Synthesis of enantiomers of 3-methyl- and 3-phenyl-3,4-dihydro-2H-[1,4]benzothiazines and their 1,1-dioxides via an acylative kinetic resolution protocol

Article abstract of DOI:10.1016/j.tetasy.2015.01.010

It has been found that acyl chlorides of (S)-naproxen, N-phthaloyl-(S)-leucine, and N-tosyl-(S)-proline are efficient chiral resolving agents for the acylative kinetic resolution of racemic 3-methyl- and 3-phenyl-3,4-dihydro-3-methyl-2H-[1,4]benzothiazines. Based on the experimental results, a preparative protocol comprising the acylative kinetic resolution followed by isolation of a single (major) diastereoisomeric amide and subsequent hydrolysis of amide bond was proposed. Using this approach with various chiral resolving agents, (S)- and (R)-enantiomers of 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine (ee >99%) were obtained. The oxidation of the corresponding diastereoisomers of the amides followed by deacylation led to the (S)- and (R)-enantiomers of 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine-1,1-dioxide (ee >97%). This method proved to be less suitable for the preparation of the (S)-enantiomer of 3,4-dihydro-3-phenyl-2H-[1,4]benzothiazine (ee up to 93%) and its sulfone (ee 82%) which were both obtained in low yields. The loss of enantioselectivity for (S)-3,4-dihydro-3-phenyl-2H-[1,4]benzothiazine and its sulfone occurred during hydrolysis of the corresponding diastereoisomerically pure amides.

Full text of DOI:10.1016/j.tetasy.2015.01.010

Tetrahedron: Asymmetry 26 (2015) 186–194
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of enantiomers of 3-methyl- and 3-phenyl-3,4-dihydro-2H-
[1,4]benzothiazines and their 1,1-dioxides via an acylative kinetic
resolution protocol
⇑
Dmitry A. Gruzdev, Evgeny N. Chulakov, Liliya Sh. Sadretdinova, Mikhail I. Kodess, Galina L. Levit ,
Victor P. Krasnov
Postovsky Institute of Organic Synthesis of RAS (Ural Branch), 22/20 S. Kovalevskoy/Akademicheskaya St., Ekaterinburg 620137, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 November 2014
Accepted 8 January 2015
It has been found that acyl chlorides of (S)-naproxen, N-phthaloyl-(S)-leucine, and N-tosyl-(S)-proline are
efficient chiral resolving agents for the acylative kinetic resolution of racemic 3-methyl- and 3-phenyl-
3,4-dihydro-3-methyl-2H-[1,4]benzothiazines. Based on the experimental results, a preparative protocol
comprising the acylative kinetic resolution followed by isolation of a single (major) diastereoisomeric
amide and subsequent hydrolysis of amide bond was proposed. Using this approach with various chiral
resolving agents, (S)- and (R)-enantiomers of 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine (ee >99%)
were obtained. The oxidation of the corresponding diastereoisomers of the amides followed by deacyla-
tion led to the (S)- and (R)-enantiomers of 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine-1,1-dioxide
(ee >97%). This method proved to be less suitable for the preparation of the (S)-enantiomer of 3,4-dihy-
dro-3-phenyl-2H-[1,4]benzothiazine (ee up to 93%) and its sulfone (ee 82%) which were both obtained in
low yields. The loss of enantioselectivity for (S)-3,4-dihydro-3-phenyl-2H-[1,4]benzothiazine and its
sulfone occurred during hydrolysis of the corresponding diastereoisomerically pure amides.
Ó 2015 Elsevier Ltd. All rights reserved.
Me
COCl
1. Introduction
PhthN
S
COCl
Tos
N
COCl
3-Substituted derivatives of 3,4-dihydro-2H-[1,4]benzothiazine
and 3,4-dihydro-2H-[1,4]benzothiazine-1,1-dioxide are of special
interest as the structural fragments of biologically active
compounds.1 However to date, a limited number of synthetic
examples for enantiomerically pure 3-substituted 3,4-dihydro-
2H-[1,4]benzothiazines have been described in the literature,2
while the corresponding enantiopure sulfones are unreported.
Over the last few years, we have studied the acylative kinetic
resolution of racemic amines3 using acyl chlorides of 2-arylpropi-
onic4 and N-protected (S)-amino acids4e,5 as chiral resolving
agents. Thus, we have developed approaches for enantiopure het-
erocyclic amines with different structures, which are based on
the acylative kinetic resolution with acyl chlorides of (S)-naproxen
1,4a,4b N-phthaloyl-(S)-leucine 2,4e,5f and N-tosyl-(S)-proline 35a,5g
(Scheme 1). We have also demonstrated that a subsequent trans-
formation of diastereoisomerically pure amides, the products of
kinetic resolution can be used for the preparation of enantiopure
functionalized amines.5e
iPr
2
1
3
MeO
4a:
R = Me
N
H
R
4b: R = Ph
Scheme 1. Resolving agents 1–3 and racemic benzothiazines 4a,b.
Recently, we have demonstrated the possibility of the diaste-
reoselective acylation of racemic amine 4a with acyl chloride 3.5g
Herein our aim was to study the acylative kinetic resolution of
racemic 3-methyl- 4a and 3-phenyl-3,4-dihydro-2H-[1,4]benzo-
thiazines 4b with acyl chlorides 1–3 and to develop the preparative
approaches to (R)- and (S)-enantiomers of these amines and
corresponding sulfones.
2. Results and discussion
The starting racemic amines 4a and 4b were obtained from 2-
aminothiophenol and appropriate chloroketone similar to the
literature method.6 In order to choose the most convenient
⇑
Corresponding author. Tel.: +7 343 3623057; fax: +7 343 3741189.
E-mail address: ca512@ios.uran.ru (G.L. Levit).
http://dx.doi.org/10.1016/j.tetasy.2015.01.010
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 26 (2015) 186–194
187
OMe
flash column
O
R
chromatography
1 (0.5 equiv.)
