 9.7, J = 3.7) and 2.56 (0.73H, ddd, J = 13.8, J = 12.1, J = 3.9, CH2CHMe2 (S,S)); 0.98 (0.81H,
d, J = 6.5, 2-CH3 (R,S)); 1.02 (2.19H, d, J = 6.6, 2-CH3 (S,S)); 1.08-1.17 (0.81H, m, CHACHMe2, 3-CHB (R,S));
1.22-1.34 (1.73H, m, 3-CHA (R,S), 3-CHB, CHMe2 (S,S)); 1.46-1.56 (0.27H, m, 4-CHB (R,S)); 2.08 (0.27H, ddd,
J = 14.1, J = 8.6, J = 5.1, CHBCHMe2 (R,S)); 2.17-2.39 (1H, m, 4-CHA (R,S), 3-CHA (S,S)); 2.45 (0.73H, m) and
2.69 (0.73H, ddd, J = 14.9, J = 4.8, J = 4.8, 4-CH2 (S,S)); 4.54 (0.27H, ddq, J = 6.9, J = 6.6, J = 6.5, H-2 (R,S));
4.59 (0.73H, ddq, J = 7.7, J = 6.9, J = 6.6, H-2 (S,S)); 5.20 (0.27H, dd, J = 9.1, J = 5.1, CHCO (R,S)); 5.55
(0.73H, dd, J = 12.1, J = 3.7, CHCO (S,S)); 6.71 (0.27H, d, J = 7.4, H-5 (R,S)); 6.82 (0.27H, ddd, J = 7.4,
J = 7.4, J = 1.0, H-6 (R,S)); 7.03-7.06 (0.27H, m, H-7 (R,S)); 7.20-7.22 (0.27H, m, H-8 (R,S)); 7.25 (0.73H, ddd,
J = 7.5, J = 7.4, J = 1.2, H-6 (S,S)); 7.30-7.32 (0.73H, m, H-5 (S,S)); 7.31-7.35 (0.73H, m, H-7 (S,S)); 7.48
(0.73H, dd, J = 7.6, J = 1.2, H-8 (S,S)); 7.60-7.65 (0.54H, m) and 7.70-7.75 (0.54H, m, H NPhth (R,S));
7.83-7.88 (2.92H, m, H NPhth (S,S)). Found, %: C 73.72; H 6.87; N 7.08. C24H26N2O3. Calculated, %: C 73.82;
H 6.71; N 7.17.
(S)-2-Methyl-6-nitro-1-[N'-phthaloyl-(S)-leucyl]-1,2,3,4-tetrahydroquinoline
((S,S)-6).
Conc.
H2SO4 (1.28 g, 12.8 mmol) and KNO3 (1.29 g, 12.8 mmol) were added at 0oC to a solution of amide (S,S)-5c
(1.00 g, 2.56 mmol) in CH2Cl2 (50 ml) with stirring. The reaction mixture was heated to room temperature and
stirred for 1 day (until disappearance of the starting amide, monitoring by TLC). The solution was washed with
water (340 ml), 5% NaHCO3 solution (230 ml), and water (240 ml). The organic layer was dried over
MgSO4 and evaporated. The residue was subjected to column flash chromatography on silica gel (eluent
hexane–EtOAc, 9:1). Yield 0.86 g (77%). Pale-yellow foam. [α]D +634o (c 1.0, CHCl3), de > 99% (HPLC:
20
hexane–2-PrOH, 80:1, τ 10.18 min). 1H NMR spectrum (DMSO-d6, 100oC), δ, ppm (J, Hz): 0.53 (3H, d, J = 6.6)
and 0.71 (3H, d, J = 6.6, СН(СН3)2); 1.09 (3H, d, J = 6.5, 2-СН3); 1.12 (1H, ddd, J = 13.9, J = 9.5, J = 4.2) and
2.60 (1H, ddd, J = 13.9, J = 11.7, J = 4.0, СH2СНМe2); 1.35-1.44 (1H, m, СHМe2); 1.44-1.52 (1H, m) and
2.25-2.33 (1H, m, 3-СH2); 2.64 (1H, ddd, J = 15.8, J = 9.4, J = 5.8) and 2.91 (1H, dt, J = 15.8, J = 5.9, 4-СH2);
4.60 (1H, tq, J = 6.6, J = 6.5, H-2); 5.47 (1H, dd, J = 11.7, J = 4.2, СHСО); 7.74 (1H, d, J = 9.5, H-8); 7.84-
13
7.89 (4H, m, H NPhth); 8.14-8.17 (2H, m, H-5,7). C NMR spectrum (DMSO-d6, 100oC), δ, ppm: 19.0; 19.8;
21.8; 24.2; 24.3; 30.2; 35.0; 49.3; 51.8; 121.3; 122.6; 122.7; 125.4; 130.8; 134.1; 135.4; 142.3; 144.4; 167.5;
