A comparative study on the acylative kinetic resolution of racemic fluorinated and non-fluorinated 2-methyl-1,2,3,4-tetrahydroquinolines and 3,4-dihydro-3-methyl-2H-[1,4]benzoxazines

Article abstract of DOI:10.1016/j.tetasy.2013.07.024

The acylative kinetic resolution of racemic 6-fluoro-2-methyl-1,2,3,4- tetrahydroquinoline, 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine, and their non-fluorinated analogues with (S)-naproxen and N-phthaloyl-(S)-amino acyl chlorides has been carried out. It has been shown that the presence of fluorine atoms in the aromatic fragment of a heterocyclic amine results in the increasing stereoselectivity of acylation with (S)-naproxen acyl chloride and in a decrease in the efficiency of acylative kinetic resolution using N-phthaloyl-(S)-amino acyl chlorides. A method for the preparation of enantiopure (S)-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (ee >99%) was developed.

Full text of DOI:10.1016/j.tetasy.2013.07.024

Tetrahedron: Asymmetry 24 (2013) 1240–1246
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A comparative study on the acylative kinetic resolution of racemic
fluorinated and non-fluorinated 2-methyl-1,2,3,4-
tetrahydroquinolines and 3,4-dihydro-3-methyl-2H-
[1,4]benzoxazines
⇑
Dmitry A. Gruzdev, Evgeny N. Chulakov, Galina L. Levit , Marina A. Ezhikova, Mikhail I. Kodess,
Victor P. Krasnov
Postovsky Institute of Organic Synthesis of RAS (Ural Branch), 22/20 S. Kovalevskoy/Akademicheskaya St., Ekaterinburg 620990, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The acylative kinetic resolution of racemic 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, 7,8-difluoro-
3,4-dihydro-3-methyl-2H-[1,4]benzoxazine, and their non-fluorinated analogues with (S)-naproxen
and N-phthaloyl-(S)-amino acyl chlorides has been carried out. It has been shown that the presence of
fluorine atoms in the aromatic fragment of a heterocyclic amine results in the increasing stereoselectivity
of acylation with (S)-naproxen acyl chloride and in a decrease in the efficiency of acylative kinetic reso-
lution using N-phthaloyl-(S)-amino acyl chlorides. A method for the preparation of enantiopure (S)-6-flu-
oro-2-methyl-1,2,3,4-tetrahydroquinoline (ee >99%) was developed.
Received 22 July 2013
Accepted 31 July 2013
Available online 4 September 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
agents.10 Previously we have shown that the electronic effects of
substituents in the phenyl fragment of the acylating agent have a
The kinetic resolution (KR) of racemic organic substances is one
of the most important methods for the preparation of enantiopure
compounds. It is widely used in industry1 and a great number of
papers are concerned with its study. Non-enzymatic acylative KR
is one of the main approaches to enantiopure amines and related
compounds.2 This method is based on the fact that under the ac-
tion of a chiral acylating agent or in the presence of a chiral catalyst
for acyl transfer, one of the enantiomers reacts faster than the
other. As a result, the reaction product is enriched with a derivative
of one of the enantiomers, while the other predominates in the
unreacted substrate.
Recently, a number of examples showing the efficiency of this
approach for the synthesis of enantiopure amines and their deriv-
atives have been demonstrated by the research teams of Birman,3
Karnik,4 Seidel,5 Miller,6 Bode,7 and others.8 At the same time, de-
spite occasional successful attempts to explain the mechanism of
the process,9 it is not always possible to put forward reasonable
assumptions about the causes of the stereoselectivity. Therefore,
studies aimed at clarifying the structural and electronic factors that
determine the stereochemical outcome of KR are of considerable
interest in terms of practical and theoretical points of view.
We have carried out a systematic study on the acylative KR of
racemic heterocyclic amines with chiral acyl chlorides as resolving
significant influence on the result of the KR of racemic amines with
N-phthaloyl-3-aryl-(S)-alanyl chlorides.10g
Herein our aim was to study the KR of racemic heterocyclic
amines 1a and 1b, which contain fluorine atom(s) in an aromatic
fragment in comparison with their non-fluorinated analogues, 1c
and 1d (Scheme 1), under the action of the acyl chlorides of (S)-na-
proxen 2 and N-phthaloyl-(S)-amino acids, such as phenylalanine
3a and leucine 3b (Scheme 2). Enantiomers of fluorine-containing
heterocyclic amines are important key intermediates in the
synthesis of antibacterials. In particular, (2S)-6-fluoro-2-methyl-
1,2,3,4-tetrahydroquinoline (S)-1a and (3S)-7,8-difluoro-3,4-dihy-
dro-3-methyl-2H-[1,4]-benzoxazine (S)-1b are the precursors in
the synthesis of (S)-flumequine11 and levofloxacin,12 respectively.
Recently we have carried out the acylative KR of amines 1c and
1d with resolving agents 3a and 3b.10e,j Investigations of the KR
of racemic amines 1b–d with (S)-naproxen acyl chloride 2 were
started earlier,10a–c and herein we give more detailed information
about the peculiarities of the KR of these amines.
F
F
O
F
O
N
H
Me
N
H
Me
Me
N
H
N
H
Me
1a
1b
1c
1d
⇑
Corresponding author. Tel.: +7 343 3623057.
E-mail address: ca512@ios.uran.ru (G.L. Levit).
Scheme 1. Substrates for kinetic resolution.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.024

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 24 (2013) 1240–1246
1241
O
Me
The absolute configuration of amides (S,S)-8, (R,S)-9, and (S,S)-
10 was confirmed by X-ray diffraction from the known configura-
tion of the acyl fragment (Figs. 1–3).
O
N
O
Cl
R
Cl
O
From the data presented in Table 1, it is clear that the presence
of fluorine atoms in the aromatic moiety of heterocyclic amines has
a significant impact on the stereochemical outcome of the KR.
Thus, the stereoselectivity of the acylation of fluorinated amines
1a, b with (S)-naproxen acyl chloride 2 at +20 °C was higher than
that of their non-fluorinated analogues 1c, d (Table 1, entries 1
and 3 vs 5 and 7). Acylation of fluorinated amines with N-phthal-
oyl-(S)-amino acyl chlorides 3a and 3b proceeded less selectively
than the acylation of amines without the fluorine atoms. For exam-
ple, the selectivity factor of the acylation of 6-fluoro amine 1a with
acyl chloride 3a at +20 °C was 5.2, whereas in the KR of amine 1c, it
was 8.9 (Table 1, entries 9 and 13). In the case of the KR of 7,8-di-
fluoro benzoxazine 1b and its non-fluorinated analogue 1d, the dif-
ferences in stereoselectivity were even more pronounced (in
acylation with acyl chloride 3a at +20 °C, s was 1.7 and 6.2, respec-
tively) (Table 1, entries 11 and 15).
MeO
2
3a: R = Ph
3b: R = iPr
Scheme 2. Resolving agents.
It should be noted that in some published examples of the acy-
lative KR of alcohols13 as well as the desymmetrization of meso-
epoxides with aryl amines,14 the fluorine atoms in the reagent
structure had no significant effect on the stereochemical results.
2. Results and discussion
2.1. Kinetic resolution of racemic amines 1a–d with acyl
chlorides 2, 3a, and 3b
Lowering the temperature in all cases (except in the KR of
amine 1c with chloride 2) contributed to an increase in the stere-
oselectivity of the acylation with a small decrease in the racemate
conversion.
