Mutual kinetic resolution of 3-methyl-3,4-dihydro-2H-1,4-benzoxazines and 2-alkoxyacyl chlorides

Article abstract of DOI:10.1007/s10593-018-2286-y

[Figure not available: see fulltext.] Stereoselective acylation of racemic 3-methyl-3,4-dihydro-2Н-1,4-benzoxazine and its 7,8-difluoro-substituted analog with racemic 2-alkoxyacyl chlorides was stidied. The reactions of 3-methyl-3,4-dihydro-2H-1,4-benzoxazines with 2-methoxyisopentanoyl chloride were found to be more selective (selectivity factor s 31–32) compared to the acylation with other studied propanoyl chlorides (s 18–21). This fact was probably caused by the significant steric hindrance due to the isopropyl substituent in acyl chloride compared to the methyl group in reagents derived from propanoic acid.

Full text of DOI:10.1007/s10593-018-2286-y

DOI 10.1007/s10593-018-2286-y
Chemistry of Heterocyclic Compounds 2018, 54(4), 437–446
Mutual kinetic resolution
of 3-methyl-3,4-dihydro-2H-1,4-benzoxazines
and 2-alkoxyacyl chlorides
Sergey A. Vakarov1*, Dmitry А. Gruzdev1, Liliya Sh. Sadretdinova1,
Mikhail I. Kodess1,2, Andrey A. Tumashov1,2, Evgeny B. Gorbunov1,2,
Galina L. Levit1, Victor P. Krasnov1
1
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 S. Kovalevskoi / 20 Akademicheskaya St., Yekaterinburg 620137, Russia;
е-mail: savakarov@ios.uran.ru
Ural Federal University named after the first President of Russia B. N. Yeltsin,
19 Mira St., Yekaterinburg 620002, Russia: е-mail: a.a.tumashov@urfu.ru
2
Submitted November 24, 2017
Accepted January 16, 2018
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(4), 437–446
Stereoselective acylation of racemic 3-methyl-3,4-dihydro-2Н-1,4-benzoxazine and its 7,8-difluoro-substituted analog with racemic
2-alkoxyacyl chlorides was stidied. The reactions of 3-methyl-3,4-dihydro-2H-1,4-benzoxazines with 2-methoxyisopentanoyl chloride
were found to be more selective (selectivity factor s 31–32) compared to the acylation with other studied propanoyl chlorides (s 18–21).
This fact was probably caused by the significant steric hindrance due to the isopropyl substituent in acyl chloride compared to the methyl
group in reagents derived from propanoic acid.
Keywords: acyl chlorides, 2-alkoxycarboxylic acids, heterocyclic amines, acylation, kinetic resolution, stereoselectivity.
Kinetic resolution (KR) of racemates is a common
method for preparation of individual enantiomers of organic
compounds belonging to various classes. The KR is based
on reaction rate differences between the two enantiomers of
racemic starting material and a chiral resolving reagent.1,2
This approach allows obtaining of a stereoisomerically
enriched product and the unreacted substrate, thus
eventually providing access to both enantiomers of the
target compound. One frequently used method for the
preparation of enantiopure amines, including practically
valuable products, involves their stereoselective acylation
with chiral agents derived from carboxylic acids.3,4
Correspondingly, enantiopure amines can be used as chiral
reagents for the resolution of racemic acids and preparation
of their optical isomers. Studying the reactions between
racemic amines and racemic acylating reagents may be
useful for the purpose of developing effective methods for
the synthesis of stereoisomers of both amines and acids.
Besides that, the investigation of stereoselective reactions
between chiral amines and acylating agents is useful for
establishing the reasons for stereoselectivity and recogniz-
ing the structural criteria for substrates and reagents that
may be suitable for KR.
The individual enantiomers of heterocyclic aromatic
amines, as well as of 2-substituted carboxylic acids are of
significant interest as precursors and structural building blocks
for natural and synthetic biologically active compounds
(drugs, herbicides, and other products).5,6 We have previously
studied diastereoselective reactions between racemic hetero-
cyclic amines and acyl chlorides derived from chiral 2-aryl-
propanoic acids,7–10 N-protected amino acids,9–17 and 2-phenoxy-
carboxylic acids.18,19 The highest stereoselectivity with respect to
3-methylbenzoxazine derivatives 1a,b (Scheme 1) was observed
in the case of reagents containing the 2-phenoxy group,
therefore we were interested in studying stereoselective
acylation of these amines with 2-alkoxyacyl chlorides.
The purpose of the current work was to study the
electronic and steric factors affecting the stereoselectivity
of reaction between 3-methylbenzoxazines 1a,b and chiral
2-alkoxyacyl chlorides 2a–e (Scheme 1).
0009-3122/18/54(4)-0437©2018 Springer Science+Business Media, LLC
437

Chemistry of Heterocyclic Compounds 2018, 54(4), 437–446
X
X
X
X
Scheme 1
O
O
R1
PhMe
O
O
O
R1
+
+
X
N
R1
NH
Me
1a b
,
X
N
20°C, 6 h
28–87%
R2
Me
R2
Me
O
R2 COCl
O
O
rac-
rac-2a–e
3a e
3a e
–
(3R*,2'S*)-
–
(3R*,2'R*)-
(3R*,2'S*)-4a–e
(3R*,2'R*)-4a–e
1a, 3a–e X = H, 1b, 4a–e X = F
a R1 = Me, R2 = Me; b R1 = Me, R2 = i-Pr; c R1 = Me, R2 = Ph; d R1 = Me, R2 = Bn; e R1 = Bn, R2 = Me
major
minor
graphy and characterized by the physicochemical data sets.
The analysis of the obtained mixtures of amides 3, 4 a–e
allowed us to unequivocally assign the chromatographic
peaks of (3S,2'R)- and (3S,2'S)-isomers of the mutual KR
products.
In order to establish the configurations of the obtained
amides 3, 4 a–e, acylation of enantiopure (S)-amines 1a,b
was performed using racemic acyl chlorides 2a–e in the
presence of N,N-diethylaniline (as an HCl acceptor) in
1:2:1 ratio of 3-methylbenzoxazine–acyl chloride–N,N-di-
ethylaniline (Scheme 2).
In this case, the maximum possible conversion of the
starting acyl chloride is 50% and KR of the racemic
acylating agent occurs. As a result of the reaction, we
obtained diastereomerically enriched amides 3, 4 a–e and
unreacted enantiomerically enriched acyl chlorides 2a–e,
which were converted to the corresponding carboxylic
acids 5a–e by alkaline hydrolysis (Scheme 2). In order to
determine the enantiomeric excess (ee, %) of carboxylic
acids obtained in this way, we performed the condensation
of acids 5a,b and (R)-1-phenylethylamine using a carbo-
diimide coupling reagent (EDC·HCl) in the presence of
1-hydroxybenzotriazole (HOBt) and N-methylmorpholine
additives (Scheme 3). The obtained mixtures of (R,S)- and
(R,R)-diаstereomers of amides 6a,b were analyzed by
HPLC. Based on the literature data on the order of elution
of diastereomeric amides 6a, we established that the
scalemic carboxylic acid obtained from the unreacted acyl
chloride was enriched in (S)-enantiomer.21
When studying the determining factors for the
stereoselectivity in acylation reactions of racemic amines
1a,b with chiral acyl chlorides, we used an approach based
on the reactions of racemic reagents, in other words, the
limiting case of mutual KR.2 In this case, the ratio of the
diastereomeric amides formed was equal to the selectivity
factor s representing a ratio of the reaction rates for the fast
and slow reacting enantiomers of the substrate. Further-
more, the ratio of the starting reagents, their concentration,
and the reaction duration does not affect the stereochemical
outcome, and therefore the value of selectivity factor s can
be determined quite accurately.20
The acylation of racemic amines 1a,b with acyl
chlorides 2a–e was performed at 20°C for 6 h at amine-
acyl chloride molar ratio 2:1 and 0.1 М initial concent-
ration of the amine (Scheme 1). We have previously
established that the acylation of amines 1a,b with acyl
chlorides derived from 2-phenoxycarboxylic acids
proceeds most selectively in toluene,18 therefore we
selected toluene as the solvent in this study as well. The
reaction resulted in the formation of a mixture consisting of
4 stereoisomers: (3R,2'R)/(3S,2'S)- and (3R,2'S)/(3S,2'R)-
amides 3 and 4 a–e (further denoted as (3R*,2'S*)- and
(3R*,2'R*)-amides). The diastereomeric ratio (dr) of
amides 3 and 4 a–e, which is equal to the selectivity factor
s, was determined by GC and HPLC.
The predominant diastereomers (3R*,2'S*)-3a,e and
(3R*,2'S*)-4a,e were obtained in diastereomerically pure
form by recrystallization of the acylation products.
Compounds (3R*,2'S*)-3b–d and (3R*,2'S*)-4b–d were
isolated from the reaction mixtures by flash chromato-
graphy on silica gel.
Scheme 3
The reactions using equimolar amounts of (S)-amines
1a,b and racemic acyl chlorides 2a–e in the presence of
N,N-diethylaniline (as an HCl acceptor) allowed us to
synthesize mixtures of (3R,2'S)- and (3R,2'R)-diаstereomers
of amides 3 and 4 a–e (1:1 ratio of diastereomers), which
were isolated from the reaction mixtures by flash chromato-
Scheme 2
438

Chemistry of Heterocyclic Compounds 2018, 54(4), 437–446
The stereoconfiguration of (1R,2'S)-diаstereomer of
This observation could be apparently explained by the fact
that the acylation of amines with acyl chlorides derived
from 2-aryloxycarboxylic acids was affected by inter-
molecular interactions between the aromatic rings of the
acylating agent and the nucleophilic reagent and were
therefore influenced by the electronic effects of aromatic
ring substituents in the amine molecule. In the case when
3-methylbenzoxazines 1a,b were acylated with acyl
chlorides derived from 2-methoxycarboxylic acids, the
stereoselectivity was likely determined exclusively by the
steric hindrance occurring during the intermolecular
interaction of amine and the acylating agent.
amide 6b was established on the basis of X-ray structural
analysis (Fig. 1), which allowed us to assign the HPLC
peaks of individual diastereomers.