HCl/AcOH 1:1
95 oC, 8-10 h
5a,b
(S,S)-
+
+
N
NH
toluene
>99% de
S
S
Me
S
5a,b
(S,S)-
R
4a,b
(R)-
NH
NH
S
S
HCl/AcOH 1:1, 90 oC for
R
R
O
R
(S,S)-6a
2
(0.5 equiv.)
recrystallization
(S)-4a, >99% ee (S)-
rac-4a,b
NPhth
(S,S)-6a,b
>99% de
NH
N
4b,
92-93% ee
CH2Cl2 or MeCN
KOH, MeOH/H2O,
S
90 oC for (S,S)-
6b
R
iPr
4a,b
6a,b
(S,S)-
(R)-
4a, 5a, 6a: R = Me
4b, 5b, 6b
: R = Ph
Tos
N
O
flash column
3 (0.5 equiv.)
chromatography
HCl/AcOH 1:1
(R,S)-7
>99% de
+
NH
N
NH
Me
NH
Me
95-100 oC, 28 h
toluene
S
S
S
S
Me
Me
(R,S)-7
de up to 94%
Scheme 2. Kinetic resolution of amines 4a,b with acyl chlorides 1–3.
rac-4a
(R)-4a 99.2% ee
(S)-4a
ee up to 36%
23% overall yield
reaction conditions for the preparation of enantiomers of amines
4a and 4b, we studied the acylative kinetic resolution with various
chiral resolving agents. Diastereoselective acylation of racemic
amines 4a and 4b with acyl chlorides 1–3 was carried out with a
2:1 amine–acyl chloride molar ratio in toluene, dichloromethane,
or acetonitrile at various temperatures for 6 h (Scheme 2, Table 1).
The initial concentration of racemic amine was 0.1 M. The choice of
the solvent was based on the results of previous studies. Thus, it
has been previously shown that in the acylative kinetic resolution
temperatures (toluene from +20 to +80 °C, dichloromethane at
+20 °C, acetonitrile from +20 to +50 °C). We consider that the phenyl
substituent at the stereogenic center of the racemic amine probably
gives rise to greater steric hindrances when compared with the
methyl one.
The predominant diastereoisomeric amides (S,S)-5a,b, (S,S)-6a,b,
and (R,S)-7 (Scheme 2) were isolated from the reaction mixtures by
recrystallization or flash column chromatography. The minor
amides (R,S)-6a and (S,S)-7 were also isolated from the reaction
mixtures by flash column chromatography. In the case of crystalline
amides (S,S)-6a, (S,S)-6b, and (R,S)-7, the absolute configuration was
confirmed by X-ray diffraction from the known configuration of the
acyl fragment (Figs. 1–3). Based on the data on which diastereoiso-
mer, (R,S) or (S,S), of amides 6a,b and 7 predominates in the kinetic
resolution products, we determined in all cases the configuration of
unreacted amines 4a and 4b. This made it possible to establish that
the (S)-enantiomers of amines 4a,b reacted faster than the (R)-enan-
tiomers with acyl chloride 1 to afford (S,S)-amides 5a,b, while the
(R)-enantiomers remained unreacted.
of different heterocyclic amines with acyl chlorides 14c,d and 3,5g
a
high stereoselectivity is achieved in toluene; when acyl chloride 2
is used as a chiral resolving agent, dichloromethane is the solvent
of choice.5e,f
Diastereoselective acylation of amines 4a and 4b with acyl chlo-
rides of (S)-naproxen 1 and N-phthaloyl-(S)-leucine 2 resulted in the
predominant formation of (S,S)-amides 5a,b and 6a,b, while the
unreacted amines were enriched with (R)-enantiomers (Table 1)
similar to the acylation of racemic 2-methyl-1,2,3,4-tetrahydro-
quinoline and 2,3-dihydro-3-methyl-4H-[1,4]benzoxazine.4a–c,5f
Diastereoselective acylation of amine 4a with acyl chloride 3 led
to the predominant formation of (R,S)-amide 7 recently shown.5g It
should be emphasized that no diastereoisomeric amides were
formed when the acylation of racemic amine 1b with acyl chloride
3 was carried out in any of the abovementioned solvents at different
Based on the values of diastereoisomeric excess (de) of amides
(S,S)-5a,b, (S,S)-6a,b, and (R,S)-7, and the enantiomeric excess (ee)
of the unreacted amine 4a or 4b, we calculated the conversion of
starting racemate C and the selectivity factor s,7 that is the ratio
of the rate constants of enantiomers (Table 1).
Table 1
Stereochemical results of the acylative kinetic resolution of amines 4a and 4b with acyl chlorides 1–3 (the initial amine concentration 0.1 M, reaction time 6 h)a
Entry
Racemic amine
Resolving agent
Solvent
T (°C)
Amide, deb (%)
Unreacted amine, eec (%)
Conversion, C (%)
Selectivity factor, s
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
1
1
2
2
2
3
3
1
1
2
2
Toluene
Toluene
CH2Cl2
CH2Cl2
MeCN
Toluene
Toluene
Toluene
CH2Cl2
CH2Cl2
MeCN
+20
ꢀ20
+20
ꢀ20
+20
+20
ꢀ20
+20
ꢀ20
+20
+20
(S,S)-5a, 82.3
(S,S)-5a, 89.7
(S,S)-6a, 51.4
(S,S)-6a, 61.7
(S,S)-6a, 49.6
(R,S)-7, 89.4
(R,S)-7, 93.5
(S,S)-5b, 82.4
(S,S)-5b, 71.6
(S,S)-6b, 53.1
(S,S)-6b, 52.2
(R)-4a, 74.2
(R)-4a, 65.2
(R)-4a, 40.5
(R)-4a, 23.7
(R)-4a, 40.0
(S)-4a, 35.9
(S)-4a, 10.6
(R)-4b, 66.0
(R)-4b, 71.6
(R)-4b, 13.8
(R)-4b, 15.4
47
42
44
27
45
29
10
44
50
21
23
23
37
4.6
5.2
4.4
255g
325g
20
13
3.8
3.7
9
10
11
a
b
c
Average values for 2–4 parallel runs are presented.
Determined by HPLC (Phenomenex Luna C18(2) or ReproSil 100 Si, see Section 4).
Determined by chiral HPLC (Chiralcel OD-H, see Section 4).