168.7. Found, %: C 66.19; H 5.93; N 9.28. C24H25N3O5. Calculated, %: C 66.19; H 5.79; N 9.65.
(R)-2-Methyl-6-nitro-1-[N'-phthaloyl-(S)-leucyl]-1,2,3,4-tetrahydroquinoline
((R,S)-6).
Conc.
H2SO4 (1.35 g, 13.45 mmol) and KNO3 (1.36 g, 13.45 mmol) were added at 0oC to a solution of amide 5c
((S,S)/(R,S) 59:41) (1.05 g, 2.69 mmol) in CH2Cl2 (50 ml) under stirring. The reaction mixture was heated to
room temperature and stirred for 8 h. The solution was washed with water (340 ml), 5% NaHCO3 solution
753

(230 ml), and water (240 ml). The organic layer was dried over MgSO4 and evaporated. The residue was
subjected to column flash chromatography on silica gel (eluent hexane–EtOAc, 9:1), and amide (R,S)-6 (0.199
g) was obtained as the fast eluting isomer (yield 41% calculated on (R,S)-5c). Yellow foam. [α]D20 -402o (c 1.0,
CHCl3), de 98% (HPLC: hexane–2-PrOH, 80:1, τ 7.00 min). 1H NMR spectrum (DMSO-d6, 100oC), δ, ppm (J,
Hz): 0.87 (3H, d, J = 6.6) and 0.94 (3H, d, J = 6.6, СН(СН3)2); 1.00 (3H, d, J = 6.5, 2-СН3); 1.31 (1H, dddd,
J = 13.0, J = 8.9, J = 6.7, J = 5.7) and 2.27 (1H, dddd, J = 13.0, J = 6.7, J = 5.9, J = 5.9, 3-СH2); 1.44-1.53 (1H,
m, СHМe2); 1.87 (1H, ddd, J = 14.3, J = 9.3, J = 4.8) and 2.08 (1H, ddd, J = 14.3, J = 8.8, J = 4.9, СH2СНМe2);
2.35 (1H, ddd, J = 15.5, J = 8.9, J = 5.9) and 2.59 (1H, ddd, J = 15.5, J = 5.9, J = 5.7, 4-СH2); 4.50 (1H, tq,
J = 6.7, J = 6.5, H-2); 5.28 (1H, dd, J = 9.3, J = 4.9, СHСО); 7.58 (1H, d, J = 8.8, H-8); 7.60 (1H, d, J = 2.7, H-
5); 7.64-7.67 (2H, m) and 7.72–7.76 (2H, m, Н NPhth); 7.88 (1H, dd, J = 8.8, J = 2.7, H-7). 13C NMR spectrum
(DMSO-d6, 100oC,), δ, ppm: 18.9; 21.2; 22.4; 23.7; 23.8; 29.9; 38.2; 49.4; 49.6; 121.6; 121.7; 122.2; 125.0;
130.1; 134.1; 134.2; 142.4; 143.6; 165.9; 168.0. Found, m/z: 436.1871 [M+H]+. C24H26N3O5. Calculated, m/z:
436.1872.