Thus, we investigated the influence of electronic and
steric factors on the stereochemical outcome of the
acylation of racemic 3-methylbenzoxazines with acyl
chlorides derived from 2-alkoxycarboxylic acids. It has
been established that the reaction of 3-methyl-3,4-dihydro-
benzoxazines with 2-methoxyisopentanoyl chloride pro-
ceeds more stereoselectively than the reactions of these
amines with acyl chlorides derived from substituted
propanoic acids. Such a result was probably associated
with the significant steric hindrance created by the
isopropyl substituent of acyl chloride. It has been found
earlier that the selectivity factors for the acylation of
3-methylbenzoxazines with 2-phenoxypropanoyl chloride
were 35 and 56, respectively, that is, 2-phenoxypropanoyl
chloride showed better stereoselectivity compared to the
structurally related 2-methoxy-2-phenylacetyl chloride,
2-methoxy-3-phenylpropanoyl chloride, and 2-benzyl-
oxypropanoyl chloride. This comparative analysis of
results of the acylation experiments using 3-methyl-
benzoxazines and acyl chlorides derived from 2-phenoxy-
carboxylic acids and 2-alkoxycarboxylic acids has made it
possible to conclude that high stereoselectivity in such
Figure 1. The molecular structure of amide (1R,2'S)-6b with
atoms represented by thermal ellipsoids of 50% probability.
It was established that (1R,2'S)-amide dominated in the
products of scalemic acid 5b derivatization, therefore the
carboxylic acid used in reaction with (R)-phenylethylamine
was enriched in the (S)-enantiomer. The configuration of
scalemic acids 5c–e obtained by KR using 3-methyl-
benzoxazines 1a,b was assigned by comparing the sign of
optical rotation of the obtained samples with published
data.22–24 It can be concluded from the obtained results that
the carboxylic acids obtained from unreacted acyl
chlorides always contained the (S)-enantiomers as the
major components, therefore, (S)-amines 1a,b reacted with
(R)-isomers of acyl chlorides 2a–e at a greater rate and the
predominant products were (3S,2'R)-diаstereomers of
amides 3, 4 a–e. Hence, the products of reactions between
racemic amines and racemic acyl chlorides were enriched
in (3R*,2'S*)-amides 3, 4a–e.
The stereochemical outcomes from acylation of amines
1a,b with acyl chlorides 2a–e are presented in Table 1.
According to these results, the best stereoselectivity (s 31–32)
was achieved in acylation of 3-methylbenzoxazines with
2-methoxyisopentanoyl chloride (2b) (entries 5 and 6).
However, the selectivity factor s was lower than for the
acylation of amines 1a,b with acyl chlorides containing the
aryloxy group, such as 2-phenoxypropanoyl chloride (s 35
and 56, entries 1 and 2). The replacement of isopropyl
group (acyl chloride 2b) at the chiral center of the acyl
chloride derived from 2-methoxycarboxylic acid with the
methyl group (acyl chloride 2a) resulted in lower
stereoselectivity of the reactions. The reactions of
3-methylbenzoxazines 1a,b and derivatives of lactic (2a),
mandelic (2c), and 3-phenyllactic acids (2d) proceeded
with equal selectivity (s about 20, entries 3, 4, 7–9).
2-(Benzyloxy)propanoyl chloride (2e) reacted with amines
1a,b with the same stereoselectivity as 2-methoxy-
propanoyl chloride (2a) (entries 3, 4 and 11, 12).
Table 1. The stereochemical results of the acylation of racemic
amines 1a,b with racemic acyl chlorides 2a–e in toluene at 20°C
(average values for two parallel runs are presented).
Amide, dr
((R*,S*):(R*,R*))
Entry Amine Acyl chloride
Selectivity factor s
1
97.2:2.818
35
56
1a
2
98.2:1.818
1b
3
4
3a, 94.9:5.1*
4a, 94.6:5.4*
3b, 96.9:3.1**
4b, 97.0:3.0*
3c, 95.4:4.6*
4c, 95.3:4.7*
3d, 95.2:4.8*
4d, 95.2:4.8*
3e, 95.4:4.6***
4e, 95.2:4.8***
19
18
31
32
21
20
20
20
21
20
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
5
6
7
8
9
10
11
12
It is interesting to note that, in contrast to the reagents
derived from 2-phenoxycarboxylic acids,18 2-methoxy-
carbonyl chlorides 2a–e reacted with 3-methylbenzoxazine
1a nearly as selectively as with its 7,8-difluoro analog 1b.
* Determined by HPLC (ReproSil 100 Si column).
** Determined by HPLC (Phenomenex Luna C18 column).
*** Determined by GC.
439

Chemistry of Heterocyclic Compounds 2018, 54(4), 437–446
reactions requires the presence of the phenyl group directly
ionization detector, ZB-5 quartz capillary column
(30 m × 0.25 mm × 0.25 µm); the initial column tempera-
ture was 40°C (maintained for 3 min), followed by
programmed temperature increase at 10 K/min rate to 280°C
(maintained for 30 min). The evaporator temperature was
250°C, detector temperature 300°C. The carrier gas was nitro-
gen, split ratio 1:30, flow through the column 1.0 ml/min,
1.0 µl injection volume of amide solution in acetonitrile at
the concentration of 1–3 mg/ml. The chromatographic
peaks of diastereomers were assigned on the basis of GC-
MS data.
linked to the oxygen atom at position 2 of acyl chloride.
Experimental
1H, 13C, and 19F NMR spectra were recorded on Bruker
DRX-400 (400, 100, and 376 MHz, respectively) or Bruker
Avance 500 (500, 126, and 470 MHz, respectively)
instruments using TMS and hexafluorobenzene as internal
1
standards. H NMR spectra of amides 3 and 4 a–e, as well
as 13C NMR spectra of amides 3 and 4 a–c,e were recorded at
100°C, while the spectra for the rest of the compounds were
recorded at room temperature. High-resolution mass spectra
of amides (3R*,2'S*)-3b, (3R*,2'S*)-4b, (3R*,2'S*)-4c, as
well as carboxylic acids (S)-5c–e were obtained on a
Bruker maXis Impact HD mass spectrometer (electrospray
ionization) in positive ion mode (compounds 3b, 4b,c) or
negative ion mode (compounds 5c–e), flow rate of carrier
gas (N2) 4 l/min, 0.4 bar, spray voltage 4.5 kV. Melting
points were determined on an SMP3 apparatus (Barloworld
Scientific, UK). Elemental analysis was performed on
PerkinElmer 2400 Series II or EuroVector EA3000
elemental analyzers. The fluorine content in the
synthesized compounds was determined by a procedure
based on mineralization according to Schöniger, followed
by spectrophotometric analysis of the obtained samples
(with comparison to reference samples). Analytical TLC
was performed on Sorbfil plates (Imid Ltd., Russia). Flash
chromatography was performed on 230–400 mesh silica
gel (Alfa Aesar, UK).
(RS)-3-Methyl-3,4-dihydro-2H-1,4-benzoxazine (1a),25
(RS)-7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine
(1b),25
(3S)-3-methyl-2,3-dihydro-4H-1,4-benzoxazine
(3S)-7,8-difluoro-3-methyl-2,3-dihydro-4H-
((S)-1a),11
1,4-benzoxazine ((S)-1b),26 (RS)-2-methoxypropanoic acid
(5a),27 (RS)-2-methoxyisopentanoic acid (5b),28 (RS)-
2-methoxy-2-phenylacetic acid (5c),29 (RS)-2-methoxy-
3-phenylpropanoic acid (5d),30,31 and (RS)-2-benzyloxy-
propanoic acid (5e)32 were obtained according to published
procedures. The other reagents were commercially
available. The solvents were purified according to the
standard procedures.
Preparation of acyl chlorides 2a–e (General method).
A solution of the appropriate carboxylic acid (5 mmol) in
20 ml of CH2Cl2 (carboxylic acids 2a–c,e) or benzene
(carboxylic acid 2d) was treated by the addition of oxalyl
chloride (0.87 ml, 10 mmol) in the case of carboxylic acid
5a, (1.31 ml, 15 mmol) in the case of carboxylic acids
5b,d,e, (4.38 ml, 50 mmol) in the case of carboxylic acid
5c, along with DMF (5 µl). The reaction mixture was
stirred at ambient temperature for 6 h, then evaporated at
reduced pressure. The residue was dried at reduced
pressure over P2O5. Acyl chloride 2a was used immediately
after evaporation of the solvent. Acylating reagents 2a–e
were unstable during storage and were therefore used in
freshly prepared form (purity not less than 97% according
to 1H NMR spectroscopy data).
HPLC analysis of 2-methoxycarboxylic acids 5a,b was
performed on a Knauer Smartline-1100 chromatograph after
preliminary derivatization with (R)-1-phenylethylamine
using ReproSil 100 Si column; detection at 220 nm, eluent
flow rate 1 ml/min. HPLC analysis of carboxylic acids 5с–e
was performed on Knauer Smartline-1100 (compounds
5c,e) and Shimadzu LC-20 Prominence (compound 5d)
chromatographs using Chiralpak AD (250 × 4.6 mm,
Daicel Corp., Japan) (compound 5c), Chiralcel OD-H
(250 × 4.6 mm, Daicel Corp., Japan) (compound 5d), and
S,S-Whelk O1 (250 × 4.6 mm, Regis Technologies Inc.)