188
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 26 (2015) 186–194
From the data shown in Table 1 it can be seen that the highest
selectivity of the acylation of racemic benzothiazine 4a was
observed when (S)-naproxen 1 and N-tosyl-(S)-prolyl 3 chlorides
were used as chiral resolving agents, and the reaction was carried
out in toluene at ꢀ20 °C (selectivity factor s was 37 and 32, respec-
tively). However, the low reaction temperature (ꢀ20 °C) contrib-
uted to a decrease in conversion, which was most pronounced in
the acylation with acyl chloride 3 (10% conversion).
In the case of diastereoselective acylation of racemic amine 4a
with acyl chloride 2, the selectivity was moderate; the selectivity
factor s was approximately 5 in dichloromethane and acetonitrile
at 20 °C at rather high conversion of racemate (Table 1, entries 3
and 5).
It should be noted that the selectivity in the kinetic resolution of
racemic 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine 4a with (S)-
naproxen chloride 1 was as high as in the kinetic resolution of its
oxygen-containing analogue, 3,4-dihydro-3-methyl-2H-[1,4]ben-
zoxazine.4e In the case of the kinetic resolution with acyl chlorides
of N-protected (S)-amino acids 2 and 3, the acylation of benzothi-
azine 4a was less selective than acylation of benzoxazine
derivative.
Figure 1. Structure of amide (S,S)-6a (thermal ellipsoids of 50% probability).
When comparing the kinetic resolution processes of racemic
3,4-dihydro-3-phenyl-2H-[1,4]benzothiazine 4b and amine 4a,
we can conclude that they occurred with a similar stereoselectivi-
ty. Thus, in the acylation of amines 4a and 4b with acyl chloride 1
in toluene at 20 °C, the selectivity factor s was 23 and 20, respec-
tively (Table 1, entries 1 and 8). In the acylation of amines 4a
and 4b with acyl chloride 2 in dichloromethane or MeCN at
20 °C, we also observed a similar stereoselectivity, but the acyla-
tion of phenyl-substituted amine 4b proceeded at a significantly
lower conversion, especially in MeCN (45% vs 23%; Table 1, entries
5 and 11). Prolonging this reaction in MeCN to 72 h led to an
increase in the conversion of amine 4b up to 47%.
The results obtained formed the basis for the synthesis of enan-
tiomerically pure (S)- and (R)-enantiomers of amines 4a and (S)-
enantiomer of amine 4b.
In order to prepare (S)-4a, the kinetic resolution of the racemate
can be carried out with either acyl chloride 1 or 2. When the acyl-
ation of amine 4a with acyl chloride 1 was carried out in toluene at
20 °C for 24 h, it resulted in amide (S,S)-5a (83.6% de) as a colorless
oil in 91% yield (relative to acyl chloride 1) and unreacted (R)-4a
(79.2% ee; s 25). Flash column chromatography on silica gel gave
individual (S,S)-5a (de >99%) in 55% overall yield (relative to acyl
chloride 1). The subsequent acidic hydrolysis of amide (S,S)-5a
(Scheme 2) resulted in enantiopure amine (S)-4a (ee >99%) in
75% yield [relative to amide (S,S)-5a]. The overall yield of (S)-amine
4a was 21% relative to the starting racemate.
Figure 2. Structure of amide (S,S)-6b (thermal ellipsoids of 50% probability).
In the case of the kinetic resolution of amine 4a with acyl chlo-
ride 2, the acylation was carried out in dichloromethane at +20 °C
for 6 h. Recrystallization of the resulting amide afforded diastereo-
isomerically pure (S,S)-6a (de >99%) in 46% yield relative to the
acylating agent 2. After acidic hydrolysis of amide (S,S)-6a
(Scheme 2), enantiopure amine (S)-4a (ee >99%) was obtained in
85% yield [relative to amide (S,S)-6a]. The overall yield of (S)-amine
4a was about 20% relative to the starting racemate.
The approach that involves acylation of racemic amine 4a with
acyl chloride 2 is preferable compared to the use of acyl chloride 1,
since it is more convenient to purify amide (S,S)-6a by
recrystallization.
In order to obtain enantiopure amine (R)-4a, we carried out the
diastereoselective acylation of the racemate with acyl chloride 3 in
toluene at 20 °C for 24 h. Diastereoisomerically pure amide (R,S)-7
(de >99%) was isolated from the reaction mixture by flash column
chromatography in 65% yield. The preparation of amine (R)-4a
required
a longer acidic hydrolysis (28 h) of amide (R,S)-7
Figure 3. Structure of amide (R,S)-7 (thermal ellipsoids of 50% probability).
compared to the acidic hydrolysis of amides (S,S)-5a and (S,S)-6a.

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 26 (2015) 186–194
189
In this approach, the amides, the products of the kinetic resolu-
tion are subjected to oxidation and further transformation instead
of amine 4a. The oxidation of amides (S,S)-6a and (R,S)-7 with hydro-
gen peroxide in a way similar to the literature10 proceeded smoothly
and led to amides (S,S)-8a and (R,S)-10, respectively (Scheme 3).
Their structure and chemical purity were confirmed by the NMR
spectroscopy and elemental analysis. In the case of amide (R,S)-10,
the structure was confirmed by X-ray diffraction (Fig. 4).
The deacylation of amides (S,S)-8a and (R,S)-10 with sodium
methoxide in methanol at room temperature as described in the
literature8b,11 resulted in the enantiomeric sulfones (S)-9a (99%
ee) and (R)-9a (97% ee), respectively, in high yields.
O
(i)
NPhth
(ii)
NH
Me
(S,S)-6a
N
96%
O
94%
O
O
S
S
Me
iPr
O
O
(S,S)-8a
(S)-9a
99% ee
O
Tos
N
(ii)
87%
(i)
N
7
NH
Me
(R,S)-
78%
S
O
S
Me
O
O
10
(R,S)-
(R)-9a 97% ee
An attempt to obtain the individual (S)-enantiomers of 3-phe-
nyl-benzothiazine 4b and the corresponding sulfone 9b in a similar
way was not so successful. Preparative kinetic resolution of race-
mic amine 4b with acyl chloride 1 in toluene at 20 °C followed
by flash column chromatography (Scheme 2) afforded amide
(S,S)-5b (de >99%) in 21% yield relative to the acylating agent. Sub-
sequent acidic hydrolysis of amide (S,S)-5b proceeded in a moder-
ate yield (61%) and was accompanied by partial racemization. The
overall yield of enantiomerically enriched (S)-4b (93% ee) was 6.4%
relative to the starting racemate.