(R)-2-Methyl-6-nitro-1-[N'-p-toluenesulfonyl-(S)-prolyl]-1,2,3,4-tetrahydroquinoline
((R,S)-8).
Conc. H2SO4 (1.160 g, 11.6 mmol) and KNO3 (1.17 g, 11.6 mmol) were added under stirring at 0oC to a
solution of amide (R,S)-7 (0.660 g, 1.66 mmol) in CH2Cl2 (40 ml). The reaction mixture was heated to room
temperature and stirred for 1 day. The solution was washed with water (330 ml), 5% NaHCO3 solution (225
ml), and water (230 ml). The organic layer was dried over MgSO4 and evaporated. The residue was purified by
column flash chromatography on silica gel (eluent hexane–EtOAc, 4:1). Yield 0.272 g (37%). Colorless
powder, mp 180-181oC. [α]D -527o (c 1.0, CHCl3), de 98% (HPLC: hexane–2-PrOH, 20:1, τ 13.80 min).
20
1H NMR spectrum (DMSO-d6, 100oC), δ, ppm (J, Hz): 1.11 (3H, d, J = 6.6, 2-СН3); 1.49 (1H, dddd, J = 13.9,
J = 8.6, J = 6.4, J = 5.8) and 2.36 (1H, m, 3-СH2); 1.58-1.66 (1H, m) and 1.98-2.15 (3H, m, 3,4-(СH2)2 proline);
2.34 (3H, s, С6Н4СН3); 2.75 (1H, ddd, J = 15.7, J = 8.6, J = 5.8) and 2.88 (1H, ddd, J = 15.7, J = 6.1, J = 5.8,
4-СH2); 3.30 (1H, ddd, J = 9.8, J = 7.3, J = 6.2) and 3.42 (1H, ddd, J = 9.8, J = 6.7, J = 6.5, 5-СH2 proline);
4.34 (1H, dd, J = 8.1, J = 4.7, СHСО); 4.69 (1H, dqd, J = 6.6, J = 6.5, J = 6.4, H-2); 7.22 (2H, d, J = 8.4, H-3,5
Ts); 7.29 (2H, d, J = 8.4, H-2,6 Ts); 7.35 (1H, d, J = 8.8, H-8); 8.02 (1H, dd, J = 8.8, J = 2.7, H-7); 8.15 (1H, d,
J = 2.7, H-5). 13C NMR spectrum (DMSO-d6, 100oC), δ, ppm: 18.9 (2-СН3); 20.2 (С6Н4СН3); 23.9 and 24.0
(C-4, C-4 proline); 29.7 (C-3); 30.6 (C-3 proline); 48.2 (C-2); 48.6 (C-5 proline); 57.4 (C-2 proline); 120.8
(C-7); 122.4 (C-5); 125.5 (C-8); 126.2 (o-C Ts); 128.9 (m-C Ts); 134.5 (i-C Ts); 135.2 (C-4a); 142.4 (C-8a);
142.7 (p-C Ts); 144.0 (C-6); 170.5 (CO). Found, %: C 59.28; H 5.66; N 9.52; S 7.44. C22H25N3O5S. Calculated,
%: C 59.58; H 5.68; N 9.47; S 7.23.