(compound 5e) columns; detection at 220 and 230 nm,
eluent flow rate 1 ml/min. Eluent hexane–i-PrOH–
CF3COOH, 40:1:0.02 (compounds 5c,d); 20:1:0.02
(compound 5e): τ(R)-5c 20.8 min; τ(S)-5c 18.8 min; τ(R)-5d 14.0
min; τ(S)-5d 20.4 min; τ(S)-5e 7.1 min; τ(R)-5e 7.8 min. The
specific rotations were determined on a PerkinElmer 341
polarimeter. HPLC analysis of amides 3a,c and 4a–c was
performed on a Knauer Smartline-1100 chromatograph
using ReproSil 100 Si column; detection at 220 nm, eluent
flow rate 1 ml/min. HPLC analyses of amides 3d and 4d
were performed on a Shimadzu LC-20 Prominence
chromatograph, using a ReproSil 100 Si column; detection
at 220 nm, eluent flow rate 1 ml/min. HPLC analysis of
amide 3b was performed on an Agilent 1100
chromatograph, using a Phenomenex Luna C18(2) column
(250 × 4.6 mm), eluent flow rate 0.8 ml/min, detection at
220 nm.
(RS)-2-Methoxypropanoyl chloride (2a). Yield 610 mg
1
(99%), yellow oil. H NMR spectrum (500 MHz, CDCl3),
δ, ppm (J, Hz): 1.53 (3H, d, J = 6.9, CH3); 3.45 (3H, s,
OCH3); 4.01 (1H, q, J = 7.1, CH).
(RS)-2-Methoxy-3-methylbutanoyl chloride (2b). Yield
1
750 mg (99%), yellow oil. H NMR spectrum (500 MHz,
CDCl3), δ, ppm (J, Hz): 0.97 (3H, d, J = 6.9, CH(CH3)2);
1.03 (3H, d, J = 6.9, CH(CH3)2); 2.27–2.57 (1H, sept d, J = 6.9;
J = 4.9, CH(CH3)2); 3.44 (1H, s, OCH3); 3.72 (1H, d, J = 4.9, CH).
(RS)-2-Methoxy-2-phenylacetyl chloride (2c). Yield
1
940 mg (98%), yellow oil. H NMR spectrum (400 MHz,
CDCl3), δ, ppm: 3.51 (3H, s, OCH3); 4.99 (1H, s, CH);
7.39–7.48 (5H, m, H Ph).
(RS)-2-Methoxy-3-phenylpropanoyl chloride (2d).
1
Yield 980 mg (99%), colorless oil. H NMR spectrum
(500 MHz, CDCl3), δ, ppm (J, Hz): 3.07 (1H, dd, J = 14.2,
J = 8.0, CH2); 3.20 (1H, dd, J = 14.2, J = 4.3, CH2); 3.40
(3H, s, OCH3); 4.18 (1H, dd, J = 8.0, J = 4.4, CH); 7.24–
7.34 (5H, m, H Ph).
GC analysis of amides 3e and 4e was performed using a
Shimadzu GC 2010 gas chromatograph with flame
(RS)-(2-Benzyloxy)propanoyl chloride (2e). Yield
1
980 mg (99%), yellow oil. H NMR spectrum (400 MHz,
440

Chemistry of Heterocyclic Compounds 2018, 54(4), 437–446
1
CDCl3), δ, ppm (J, Hz): 1.57 (3H, d, J = 6.8, CH3); 4.28
(1H, q, J = 6.8, CH); 4.46 (1H, d, J = 11.4, CH2); 4.75 (1H,
d, J = 11.4, CH2); 7.29–7.39 (5H, m, H Ph).
τ(3R*,2'R*)-3b 16.7 min; (R*,S*)/(R*,R*) = 99.0:1.0. H NMR
spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 0.95 (3H,
d, J = 6.8, CH(CH3)2); 0.99 (3H, d, J = 6.6, CH(CH3)2);
1.15 (3H, d, J = 6.8, CHCH3); 2.01–2.12 (1H, m, CH(CH3)2);
3.23 (3H, s, OCH3); 3.92 (1H, d, J = 7.8, CH i-Pr); 4.09
(1H, dd, J = 11.0, J = 2.9, CH2); 4.24 (1H, dd, J = 11.0,
J = 1.7, CH2); 4.83 (1H, qdd, J = 6.8, J = 2.9, J = 1.7,
CHСH3); 6.86–6.89 (2H, m, H-6,8); 7.02–7.06 (1H, m,
H-7); 7.80 (1H, dd, J = 8.5, J = 1.1, H-5). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm (J, Hz): 14.9; 17.5; 18.0;
29.4; 44.7; 56.4; 69.3; 84.8; 115.9; 119.4; 123.2; 124.5;
124.9; 145.6; 168.5. Found, m/z: 264.1598 [M+H]+.
C15H22NO3. Calculated, m/z: 264.1594.
Stereoselective acylation of racemic amines 1a,b with
acyl chlorides 2a–e (General method). A solution of amine
1a or 1b (1.0 mmol) in the appropriate solvent (5 ml) was
treated with a solution of the appropriate acyl chloride
(0.5 mmol) in the same solvent (5 ml) at 20°C. The reaction
mixture was kept at 20°C for 6 h. The reaction mixture was
successively washed with 4 N HCl (2×4 ml), saturated
aqueous NaCl solution (4×5 ml), aqueous 5% NaHCO3
solution (2×5 ml), and H2O (2×5 ml), then dried over
Na2SO4, and evaporated at reduced pressure. The
diastereomers of amides were isolated by recrystallization
or by flash chromatography on silica gel.
(2S*)-2-Methoxy-1-((3R*)-3-methyl-2,3-dihydro-4H-
1,4-benzoxazin-4-yl)propan-1-one ((2S*,3R*)-3a). Yield
54 mg (46%) after recrystallization from hexane, colorless
powder, mp 86–87°C (hexane). HPLC analysis (ReproSil
100 Si column; hexane–i-PrOH, 20:1): τ(3R*,2'S*)-3a 8.5 min,
τ(3R*,2'R*)-3a 6.5 min; (3R*,2'S*)/(3R*,2'R*) = 99.5:0.5.
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz):
1.15 (3H, d, J = 6.8, 3-CH3); 1.33 (3H, d, J = 6.4, CHCH3);
3.20 (3H, s, OCH3); 4.12 (1H, dd, J = 11.0, J = 2.7, CH2);
4.21 (1H, dd, J = 11.0, J = 1.6, CH2); 4.43 (1H, q, J = 6.4,
CHCH3); 4.64–4.68 (1H, m, 3-CH); 6.83–6.90 (2H, m,
H-6,8); 7.03 (1H, ddd, J = 8.2, J = 7.2, J = 1.2, H-7); 7.70–
7.71 (1H, m, H-5). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm: 14.8; 15.9; 45.0; 54.9; 69.2; 73.9; 115.8; 119.4;
123.2; 124.2; 124.7; 145.5; 169.2. Found, %: C 66.37;
H 7.27; N 5.96. C13H17NO3. Calculated, %: C 66.36;
H 7.28; N 5.95.
(2S*)-1-((3R*)-7,8-Difluoro-3-methyl-2,3-dihydro-4H-
1,4-benzoxazin-4-yl)-2-methoxy-3-methylbutan-1-one
((2S*,3R*)-4b). Yield 153 mg (85%) after flash
chromatography (eluent hexane–EtOAc, 95:5), colorless
oil. HPLC analysis (ReproSil 100 Si column; hexane–i-PrOH,
40:1): τ(3R*,2'S*)-4b 4.2 min, τ(3R*,2'R*)-4b 4.7 min; (3R*,2'S*)/
(3R*,2'R*) = 99.5:0.5. 1H NMR spectrum (500 MHz,
DMSO-d6), δ, ppm (J, Hz): 0.94 (3H, d, J = 6.8, CH(CH3)2);
0.99 (3H, d, J = 6.6, CH(CH3)2); 1.17 (3H, d, J = 6.8,
CHCH3); 2.01–2.10 (1H, m, CH(CH3)2); 3.26 (3H, s,
OCH3); 3.90 (1H, d, J = 7.8, CH i-Pr); 4.16 (1H, dd,
J = 11.0, J = 2.7, CH2); 4.40 (1H, dd, J = 11.0, J = 1.5,
CH2); 4.87 (1H, qdd, J = 6.8, J = 2.8, J = 1.6, CHCH3);
6.87 (1H, td, J = 9.9, J = 8.2, H-6); 7.62 (1H, ddd, J = 9.4,
J = 5.5, J = 2.6, H-5). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm (J, Hz): 14.8; 17.5; 17.9; 29.4; 44.7;
56.5; 69.8; 85.1; 106.2 (d, J = 18.1); 119.0 (dd, J = 7.9,
J = 4.2); 121.0; 136.0 (dd, J = 9.9, J = 3.3); 138.6 (dd,
J = 244.0, J = 15.5); 146.5 (dd, J = 242.7, J = 9.9); 168.7.
19F NMR spectrum (470 MHz, DMSO-d6), δ, ppm (J, Hz):
2.0 (ddd, J = 21.0, J = 8.2, J = 2.4, F-8); 20.8 (ddd,
J = 20.8, J = 10.1, J = 5.5, F-7). Found, m/z: 300.1405
[M+H]+. C15H20F2NO3. Calculated, m/z: 300.1406.
(2S*)-2-Methoxy-1-((3R*)-3-methyl-2,3-dihydro-4H-
1,4-benzoxazin-4-yl)-2-phenylethanone ((2S*,3R*)-3c).
Yield 110 mg (74%) after flash chromatography (eluent
hexane–EtOAc, 95:5), colorless oil. HPLC analysis (ReproSil
100 Si column; hexane–i-PrOH, 100:1): τ(3R*,2'S*)-3c 6.1 min,
τ(3R*,2'R*)-3c 7.0 min; (3R*,2'S*)/(3R*,2'R*) = 98.1:1.9.