Since the fluorine atoms in the structure of amines 1a and 1b
are remote from the reaction center and do not create spatial hin-
drance, the cause of the observed differences in stereoselectivity of
acylation may be associated with other types of molecular interac-
tions. It is known that the introduction of fluorine atoms into an
The acylative kinetic resolution of racemic amines 1a–d with
acyl chlorides 2, 3a, and 3b was carried out with an amine–acyl
chloride molar ratio of 2:1 in CH2Cl2 at +20 or ꢀ20 °C for 6 h
(Scheme 3). After the acylation, amides 4–15 and unreacted amines
1a–d were isolated from the reaction mixtures. The diastereoiso-
meric excess (de) of the amides was determined by HPLC on silica
gel, and the enantiomeric excess (ee) of the unreacted amines, by
chiral HPLC (Chiralcel OD-H). Based on the de and ee values, we cal-
culated the conversion of the starting racemate C = eeamine
/
aromatic system leads to significant changes in the
p–p aromatic
and CH–
p
interactions.16 In our case, the differences in stereoselec-
(eeamine + deamide) and the selectivity factor that is the ratio of the
rate constants of enantiomers: s ¼ kfast=kslow ¼ ln½ð1 ꢀ CÞꢁ
ð1 ꢀ eeamineÞꢂ= ln½ð1 ꢀ CÞ ꢁ ð1 þ eeamineÞꢂ.15 The stereochemical re-
sults of the KR of amines 1a–d are presented in Table 1.
It was found that in all cases, the (S,S)-diastereoisomers of
amides 4–15 predominate in the products of the acylation of
amines 1a–d with acyl chlorides 2, 3a, and 3b, and the unreacted
amines are enriched with the (R)-enantiomer (Scheme 3). Major
(S,S)-amides 4, 8–11 were isolated from the mixtures of diastereo-
isomers by recrystallization or flash column chromatography on
silica gel. For amides 8–11 we managed to isolate the minor
(R,S)-amides by flash column chromatography. In order to assign
the peaks in the HPLC chromatograms and signals in the NMR
spectra of amide 4, we obtained a mixture of diastereoisomeric
amides 4 (S,S–R,S 53:47) starting from equimolar amounts of race-
mic amine 1a, acyl chloride 2, and N,N-diethylaniline as an HCl-
acceptor.
tivity are likely due to the electronic factors determined primarily
by the interactions of the aromatic fragments of the reactants in
the transition states.
2.2. Preparation of enantiopure (S)-6-fluoro-2-methyl-1,2,3,4-
tetrahydroquinoline (S)-1a
In order to prepare the (S)-enantiomer of 6-fluoro-2-methyl-
1,2,3,4-tetrahydroquinoline 1a, we carried out the KR of its race-
mate with (S)-naproxen acyl chloride 2 at ꢀ20 °C (Scheme 4).
Amide (S,S)-4 (de >99%) was isolated from the acylation product
by a single recrystallization in 58% yield relative to the acylating
agent. Acidic hydrolysis of amide (S,S)-4 by heating in a mixture
of acetic and hydrochloric acids gave (S)-amine 1a in 84% yield
without a loss of enantiomeric purity (ee >99%). The overall yield
of (S)-1a was 24% relative to the starting racemate.
OMe
X
Y
Z
Z
Y
Z
Y
Z
Y
Me
N
4
CH2
H
F
Me
5
6
O
CH2
O
F
F
Cl
NH
O
+
CH2Cl2,
+
NH
NH
H
H
H
+20 or -20 oC, 6 h
X
O
X
X
OMe
7
H
Me
Me
Me
Me
(S,S)-4-7
(R)-1a-d
0.5 equiv.
O
2
1a-d
R
Z
R
X
Y
Z
Z
Z
Y
NPhth
O
8
Ph CH2
Ph
iPr CH2
iPr
H
F
F
PhthN
+
Y
NH
Cl
+
CH2Cl2,
+20 or -20 oC, 6 h
Y
N
9
10
11
O
F
X
X
X
Me
R
H
F
F
Me
(S,S)-8-15
(R)-1a-d
3a,b
0.5 equiv.
O
F
1a-d
12 Ph CH2
13 Ph
14 iPr CH2
15
H
H
H
H
H
H
3a: R = Ph
3b: R = iPr
O
iPr
O
H
H
Scheme 3. Kinetic resolution of amines 1a–d with acyl chlorides 2, 3a, and 3b.

1242
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 24 (2013) 1240–1246
Table 1
a
Stereochemical results of the acylative KR of racemic amines 1a–d with acyl chlorides 2, 3a, and 3b in CH2Cl2
Entry
Resolving agent
Racemic amine
T (°C)
(S,S)-Amideb (de %)
Unreacted (R)-aminec (ee %)
Conversion C (%)
Selectivity factor (s)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
1a
1a
1b
1b
1c
1c
1d
1d
1a
1a
1b
1b
1c
1c
1d
1d
1a
1a
1b
1b
1c
1c
1d
1d
+20
ꢀ20
+20
ꢀ20
+20
ꢀ20
+20
ꢀ20
+20
ꢀ20
+20
ꢀ20
+20
ꢀ20
+20
ꢀ20
+20
ꢀ20
+20
ꢀ20
+20
ꢀ20
+20
ꢀ20
4, 87.2
4, 91.6
5, 80.7
5, 84.0
6, 77.0
6, 72.8
7, 74.2
7, 86.0
8, 51.3
74.4
76.0
72.5
68.8
66.0
61.6
71.1
40.5
49.9
49.0
8.9
46
45
47
45
46
46
49
32
49
44
35
18
46
45
45
42
49
47
33
14
44
44
46
42
32
53
20
24
15
12
14
19
5.2
7.2
1.7
1.8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
8, 63.7
9, 21.8
9, 26.0
5.8
12, 67.1
12, 74.4
13, 59.2
13, 64.3
10, 64.6
10, 73.7
11, 48.4
11, 53.6
14, 76.0
14, 80.2
15, 69.5
15, 77.6
56.9
60.4
48.0
46.4
63.0
64.4
24.1
8.8
60.4
64.7
59.1
56.5
8.910e
1210e
6.210e
7.210e
8.9
13
3.6
3.6
1310j
1910j
9.910j
1410j
a
b
c
Average values for 2–4 parallel runs are presented.
Determined by HPLC (see Section 4).
Determined by chiral HPLC (Chiralcel OD-H, see Section 4).
Figure 3. Structure of amide (S,S)-10 (thermal ellipsoids of 50% probability).
Figure 1. Structure of amide (S,S)-8 (thermal ellipsoids of 50% probability).
OMe
F
1. 2 (0.5 equiv.), CH2Cl2, -20 o
C
F
Me
N
2. recrystallization
NH
O
4
(S,S)-
Me
1a
de >99%
Me
1. HCl, AcOH, 95 oC, 10 h
2. Na2CO3, H2O
F
NH
(S)-1a ee >99%
Me
Scheme 4. Preparation of enantiopure amine (S)-1a from the racemate via a KR
protocol using acyl chloride 2.
Figure 2. Structure of amide (R,S)-9 (thermal ellipsoids of 50% probability).

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 24 (2013) 1240–1246
1243
Although, the selectivity in the acylation of racemic amine 1a
with N-phthaloyl-(S)-amino acyl chlorides was lower than that
with (S)-naproxen acyl chloride, this KR protocol can also be used
for the preparation of enantiopure (S)-1a from the racemate. Thus,
the acylation of racemic amine 1a with 0.5 equiv of acyl chloride
3a followed by recrystallization of the product led to diastereoiso-
merically pure amide (S,S)-8 (de >99%) in 46% yield. Acidic hydro-
lysis of amide (S,S)-8 resulted in enantiopure amine (S)-1a in 18%
overall yield relative to the starting racemate.