Reagents and conditions: (i) H2O2, AcOH, Δ; (ii) NaOMe, MeOH, rt
Scheme 3. Preparation of (R)- and (S)-enantiomers of 3,4-dihydro-3-methyl-2H-
[1,4]benzothiazine-1,1-dioxide 9a.
In the case of the kinetic resolution of racemate 4b with acyl
chloride 2 (acetonitrile, +20 °C, 72 h), recrystallization of the
kinetic resolution product gave amide (S,S)-6b (de >99%) in 41%
yield. However, the acidic hydrolysis (heating in a mixture of con-
centrated HCl and AcOH) of amide (S,S)-6b failed. Hydrolysis of the
amide bond in (S,S)-6b under the action of KOH in a MeOH–H2O
mixture resulted in the partially racemized amine (S)-4b (91% ee)
in 37% yield. The overall yield was 7.6% relative to the starting
racemate 4b.
The oxidation of amide (S,S)-6b carried out in a similar manner
to the preparation of sulfone (S)-9a smoothly afforded the
corresponding amide (S,S)-8b (de >99% according to the 1H NMR
spectra) (Scheme 4). Deacylation of amide (S,S)-8b under the con-
ditions described above for 3-methyl substituted analogue (S,S)-8a
(NaOMe, MeOH, rt) resulted in (S)-9b (82% ee) in 77% yield. Such
significant racemization of the target amine (S)-4b and sulfone
(S)-9b is likely due to the effect of the phenyl substituent at the
3-position, since its presence facilitates the deprotonation at the
stereogenic carbon atom under the conditions of deacylation of
diastereoisomerically pure amides.
Figure 4. Structure of amide (R,S)-10 (ellipsoids of 50% probability).
3. Conclusion
As a result we obtained enantiopure amine (R)-4a (ee >99%) in 23%
overall yield relative to the racemate.
In conclusion, as a result of studying the acylative kinetic reso-
lution of racemic 3,4-dihydro-3-methyl-2H-[1,4]benzothiazine
with various chiral acyl chlorides, such as (S)-naproxen chloride,
N-phthaloyl-(S)-leucyl chloride, and N-tosyl-(S)-prolyl chloride,
we found conditions that gave the highest efficiency of the process.
A synthetic sequence involving acylative kinetic resolution with
subsequent isolation of the major diastereoisomeric amide fol-
lowed by its deacylation made it possible to obtain enantiopure
(S)- and (R)-enantiomers (ee >99%) of the titled compound. Oxida-
tion of the corresponding diastereoisomerically pure amides fol-
lowed by deacylation resulted in enantiopure (S)- and (R)-
sulfones (ee from 97 to >99%). Application of the same approach
for the preparation of enantiomers of 3,4-dihydro-3-phenyl-2H-
The derivatives of 3,4-dihydro-2H-[1,4]benzothiazine-1,1-diox-
ide with a free NH group are hard-to-obtain compounds; the oxi-
dation of the corresponding dihydrobenzothiazines results in the
formation of by-products of quinoid nature.8 Our attempts to
obtain racemic 3-methyl- and 3-phenyl-3,4-dihydro-2H-[1,4]ben-
zothiazine-1,1-dioxides 9a,b by the oxidation of amines 4a,b in a
way similar to the known approach9 were unsuccessful. The target
racemic sulfones 9a,b were isolated in 18% and 24% yield,
respectively.
Hence, we developed a synthetic approach for both enantio-
mers of sulfone 9a based on the oxidation of diastereoisomerically
pure amides (S,S)-6a and (R,S)-7 resulting in amides (S,S)-8a and
(R,S)-10, respectively (Scheme 3).
O
H2O2
MeONa
MeOH, rt, 4h
77%
NPhth
6b
(S,S)-
N
NH
Δ
AcOH, , 20 min
O
O
S
S
Ph
iPr
Ph
82% ee
93%
O
O
(S,S)-8b
(S)-9b
Scheme 4. Preparation of (S)-3,4-dihydro-3-phenyl-2H-[1,4]benzothiazine-1,1-dioxide 9b.

190
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 26 (2015) 186–194
[1,4]benzothiazine proved to be not so successful. The (S)-enantio-
mer of 3-phenyl-benzothiazine was obtained in a low yield and
approximately 93% ee; the corresponding (S)-sulfone was obtained
with 82% ee. The loss of enantiomeric purity took place during the
deacylation step of corresponding amides.
were washed with water (2 ꢁ 75 mL), dried over Na2SO4, and evap-
orated under reduced pressure. The residue was purified by flash
column chromatography (hexane to hexane–EtOAc 99:1 as an elu-
ent) to give compound 4b (2.42 g, 24%). Yellow crystals, mp 52–
53 °C (lit.14 mp 58–59 °C). HPLC (Chiralcel OD-H; hexane–iPrOH
5:1): s(R)-4b 14.0 min, s(S)-4b 15.0 min. NMR spectra were identical
to the published for (S)-4b.2d Anal. Calcd for C14H13NS: C, 73.97;
H, 5.76; N, 6.16; S, 14.11. Found: C, 73.82; H, 5.81; N, 5.91; S, 14.40.
4. Experimental
4.1. General
4.3. Kinetic resolution of racemic amines 4a,b. General procedure
(S)-Naproxen chloride 1,12 N-phthaloyl-(S)-leucyl chloride 2;5e
N-tosyl-(S)-prolyl chloride 3, racemic 3,4-dihydro-3-methyl-2H-
[1,4]benzothiazine 4a, (3S,20S)-3,4-dihydro-3-methyl-4-(N0-tos-
ylprolyl)-2H-[1,4]-benzothiazine (S,S)-7, and (3R,20S)-3,4-dihydro-
3-methyl-4-(N0-tosylprolyl)-2H-[1,4]-benzothiazine (R,S)-75g were
obtained as described in the literature. Other reagents are com-
mercially available.