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz):
0.98 (3H, d, J = 6.8, CHСH3); 3.35 (3H, s, OCH3); 3.86
(1H, dd, J = 10.9, J = 2.8, CH2); 4.12 (1H, dd, J = 10.9,
J = 1.7, CH2); 4.66 (1H, qdd, J = 6.8, J = 2.7, J = 1.7,
CHСH3); 5.29 (1H, s, CHPh); 6.81–6.90 (2H, m, H-6,8);
7.03 (1H, td, J = 7.7, J = 1.5, H-7); 7.32–7.45 (5H, m,
H Ph); 7.82–7.83 (1H, m, H-5). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm (J, Hz): 14.6; 45.1; 56.4; 68.9; 81.8;
115.8; 119.4; 123.1; 124.2; 124.9; 126.7; 127.6; 127.8;
136.0; 145.4; 167.1. Found, %: C 72.73; H 6.71; N 4.65.
C18H19NO3. Calculated, %: C 72.71; H 6.44; N 4.71.
(2S*)-((3R*)-7,8-Difluoro-3-methyl-2,3-dihydro-4H-1,4-
benzoxazin-4-yl)-2-methoxypropan-1-one ((2S*,3R*)-4a).
Yield 80 mg (59%) after recrystallization from a mixture of
hexane–EtOAc, colorless powder, mp 78–80°C (hexane–
EtOAc). HPLC analysis (Reprosil 100 Si column; hexane–
i-PrOH, 40:1): τ(3R*,2'S*)-4a 17.9 min, τ(3R*,2'R*)-4a 12.8 min;
1
(3R*,2'S*)/(3R*,2'R*) = 99.9:0.1. H NMR spectrum (500
MHz, DMSO-d6), δ, ppm (J, Hz): 1.18 (3H, d, J = 6.8, 3-CH3);
1.32 (3H, d, J = 6.4, CHCH3); 3.23 (3H, s, OCH3); 4.19
(1H, dd, J = 11.0, J = 2.6, CH2); 4.37 (1H, dd, J = 11.0,
J = 1.4, CH2); 4.43 (1H, q, J = 6.4, CHCH3); 4.69 (1H, qdd,
J = 6.7, J = 2.6, J = 1.5, 3-CH); 6.86 (1H, ddd, J = 9.8, J = 9.8,
J = 8.4, H-6); 7.62 (1H, ddd, J = 9.4, J = 5.5, J = 2.6, H-5).
13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm (J, Hz):
14.7; 15.6; 45.0; 54.9; 69.7; 74.0; 106.2 (d, J = 18.2); 118.8
(dd, J = 7.9, J = 4.2); 121.2; 135.8 (dd, J = 10.1, J = 3.2);
138.6 (dd, J = 243.9, 15.5); 146.4 (dd, J = 242.2, J = 10.4);
169.4. 19F NMR spectrum (470 MHz, DMSO-d6), δ, ppm
(J, Hz): 2.0 (ddd, J = 20.6, J = 8.6, J = 2.4, F-8); 20.5 (ddd,
J = 21.0, J = 10.1, J = 5.4, F-7). Found, %: C 57.71;
H 5.71; F 14.07; N 5.23. C13H15F2NO3. Calculated, %:
C 57.56; H 5.57; F 14.01; N 5.16.
(2S*)-1-((3R*)-7,8-Difluoro-3-methyl-2,3-dihydro-4H-1,4-
benzoxazin-4-yl)-2-methoxy-2-phenylethanone ((2S*,3R*)-4c).
Yield 145 mg (87%) after flash chromatography (eluent
hexane–EtOAc, 95:5), colorless oil. HPLC analysis
(ReproSil 100 Si column; hexane–i-PrOH, 100:1): τ(3R*,2'S*)-4c
7.1 min, τ(3R*,2'R*)-4c 8.3 min; (3R*,2'S*)/(3R*,2'R*) = 96.8:3.2.
(2S*)-2-Methoxy-3-methyl-1-((3R*)-3-methyl-2,3-dihydro-
4H-1,4-benzoxazin-4-yl)butan-1-one ((2S*,3R*)-3b). Yield
112 mg (85%) after flash chromatography (eluent hexane–
EtOAc, 95:5), colorless oil. HPLC analysis (Phenomenex
Luna C 18(2) column; 50% MeCN): τ(3R*,2'S*)-3b 17.5 min,
441

Chemistry of Heterocyclic Compounds 2018, 54(4), 437–446
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz):
mixture, colorless crystalline powder, mp 77–80°C (hexane–
EtOAc). GC: τ(3R*,2'S*)-3e 28.0 min, τ(3R*,2'R*)-3e 28.3 min;
(3R*,2'S*)/(3R*,2'R*) = 97.4:2.6. 1H NMR spectrum
(500 MHz, DMSO-d6), δ, ppm (J, Hz): 1.09 (3H, d, J = 6.8,
CHCH3); 1.40 (3H, d, J = 6.4, CHOCH3); 4.09 (1H, dd,
J = 11.0, J = 2.6, CH2); 4.18 (1H, dd, J = 11.0, J = 1.6,
CH2); 4.40 (1H, d, J = 11.7, CH2Ph); 4.44 (1H, d, J = 11.7,
CH2Ph); 4.64 (1H, q, J = 6.4, CHOCH3); 4.70 (1H, qdd,
J = 6.7, J = 2.8, J = 1.7, CHCH3); 6.84–6.87 (2H, m, H-6,8);
7.03 (1H, ddd, J = 8.3, J = 7.1, J = 1.4, H-7); 7.18–7.30
(5H, m, H Ph); 7.67 (1H, d, J = 8.2, H-5). 13C NMR
spectrum (126 MHz, DMSO-d6), δ, ppm (J, Hz): 14.8;
16.6; 44.7; 69.2; 69.7; 72.2; 115.8; 119.4; 123.2; 124.3;
124.9; 126.9; 127.1; 127.5; 137.4; 145.6; 169.2. Found, %:
C 73.45; H 6.80; N 4.61. C19H21NO3. Calculated, %:
C 73.29; H 6.80; N 4.50.
0.99 (3H, d, J = 6.8, CHСH3); 3.37 (1H, s, OCH3); 3.92
(1H, dd, J = 10.9, J = 2.6, CH2); 4.29 (1H, dd, J = 11.0,
J = 1.5, CH2); 4.70 (1H, qdd, J = 6.8, J = 2.7, J = 1.6,
CHСH3); 5.30 (1H, s, CHPh); 6.87 (1H, td, J = 9.9, J = 8.2,
H-6); 7.32–7.43 (5H, m, H Ph); 7.71 (1H, ddd, J =9.5,
J = 5.5, J = 2.6, H-5). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm (J, Hz): 14.4; 45.1; 56.5; 69.4; 81.9;
106.3 (d, J = 18.1); 118.9 (dd, J = 7.8, J = 4.3); 121.0; 126.6;
127.7; 127.9; 135.7; 135.9 (dd, J = 12.8, J = 9.7); 138.6
(dd, J = 244.0, J = 15.3); 146.5 (dd, J = 242.7, J = 9.9);
167.4. 19F NMR spectrum (470 MHz, DMSO-d6), δ, ppm
(J, Hz): 2.0 (ddd, J = 21.0, J = 8.2, J = 2.5, F-8); 20.8 (ddd,
J = 21.0, J = 10.3, J = 5.5, F-7). Found, m/z: 356.1071
[M+Na]+. C18H17F2NNaO3. Calculated, m/z: 356.1069.
(2S*)-2-Methoxy-1-((3R*)-3-methyl-2,3-dihydro-4H-
1,4-benzoxazin-4-yl)-3-phenylpropan-1-one ((2S*,3R*)-3d).
Yield 65 mg (42%) after recrystallization from hexane–
EtOAc mixture, yellowish crystalline powder, mp 76–78°C
(hexane–EtOAc). HPLC analysis (ReproSil 100 Si column;
hexane–i-PrOH, 60:1): τ(3R*,2'S*)-3d 6.8 min, τ(3R*,2'R*)-3d 6.1 min;
(3R*,2'S*)/(3R*,2'R*) = 99.5:0.5. 1H NMR spectrum
(500 MHz, DMSO-d6), δ, ppm (J, Hz): 1.12 (3H, d, J = 6.8,
CHCH3); 3.02 (1H, d, J = 14.0, J = 7.2, CH2Ph); 3.09 (1H,
d, J = 14.0, J = 6.4, CH2Ph); 3.19 (3H, s, OCH3); 3.81 (1H, dd,
J = 11.0, J = 2.7, CH2); 4.10 (1H, dd, J = 11.0, J = 1.3,
CH2); 4.55–4.65 (2H, m, CHCH3, CHBn); 6.80–6.87 (2H,
m, H-6,8); 7.02 (1H, td, J = 7.7, J = 1.2, H-7); 7.17–7.30
(5H, m, H Ph); 7.56–7.61 (1H, m, H-5). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm (J, Hz): 15.4; 37.2; 46.0; 55.8;
69.0; 78.7; 116.5; 120.0; 122.9; 124.8; 125.4; 126.5; 128.3;
129.5; 137.1; 145.5; 168.9. Found, %: C 73.09; H 6.98;
N 4.31. C19H21NO3. Calculated, %: C 73.29; H 6.80; N 4.50.
(2S*)-1-((3R*)-7,8-Difluoro-3-methyl-2,3-dihydro-4H-
1,4-benzoxazin-4-yl)-2-methoxy-3-phenylpropan-1-one
((2S*,3R*)-4d). Yield 111 mg (64%) after recrystallization
from hexane–EtOAc mixture, colorless crystalline powder,
mp 72–74°C (hexane–EtOAc). HPLC analysis (ReproSil 100
Si column; hexane–i-PrOH, 60:1): τ(3R*,2'S*)-4d 8.3 min,
τ(3R*,2'R*)-4d 7.5 min; (3R*,2'S*)/(3R*,2'R*) = 98.9:1.1.