It should be noted that two main approaches have recently been
applied for the preparation of (S)-1a; the resolution of the race-
mate via diastereoisomeric salts11,17 (the enantiomeric purity of
the target compound was up to 99.2% ee17b) and the metal-cata-
lyzed asymmetric hydrogenation of 6-fluoro-2-methylquinoline18
(the enantiomeric purity of the target (S)-1a was up to 98% ee18f).
Herein, based on the KR protocol, we prepared the (S)-enantiomer
of amine 1a with ee >99%.
The high-resolution mass spectra were obtained on a Bruker Dal-
tonics series MicrOTOF-Q II mass spectrometer, electrospray ioni-
zation with direct sample inlet (flow rate 180
Analytical HPLC of amide 4 was performed on an Agilent 1100
instrument using Phenomenex Luna C18(2) column
(250 ꢁ 4.6 mm, 5 m), detection at 230 nm, 0.8 mL/min flow rate,
lL/h).
a
l
MeCN–H2O 7:3 as eluting solvent. Analytical HPLC was also per-
formed on a Knauer Smartline-1100 instrument using a ReproSil
100 Si column (250 ꢁ 4.6 mm, 5
lm) for amides 8–11, detection
at 220 nm, 1 mL/min flow rate, n-hexane–i-PrOH 80:1 mixture as
eluting solvent; and a Chiralcel OD-H column (250 ꢁ 4.6 mm) for
amines 1a–d, detection at 200 nm, 1 mL/min flow rate, n-hex-
ane–i-PrOH–MeOH 100:1:1 for 1a (s(R)-1a 5.8–6.0 min, s(S)-1a 7.6–
7.8 min); n-hexane–i-PrOH 40:1 for 1b (s(R)-1b 11.8–12.0 min,
s(S)-1b 14.7–14.9 min); n-hexane–i-PrOH–MeOH 140:0.7:0.3 for 1c
(s(R)-1c 9.5–9.6 min, s(S)-1c 10.5–10.7 min); n-hexane–i-PrOH–
MeOH 100:1.5:1.5 for 1d
(s(R)-1d 9.6–9.8 min, s(S)-1d 10.5–
10.6 min).
Crystallographic data for (S,S)-8, (R,S)-9, and (S,S)-10 have been
deposited with the Cambridge Crystallographic Data Centre (CCDC
Nos. 926802–926804). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.cam.
ac.uk].
3. Conclusion
In conclusion, we have studied the acylative kinetic resolution of
racemic fluorinated heterocyclic amines, 6-fluoro-2-methyl-1,2,
3,4-tetrahydroquinoline, and 7,8-difluoro-3,4-dihydro-3-methyl-
2H-[1,4]benzoxazine, in comparison with their non-fluorinated
analogues. It has been shown that the acylation of fluorinated
amines with (S)-naproxen acyl chloride is more selective when
compared with the non-fluorinated analogues, and in the case of
N-phthaloyl-(S)-amino acyl chlorides the selectivity of acylation is
lower than that of non-substituted analogues. The data obtained
pointed to different mechanisms of stereoselectivity in the case of
acylation with (S)-naproxen acyl chloride or N-phthaloyl-(S)-amino
acyl chlorides. Based on the acylative kinetic resolution using (S)-
naproxen or N-phthaloyl-(S)-phenylalanyl chlorides we have put
forward a method for the preparation of enantiopure (S)-6-fluoro-
2-methyl-1,2,3,4-tetrahydroquinoline from the racemate.
4.2. (RS)-6-Fluoro-2-methyl-1,2,3,4-tetrahydroquinoline 1a
Metallic sodium (3.5 g) was added portionwise to a stirred solu-
tion of 6-fluoro-2-methylquinoline (2.0 g, 12.4 mmol) in EtOH
(40 mL) at 50 °C. The reaction mixture was stirred at 50 °C for 3 h
and kept at ambient temperature overnight. Then, water (100 mL)
and concentrated HCl (20 mL) were added, and the reaction mix-
ture was concentrated to a volume of 110 mL, washed with benzene
(2 ꢁ 20 mL), alkalized with NaOH to pH 9–10, and extracted with
benzene (3 ꢁ 20 mL). Organic layer was dried over MgSO4 and
evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel using benzene as an elu-
ent. Yield 1.4 g (68%). Colorless solid, mp 34–36 °C. 1H NMR
(500 MHz): d 1.12 (3H, d, J 6.3 Hz, Me), 1.39 (1H, dddd, J 12.6,
11.3, 9.5, 5.2 Hz, H-3B), 1.82 (1H ddt, J 12.6, 5.8, 3.2 Hz, , H-3A),
2.61 (1H, ddd, J 16.7, 5.2, 3.7 Hz, H-4B), 2.72 (1H, ddd, J 16.7, 11.3,
5.8 Hz, H-4A), 3.24 (1H, dqd, J 9.5, 6.3, 3.1 Hz, H-2), 5.63 (1H, br s,
NH), 6.43 (1H, m, H-8), 6.65–6.70 (2H, m, H-5, H-7). 13C NMR
(126 MHz): d 21.88 (Me), 25.96 (C-4), 29.22 (C-3), 46.21 (C-2),
4. Experimental
4.1. General
(RS)-7,8-Difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine
1b,19 (RS)-2-methyl-1,2,3,4-tetrahydroquinoline 1c,20 (RS)-3,4-
dihydro-3-methyl-2H-[1,4]benzoxazine 1d,19 N-phthaloyl-(S)-
phenylalanyl 3a,10e and N-phthaloyl-(S)-leucyl chlorides 3b10j were
obtained as described earlier. (RS)-6-Fluoro-2-methyl-1,2,3,4-tet-
rahydroquinoline 1a was prepared in a similar way as described
for amine 1c.20 (S)-Naproxen acyl chloride 2 was obtained by the
treatment of (S)-naproxen with oxalyl chloride according to the lit-
erature.10c Other reagents were commercially available. Amides 5–
2
3
112.63 (d, JCF 22.0 Hz, C-7), 114.06 (d, JCF 7.4 Hz, C-8), 114.62 (d,
2JCF 21.2 Hz, C-5), 121.15 (d, JCF 6.8 Hz, C-4a), 141.60 (C-8a),
3
1
154.91 (d, JCF 230.8 Hz, C-6). 19F NMR (376 MHz): d 32.50 (td,
J = 9.1, 5.2 Hz, F-6). Anal. Calcd for C10H12FN (M 165.21): C 72.70,
H 7.32, F 11.50, N 8.48. Found: C 72.63, H 7.15, F 11.16, N 8.58.
7
10a,b and 12–1510e,i,j have been described previously.
4.3. (2RS)-6-Fluoro-N-[(2S)-2-(6-methoxynaphth-2-yl)-propan-
oyl]-2-methyl-1,2,3,4-tetrahydroquinoline 4 (diastereomeric
mixture)
The solvents were dried according to standard methods21 and
used freshly prepared. Flash column chromatography was per-
formed using Silica gel 60 (230–400 mesh) (Alfa Aesar). Melting
points were obtained on an SMP3 apparatus (Barloworld Scientific)
and are uncorrected. Optical rotations were measured on a Perkin
Elmer M341 polarimeter. The 1H, 13C, and 19F NMR spectra were re-
corded on Bruker DRX-400 (400, 100, and 376 MHz, respectively)
or Bruker Avance 500 (500, 126, and 470 MHz, respectively) spec-
trometers with TMS and hexafluorobenzene as the internal stan-
dards. The NMR spectra of amides were recorded in DMSO-d6 at
100 °C; the NMR spectra of amine 1a, in CDCl3 at ambient temper-
ature. All of the signals in the 1H and 13C NMR spectra of the
compounds obtained were assigned on the basis of 2D 1H–1H
COSY, 1H–13C HSQC, and HMBC experiments at 100 °C. Elemental
analysis was performed using a Perkin Elmer 2400 II analyzer.