A solution of the appropriate acyl chloride (0.15 mmol) in an
appropriate solvent (1.5 mL) was added to a solution of amine 4a
or 4b (0.30 mmol) in the same solvent (1.5 mL) at specified tem-
perature. The reaction mixture was kept at the appropriate tem-
perature for 6 h, then washed with 4 M HCl (2 ꢁ 3 mL), saturated
NaCl (3 ꢁ 3 mL), 5% NaHCO3 (3 mL) and water (2 ꢁ 3 mL); in the
case of the kinetic resolution in MeCN, the reaction mixture was
diluted with 5 mL of EtOAc prior to work-up.
Work-up procedure for the kinetic resolution of amine 4a: (i)
the organic layers were separated, dried over MgSO4, and evapo-
rated under reduced pressure to give a mixture of diastereoiso-
meric amides 5a (6a or 7), which was then analyzed by HPLC;
(ii) acidic washings were collected and alkalized with Na2CO3 up
to pH 8–9 and extracted with CHCl3 (2 ꢁ 3 mL); the organic layers
were separated, dried over MgSO4, and evaporated under reduced
pressure to give the unreacted amine 4a.
Work-up procedure for kinetic resolution of amine 4b: the
organic layers were separated, dried over MgSO4, and evaporated
under reduced pressure; the residue was subjected to flash column
chromatography (10–30% hexane in EtOAc as an eluent) to give
unreacted amine 4b which was analyzed by chiral HPLC, and a
mixture of diastereoisomeric amides 5b or 6b that was analyzed
by HPLC.
The solvents were purified according to standard methods.13
Flash column chromatography was performed using Silica gel 60
(230–400 mesh) (Alfa Aesar, UK). Melting points were obtained
on a SMP3 apparatus (Barloworld Scientific, UK) and are uncor-
rected. Optical rotations were measured on a Perkin Elmer M341
polarimeter. The 1H and 13C NMR spectra were recorded on Bruker
Avance 500 spectrometer operating at frequencies 500 MHz for 1H
and 126 MHz for 13C with TMS as internal reference. The NMR
spectra of amides 5a,b, 6a,b, 8a,b, and 10 were recorded in
DMSO-d6 at 100 °C; the NMR spectra of amines 4a,b and 9a,b
were recorded in CDCl3 at ambient temperature. Elemental
analysis was performed using Perkin Elmer 2400 II analyzer.
Analytical HPLC of amides 5a,b and 6a,b was performed on an
Agilent 1100 instrument using a Phenomenex Luna C18(2) column
(250 ꢁ 4.6 mm,
5 lm) (Phenomenex Inc., USA), detection at
230 nm, 0.8 mL/min flow rate. Analytical HPLC of amide 7 was per-
formed on a Knauer Smartline-1100 instrument using a ReproSil
100 Si column (250 ꢁ 4.6 mm, 5
lm) (Dr. Maisch GmbH, Ger-
many), detection at 220 nm, 1 mL/min flow rate. Analytical HPLC
of amines 4a,b and 9a,b was performed on a Knauer Smartline-
1100 instrument using a Chiralcel OD-H column (250 ꢁ 4.6 mm)
(Daicel Corp., Japan), detection at 220 nm, 1 mL/min flow rate.
The HRMS spectra were registered on 1200 Infinity (Agilent
Technologies) instrument using 6540 Accurate-Mass Q-TOF (Agi-
lent Technologies) detector operating in positive ion mode with
ESI probe installed at N2 flow rate 10 L/min, nebulizer pressure
40 psi. The probe voltage was set to 3.5 kV.
Crystallographic data for compounds (S,S)-6a, (S,S)-6b, (R,S)-7,
and (R,S)-10 have been deposited with the Cambridge Crystallo-
graphic Data Centre (CCDC Nos. 979743, 979744, 1035103, and
979745) Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: (+44) 1223 336033; or e-mail: deposit@ccdc.cam.ac.uk].
4.4. Diastereoisomers of 3,4-dihydro-3-methyl-4-[20-(600-meth-
oxynaphth-200-yl)propionyl]-2H-[1,4]benzothiazine 5a
A solution of (S)-naproxen chloride 1 (0.77 g, 3.11 mmol) in tol-
uene (42 mL) was added to a solution of amine 4a (1.03 g,
6.22 mmol) in toluene (40 mL) at +20 °C. The reaction mixture
was kept at +20 °C for 24 h, then successively washed with 4 M
HCl (2 ꢁ 15 mL), saturated NaCl (3 ꢁ 20 mL), 5% aqueous NaHCO3
(20 mL), water (2 ꢁ 20 mL), dried over MgSO4 and evaporated. Dia-
stereoisomeric mixture 5a and amide (S,S)-5a (slow eluting diaste-
reoisomer) were isolated by flash column chromatography using a
9:1 hexane–EtOAc mixture as an eluent.
4.4.1. (3S,20S)-3,4-Dihydro-3-methyl-4-[20-(600-methoxynaphth-
200-yl)propionyl]-2H-[1,4]benzothiazine (S,S)-5a
4.2. (3RS)-3,4-Dihydro-3-phenyl-2H-[1,4]benzothiazine 4b
Yield 0.65 g (55%). Colorless oil. [
De >99.8%; HPLC (Phenomenex Luna C18(2), MeCN–H2O 7:3):
a]
20 = +35.7 (c 1.07, CHCl3).