(S)-2-Methyl-6-nitro-1,2,3,4-tetrahydroquinoline ((S)-1). Conc. H2SO4 (2 ml) was added to a solution
of amide (S,S)-6 (670 mg, 1.54 mmol) in 1,4-dioxane (15 ml). The obtained solution was heated for 13 h at 95-
100oC. The reaction mixture was cooled to room temperature and poured into water (150 ml). Na2CO3 was
added to the obtained suspension to pH 8.0-8.5, and the amine was extracted with CHCl3. The organic layer was
washed with water, dried over MgSO4 and evaporated in vacuum. The residue was recrystallized from a 1:1
mixture of hexane and CHCl3. Yield 216 mg (73%). Orange powder, mp 140-142oC (mp for (R,S)-1 135-137oC
[5]). [α]D15 -189o (c 0.59, CHCl3), ee 96% (HPLC: hexane–2-PrOH–MeOH, 95:4:1, τ 20.0 min) ([α]D20 -14.7o (c
1
0.50, CHCl3) for (S)-1, ee 75% [6]). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.28 (3H, d, J = 6.4, 2-СН3);
1.57 (1H, dtd, J = 13.1, J = 9.6, J = 6.3) and 2.00 (1H, dtd, J = 13.1, J = 4.4, J = 3.7, 3-СH2); 2.77–2.83 (2H, m,
4-СH2); 3.55 (1H, dqdd, J = 6.5, J = 6.4, J = 3.7, J = 3.2, H-2); 4.55 (1H, br. s, NH); 6.36 (1H, m, H-8); 7.87–
7.90 (2H, m, H-5,7). 13C NMR spectrum (CDCl3), δ, ppm: 22.2; 26.2; 28.8; 47.4; 112.1; 119.7; 124.2; 125.7;
137.4; 150.2. Found, %: C 62.17; H 6.59; N 14.25. C10H12N2O2. Calculated, %: C 62.49; H 6.29; N 14.57.
(R)-2-Methyl-6-nitro-1,2,3,4-tetrahydroquinoline ((R)-1) was obtained analogously to compound (S)-1,
starting from amide (R,S)-6 (121 mg, 0.28 mmol). Yield 40 mg (75%). Orange powder, mp 139-140oC (hexane–
CHCl3, 1:1). [α]D +188o (c 0.55, CHCl3), ee 98% (HPLC: hexane–2-PrOH–MeOH, 95:4:1, τ 18.22 min). The
20
NMR spectra were analogous to the spectra of compound (S)-1. Found, %: C 62.63; H 6.37; N 14.40.
C10H12N2O2. Calculated, %: C 62.49; H 6.29; N 14.57.
754

(S)-2-Methyl-6-nitro-1-trifluoracetyl-1,2,3,4-tetrahydroquinoline ((S)-9). Trifluoroacetic anhydride
(315 mg, 1.5 mmol) was added to a solution of amine (S)-1 (192 mg, 1 mmol) in CH2Cl2 (2.5 ml). The solution
obtained was heated at 40oC for 30 min. The solution was then cooled to room temperature, washed with 5%
NaHCO3 solution (33 ml) and water (33 ml), dried over MgSO4 and evaporated in vacuum. The residue was
recrystallized from hexane. Yield 225 mg (78%). Pale-yellow needle-shaped crystals, mp 93-94oC (hexane).
[α]D +256o (c 0.62, CHCl3). H NMR spectrum (DMSO-d6, 100oC), δ, ppm (J, Hz): 1.14 (3H, d, J = 6.5,
2-СН3); 1.64 (1H, dddd, J = 13.6, J = 6.9, J = 6.8, J = 6.2) and 2.35 (1H, dddd, J = 13.6, J = 6.9, J = 6.8, J = 6.5,
3-СH2); 2.80 (1H, dt, J = 16.4, J = 6.8) and 2.95 (1H, dt, J = 16.4, J = 6.9, 4-СH2); 4.65 (1H, dqd, J = 6.5, J = 6.5,
J = 6.2, H-2); 7.69 (1H, d, J = 8.9, H-8); 8.08 (1H, dd, J = 8.9, J = 2.7, H-7); 8.14 (1H, d, J = 2.7, H-5). 19F NMR
spectrum (DMSO-d6, 100oC), δ, ppm: 95.9 (s, CF3). 13C NMR spectrum (DMSO-d6, 100oC), δ, ppm (J, Hz): 18.0;
23.1; 28.7; 50.1; 115.7 (q, 1JC–F = 289, CF3); 120.8; 122.8; 125.8; 134.6; 139.6; 145.0; 154.8 (q, 2JC–F = 36.2, CO).