A solution of acyl chloride 2 (64.7 mg, 0.26 mmol) in CH2Cl2
(2.0 mL) was added to a solution of amine 1a (42.9 mg, 0.26 mmol)
and N,N-diethylaniline (38.8 mg, 0.26 mmol) in CH2Cl2 (3.1 mL)
with stirring at +20 °C. The reaction mixture was stirred at +20 °C
for 24 h and washed successively with 4 N HCl (2 ꢁ 3 mL), satu-
rated aqueous NaCl (4 ꢁ 4 mL), 5% aqueous NaHCO3 (2 ꢁ 3 mL),
and water (2 ꢁ 4 mL). The organic layer was separated, dried over
MgSO4, and evaporated under reduced pressure. The residue was
purified by flash column chromatography on silica gel using ben-
zene–EtOAc as eluting solvent. Yield 58.9 mg, 60%. Colorless oil.
(S,S-R,S) 53:47 (HPLC: Phenomenex Luna C18(2), MeCN–H2O 7:3,
s(S,S)-4 17.8 min, s(R,S)-4 22.5 min). 1H NMR (500 MHz): d 0.89

1244
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 24 (2013) 1240–1246
(1.59H, d, J 6.6 Hz, Me-2 (S,S)), 1.02 (1.41H, d, J 6.5 Hz, Me-2 (R,S)),
1.14 (0.53H, m, H-3B (S,S)), 1.27 (0.47H, ddt, J 13.2, 9.1, 5.9 Hz, H-
3B (R,S)), 1.37 (1.41H, d, J 6.8 Hz, Me-20 (R,S)), 1.44 (1.59H, d, J
6.9 Hz, Me-20 (S,S)), 1.74 (0.53H, m, H-4B (S,S)), 2.03 (0.47H, m,
H-4B (R,S)), 2.11 (0.53H, dddd, J 13.2, 7.6, 5.7, 5.2 Hz, H-3A (S,S)),
2.29 (0.53H, dt, J 15.0, 5.2, Hz, H-4A (S,S)), 2.43 (0.47H, m, H-3A
(R,S)), 2.63 (0.47H, dt, J 15.5, 5.9 Hz, H-4A (R,S)), 3.84 (1.59H, s,
OMe (S,S)), 3.86 (1.41H, s, OMe (R,S)), 4.12 (0.47H, q, J 6.8 Hz, H-
20 (R,S)), 4.36 (0.53H, q, J 6.9 Hz, H-20 (S,S)), 4.67 (0.53H, dqw, J
7.6, 6.6 Hz, H-2 (S,S)), 4.75 (0.47H, m, H-2 (R,S)), 6.78 (0.53H, dd,
J 9.0, 2.9 Hz, H-5 (S,S)), 6.93 (0.47H, td, J 9.0, 2.9 Hz, H-7 (R,S)),
6.98 (0.53H, m, H-300 (S,S)), 7.02 (0.47H, dd, J 9.0, 2.9 Hz, H-700
(R,S)), 7.05 (0.53H, td, J 9.0, 2.9 Hz, H-7 (S,S)), 7.08 (0.53H, dd, J
9.0, 2.6 Hz, H-700 (S,S)), 7.12-7.15 (0.94H, m, H-5 and H-8 (R,S)),
7.17 (1.06H, m, H-500 and H-100 (S,S)), 7.27 (0.47H, d, J 2.9 Hz, H-500
(R,S)), 7.41 (0.53H, dd, J 8.7, 5.2 Hz, H-8 (S,S)), 7.45 (0.47H, dd, J
8.5, 1.9 Hz, H-300 (R,S)), 7.56–7.58 (1.06H, m, H-800 and H-400 (S,S)),
7.72 (0.47H, d, J 1.9 Hz, H-100 (R,S)), 7.75–7.77 m (0.94H, m, H-400
and H-800 (R,S)). 19F NMR (470 MHz): d 45.44 (0.47F, m, F-6 (R,S)),
45.61 (0.53F, m, F-6 (S,S)). Anal. Calcd for C24H24FNO2: C, 76.37;
H, 6.41; N, 3.71; F, 5.03. Found: C, 76.33; H, 6.67; N, 3.51; F, 4.83.
7.6, 5.2 Hz, H-3A), 2.34 (1H, ddd, J 14.6, 5.2 Hz, H-4A), 3.18 (1H,
dd, J 14.1, 9.8 Hz, H-30B), 3.53 (1H, dd, J 14.1, 5.3 Hz, H-30A), 4.56
(1H, m, H-2), 5.46 (1H, dd, J 9.8, 5.3 Hz, H-20), 6.52 (1H, dd, J 8.8,
2.9 Hz, H-5), 6.77 (1H, td, J 8.7, 2.9 Hz, H-7), 7.04–7.10 (5H, m,
Ph), 7.26 (1H, dd, J 8.7, 5.2 Hz, H-8), 7.58 (2H, m, H-400, 700 Phth),
7.70 (2H, m, H-500, 600 Phth). 13C NMR (126 MHz): d 19.14 (Me-2),
24.24 (C-4), 30.78 (C-3), 34.99 (C-30), 48.71 (C-2), 52.06 (C-20),
2
112.86 and 112.90 (both d, JCF 22.7 Hz, C-5 and C-7), 122.02 (C-
3
400, 700), 125.67 (Cp), 125.92 (d, JCF 8.9 Hz, C-8), 127.36 (Co),
4
128.64 (Cm), 130.04 (C-300a, 700a), 132.09 (d, JCF 2.7 Hz, C-8a),
3
133.82 (C-500, 600), 136.25 (d, JCF 8.2 Hz, C-4a), 137.03 (Ci),
1
.158.89 (d, JCF 243.1 Hz, C-6), 165.39 (C-100, 300), 166.70 (C-10). 19F
NMR (470 MHz, DMSO-d6): d 45.37 (m, F-6). HRMS (ESI) m/z, Calcd
for C27H24FN2O3 ([M+H]+): 443.1771; found: 443.1765.
4.4.3. (3S)-7,8-Difluoro-3,4-dihydro-3-methyl-N-(N0-phthaloyl-
(S)-phenylalanyl)-2H-[1,4]benzoxazine (S,S)-9
Yield 58.6 mg, 13% (flash column chromatography, eluent ben-
zene–ethyl acetate, slow eluting isomer). Yellowish foam.