D
s
A solution of 2-aminothiophenol (5.56 g, 44.38 mmol) and chlo-
roacetophenone (6.86 g, 44.38 mmol) in Et2O (90 mL) was stirred
at room temperature for 24 h in the dark, after which the precipi-
tate was filtered off. The filtrate was successively washed with 1 M
NaOH (2 ꢁ 40 mL) and water (2 ꢁ 40 mL), dried over Na2SO4 and
evaporated to dryness. The residue and the precipitate were com-
bined and dissolved in a 1:1 MeOH–AcOH mixture (120 mL); next
NaBH4 (10.49 g, 277.38 mmol) was added in several portions to the
reaction mixture under stirring at 0 °C. The suspension was stirred
at ambient temperature for 2 days then concentrated to half-vol-
ume under reduced pressure and poured into cold water
(300 mL). The aqueous solution was alkalized with Na2CO3 (to
pH 8–9) and extracted with CH2Cl2 (4 ꢁ 60 mL). The organic layers
18.3 min. 1H NMR (DMSO-d6, 100 °C): d 0.92 (d, 3H, Me-3,
J = 6.7 Hz), 1.46 (d, 3H, Me-20, J = 6.8 Hz), 2.64 (dd, 1H, H-2B,
J = 12.2, 4.4 Hz), 3.12 (dd, 1H, H-2A, J = 12.2, 5.9 Hz), 3.84 (s, 3H,
OMe), 4.32 (q, 1H, H-20, J = 6.8 Hz), 5.14 (qdd, 1H, H-3, J = 6.7, 5.9,
4.4 Hz), 6.96 (dd, 1H, H-700, J = 8.9, 1.6 Hz), 7.04 (dd, 1H, H-8,
J = 7.8, 1.4 Hz), 7.07 (dd, 1H, H-300, J = 8.7, 2.5 Hz), 7.12 (td, 1H, H-
7, J = 7.6, 1.4 Hz), 7.15–7.17 (m, 2H, H-100 and H-500), 7.22 (td, 1H,
H-6, J = 7.6, 1.4 Hz), 7.39 (dd, 1H, H-5, J = 8.0, 1.4 Hz), 7.55 (d, 1H,
H-400, J = 8.7 Hz), 7.56 (d, 1H, H-800, J = 8.9 Hz). 13C NMR (DMSO-
d6, 100 °C): d 16.61, 18.30, 33.60, 41.69, 45.03, 54.72, 105.79,
124.46, 124.70, 125.12, 125.68, 126.00, 126.40, 127.98, 128.03,
128.36, 130.54, 132.58, 134.51, 135.50, 156.68, 172.29. Anal. Calcd

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 26 (2015) 186–194
191
for C23H23NO2S: C, 73.18; H, 6.14; N, 3.71; S, 8.49. Found: C, 73.36;
H, 6.22; N, 3.66; S, 8.34.
4.6. (3S,20S)-3,4-Dihydro-3-methyl-4-(N0-phthaloylleucyl)-2H-
[1,4]benzothiazine (S,S)-6a
solution of N-phthaloyl-(S)-leucyl chloride
A
2
(2.02 g,
4.4.2. 3,4-Dihydro-3-methyl-4-[20-(600-methoxynaphth-200-yl)pro
pionyl]-2H-[1,4]benzothiazine 5a (diastereoisomeric mixture)
Yield 0.36 g (31%). Colorless oil. S,S/R,S 80:20, HPLC (Phenome-
nex Luna C18(2), MeCN–H2O 7:3): s(S,S)-5a 18.3 min, s(R,S)-5a
24.3 min. 1H NMR (DMSO-d6, 100 °C): d 0.92 (d, 2.4H, Me-3 (S,S),
J = 6.7 Hz), 1.01 (d, 0.6H, Me-3 (R,S), J = 6.7 Hz), 1.32 (d, 0.6H, Me-
20 (R,S), J = 6.8 Hz), 1.46 (d, 2.4H, Me-20 (S,S), J = 6.8 Hz), 2.65 (dd,
0.8H, H-2B (S,S), J = 12.3, 4.4 Hz), 2.74 (dd, 0.2H, H-2B (R,S),
J = 12.2, 4.5 Hz), 3.12 (dd, 0.8H, H-2A (S,S), J = 12.3, 5.9 Hz), 3.21
(dd, 0.2H, H-2A (R,S), J = 12.2, 6.0 Hz), 3.84 (s, 2.4H, OMe (S,S)),
3.88 (s, 0.6H, OMe (R,S)), 4.04 (q, 0.2H, H-20 (R,S), J = 6.8 Hz), 4.32
(q, 0.8H, H-20 (S,S), J = 6.8 Hz), 5.14 (qdd, 0.8H, H-3 (S,S), J = 6.7,
5.9, 4.4 Hz), 5.22 (qdd, 0.2H, H-3 (R,S), J = 6.7, 6.0, 4.5 Hz), 6.95-
7.78 (m, 10H, arom. H (S,S) + (R,S)). Anal. Calcd for C23H23NO2S: C,
73.18; H, 6.14; N, 3.71; S, 8.49. Found: C, 73.03; H, 6.35; N, 3.67;
S, 8.53.
7.22 mmol) in CH2Cl2 (70 mL) was added to a solution of amine
4a (2.39 g, 14.44 mmol) in CH2Cl2 (74 mL) at +20 °C. The reaction
mixture was kept at +20 °C for 6 h, then successively washed with
4 M HCl (3 ꢁ 50 mL), saturated NaCl (4 ꢁ 70 mL), 5% aqueous
NaHCO3 (2 ꢁ 70 mL) and water (2 ꢁ 70 mL), dried over MgSO4
and evaporated. The residue was recrystallized from hexane–
EtOAc. Yield 1.36 g (46%). Colorless crystalline powder, mp 177–
178 °C (hexane–EtOAc). [
(Phenomenex Luna C18; MeCN–H2O 9:1):
a]