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz):
1.15 (3H, d, J = 6.8, CHCH3); 3.03 (1H, dd, J = 14.0,
J = 7.2, CH2Ph); 3.08 (1H, dd, J = 14.0, J = 6.4, CH2Ph);
3.22 (3H, s, OCH3); 3.85 (1H, dd, J = 11.0, J = 2.7, CH2);
4.27 (1H, dd, J = 11.0, J = 1.4, CH2); 4.59 (1H, t, J = 6.8,
CHBn); 4.61–4.68 (1H, m, CHCH3); 6.85 (1H, td, J = 9.8,
J = 2.3, H-6); 7.18–7.30 (5H, m, H Ph); 7.50–7.58 (1H, m,
H-5). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm
(J, Hz): 15.3; 36.9; 45.8; 55.7; 69.7; 78.6, 106.9 (d, J = 17.9);
119.4 (dd, J = 7.5, J = 3.9); 120.9; 126.4; 128.2; 129.4;
136.0 (dd, J = 9.8, J = 2.1); 137.0, 138.9 (dd, J = 243.5,
J = 15.4); 145.6–147.9 (m); 169.15. 19F NMR spectrum
(470 MHz, DMSO-d6), δ, ppm (J, Hz): 2.1 (ddd, J = 21.0,
J = 8.0, J = 1.7, F-8); 20.8–21.0 (м, F-7). Found, %:
C 65.91; H 5.77; F 10.92; N 3.86. C19H19F2NO3. Calculated,
%: C 65.70; H 5.51; F 10.94; N 4.03.
(2S*)-2-Benzyloxy-1-((3R*)-7,8-difluoro-3-methyl-2,3-di-
hydro-4H-1,4-benzoxazin-4-yl)propan-1-one ((2S*,3R*)-4e).
Yield 49 mg (28%) after recrystallization from hexane–
EtOAc mixture, colorless crystalline powder, mp 90–92°C
(hexane–EtOAc). GC: τ(3S,2'R)-4e 28.1 min, τ(R,S)-4e 28.5 min;
(3R*,2'S*)/(3R*,2'R*) = 98.5:1.5. 1H NMR spectrum
(500 MHz, DMSO-d6), δ, ppm (J, Hz): 1.10 (3H, d, J = 6.8,
CHCH3); 1.40 (3H, d, J = 6.4, CHOCH3); 4.16 (1H, dd,
J = 11.0, J = 2.8, CH2); 4.33 (1H, dd, J = 11.0, J = 1.3,
CH2); 4.44 (1H, d, J = 11.8, CH2Ph); 4.47 (1H, d, J = 11.8,
CH2Ph); 4.62 (1H, q, J = 6.4, CHOCH3); 4.74 (1H, qdd,
J = 6.8, J = 2.8, J = 1.5, CHCH3); 6.81–6.87 (1H, m, H-6);
7.23–7.31 (5H, m, H Ph); 7.56 (1H, ddd, J = 9.0, J = 5.8,
J = 2.8, H-5). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm (J, Hz): 14.7; 16.3; 44.7; 69.7 (2C); 72.2; 106.2 (d,
J = 18.2); 118.8 (dd, J = 8.0, J = 4.2); 121.1; 126.9; 127.1;
127.5; 135.9 (dd, J = 10.2, J = 3.3); 137.3; 138.6 (dd,
J = 244.1, J = 15.5); 146.5 (dd, J = 242.5, J = 10.0); 169.4.
19F NMR spectrum (470 MHz, DMSO-d6), δ, ppm (J, Hz):
2.0 (ddd, J = 20.9, J = 8.1, J = 2.2, F-8); 20.7 (ddd,
J = 20.7, J = 9.8, J = 5.3, F-7). Found, %: C 65.68; H 5.61;
F 11.05; N 4.07. C19H19F2NO3. Calculated, %: C 65.70;
H 5.51; F 10.94; N 4.03.
Preparation of mixtures of (3S,2'R)- and (3S,2'S)-
diаstereomers 3, 4 a–e (General method). A solution of
the appropriate acyl chloride (0.5 mmol) in CH2Cl2 (5 ml)
was added to a solution of (S)-amine 1a or 1b (0.5 mmol)
and PhNEt2 (75 mg, 0.5 mmol) in CH2Cl2 (10 ml) at 20°C,
then kept at 20°C for 24 h. The reaction mixture was then
washed with aqueous 4 N solution of HCl (2×5 ml),
saturated aqueous NaCl solution (3×15 ml), 5% NaHCO3
solution (10 ml), and H2O (2×15 ml). The organic layer was
dried over Na2SO4, and the solvent was removed by
evaporation under reduced pressure. The residue was
purified by flash chromatography on silica gel (eluent
hexane–EtOAc, 95:5).
2-Methoxy-1-(3-methyl-2,3-dihydro-4H-1,4-benzoxazin-
4-yl)propan-1-one (3a) (mixture of diastereomers). Yield
95 mg (81%), colorless oil. HPLC analysis (ReproSil 100
Si column; hexane–i-PrOH, 20:1): τ(3S,2'R)-3a 8.5 min, τ(3S,2'S)-3a
1
(2S*)-2-(Benzyloxy)-1-((3R*)-3-methyl-2,3-dihydro-
4H-1,4-benzoxazin-4-yl])propan-1-one ((2S*,3R*)-3e).
Yield 86 mg (55%) after recrystallization from hexane–EtOAc
6.5 min; (3S,2'R)/(3S,2'S) = 50.5:49.5. H NMR spectrum
(500 MHz, DMSO-d6), δ, ppm (J, Hz): 1.13 (1.5H, d,
J = 6.8, CHCH3 (S,S)); 1.15 (1.5H, d, J = 6.8, CHCH3
442

Chemistry of Heterocyclic Compounds 2018, 54(4), 437–446
(S,R)); 1.26 (1.5H, d, J = 6.4, CHOCH3 (S,S)); 1.33 (1.5H,
analysis (ReproSil 100 Si column; hexane–i-PrOH, 40:1):
τ(3S,2'R)-4b 4.2 min, τ(3S,2'S)-4b 4.7 min; (3S,2'R)/(3S,2'S) = 58.7:41.3.
1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz):
0.85 (1.23H, d, J = 6.7, CH(CH3)2 (S,S)); 0.93 (1.23H, d,
J = 6.7, CH(CH3)2 (S,S)); 0.94 (1.77H, d, J = 6.8, CH(CH3)2
(S,R)); 0.99 (1.77H, d, J = 6.7, CH(CH3)2 (S,R)); 1.15–1.18
(3H, m, CHCH3 (S,R) and (S,S)); 1.97–2.11 (1H, m, CHi-Pr
(S,R) and (S,S)); 2.61 (1.77H, s, OCH3 (S,R)); 2.66 (1.23H,
s, OCH3 (S,S)); 3.90 (0.59H, d, J = 7.8, CH(CH3)2 (S,R));
3.99 (0.41H, d, J = 7.4, CH(CH3)2 (S,S)); 4.10–4.18 (2H,
m, CH2 (S,R) and (S,S)); 4.39 (0.41H, dd, J = 11.0, J = 1.5,
CH2 (S,S)); 4.40 (0.59H, dd, J = 11.1, J = 1.4, CH2 (S,R));
4.84–4.92 (1H, m, CHCH3 (S,R) and (S,S)); 6.84–6.91 (1H,
m, H-6 (S,R) and (S,S)); 7.50 (0.41H, ddd, J = 9.3, J = 5.5,
J = 2.6, H-5 (S,S)); 7.71 (0.59H, ddd, J = 9.5, J = 5.5,
J = 2.6, H-5 (S,R)). 19F NMR spectrum (376 MHz,
DMSO-d6), δ, ppm (J, Hz): 2.03 (0.59F, ddd, J = 21.0,
J = 8.7, J = 2.2, F-8 (S,R)); 2.05–2.15 (0.41F, m, F-8 (S,S));
20.8 (0.59F, ddd, J = 20.9, J = 10.1, J = 5.4, F-7 (S,R));
20.9–21.0 (0.41F, m, F-7 (S,S)). Found, %: C 60.14;
H 6.63; F 12.95; N 4.64. C15H19F2NO3. Calculated, %:
C 60.19; H 6.40; F 12.69; N 4.68.
d, J = 6.4, CHOCH3 (S,R)); 3.20 (1.5H, s, OCH3 (S,R));
3.31 (1.5H, s, OCH3 (S,S)); 4.08–4.13 (1H, m, CH2 (S,R)
and (S,S)); 4.20–4.22 (1H, m, CH2 (S,R) and (S,S)); 4.41
(1H, m, CHOCH3 (S,R) and (S,S)); 4.63–4.68 (1H, m,
CHСH3 (S,R)); 4.77 (0.5H, qdd, J = 6.8, J = 2.9, J = 1.7,
CHСH3 (S,S)); 6.84–6.89 (2H, m, H-6,8 (S,R) and (S,S));
7.01–7.05 (1H, m, H-7 (S,R) and (S,S)); 7.70–7.71 (1H, m,
H-5 (S,R) and (S,S)). Found, %: C 66.38; H 7.11; N 5.90.
C13H17NO3. Calculated, %: C 66.36; H 7.28; N 5.95.