½
a 2D0
ꢂ
¼ þ280 (c 1.0, CHCl3). De 99.8% (HPLC: ReproSil 100 Si, hex-
ane–iPrOH 80:1,
s
11.65 min). 1H NMR (500 MHz): d 1.07 (3H, d,
J 6.8 Hz, Me-3), 3.40 (1H, dd, J 14.1, 6.5 Hz, H-30B), 3.71 (1H, dd, J
14.1, 9.3 Hz, H-30A), 4.06 (1H, dd, J 11.1, 3.0 Hz, H-2B); 4.32 (1H,
dd, J 11.1, 1.5 Hz, H-2A), 4.79 (1H, qdd, J 6.8, 3.0, 1.5 Hz, H-3),
5.69 (1H, dd, J 9.3, 6.4 Hz, H-20), 6.95 (1H, td, J 9.8, 8.1 Hz, H-6),
7.04-7.18 (5H, m, Ph), 7.61 (1H, ddd, J 9.4, 5.3, 2.4 Hz, H-5), 7.82
4.4. Synthesis of diastereoisomeric amides 8–11. General
procedure
A solution of the appropriate acyl chloride (1 mmol) in CH2Cl2
(10 mL) was added to a solution of amine 1a or 1b (2 mmol) in
CH2Cl2 (10 mL) at +20 °C. The reaction mixture was kept in a ther-
mostat at a given temperature for 6 h, then successively washed
with 4 M HCl (2 ꢁ 5 mL), saturated aqueous NaCl (3 ꢁ 15 mL), 5%
NaHCO3 (10 mL), and water (2 ꢁ 15 mL). The organic layer was
separated, dried over MgSO4, and evaporated under reduced pres-
sure. The diastereoisomers of amides 8–11 were isolated by recrys-
tallization or flash column chromatography on silica gel.
13
(4H, s, Phth). C NMR (126 MHz): d 14.40 (Me-3), 33.58 (C-30),
2
45.14 (C-3), 53.59 (C-20), 69.77 (C-2), 106.63 (d, JCF 18.5 Hz, C-6),
3
4
3
4
118.95 (dd, JCF 8.1, JCF 4.2 Hz, C-5), 120.75 (dd, JCF 3.1, JCF
1.9 Hz, C-4a), 122.59 (C-400, 700), 126.11 (Cp), 127.70 Cm), 128.12
(Co), 130.56 (C-300a, 700a), 134.14 (C-500, 600), 136.14 (Ci), 136.23
2
3
1
2
(dd, JCF 10.0, JCF 3.5 Hz, C-8a), 138.76 (dd, JCF 245.3, JCF
1
2
15.6 Hz, C-8), 147.02 (dd, JCF 243.1, JCF 10.0 Hz, C-7), 166.74 (C-
10), 167.10 (C-100, 300). 19F NMR (470 MHz): d 2.63 (1F, ddd, J 21.0,
8.1, 2.4 Hz, F-8), 21.71 (1F, ddd, J 21.0, 9.8, 5.3 Hz, F-7). Anal. Calcd
for C26H20F2N2O4: C, 67.53; H, 4.36; N, 6.06. Found: C, 67.70; H,
4.32; N, 5.97.
4.4.1. (2S)-6-Fluoro-2-methyl-N-[N0-phthaloyl-(S)-phenylalanyl]-
1,2,3,4-tetrahydroquinoline [(S,S)-8]
Yield 204 mg, 46% (recrystallization from hexane–ethyl acetate).
Colorless solid, mp 189–190 °C. ½a D20
ꢂ
¼ þ346 (c 1.0, CHCl3). De
4.4.4. (3R)-7,8-Difluoro-3,4-dihydro-3-methyl-N-(N’-phthaloyl-
(S)-phenylalanyl)-2H-[1,4]benzoxazine (R,S)-9
>99.8% (HPLC: ReproSil 100 Si, hexane–iPrOH 80:1,
s
10.33 min).
1H NMR (500 MHz): d 1.02 (3H, d, J 6.5 Hz, Me-2), 1.30 (1H, dddd,
J 13.1, 10.4, 6.9, 5.3 Hz, H-3B), 2.31 (1H, ddt, J 13.1, 7.4, 5.3 Hz, H-
3A), 2.46 (1H, ddd, J 15.2, 10.4, 5.2 Hz, H-4B), 2.69 (1H, dt, J 15.2,
5.3 Hz, H-4A), 2.73 (1H, dd, J 14.2, 4.7 Hz, H-30B), 3.71 (1H, dd, J
14.2, 11.2 Hz, H-30A), 4.64 (1H, ddq, J 7.4, 6.9, 6.5 Hz, H-2), 5.69
(1H, dd, J 11.2, 4.7 Hz, H-20), 6.78 (2H, m, Ho), 7.03–7.11 (3H, m,
Hp and Hm), 7.14 (1H, dd, J 8.9, 2.9 Hz, H-5), 7.19 (1H, td, J 8.8,
2.9 Hz, H-7), 7.56 (1H, dd, J 8.7, 5.1 Hz, H-8), 7.82 (4H, m, Phth).
13C NMR (126 MHz): d 19.20 (Me-2), 24.82 (C-4), 31.04 (C-3),
Yield 32.9 mg, 7.3% (flash column chromatography, eluent ben-
zene–ethyl acetate, fast eluting isomer). Colorless powder, mp
185 °C. ½a 2D0
ꢂ
¼ ꢀ391 (c 1.0, CHCl3). De 99.2% (HPLC: ReproSil 100
Si, hexane–iPrOH 80:1,
s
4.85 min). 1H NMR (500 MHz): d 0.86
(3H, d, J 6.9 Hz, Me-3), 3.28 (1H, dd, J 14.2, 9.7 Hz, H-30B), 3.48
(1H, dd, J 14.2, 5.3 Hz, H-30A), 4.17 (1H, dd, J 10.8, 3.0 Hz, H-2B),
4.27 (1H, dd, J 10.8, 1.6 Hz, H-2A), 4.54 (1H, m, H-3), 5.63 (1H,
dd, J 9.7, 5.3 Hz, H-20), 6.76 (1H, ddd, J 9.9, 9.3, 8.4 Hz, H-6), 7.07-
7.15 (5H, m, Ph), 7.32 (1H, ddd, J 9.3, 5.4, 2.5 Hz, H-5), 7.72 (2H,
m, Phth), 7.77 (2H, m, Phth). 13C NMR (126 MHz): d 14.09 (Me-
3), 34.79 (C-30), 44.92 (C-3), 51.93 (C-20), 69.61 (C-2), 106.60 (d,
2
31.72 (C-30), 48.72 (C-2), 54.38 (C-20), 112.82 (d, JCF 23.0 Hz, C-7),
2
114.17 (d, JCF 22.7 Hz, C-5), 122.52 (C-400, 700), 125.98 (Cp), 126.45
3
3
4
(d, JCF 8.7 Hz, C-8), 127.50 (Co), 127.71 (Cm), 130.61 (C-300a, 700a),
2JCF 18.5 Hz, C-6), 119.00 (dd, JCF 8.2, JCF 3.8 Hz, C-5), 120.52
4
3
4
132.20 (d, JCF 2.7 Hz, C-8a), 134.10 (C-500, 600), 136.49 (Ci), 137.84
(dd, JCF 2.7, JCF 1.9 Hz, C-4a), 122.49 (C400, 700), 125.88 (Cp),
3
1
(d, JCF 8.1 Hz, C-4a), 159.67 (d, JCF 244.2 Hz, C-6), 166.84 (C-10),
167.39 (C-100, 300). 19F NMR (470 MHz, DMSO-d6): d 46.96 (m, F-6).
Anal. Calcd for C27H23FN2O3: C, 73.29; H, 5.24; N, 6.22; F, 4.29.
Found: C, 73.13; H, 5.12; N, 6.35; F, 4.04.
127.48 (Cm), 128.69 (Co), 130.04 (C-300a, 700a), 134.24 (C-500, 600),
2
3
135.51 (dd, JCF 10.0, JCF 3.5 Hz, C-8a), 136.56 (Ci), 138.35 (dd,
1JCF 245.1, JCF 15.5 Hz, C-8), 146.63 (dd, JCF 242.9, JCF 10.0 Hz,
C-7), 165.90 (C-100, 300), 166.82 (C-10). 19F NMR (470 MHz, DMSO-
d6): d 1.71 (1F, ddd, J 20.8, 8.4, 2.5 Hz, F-8), 21.04 (1F, m, F-7). Anal.