20 = +382 (c 0.94, CHCl3). De >99%; HPLC
D
s
8.1 min; 1H NMR
(DMSO-d6, 100 °C): d 0.33 (d, 3H, Me-40, J = 6.6 Hz), 0.63 (d, 3H,
Me-40, J = 6.6 Hz), 0.96 (ddd, 1H, H-30B, J = 13.9, 9.8, 3.7 Hz), 1.03
(d, 3H, Me-3, J = 6.6 Hz), 1.28 (m, 1H, H-40), 2.56 (ddd, 1H, H-30A,
J = 13.9, 12.0, 3.9 Hz,), 2.76 (dd, 1H, H-2B, J = 12.5, 5.4 Hz,), 3.39
(dd, 1H, H-2A, J = 12.5, 6.5 Hz), 5.08 (qdd, 1H, H-3, J = 6.6, 6.5,
5.4 Hz), 5.39 (dd, 1H, H-20, J = 12.0, 3.7 Hz), 7.29 (td, 1H, H-7,
J = 7.5, 1.5 Hz), 7.32 (td, 1H, H-6, J = 7.5, 1.7 Hz), 7.42 (dd, 1H, H-
8, J = 7.5, 1.7 Hz), 7.51 (dd, 1H, H-5, J = 7.5, 1.5 Hz), 7.86 (m, 4H,
Phth). 13C NMR (DMSO-d6, 100 °C): d 17.03, 19.51, 21.87, 24.17,
33.78, 34.85, 47.60, 51.91, 122.49 (2C), 125.51, 126.66, 127.28,
127.53, 130.88 (2C), 131.94, 134.03 (2C), 134.41, 167.66 (2C),
168.34. Anal. Calcd for C23H24N2O3S: C, 67.62; H, 5.92; N, 6.86; S,
7.85. Found: C, 67.50; H, 5.85; N, 7.13; S, 7.94.
4.5. Diastereoisomers of 3,4-dihydro-3-phenyl-4-[20-(600-meth-
oxynaphth-200-yl)propionyl]-2H-[1,4]benzothiazine 5b
A solution of (S)-naproxen chloride 1 (0.22 g, 0.88 mmol) in tol-
uene (9 mL) was added to
a solution of amine 4b (0.40 g,
1.76 mmol) in toluene (9 mL) at +20 °C. The reaction mixture was
kept at +20 °C for 24 h, then successively washed with 5% aqueous
NaHCO3 (2 ꢁ 10 mL) and water (2 ꢁ 10 mL), dried over MgSO4, and
evaporated. Amides (R,S)-5b (fast eluting diastereoisomer) and
(S,S)-5b (slow eluting diastereoisomer) were isolated by flash col-
umn chromatography using a 9:1 hexane–EtOAc mixture as an
eluent.
4.7. (3R,20S)-3,4-Dihydro-3-methyl-4-(N0-phthaloylleucyl)-2H-
[1,4]benzothiazine [(R,S)-6a]
The mother liquid after recrystallization of amide (S,S)-6a (see
above) was evaporated to dryness, and the residue was purified
by flash column chromatography (eluent benzene–EtOAc) to give
amide (R,S)-6a as fast eluting diastereoisomer. Yield 0.17 g (5.7%).
Amorphous solid. [
(Phenomenex Luna C18; MeCN–H2O 9:1):
a
]
20 = ꢀ215 (c 0.67, CHCl3). De 94.6%; HPLC
D
4.5.1. (3R,20S)-3,4-Dihydro-3-phenyl-4-[20-(600-methoxynaphth-
200-yl)propionyl]-2H-[1,4]benzothiazine (R,S)-5b
s
6.2 min. 1H NMR
(DMSO-d6, 100 °C): d 0.85 (d, 3H, Me-3, J = 6.6 Hz), 0.91 (d, 3H,
Me-40, J = 6.6 Hz,), 0.92 (d, 3H, Me-40, J = 6.6 Hz,), 1.44 (m, 1H, H-
40), 1.79 (ddd, 1H, H-30B, J = 14.1, 9.0, 5.2 Hz), 2.05 (ddd, 1H, H-
30A, J = 14.1, 8.5, 5.3 Hz), 2.69 (dd, 1H, H-2B, J = 12.0, 4.0 Hz), 3.30
(dd, 1H, H-2A, J = 12.0, 5.9 Hz), 5.11 (qdd, 1H, H-3, J = 6.6, 5.9,
4.0 Hz), 5.13 (dd, 1H, H-20, J = 9.0, 5.3 Hz), 6.71 (dd, 1H, H-8,
J = 7.8, 1.5 Hz), 6.88 (td, 1H, H-6, J = 7.7, 1.5 Hz), 7.04 (td, 1H, H-7,
J = 7.7, 1.5 Hz), 7.25 (dd, 1H, H-5, J = 7.9, 1.5 Hz), 7.62 (m, 2H, Phth),
7.73 (m, 2H, Phth). 13C NMR (DMSO-d6, 100 °C): d 16.43, 21.38,
22.33, 23.75, 33.58, 38.10, 45.43, 48.88, 122.13 (2C), 125.41,
125.52, 125.95, 126.44, 129.10, 130.47 (2C), 133.52, 133.56 (2C),
165.35 (2C), 167.28. Anal. Calcd for C23H24N2O3S: C, 67.62; H,
5.92; N, 6.86; S, 7.85. Found: C, 67.77; H, 6.05; N, 6.60; S, 7.66.
Yield 0.019 g (5%). Pale yellow oil. [
a
]
20 = ꢀ298 (c 1.4, CHCl3).
D
De >99.8%; HPLC (Phenomenex Luna C18(2), MeCN–H2O 8:2):
s
1
13.7 min; H NMR (DMSO-d6, 100 °C): d 1.33 (d, 3H, Me-20,
J = 6.9 Hz), 3.14 (dd, 1H, H-2B, J = 13.0, 7.1 Hz), 3.61 (dd, 1H, H-
2A, J = 13.0, 6.8 Hz), 3.88 (s, 3H, OMe), 4.04 (q, 1H, H-20,
J = 6.9 Hz), 6.18 (m, 1H, H-3), 7.06–7.29 (m, 10H, arom.), 7.33 (m,
1H, arom.), 7.42 (dd, 1H, arom., J = 8.5, 1.8 Hz), 7.69 m (1H, arom.),
7.76 m (2H, arom.). 13C NMR (DMSO-d6, 100 °C): d 20.38, 34.43,
42.07, 54.81, 56.22, 105.95, 117.92, 124.93, 125.18, 125.72 (2C),
125.79, 125.96, 126.46 (2C), 127.69 (2C), 127.84, 128.07, 128.16,
128.55, 131.99, 132.78, 136.44, 136.66, 139.24, 156.93, 172.96.
Anal. Calcd for C28H25NO2S: C, 76.51; H, 5.73; N, 3.19; S, 7.29.
Found: C, 76.75; H, 5.91; N, 3.02; S, 7.12.