1-(7,8-Difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxa-
zin-4-yl)-2-methoxypropan-1-one (4a) (mixture of
diastereomers). Yield 103 mg (76%), yellowish oil. HPLC
analysis (ReproSil 100 Si column; hexane–i-PrOH, 40:1):
τ(3S,2'R)-4a 17.9 min, τ(3S,2'S)-4a 12.8 min; (3S,2'R)/(3S,2'S) =
52.3:47.7. 1H NMR spectrum (500 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.16 (1.5H, dd, J = 6.9, J = 0.5, СHCH3
(S,S)); 1.18 (1.5H, dd, J = 6.8, J = 0.5, СHCH3 (S,R)); 1.29
(1.5H, d, J = 6.5, СHCH3 (S,S)); 1.29 (1.5H, d, J = 6.5,
СHCH3 (S,R)); 3.23 (1.5H, s, OCH3 (S,R)); 3.30 (1.5H, s,
OCH3 (S,S)); 4.16 (0.5H, ddd, J = 10.0, J = 2.8, J = 0.6,
CH2 (S,S)); 4.19 (0.5H, ddd, J = 11.2, J = 2.9, J = 0.5, CH2
(S,R)); 4.35–4.44 (2H, m, CH2 (S,R) and (S,S)); 4.69 (0.5H,
qdd, J = 6.8, J = 2.8, J = 1.6, CHOCH3 (S,R)); 4.82 (0.5H,
qdd, J = 6.8, J = 2.9, J = 1.6, CHOCH3 (S,S)); 6.85 (0.5H,
ddd, J = 10.2, J = 8.2, J = 6.5, H-6 (S,R)); 6.88 (0.5H, ddd,
J = 10.2, J = 8.2, J = 6.5, H-6 (S,S)); 7.56 (0.5H, ddd,
J = 9.5, J = 5.5, J = 2.6, H-5 (S,S)); 7.62 (0.5H, ddd,
J = 9.5, J = 5.5, J = 2.6, H-5 (S,R)). 19F NMR spectrum
(470 MHz, DMSO-d6), δ, ppm (J, Hz): 1.9 (0.5F, ddd,
J = 21.0, J = 8.2, J = 2.5, F-8 (S,S)); 2.0 (0.5F, ddd,
J = 21.0, J = 8.1, J = 2.4, F-8 (S,R)); 20.5 (0.5F, ddd,
J = 20.8, J = 10.2, J = 5.4, F-7 (S,R)); 20.7–21.0 (0.5F, m,
F-7 (S,S)). Found, %: C 57.67; H 5.80; F 13.88; N 5.22.
C13H15F2NO3. Calculated, %: C 57.56; H 5.57; F 14.01; N 5.16.
2-Methoxy-3-methyl-1-(3-methyl-2,3-dihydro-4H-1,4-
benzoxazin-4-yl)butan-1-one (3b) (mixture of diastereo-
mers). Yield 84 mg (64%), yellowish oil. HPLC analysis
(Phenomenex Luna C 18(2) column; 50% MeCN): τ(3S,2'R)-3b
17.5 min, τ(3S,2'S)-3b 16.7 min; (3S,2'R)/(3S,2'S) = 53.5:46.5.
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz):
0.83 (1.38H, d, J = 6.8, CH(CH3)2 (S,S)); 0.91 (1.38H, d,
J = 6.7, CH(CH3)2 (S,S)); 0.95 (1.62H, d, J = 6.8 CH(CH3)2
(S,R)); 0.99 (1.62H, d, J = 6.6, CH(CH3)2 (S,R)); 1.13
(1.38H, d, J = 6.8, CHCH3 (S,S)); 1.15 (1.62H, d, J = 6.8,
CHCH3 (S,R)); 1.96–2.11 (1H, m, CH(CH3)2); 3.23 (1.5H,
s, OCH3, (S,R)); 3.34 (1.38H, s, OCH3, (S,S)); 3.92 (0.54H,
d, J = 7.8, CHCH(CH3)2 (S,R)); 4.03 (0.46H, d, J = 7.4,
CHCH(CH3)2 (S,S)); 4.06 (0.46H, dd, J = 11.2, J = 3.2,
CH2 (S,S)); 4.09 (0.54H, dd, J = 11.0; J = 2.9, CH2 (S,R));
4.22 (0.46H, dd, J = 11.0, J = 1.7, CH2 (S,S)); 4.24 (0.54H,
dd, J = 11.0, J = 1.7, CH2 (S,R)); 4.80–4.84 (1H, m,
CHCH3); 6.86–6.89 (2H, m, H-6,8); 7.02–7.06 (1H, m,
H-7); 7.61–7.62 (0.46H, m, H-5 (S,S)) 7.79–7.81 (0.54H, m,
H-5 (S,R)). Found, %: C 68.43; H 8.10; N 5.26. C15H21NO3.
Calculated, %: C 68.42; H 8.04; N 5.32.
2-Methoxy-1-(3-methyl-2,3-dihydro-4H-1,4-benzoxazin-
4-yl)-2-phenylethanone (3c) (mixture of diastereomers).
Yield 123 mg (83%), colorless oil. HPLC analysis (ReproSil
100 Si column; hexane–i-PrOH, 100:1): τ(3S,2'R)-3c 6.1 min, τ(3S,2'S)-3c
1
7.0 min; (3S,2'R)/(3S,2'S) = 50.2:49.8. H NMR spectrum
(500 MHz, DMSO-d6), δ, ppm (J, Hz): 0.93 (1.5H, d,
J = 6.8, СHCH3 (S,S)); 0.98 (1.5H, d, J = 6.8, СHCH3
(S,R)); 3.35 (1.5H, s, OCH3 (S,R)); 3.41 (1.5H, s, OCH3
(S,S)); 3.75 (0.5H, dd, J = 10.9, J = 2.9, CH2 (S,S)); 3.86
(0.5H, dd, J = 11.0, J = 2.5, CH2 (S,R)); 4.03 (0.5H, dd,
J = 10.9, J = 1.6, CH2 (S,S)); 4.12 (0.5H, dd, J = 10.9,
J = 1.6, CH2 (S,R)); 4.62–4.68 (1H, m, СHCH3 (S,R) and
(S,S)); 5.29 (0.5H, s, CHPh (S,R)); 5.39 (0.5H, s, CHPh
(S,S)); 6.80–6.90 (2H, m, H Ph); 7.01–7.05 (1H, m, H Ph);
7.28–7.35 (5H, m, H Ph); 7.37–7.41 (1H, m, H Ph); 7.69
(0.5H, dd, J = 8.1, J = 1.4, H-5 (S,S)); 7.81–7.83 (0.5H, m,
H-5 (S,R)). Found, %: C 72.53; H 6.69; N 4.71.
C18H19NO3. Calculated, %: C 72.71; H 6.44; N 4.71.
1-(7,8-Difluoro-3-methyl-2,3-dihydro-4H-1,4-benz-
oxazin-4-yl)-2-methoxy-2-phenylethanone (4c) (mixture
of diastereomers). Yield 162 mg (97%), colorless oil.
HPLC analysis (ReproSil 100 Si column; hexane–i-PrOH,
100:1): τ(3S,2'R)-4c 7.1 min, τ(3S,2'S)-4c 8.3 min; (3S,2'R)/(3S,2'S)
= 50.1:49.9. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm
(J, Hz): 0.91 (1.5H, d, J = 6.8, CHCH3 (S,S)); 0.99 (1.5H,
d, J = 6.9, CHCH3 (S,R)); 3.37 (1.5H, s, OCH3 (S,R)); 3.40
(1.5H, s, OCH3 (S,S)); 3.85 (0.5H, dd, J = 11.0, J = 2.7,
CH2 (S,S)); 3.92 (0.5H, dd, J = 11.0, J = 2.8, CH2 (S,R));
4.21 (0.5H, dd, J = 11.0, J = 1.4, CH2 (S,S)); 4.29 (0.5H,
dd, J = 11.0; J = 1.5, CH2 (S,R)); 4.67–4.72 (1H, m,
CHCH3 (S,R) and (S,S)); 5.30 (0.5H, s, CHPh (S,R)); 5.37
(0.5H, m, CHPh (S,S)); 6.84–6.91 (1H, m, H-6 (S,R) and
(S,S)); 7.30–7.43 (5H, m, H Ph); 7.56 (0.5H, ddd, J = 9.4,
J = 5.5, J = 2.5, H-5 (S,S)); 7.71 (0.5H, ddd, J = 9.5,
J = 5.5, J = 2.6, H-5 (S,R)). 19F NMR spectrum (470 MHz,
DMSO-d6), δ, ppm (J, Hz): 1.9–2.0 (1F, m, F-8); 20.8
(0.5F, ddd, J = 21.2, J = 10.0, J = 5.4, F-7 (S,R)); 21.0–
1-(7,8-Difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxa-
zin-4-yl)-2-methoxy-3-methylbutan-1-one (4b) (mixture of
diastereomers). Yield 105 mg (70%), yellowish oil. HPLC
443

Chemistry of Heterocyclic Compounds 2018, 54(4), 437–446
21.1 (0.5F, m, F-7 (S,S)). Found, %: C 64.58; H 5.18;
4.18 (0.75H, dd, J = 11.0, J = 1.6, CH2 (S,R)); 4.39 (0.75H,
d, J = 11.7, CH2Ph (S,R)); 4.44 (0.75H, d, J = 11.7, CH2Ph
(S,R)); 4.54 (0.25H, d, J = 11.7, CH2Ph (S,S)); 4.58 (0.25H,
d, J = 11.7, CH2Ph (S,S)); 4.63 (0.75H, q, J = 6.4,
CHOCH3 (S,R), overlapped with the signal of CHOCH3 (S,S));
4.66 (0.25H, q, J = 6.5, CHOCH3 (S,S)); 4.69 (0.75H, qdd,
J = 6.7, J = 2.5, J = 1.7, CHCH3 (S,R), overlapped with the
signal of CHCH3 (S,S)); 4.74 (0.25H, qdd, J = 6.7, J = 2.7,
J = 1.7, CHCH3 (S,S)); 6.81–6.87 (2H, m, H-6,8); 7.01–
7.05 (1H, m, H-7); 7.23–7.35 (5H, m, H Ph); 7.63 (0.25H,
d, J = 8.4, H-5 (S,S)); 7.67 (0.75H, d, J = 8.1, H-5 (S,R)).
Found, %: C 73.44; H 7.08; N 4.31. C19H21NO3.
Calculated, %: C 73.29; H 6.80; N 4.50.