Calcd for C26H20F2N2O4: C, 67.53; H, 4.36; N, 6.06. Found: C, 67.36;
H, 4.34; N, 6.19.
2
1
2
4.4.2. (2R)-6-Fluoro-2-methyl-N-[N0-phthaloyl-(S)-phenylalanyl]-
1,2,3,4-tetrahydroquinoline (R,S)-8
Yield 48.7 mg, 11% (flash column chromatography of mother
liquor after recrystallization, eluent hexane–ethyl acetate, fast
4.4.5. (2S)-6-Fluoro-2-methyl-N-[N0-phthaloyl-(S)-leucyl]-1,2,3,
4-tetrahydroquinoline (S,S)-10
eluting isomer). Amorphous solid. ½a D20
ꢂ
¼ ꢀ311 (c 0.5, CHCl3). De
97% (HPLC: ReproSil 100 Si, hexane–iPrOH 80:1,
s
7.25 min). 1H
Yield 221 mg, 54% (flash column chromatography, eluent hex-
ane–ethyl acetate, slow eluting isomer). Colorless crystals, mp
NMR (500 MHz): d 0.97 (3H, d, J 6.5 Hz, Me-2), 1.13 (1H, m, H-
3B), 2.18 (1H, ddd, J 14.6, 9.9, 5.2 Hz, H-4B), 2.25 (1H, ddt, J 12.8,
115–116 °C. ½a 2D0
¼ þ387 (c 1.0, CHCl3). De 99.8% (HPLC: ReproSil
ꢂ

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 24 (2013) 1240–1246
1245
100 Si, hexane–iPrOH 80:1,
s
9.75 min). 1H NMR (500 MHz): d 0.44
4.4.8. (3R)-7,8-Difluoro-3,4-dihydro-3-methyl-N-[N0-phthaloyl-
(S)-leucyl]-2H-[1,4]benzoxazine (R,S)-11
(3H, d, J 6.6 Hz, Me-40), 0.67 (3H, d, J 6.6 Hz, Me-40), 0.92 (1H, ddd, J
13.8, 9.8, 3.8 Hz, H-30B), 1.01 (3H, d, J 6.6 Hz, Me-2), 1.27 (1H, dddd,
J 13.2, 10.7, 7.2, 5.1 Hz, H-3B), 1.33 (1H, dseptd, J 9.8, 6.6, 3.9 Hz, H-
40), 2.34 (1H, dddd, J 13.2, 7.5, 5.4, 4.8 Hz, H-3A), 2.45 (1H, ddd, J
15.1, 10.7, 5.4 Hz, H-4B), 2.58 (1H, ddd, J 13.8, 12.0, 3.9 Hz, H-
30A), 2.71 (1H, dt, J 15.1, 4.9 Hz, H-4A), 4.59 (1H, tq, J 7.3, 6.6 Hz,
H-2), 5.46 (1H, dd, J 12.0, 3.8 Hz, H-20), 7.13–7.17 (2H, m, H-5
and H-7), 7.49 (1H, dd, J 8.9, 5.2 Hz, H-8), 7.86 (4H, m, Phth). 13C
NMR (126 MHz): d 19.36 (Me-2), 19.61 (Me-40), 21.90 (Me-40),
24.26 (C-40), 25.02 (C-4), 31.35 (C-3), 34.24 (C-30), 48.63 (C-2),
Yield 64.3 mg, 15% (flash column chromatography, eluent ben-
zene–ethyl acetate, fast eluting isomer). Colorless powder, mp
75–78 °C. ½a 2D0
ꢂ
¼ ꢀ217 (c 1.1, CHCl3). De 99% (HPLC: ReproSil 100
Si, hexane–iPrOH 80:1,
s
4.93 min). 1H NMR (500 MHz): d 0.88
(3H, d, J 6.7 Hz, Me-3), 0.89 (3H, d, J 6.6 Hz, Me-40), 0.95 (3H, d, J
6.6 Hz, Me-40), 1.54 (1H, dseptd, J 8.5, 6.6, 5.0 Hz, H-40), 1.95 (1H,
ddd, J 14.1, 9.1, 5.0 Hz, H-30B), 2.01 (1H, ddd, J 14.1, 8.5, 5.3 Hz,
H-30A), 4.19 (1H, dd, J 10.9, 3.2 Hz, H-2B), 4.27 (1H, dd, J 10.9,
1.4 Hz, H-2A), 4.56 (1H, m, H-3), 5.32 (1H, dd, J 9.1, 5.3 Hz, H-20),
6.76 (1H, ddd, J 10.1, 9.3, 8.2 Hz, H-6), 7.31 (1H, ddd, J 9.3, 5.4,
2.5 Hz, H-5), 7.81 (4H, m, Phth). 13C NMR (126 MHz): d 14.16
(Me-3), 21.21 (Me-40), 22.39 (Me-40), 23.81 (C-40), 37.99 (C-30),
2
2
51.73 (C-20), 112.77 (d, JCF 23.0 Hz, C-7), 113.92 (d, JCF 22.8 Hz,
3
C-5), 122.49 (C-400, 700), 126.44 (d, JCF 8.9 Hz, C-8), 130.91 (C-300a,
4
3
700a), 132.23 (d, JCF 2.8 Hz, C-8a), 134.01 (C-500, 600), 138.05 (d, JCF
1
2
8.5 Hz, C-4a), 159.71 (d, JCF 244.1 Hz, C-6), 167.72 (C-100, 300),
44.81 (C-3), 49.21 (C-20), 69.94 (C-2), 106.59 (d, JCF 18.5 Hz, C-6),
168.14 (C-10). 19F NMR (470 MHz): d 46.82 (td, J 9.1, 5.2 Hz, F-6).
Anal. Calcd for C24H25FN2O3: C, 70.57; H, 6.17; N, 6.86; F, 4.65.
Found: C, 70.60; H, 6.05; N, 6.82; F, 4.63.
118.97 (dd, JCF 8.1, JCF 3.8 Hz, C-5), 120.71 (t, JCF 2.3 Hz, C-4a),
3
4
122.57 (C-400, 700), 130.29 (C-300a, 700a), 134.26 (C-500, 600), 135.53
2
3
1
2
(dd, JCF 10.0, JCF 3.5 Hz, C-8a), 138.35 (dd, JCF 244.9, JCF
15.2 Hz, C-8), 146.63 (1JCF 242.5, JCF 10.2 Hz, C-7), 166.32 (C-100,
2
4.4.6. (2R)-6-Fluoro-2-methyl-N-[N0-phthaloyl-(S)-leucyl]-1,2,3,
4-tetrahydroquinoline (R,S)-10
300), 167.32 (C-10). 19F NMR (470 MHz): d 1.69 (1F, ddd, J 20.9,
8.2, 2.5 Hz, F-8), 20.97 (1F, m, F-7). HRMS (ESI) m/z, calcd for
Yield 73.5 mg, 18% (flash column chromatography, eluent hex-
C
23H23F2N2O4 ([M+H]+): 429.1626; found: 429.1620.