Found, %: C 49.98; H 3.95; F 19.56; N 9.63. C12H11F3N2O3. Calculated, %: C 50.01; H 3.85; F 19.77; N 9.72.
(R)-2-Methyl-6-nitro-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline ((R)-9) was obtained analogously to
20
1
compound (S)-9, starting from amine (R)-1 (30.8 mg, 0.16 mmol). Yield 36.8 mg (80%). [α]D -245o (c 0.54,
20
CHCl3). The NMR spectra were analogous to the spectra of compound (S)-9. Found, %: C 50.05; H 3.86;
F 19.79; N 9.64. C12H11F3N2O3. Calculated, %: C % 50.01; H 3.85; F 19.77; N 9.72.
(S)-6-Amino-2-methyl-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline ((S)-10). 10% Pd/C (16 mg)
was added to a solution of amine (S)-9 (161 mg, 0.56 mmol) in EtOH (10 ml). The suspension was stirred in an
atmosphere of H2 (3 bar) for 3 h. The solution was filtered, and the filtrate was evaporated. The residue was
purified by column flash chromatography on silica gel (eluent: benzene). Yield 127 mg (88%). Colorless
crystals, mp 65-66oC (hexane). [α]D +266o (c 0.78, CHCl3). HPLC: hexane–2-PrOH, 5:1, τ 18.90 min. H
NMR spectrum (DMSO-d6, 100oC), δ, ppm (J, Hz): 1.05 (3H, d, J = 6.5, 2-СН3); 1.22–1.43 (1H, br. m) and
2.29 (1H, ddt, J = 12.8, J = 6.6, J = 5.9, 3-СH2); 2.37–2.46 (1H, m) and 2.52 (1H, dt, J = 15.1, J = 5.6, 4-СH2); 4.57
(1H, ddq, J = 6.8, J = 6.6, J = 6.5, H-2); 4.87 (2H, br. s, NH2); 6.44 (1H, dd, J = 8.4, J = 2.5, H-7); 6.46 (1H, d,
20
1
J = 2.5, H-5); 6.93 (1H, br. d, J  8, H-8). F NMR spectrum (DMSO-d6, 100oC), δ, ppm: 96.4 (br. s, CF3). C
19
13
1
NMR spectrum (DMSO-d6, 100oC), δ, ppm (J, Hz): 18.6; 24.3; 30.4; 49.7; 111.2; 112.0; 116.2 (q, JC–F = 289.5,
2
CF3); 122.4; 125.2; 134.9 (br. s); 147.2; 154.1 (q, JC–F = 33.1, CO). Found, %: C 55.93; H 5.04; N 10.76.
C12H13F3N2O. Calculated, %: C 55.81; H 5.07; N 10.85.
X-Ray Structural Investigation of Compounds (S,S)-5c and (R,S)-8 was carried out on an Xcalibur-3
X-ray diffractometer with a CCD detector according to the standard procedure (λMoKα, graphite monochromator, ω
scanning). Fragments of colorless crystals of size 0.250.090.01 mm (compound (S,S-5)) and 0.220.150.09 mm
(compound (R,S)-8) were used for analysis. Collection and processing of data were carried using the CrysAlis set of
programs [33]. The structures of compounds were solved by a direct method with the SHELXS-97 program and
were refined with the aid of the SHELXL-97 program [34] in an anisotropic (isotropic for hydrogen atoms)
approximation. The positions of hydrogen atoms were solved partially and were refined independently, and partially
including refinement according to the "rider" model with dependent thermal parameters. The X-ray structural
analysis data are registered in the Cambridge Crystallographic Data Center (deposition CCDC 866868 and 866869).