2-Benzyloxy-1-(7,8-difluoro-3-methyl-2,3-dihydro-4H-
1,4-benzoxazin-4-yl)propan-1-one (4e) (mixture of
diastereomers). Yield 135 mg (78%), yellow amorphous
powder. GC: τ(3S,2'R)-4e 28.1 min, τ(3S,2'S)-4e 28.5 min; (3S,2'R)/
(3S,2'S) = 58.3:41.7. 1H NMR spectrum (500 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.10 (1.56H, d, J = 6.8, CHCH3 (S,R)); 1.12
(1.44H, d, J = 6.8, CHCH3 (S,S)); 1.37 (1.44H, d, J = 6.5,
CHOCH3 (S,S)); 1.40 (1.56H, d, J = 6.4, CHOCH3 (S,R));
4.12 (0.48H, dd, J = 11.0, J = 2.9, CH2 (S,S)); 4.16 (0.52H,
dd, J = 11.0, J = 2.9, CH2 (S,R)); 4.327 (0.52H, dd,
J = 11.0, J = 1.6, CH2 (S,R), overlapped with the signal of
CH2 (S,S)); 4.330 (0.48H, dd, J = 11.0, J = 2.0, CH2 (S,S));
4.44 (1H, d, J = 11.8, CH2Ph (S,R) and (S,S)); 4.47 (1H, d,
J = 11.8, CH2Ph (S,R) and (S,S)); 4.62 (1H, q, J = 6.4,
CHOCH3 (S,R) and (S,S)); 4.73 (0.52H, qdd, J = 6.8,
J = 2.8, J = 1.5, CHCH3 (S,R)); 4.79 (0.48H, qdd, J = 6.8,
J = 2.8, J = 1.5, CHCH3 (S,S)); 6.81–6.87 (1H, m, H-6);
7.23–7.35 (5H, m, H Ph); 7.53 (0.48H, ddd, J = 9.3, J = 5.4,
J = 2.5, H-5 (S,S)); 7.56 (0.52H, ddd, J = 9.0, J = 5.3, J = 2.6,
H-5 (S,R)). 19F NMR spectrum (470 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.9 (0.52F, ddd, J = 21.0, J = 8.3, J = 2.3, F-8
(S,R)); 2.0 (0.48F, ddd, J = 21.7, J = 8.6, J = 1.7, F-8 (S,S));
20.7 (0.52F, ddd, J = 20.8, J = 10.1, J = 5.4, F-7 (S,R)); 20.8
(0.48F, ddd, J = 20.6, J = 10.0, J = 5.5, F-7 (S,S)). Found,
%: C 65.74; H 5.64; F 10.98; N 4.06. C19H19F2NO3.
Calculated, %: C 65.70; H 5.51; F 10.94; N 4.03.
Derivatization of racemic carboxylic acids 5a,b
(General method). N-Methylmorpholine (0.17 ml, 1.5 mmol),
(R)-1-phenylethylamine (0.13 ml, 1 mmol), HOBt (200 mg,
1.5 mmol), and EDC·HCl (290 mg, 1.5 mmol) were added
to a solution of racemic 2-methoxycarboxylic acid 5a or 5b
(1 mmol) in DMF (3 ml) under stirring. The reaction
mixture was stirred until dissolution of the reagents and
then kept at ambient temperature for 48 h. The reaction
mixture was diluted with EtOAc (20 ml), washed with 1 N
HCl (3×15 ml), saturated aqueous NaCl solution (3×20 ml),
aqueous 1 N NaOH solution (2×15ml), saturated aqueous
NaCl solution (3×20 ml), then dried over Na2SO4, and
evaporated. The diastereomeric excess of the synthesized
amides was determined by HPLC on silica gel. The
diastereomeric amides were isolated by flash chromato-
graphy on silica gel.
F 11.25; N 4.19. C18H17F2NO3. Calculated, %: C 64.86;
H 5.14; F 11.40; N 4.20.
2-Methoxy-1-(3-methyl-2,3-dihydro-4H-1,4-benzoxa-
zin-4-yl)-3-phenylpropan-1-one (3d) (mixture of diastereo-
mers). Yield 112 mg (72%), colorless oil. HPLC analysis
(ReproSil 100 Si column; hexane–i-PrOH, 60:1): τ(3S,2'R)-3d
6.7 min, τ(3S,2'S)-3d 5.9 min; (3S,2'R)/(3S,2'S) = 49.3:50.7.
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz):
1.00 (1.5H, d, J = 6.8, CHCH3 (S,S)); 1.12 (1.5H, d,
J = 6.8, CHCH3 (S,R)); 2.97 (0.5H, dd, J = 13.6, J = 6.8,
CH2Ph (S,S), overlapped with the signal of CH2Ph (S,S));
3.00 (0.5H, dd, J = 13.6, J = 6.6, CH2Ph (S,R), overlapped
with the signals of CH2Ph (S,S) and CH2Ph (S,R)); 3.02
(0.5H, dd, J = 14.0, J = 7.2, CH2Ph (S,R)); 3.09 (0.5H, dd,
J = 14.0, J = 6.4, CH2Ph (S,R)); 3.19 (1.5H, s, OCH3
(S,R)); 3.35 (1.5H, s, OCH3 (S,S)); 3.71–3.78 (0.5H, m,
CH2 (S,S)); 3.81 (0.5H, dd, J = 11.0, J = 2.9, CH2 (S,R));
4.09 (0.5H, dd, J = 10.9, J = 1.6, CH2 (S,S)); 4.10 (0.5H,
dd, J = 11.0, J = 1.7, CH2 (R,S)); 4.56–4.64 (1.5H, m,
CHBn (S,R) and (S,S); CHCH3 (S,R)); 4.72 (0.5H, qdd,
J = 6.8, J = 3.0, J = 1.6, CHBn (S,S)); 6.80–6.90 (2H, m,
H Ph); 6.99–7.30 (5H, m, H Ph); 7.50–7.62 (1H, m, H-5
(S,R) and (S,S)). Found, %: C 73.30; H 6.98; N 4.63.
C19H21NO3. Calculated, %: C 73.29; H 6.80; N 4.50.
1-(7,8-Difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxa-
zin-4-yl)-2-methoxy-3-phenylpropan-1-one (4d) (mixture of
diastereomers). Yield 111 mg (64%), colorless oil. HPLC
analysis (ReproSil 100 Si column; hexane–i-PrOH, 60:1):
τ(3S,2'R)-4d 8.1 min, τ(3S,2'S)-4d 7.3 min; (3S,2'R)/(3S,2'S) = 51.3:48.7.
1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz):
1.02 (1.44H, d, J = 6.9, CHCH3 (S,S)); 1.15 (1.56H, d,
J = 6.8, CHCH3 (S,R)); 2.95–3.11 (2H, m, CH2Ph (S,R) and
(S,S)); 3.26 (1.56H, s, OCH3 (S,R)); 3.34 (1.44H, s, OCH3
(S,S)); 3.81–3.89 (1H, m, CH2 (S,R) and (S,S)); 4.27 (1H,
dd, J = 11.0, J = 1.3, CH2 (S,R) and (S,S)); 4.59 (0.52H, t,
J = 6.7, CHBn (S,R), overlapped with the signal of CHBn
(S,S)); 4.60 (0.48H, t, J = 6.6, CHBn (S,R), overlapped with
the signals of CHBn (S,S) and CHCH3 (S,R)); 4.61–4.68
(0.52H, m, CHCH3 (S,R)); 4.78 (0.48H, qdd, J = 6.7,
J = 2.9, J = 1.4, CHBn (S,S)); 6.81–6.91 (1H, m, 6-H);
7.12–7.31 (5H, m, H Ph); 7.38–7.44 (0.48H, m, H-5 (S,S))
7.50–7.58 (0.52H, m, H-5 (S,R)). 19F NMR spectrum
(470 MHz, DMSO-d6), δ, ppm (J, Hz): 2.0–2.1 (0.52F, m,
F-8 (S,R)); 2.1–2.2 (0.48F, m, F-8 (S,S)); 20.8–21.0 (0.52F,
m, F-7 (S,R)); 21.0–21.2 (0.48F, m, F-7 (S,S)). Found, %:
C 65.48; H 5.72; F 10.99; N 4.23. C19H19F2NO3.
Calculated, %: C 65.70; H 5.51; F 10.94; N 4.03.
2-Benzyloxy-1-(3-methyl-2,3-dihydro-4H-1,4-benzoxa-
zin-4-yl)propan-1-one (3e) (mixture of diastereomers).
Yield 72 mg (46%), yellow amorphous powder. GC data:
τ(3S,2'R)-3e 28.0 min, τ(3S,2'S)-3e 28.3 min; (3S,2'R)/
(3S,2'S) = 79.2:20.8. 1H NMR spectrum (500 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.09 (2.25H, d, J = 6.6, СHCH3 (S,R)); 1.10
(0.75H, d, J = 6.6, CHCH3 (S,S)); 1.34 (0.75H, d, J = 6.5,
CHOCH3 (S,S)); 1.40 (2.25H, d, J = 6.4, CHOCH3 (S,R));
4.06 (0.25H, dd, J = 10.9, J = 2.9, CH2 (S,S)); 4.09 (0.75H,
dd, J = 11.0, J = 2.9, CH2 (S,R)); 4.17 (0.25H, dd, J = 10.9;
J = 1.6, CH2 (S,S), overlapped with the signal of CH2 (S,R));
(2S)-2-Methoxy-N-((1R)-1-phenylethyl)propanamide
(6a) (mixture of diastereomers).21 Yield 153 mg (74%) after
flash chromatography (eluent hexane–EtOAc, gradient
from 4:1 to 3:2), white amorphous powder. HPLC analysis
444

Chemistry of Heterocyclic Compounds 2018, 54(4), 437–446
(ReproSil 100 Si column; hexane–i-PrOH, 40:1): τ(1R,2'S)-6a
(2S)-2-Methoxypropanoic acid ((S)-5a). Yield 15 mg
(49%), yellowish oil. The obtained carboxylic acid was
derivatized with (R)-1-phenylethylamine according to the
general method for carboxylic acids 5a,b. The
chromatographic peaks of the diastereomeric amides 6a
were assigned on the basis of literature data.21 The de of
(1R,2'S)-amide 6a was 63%, HPLC analysis (ReproSil 100
Si column; hexane–i-PrOH, 40:1): τ(1R,2'S)-6a 8.8 min,
τ(1R,2'R)-6a 7.5 min.