ane–ethyl acetate, fast eluting isomer). Semi-solid. ½a D20
¼ ꢀ176
ꢂ
(c 1.0, CHCl3). De 99% (HPLC: ReproSil 100 Si, hexane–iPrOH 80:1,
4.5. Kinetic resolution of racemic amines 1a and 1b. General
procedure
1
s
6.78 min). H NMR (500 MHz): d 0.86 (3H, d, J 6.6 Hz, Me-40),
0.93 (3H, d, J 6.6 Hz, Me-40), 0.97 (3H, d, J 6.5 Hz, Me-2), 1.13
(1H, m, H-3B), 1.48 (1H, dseptd, J 8.4, 6.6, 4.9 Hz, H-40), 1.85 (1H,
ddd, J 14.2, 9.3, 4.9 Hz, H-30B), 2.06 (1H, ddd, J 14.2, 8.4, 5.1 Hz,
H-30A), 2.18 (1H, ddd, J 14.6, 9.9, 5.3 Hz, H-4B), 2.24 (1H, m, H-
3A), 2.34 (1H, ddd, J 14.6, 5.0, 4.7 Hz, H-4A), 4.52 (1H, dqw, J 7.3,
6.6 Hz, H-2), 5.18 (1H, dd, J 9.3, 5.1 Hz, H-20), 6.54 (1H, dd, J 8.8,
2.9 Hz, H-5), 6.83 (1H, td, J 8.8, 2.9 Hz, H-7), 7.28 (1H, dd, J 8.7,
5.1 Hz, H-8), 7.67 (2H, m, H-400, 700 Phth), 7.76 (2H, m, H-500, 600
A solution of the appropriate acyl chloride (0.15 mmol) in
CH2Cl2 (1.5 mL) was added to a solution of amine (0.30 mmol) in
CH2Cl2 (1.5 mL) at a specified temperature. The reaction mixture
was kept at the appropriate temperature for 6 h, then washed with
4 M HCl (2 ꢁ 3 mL), saturated aqueous NaCl (3 ꢁ 3 mL), 5% NaHCO3
(3 mL), and water (2 ꢁ 3 mL). The organic layer was separated,
dried over MgSO4, and evaporated under reduced pressure to give
a mixture of diastereoisomeric amides, which was analyzed by
HPLC. Acidic washing solutions were collected and alkalized with
Na2CO3 up to pH 8–9, and extracted with CHCl3 (2 ꢁ 3 mL). The or-
ganic layer was separated, dried over MgSO4, and evaporated under
reduced pressure to give an enantiomeric mixture of unreacted
amine 1a or 1b, which was analyzed by chiral HPLC.
13
Phth). C NMR (126 MHz): d 19.20 (Me-2), 21.26 (Me-40), 22.40
(Me-40), 23.82 (C-40), 24.30 (C-4), 30.82 (C-3), 38.24 (C-30), 48.62
2
(C-2), 49.25 (C-20), 112.89 and 112.94 (both d, JCF 22.8 Hz, C-5
3
and C-7), 122.11 (C-400, 700), 125.94 (d, JCF 8.8 Hz, C-8), 130.29 (C-
4
300a, 700a), 132.21 (d, JCF 2.6 Hz, C-8a), 133.87 (C-500, 600), 136.39
3
1
(d, JCF 7.7 Hz, C-4a), 159.93 (d, JCF 243.0 Hz, C-6), 165.87 (C-100,
300), 167.12 (C-10). 19F NMR (470 MHz): d 45.39 (td, J 8.8, 5.1 Hz,
F-6). HRMS (ESI) m/z, calcd for C24H26FN2O3 ([M+H]+): 409.1928;
found: 409.1922.
4.6. (2S)-6-Fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (S)-1a
A solution of acyl chloride 2 (550 mg, 2.21 mmol) in CH2Cl2
(22 mL) was added to a solution of amine 1a (731 mg, 4.42 mmol)