Compound (S,S)-5c (C24H26N2O3, M 390.47). Orthorhombic, a 7.7347(6), b 12.9364 (10), c 22.1742(15)
Å; β 90.00o, V 2218.7(3) Å3; space group P212121; Z 4; dcalc 1.169 g/cm3; μ 0.077 mm-1; F(000) 832. 2.79 < Θ <
26.39. Completeness for Θ 26.39o 95.6%. 9309 reflections were collected with I > 2σ(I) (2492 independent, Rint
0.0516). S on F2 was 0.987. Final probability factors R1 (I > 2σ(I)) 0.0357, wR2 (I > 2σ(I)) 0.0301. R1 0.1353 (all
data), wR2 0.0336 (all data).
Compound (R,S)-8 (C22H25N3O5S, M 443.52). Orthorhombic, a 8.5524(16), b 25.401(4), c 10.1677(18)
Å; β 90.00o; V 2208.9(6) Å3; space group P212121; Z 4; dcalc 1.334 g/cm3; μ 0.185 mm-1; F(000) 936. 2.87 < Θ <
25.76. Completeness for Θ 25.76o 99.0%. 13896 reflections were collected with I > 2σ(I) (4135 independent,
Rint 0.0866). S on F2 was 0.823. Final probability factors R1 (I > 2σ(I) 0.0425, wR2 (I > 2σ(I)) 0.0311. R1 0.1849
(all data), wR2 0.0381 (all data).
755

The authors are grateful to Dr. P. A. Slepukhin for carrying out the X-ray structural analysis.
The work was financially supported by the Russian Foundation for Basic Research (grant 10-03-00084),
Ural Branch of the Russian Academy of Sciences (grant 12-P-3-1030), and also the Grants Council of the
President of the Russian Federation (grant NSh-5505.2012.3).
REFERENCES
1.
2.
K. Hanada, K. Furuya, N. Yamamoto, H. Nejishima, K. Ichikawa, T. Nakamura, M. Miyakawa, S.
Amano, Y. Sumita, and N. Ogura, Biol. Pharm. Bull., 26, 1563 (2003).
F. L. Ciske, M. R. Barbachyn, M. J. Genin, K. C. Grega, C. S. Lee, L. A. Dolak, E. P. Seest, W. Watt,
W. J. Adams, J. M. Friis, C. W. Ford, and G. E. Zurenko, Bioorg. Med. Chem. Lett., 13, 4235 (2003).
W. Gao, J. Kim, and J. T. Dalton, Pharm. Res., 23, 1641 (2006).
3.
4.
W. Gao and J. T. Dalton, Drug Discovery Today, 12, 241 (2007).
5.
R. A. Bunce and T. Nago, J. Heterocycl. Chem., 45, 1155 (2008).
6.
7.
F.-R. Gou, W. Li, X. Zhang, and Y.-M. Liang, Adv. Synth. Catal., 352, 2441 (2010).
L. Hoffman and W. Königs, Chem. Ber., 16, 727 (1883).
8.
R. Stoermer, Chem. Ber., 31, 2523 (1898).
9.
J. v. Braun, A. Grabowski, and M. Rawicz, Ber. Dtsch. Chem. Ges., 46, 3169 (1913).
R. P. Dikshoorn, Recl. Trav. Chim. Pays-Bas, 48, 147 (1929).
M. Kulka and R. H. F. Manske, Can. J. Chem., 30, 720 (1952).
A. L. Mndzhoyan and A. S. Azaryan, in: Synthesis of Heterocyclic Compounds [in Russian], Izd. Akad.
Nauk ArmSSR, Erevan (1964), Sect. 6, p. 55; Chem. Abs., 66, 55361m (1967).
A. P. Terent'ev, I. G. Il'ina, L. G. Yudin, N. B. Kazennova, and E. I. Levkoeva, Khim. Geterotsikl.
Soedin., 1663 (1970). [Chem. Heterocycl. Compd., 6, 1553 (1970).