8.8 min, τ(1R,2'R)-6a 7.5 min; (1R,2'S)/(1R,2'R) = 46.7:53.3.
(2R)-2-Methoxy-3-methyl-N-((1R)-1-phenylethyl)butan-
amide ((1R,2'R)-6b). Yield 61 mg (26%) after flash
chromatography (eluent hexane–EtOAc, 98:2), colorless
crystalline powder, mp 73–76°C. HPLC analysis (ReproSil
100 Si column; hexane–i-PrOH, 40:1): τ(1R,2'S)-6b 4.2 min,
20
τ(1R,2'R)-6b 4.7 min; (1R,2'S)/(1R,2'R) = 1.4:98.6. [α]D +125
1
(c 0.9, CHCl3). H NMR spectrum (500 MHz, DMSO-d6),
δ, ppm (J, Hz): 0.92 (3H, d, J = 6.9, CH(CH3)2); 1.01 (3H,
d, J = 6.9, CH(CH3)2); 1.51 (3H, d, J = 6.9, NHCHCH3);
2.07–2.16 (1H, m, CH(CH3)2); 3.34 (3H, s, OCH3); 3.41
(1H, d, J = 4.0, CHOCH3); 5.18 (1H, dq, J = 7.1, J = 6.9,
NHCHCH3); 6.73 (1H, d, J = 7.1, NHCHCH3); 7.26–7.29
(1H, m, H Ph); 7.32–7.37 (4H, m, H Ph). Found, %:
C 71.20; H 9.14; N 5.82. C14H21NO2. Calculated, %:
C 71.46; H 8.99; N 5.95.
(2S)-2-Methoxy-3-methylbutanоic acid ((S)-5b). Yield
7 mg (17%), yellowish oil. The obtained carboxylic acid
was derivatized with (R)-1-phenylethylamine according to
the general method for carboxylic acids 5a,b. The de of
(1R,2'S)-amide 6b 74%, HPLC analysis (ReproSil 100 Si
column; hexane–i-PrOH, 40:1): τ(1R,2'S)-6b 4.2 min,
τ(1R,2'R)-6b 4.7 min.
(2S)-2-Methoxy-2-phenylacetic acid ((S)-5c). Yield
44 mg (89%), yellow amorphous powder. The ee was 65%,
HPLC analysis (hexane–i-PrOH–CF3COOH mobile phase,
((2S)-2-Methoxy-3-methyl-N-((1R)-1-phenylethyl)butan-
amide ((1R,2'S)-6b). Yield 73 mg (31%) after flash
chromatography (eluent hexane–EtOAc, 98:2), colorless
crystalline powder, mp 90–91°C. HPLC analysis (ReproSil
100 Si column; hexane–i-PrOH, 40:1): τ(1R,2'S)-6b 4.2 min,
τ(1R,2'R)-6b 4.7 min; (1R,2'S)/(1R,2'R) = 99.7:0.3. [α]D20 +18.2
20
40:1:0.02): τ(S)-5c 20.8 min, τ(R)-5c 18.8 min. [α]D +104
20
1
(c 1.0, EtOH) ([α]D +146.0 (c 1.04, EtOH)22). H NMR
spectrum was identical to the published one.33 Found, m/z:
165.0555 [M–H]–. C9H9O3. Calculated, m/z: 165.0557.
(2S)-2-Methoxy-3-phenylpropanoic acid ((S)-5d).
Yield 36 mg (67%), colorless oil. The ee was 67%, HPLC
analysis (hexane–i-PrOH–CF3COOH mobile phase,
1
(c 1.3, CHCl3). H NMR spectrum (500 MHz, DMSO-d6),
δ, ppm (J, Hz): 0.81 (3H, d, J = 6.9, CH(CH3)2); 0.95 (3H, d,
J = 6.9, CH(CH3)2); 1.52 (3H, d, J = 6.9, NHCHCH3); 2.01–
2.10 (1H, m, CH(CH3)2); 3.41–3.43 (4H, m, OCH3 and
CHOCH3); 5.14–5.20 (1H, m, NHCHCH3); 6.72 (1H, d,
J = 6.6, NHCHCH3); 7.24–7.27 (1H, m, H Ph); 7.30–7.35
(4H, m, H Ph). Found, %: C 71.44; H 8.92; N 5.91.
C14H21NO2. Calculated, %: C 71.46; H 8.99; N 5.95.
Kinetic resolution of acyl chlorides 2a–e by (S)-amines
1а,b (General method). A solution of the appropriate acyl
chloride (0.6 mmol) in PhMe (2 ml) was added at 20°C to a
solution of amine 1a or 1b (0.3 mmol) and N,N-diethyl-
aniline (44.8 mg, 0.3 mmol) in PhMe (4 ml). The reaction
mixture was kept at 20°C for 24 h. In order to perform KR
of acyl chlorides 2a,b, the reaction mixture was treated by
the addition of saturated Na2CO3 solution and vigorously
stirred for 1 h. In the rest of the cases, the reaction mixture
was evaporated, the residue was dissolved in MeCN (10 ml)
and added to a saturated solution of Na2CO3 (10 ml). The
mixture was vigorously stirred for 1 h, then concentrated
by evaporation at reduced pressure, and extracted with
CHCl3 (2×5 ml). The organic layer was washed with
aqueous 4 N HCl solution (2×4 ml), saturated NaCl
solution (4×5 ml), and H2O (2×5 ml), dried over Na2SO4,
and evaporated. The ratio of diastereomeric amides in the
mixture was determined by GC.
20
40:1:0.02): τ(S)-5d 20.4 min, τ(R)-5d 14.0 min. [α]D –21.4
(c 0.5, Me2CO) ([α]D20 –36.7 (c 0.6, Me2CO) (ee 99.3%)31).
1H NMR spectrum was identical to the published one.31
Found, m/z: 179.0715 [M–H]–. C10H11O3. Calculated, m/z:
179.0714.
(2S)-(2-Benzyloxy)propanoic acid ((S)-5e). Yield 20 mg
(37%) after flash chromatography (eluent PhH–EtOAc,
9:1), yellow oil, ee 63%, HPLC analysis (hexane–i-PrOH–
CF3COOH mobile phase, 20:1:0.02): τ(S)-5c 7.1 min, τ(R)-5c
20
20
7.8 min. [α]D –42.9 (c 2.4, PhH) ([α]D –74.2 (c 4.6,
PhH)24). H NMR spectrum was identical to the published
1
one.24 Found, m/z: 179.0713 [M–H]–. C10H11O3. Calculated,
m/z: 179.0714.
X-ray structural analysis of (R,S)-amide 6b was
performed on an Xcalibur-3 (Oxford Diffraction)
diffractometer equipped with a CCD-detector, using the
standard procedure (λ(MoKa) 0.07107 nm, graphite
monochromator, ω-scanning). Crystals suitable for the
analysis were obtained by evaporation of amide solution in
MeOH at room temperature. The data were acquired and
processed with the CrysAlis software package.34 The
structures of compounds were solved by direct method
using the SHELXS-97 program and refined with the
SHELXL-97 program35 in anisotropic approximation (iso-
tropically for hydrogen atoms). The hydrogen atom positions
were partially solved and refined independently, and
partially included in the refinement according to the ''rider''
model with dependent temperature parameters. The
crystallographic data: crystal size 0.25 × 0.12 × 0.03 mm;
colorless needles; monoclinic syngony; space group P21;
a 9.325(3), b 5.2567(7), c 14.973(4) Å; α 90, β 104.20(3),
γ 90°; V 711.5(3) Å3; Z 2; dcalc 1.0983 g/cm3; μ 0.073 mm−1;
2.2770 < θ < 20.5630. The completeness for θ ≤ 28.22°
The alkaline aqueous solutions were acidified with 4 N
HCl solution to pH 1–2 and extracted with CHCl3 (2×5 ml).
The organic layer was washed with saturated aqueous NaCl
solution (2×5 ml), dried over Na2SO4, and evaporated. The
obtained carboxylic acids 5a–e were purified by flash
chromatography on silica gel and analyzed by HPLC.
Carboxylic acids 5a,b were derivatized with (R)-1-
phenylethylamine prior to the analysis, the obtained
diastereomeric amides were analyzed by HPLC on silica
gel.
445

Chemistry of Heterocyclic Compounds 2018, 54(4), 437–446
was 99.9%. A total of 3867 reflections were collected
(2741 independent, Rint 0.0616), including 899 reflections
with I ≥ 2σ(I). The value of S by F2 was 0.958786. The
final probability factors were R1 (I > 2σ(I)) 0.053388,
R1 0.213027 (all data), wR2 0.150363 (all data). The X-ray
structural dataset was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 1434293).
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This work financially supported by the Russian Science
Foundation (grant 14-13-01077).
The authors would like to express their gratitude to
Candidate of Chemical Sciences I. N. Ganebnykh for
recording high-resolution mass spectra, Candidate of
Chemical Sciences M. G. Pervova for performing GLC
analyses, and Candidate of Chemical Sciences P. A.
Slepukhin for X-ray structural analysis. Analytical studies
were carried out using the equipment of the Center for
Joint Use ''Spectroscopy and Analysis of Organic
Compounds'' at the Postovsky Institute of Organic
Synthesis of the Russian Academy of Sciences (Ural
Branch).
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