in CH2Cl2 (22 mL) with stirring at ꢀ20 °C. The reaction mixture was
kept at ꢀ20 °C for 24 h and then washed successively with 4 M HCl
(2 ꢁ 15 mL), saturated aqueous NaCl (4 ꢁ 20 mL), 5% aqueous
NaHCO3 (2 ꢁ 15 mL), and water (2 ꢁ 20 mL). The organic layer
was separated, dried over MgSO4, and evaporated under reduced
pressure. The residue was recrystallized from a hexane–EtOAc
mixture to afford amide (S,S)-4 (474 mg, 58%). Colorless crystals,
4.4.7. (3S)-7,8-Difluoro-3,4-dihydro-3-methyl-N-[N0-phthaloyl-
(S)-leucyl]-2H-[1,4]benzoxazine (S,S)-11
Yield 137 mg, 32% (flash column chromatography, eluent ben-
zene–ethyl acetate, slow eluting isomer). Colorless powder, mp
160–161 °C. ½a 2D0
ꢂ
¼ þ279 (c 1.0, CHCl3). De 98% (HPLC: ReproSil
100 Si, hexane–iPrOH 80:1,
s
9.33 min). 1H NMR (500 MHz): d
0.76 (3H, d, J 6.4 Hz, Me-40), 0.83 (3H, d, J 6.4 Hz, Me-40), 1.17
(3H, d, J 6.8 Hz, Me-3), 1.51 (1H, ddd, J 12.9, 9.1, 3.9 Hz, H-
30B), 1.56 (1H, m, H-40), 2.60 (1H, ddd, J 12.9, 11.2, 3.4 Hz, H-
30A), 4.15 (1H, dd, J 11.1, 3.1 Hz, H-2B), 4.39 (1H, dd, J 11.1,
1.5 Hz, H-2A), 4.77 (1H, qdd, J 6.8, 3.1, 1.5 Hz, H-3), 5.47 (1H,
dd, J 11.2, 3.9 Hz, H-20), 6.97 (1H, td, J 9.8, 8.2 Hz, H-6), 7.48
(1H, ddd, J 9.4, 5.3, 2.5 Hz, H-5), 7.86 (4H, m, Phth). 13C NMR
(126 MHz): d 14.44 (Me-3), 20.25 (Me-40), 21.90 (Me-40), 24.51
(C-40), 35.47 (C-30), 45.06 (C-3), 51.32 (C-20), 70.04 (C-2),
mp 90 °C. ½a 2D0
ꢂ
¼ þ58:0 (c 1.0, CHCl3). De >99% (HPLC: Phenomenex
Luna C18(2), MeCN–H2O 7:3,
s
17.8 min). 1H NMR (500 MHz): d
0.89 (3H, d, J 6.6 Hz, Me-2), 1.14 (1H, m, H-3B), 1.45 (3H, d, J
6.8 Hz, Me-20), 1.74 (1H, m, H-4B), 2.11 (1H, dddd, J 13.2, 7.6, 5.6,
5.2 Hz, H-3A), 2.29 (1H, dt, J 15.0, 5.2 Hz, H-4A), 3.84 (3H, s,
OMe), 4.36 (1H, q, J 6.8 Hz, H-20), 4.67 (1H, dq, J 7.6, 6.6 Hz, H-2),
6.77 (1H, dd, J 9.0, 2.9 Hz, H-5), 6.98 (1H, dd, J 8.4, 1.5 Hz, H-300
Naph), 7.05 (1H, td, J 8.7, 9.0 Hz, H-7), 7.08 (1H, dd, J 8.9, 2.5 Hz,
H-700 Naph), 7.17 (2H, m, H-500 and H-100 Naph), 7.41 (1H, dd, J
8.7, 5.2 Hz, H-8), 7.57 (2H, m, H-800 and H-400 Naph). 13C NMR
(126 MHz): d 18.58 (Me-20), 19.28 (Me-2), 24.27 (C-4), 31.00 (C-
3), 41.73 (C-20), 47.44 (C-2), 54.72 (OMe), 105.82 (C-500), 112.18
2
3
4
106.84 (d, JCF 18.5 Hz, C-6), 119.04 (dd, JCF 8.5, JCF 4.6 Hz, C-
5), 120.79 (m, C-4a), 122.61 (C-400, 700), 130.78 (C-300a, 700a),
2
3
134.12 (C-500, 600), 136.32 (dd, JCF 10.0, JCF 3.1 Hz, C-8a),
1
2
1
138.81 (dd, JCF 245.8, JCF 15.4 Hz, C-8), 147.13 (dd, JCF 243.5,
2JCF 10.0 Hz, C-7), 167.43 (C-100, 300), 167.85 (C-10). 19F NMR
(470 MHz): d 2.80 (1F, dd, J 21.2, 8.2 Hz, F-8), 22.02 (1F, m, F-
7). Anal. Calcd for C23H22F2N2O4: C, 64.48; H, 5.18; N, 6.54; F,
8.87. Found: C, 64.48; H, 5.08; N, 6.36; F, 8.61.
2
2
(d, JCF 22.6 Hz, C-7), 113.10 (d, JCF 22.6 Hz, C-5), 117.76 (C-700),
124.62 (C-100), 125.13 (C-300), 126.02 and 128.25 (C-400 and C-800),
3
127.39 (d, JCF 8.5 Hz, C-8), 127.92 (C-800a), 132.52 (C-400a), 133.00

1246
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 24 (2013) 1240–1246
4
(d, JCF 2.7 Hz, C-8a), 136.15 (C-200), 137.41 (C-4a), 156.70 (C-600),
Chem. 2012, 49, 1108–1113; (c) Kolleth, A.; Christoph, S.; Arseniyadis, S.; Cossy,
J. Chem. Commun. 2012, 10511–10513.
9. Kida, T.; Iwamoto, T.; Asahara, H.; Hinoue, T.; Akashi, M. J. Am. Chem. Soc. 2013,
135, 3371–3374.
159.23 (d, JCF 242.8 Hz, C-6), 172.24 (C-10). 19F NMR (376 MHz):
d 46.6 (m, F-6). Anal. Calcd for C24H24FNO2: C, 76.37; H, 6.41; N,
3.71, F, 5.03. Found: C, 76.32; H, 6.47; N, 3.67; F, 5.05.
1
10. (a) Charushin, V. N.; Krasnov, V. P.; Levit, G. L.; Korolyova, M. A.; Kodess, M. I.;
Chupakhin, O. N.; Kim, M. H.; Lee, H. S.; Park, Y. G.; Kim, K.-C. Tetrahedron:
Asymmetry 1999, 10, 2691–2702; (b) Krasnov, V. P.; Levit, G. L.; Andreyeva, I.
N.; Grishakov, A. N.; Charushin, V. N.; Chupakhin, O. N. Mendeleev Commun.
2002, 12, 27–28; (c) Krasnov, V. P.; Levit, G. L.; Korolyova, M. A.; Bukrina, I. M.;
Sadretdinova, L. Sh.; Andreeva, I. N.; Charushin, V. N.; Chupakhin, O. N. Russ.
Chem. Bull. 2004, 53, 1253–1256; (d) Krasnov, V. P.; Levit, G. L.; Kodess, M. I.;
Charushin, V. N.; Chupakhin, O. N. Tetrahedron: Asymmetry 2004, 15, 859–862;
(e) Gruzdev, D. A.; Levit, G. L.; Krasnov, V. P.; Chulakov, E. N.; Sadretdinova, L.
Sh.; Grishakov, A. N.; Ezhikova, M. A.; Kodess, M. I.; Charushin, V. N.
Tetrahedron: Asymmetry 2010, 21, 936–942; (f) Chulakov, E. N.; Gruzdev, D.
A.; Levit, G. L.; Sadretdinova, L. Sh.; Krasnov, V. P.; Charushin, V. N. Russ. Chem.
Bull. 2011, 60, 948–954; (g) Levit, G. L.; Gruzdev, D. A.; Krasnov, V. P.; Chulakov,
E. N.; Sadretdinova, L. Sh.; Ezhikova, M. A.; Kodess, M. I.; Charushin, V. N.
Tetrahedron: Asymmetry 2011, 22, 185–189; (h) Chulakov, E. N.; Levit, G. L.;
Tumashov, A. A.; Sadretdinova, L. Sh.; Krasnov, V. P. Chem. Heterocycl. Compd.
2012, 48, 724–732; (i) Gruzdev, D. A.; Levit, G. L.; Kodess, M. I.; Krasnov, V. P.
Chem. Heterocycl. Compd. 2012, 48, 748–757; (j) Gruzdev, D. A.; Levit, G. L.;
Krasnov, V. P. Tetrahedron: Asymmetry 2012, 23, 1640–1646.
Concentrated HCl (10 mL) was added to a solution of amide
(S,S)-4 (474 mg, 1.27 mmol) in glacial AcOH (10 mL). The reaction
mixture was heated at 95 °C for 10 h, then evaporated to a half vol-
ume and poured into water (150 mL). The precipitate was filtered
off and the filtrate was alkalized with Na2CO3 to pH 8–9 and then
extracted with benzene (4 ꢁ 30 mL). Combined organic layers
were washed with water (2 ꢁ 15 mL), dried over MgSO4, and evap-
orated under reduced pressure to afford amine (S)-1a (176 mg,
84%). Colorless solid, mp 40–41 °C (lit.17b mp 40–42 °C).
½
a 2D0
ꢂ
¼ ꢀ74:2 (c 0.7, CHCl3) {lit.18i
½
a 2D0
ꢂ
¼ ꢀ59:6 (c 0.5, CHCl3, 91%
ee)}. Ee >99% (HPLC: Chiralcel OD-H, hexane–iPrOH–MeOH
100:1:1
pound 1a. Anal. Calcd for C10H12FN: C, 72.70; H, 7.32; N, 8.48; F,
11.50. Found: C, 72.70; H, 7.60; N, 8.50; F, 11.52.
s 7.62 min). NMR spectra were identical to those of com-
11. (a) Bálint, J.; Egri, G.; Fogassy, E.; Böcskei, Z.; Simon, K.; Gajáry, A.; Friesz, A.
Tetrahedron: Asymmetry 1999, 10, 1079–1087; (b) Bálint, J.; Egri, G.; Vass, G.;
Schindler, J.; Gajáry, A.; Friesz, A.; Fogassy, E. Tetrahedron: Asymmetry 2000, 11,
809–813.
Acknowledgments
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Chem. Pharm. Bull. 1987, 35, 1896–1902.
13. (a) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347–1349; (b) Cheng, Y.;
Xu, G.; Wu, J.; Zhang, C.; Yang, L. Tetrahedron Lett. 2010, 51, 2366–2369.
14. Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett 2008, 1574–1578.
15. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249–330.
16. (a) Hunter, C. A.; Lu, X.-J.; Kapteijn, G. M.; van Koten, G. J. Chem. Soc. Faraday
Trans. 1995, 91, 2009–2015; (b) Mecozzi, S.; West, A. P., Jr.; Dougherty, D. A.
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The authors thank Liliya Sh. Sadretdinova and Dr. Andrey A.
Tumashov for performing HPLC analyses, Dr. Pavel A. Slepukhin
for performing X-ray crystallography analysis. The work was finan-
cially supported by the Russian Foundation for Basic Research
(grants Nos. 12-03-31615, 12-03-33029, 13-03-00674); the Ural
Branch of RAS (grant 12-P-3-1030) and the State Program for Sup-
porting of Leading Scientific Schools of the Russian Federation
(grant NSh-5505.2012.3).
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