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
J. H. P. Utley, and T. A. Vaughan, J. Chem. Soc., Perkin Trans. 2, 2343 (1972).
B. Amit, D. A. Ben-Efraim, and A. Patchornik, J. Chem. Soc., Perkin Trans. 1, 57 (1976).
A. Cordeiro, J. Shaw, J. O'Brien, F. Blanco, and I. Rozas, Eur. J. Org. Chem., 1504 (2011).
H. B. Kagan and J. C. Fiaud, Top. Stereochem., 18, 249 (1988).
E. Vedejs and M. Jure, Angew. Chem., Int. Ed., 44, 3974 (2005).
C. E. Müller and P. R. Schreiner, Angew. Chem., Int. Ed., 50, 6012 (2011).
H. Pellissier, Adv. Synth. Catal., 353, 1613 (2011).
S. Anas and H. B. Kagan, Tetrahedron: Asymmetry, 20, 2193 (2009).
V. P. Krasnov, D. A. Gruzdev, and G. L. Levit, Eur. J. Org. Chem., 1471 (2012).
V. P. Krasnov, G. L. Levit, I. M. Bukrina, I. N. Andreeva, L. Sh. Sadretdinova, M. A. Korolyova,
M. I. Kodess, V. N. Charushin, and O. N. Chupakhin, Tetrahedron: Asymmetry, 14, 1985 (2003).
V. P. Krasnov, G. L. Levit, M. I. Kodess, V. N. Charushin, and O. N. Chupakhin, Tetrahedron:
Asymmetry, 15, 859 (2004).
D. A. Gruzdev, G. L. Levit, V. P. Krasnov, E. N. Chulakov, L. Sh. Sadretdinova, A. N. Grishakov,
M. A. Ezhikova, M. I. Kodess, and V. N. Charushin, Tetrahedron: Asymmetry, 21, 936 (2010).
G. L. Levit, D. A. Gruzdev, V. P. Krasnov, E. N. Chulakov, L. Sh. Sadretdinova, M. A. Ezhikova,
M. I. Kodess, and V. N. Charushin, Tetrahedron: Asymmetry, 22, 185 (2011).
V. N. Charushin, V. P. Krasnov, G. L. Levit, M. A. Korolyova, M. I. Kodess, O. N. Chupakhin,
M. H. Kim, H. S. Lee, Y. J. Park, and K.-C. Kim, Tetrahedron: Asymmetry, 10, 2691 (1999).
V. P. Krasnov, G. L. Levit, I. N. Andreeva, A. I. Grishakov, V. N. Charushin, and O. N. Chupakhin,
Mendeleev Commun., 12, 27 (2002).
24.
25.
26.
27.
28.
756

29.
30.
V. P. Krasnov, L. G. Levit, M. A. Korolyova, I. M. Bukrina, L. Sh. Sadretdinova, I. N. Andreeva,
V. N. Charushin, and O. N. Chupakhin, Izv. Akad. Nauk, Ser. Khim., 1203 (2004) [Russ. Chem. Bull.,
53, 1253 (2004)].
E. N. Chulakov, D. A. Gruzdev, L. G. Levit, L. Sh. Sadretdinova, V. P. Krasnov, and V. N. Charushin,
Izv. Akad. Nauk, Ser. Khim., 926 (2011) [Russ. Chem. Bull., 60, 948 (2011)].
M. Prashad, B. Hu, D. Har, O. Repič, and T. J. Blacklock, Org. Process Res. Dev., 10, 135 (2006).
W. Oldham and I. B. Johns, J. Am. Chem. Soc., 61, 3289 (1939).
31.
32.
33.
34.
R. C. Clark and J. S. Reid, Acta Crystallogr., Sect. A: Found. Crystallogr., A51, 887 (1995).
G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., A64, 112 (2008).
757