4.8. (3S,20S)-3,4-Dihydro-3-phenyl-4-(N0-phthaloylleucyl)-2H-
[1,4]benzothiazine (S,S)-6b
4.5.2. (3S,20S)-3,4-Dihydro-3-phenyl-4-[20-(600-methoxynaphth-
200-yl)propionyl]-2H-[1,4]benzothiazine (S,S)-5b
A solution of acyl chloride 2 (0.44 g, 1.57 mmol) in MeCN
(16 mL) was added to a solution of amine 4b (0.71 g, 3.14 mmol)
in MeCN (16 mL) at +20 °C. The reaction mixture was kept at
+20 °C for 72 h, then diluted with EtOAc (25 mL) and successively
washed with 5% aqueous NaHCO3 (2 ꢁ 25 mL) and water
(2 ꢁ 25 mL), dried over Na2SO4, and evaporated. The residue was
subjected to flash column chromatography (10–30% EtOAc in hex-
ane) to separate crude amide (S,S)-6b which was then further puri-
fied by recrystallization from hexane–EtOAc. Yield 0.30 g (41%).
Yield 0.082 g (21%). Pale yellow oil. [
De >99.8%; HPLC (Phenomenex Luna C18(2), MeCN–H2O 8:2):
a]
20 = +132 (c 1.0, CHCl3).
D
s
1
10.7 min. H NMR (DMSO-d6, 100 °C): d 1.48 (d, 3H, Me-20,
J = 6.9 Hz), 3.03 (dd, 1H, H-2B, J = 13.0, 7.0 Hz), 3.41 (dd, 1H, H-
2A, J = 13.0, 6.7 Hz), 3.84 (s, 3H, OMe), 4.38 (q, 1H, H-20,
J = 6.9 Hz), 6.07 (m, 1H, H-3), 6.94 (dd, 1H, arom., J = 8.4, 1.7 Hz),
7.02 (dd, 1H, arom., J = 7.8, 1.4 Hz), 7.05–7.26 (m, 10H, arom.),
7.49 m (1H, arom.), 7.54 m (2H, arom.). 13C NMR (DMSO-d6,
100 °C):
d
18.33, 33.99, 41.70, 54.72, 55.96, 105.80, 117.63,
Colorless powder, mp 184–185 °C (hexane–EtOAc). [
1.0, CHCl3). De >99%; HPLC (Phenomenex Luna C18; MeCN–H2O
a]
20 = +476 (c
D
124.78, 125.16, 125.27, 125.72, 125.87 (2C), 125.93, 126.32,
127.37, 127.57 (2C), 127.92, 128.31, 128.36, 132.55, 132.60,
135.33, 136.57, 139.24, 156.67, 173.05. Anal. Calcd for C28H25NO2S:
C, 76.51; H, 5.73; N, 3.19; S, 7.29. Found: C, 76.31; H, 6.01; N, 3.06;
S, 7.12.
7:3):
s
26.6 min. 1H NMR (DMSO-d6, 100 °C): d 0.31 (d, 3H, Me-
40, J = 6.6 Hz), 0.63 (d, 3H, Me-40, J = 6.7 Hz), 0.99 (ddd, 1H, H-30B,
J = 13.8, 9.9, 3.5 Hz), 1.22–1.32 (m, 1H, H-40), 2.60 (ddd, 1H, H-
30A, J = 13.8, 12.0, 3.9 Hz), 3.09 (dd, 1H, H-2B, J = 13.2, 8.0 Hz,),

192
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 26 (2015) 186–194
3.70 (dd, 1H, H-2A, J = 13.2, 7.2 Hz), 5.45 (dd, 1H, H-20, J = 12.0,
3.5 Hz), 5.95 (dd, 1H, H-3, J = 8.0, 7.2 Hz), 7.14–7.18 (m, 1H, Ph),
7.21–7.25 (m, 4H, Ph), 7.26–7.30 (m, 1H, H-7), 7.34–7.38 (m, 1H,
H-6), 7.46 (dd, 1H, H-8, J = 7.7, 1.5 Hz), 7.60 (d, 1H, H-5,
J = 7.5 Hz), 7.83–7.87 (m, 4H, Phth). 13C NMR (DMSO-d6, 100 °C):
d 19.49, 21.86, 24.19, 33.84, 35.43, 51.96, 58.43, 122.51 (2C),
125.71 (2C), 126.30, 126.58, 126.66, 127.48, 127.76 (2C), 128.47,
130.85 (2C), 133.65, 134.04 (2C), 136.38, 139.18, 167.66 (2C),
169.07. Anal. Calcd for C28H26N2O3S: C, 71.46; H, 5.57; N, 5.95; S,
6.81. Found: C, 71.30; H, 5.64; N, 5.81; S, 6.81.
heated at 90–92 °C for 16 h, then concentrated under reduced
pressure to a half-volume and poured into water (100 mL). The
resulting mixture was alkalized with Na2CO3 and extracted with
benzene (3 ꢁ 25 mL). The organic layers were washed with water
(2 ꢁ 25 mL), dried over MgSO4, and evaporated. The residue was
purified by flash column chromatography on silica gel using hex-
ane–benzene 3:7 mixture as an eluent. Yield 0.45 g (85%). Colorless
oil. [
a
]
20 = ꢀ79.0 (c 1.2, CHCl3). Ee 99.4%; HPLC (Chiralcel OD-H;
D
hexane–iPrOH–MeOH 100:1.5:1.5):
s
13.8 min. 1H NMR (DMSO-
d6): d 1.21 (d, 3H, Me-3, J = 6.3 Hz), 2.67 (dd, 1H, H-2B, J = 12.3,
7.9 Hz), 2.90 (ddd, 1H, H-2A, J = 12.3, 2.8, 1.0 Hz), 3.54 (dqdd, 1H,
H-3, J = 7.9, 6.3, 2.8, 1.7 Hz), 5.91 (s, 1H, NH), 6.44 (ddd, 1H, H-7,
J = 7.7, 7.2, 1.3 Hz), 6.52 (dd, 1H, H-5, J = 8.1, 1.3 Hz), 6.80 (ddd,
1H, H-6, J = 8.1, 7.2, 1.4 Hz), 6.84 (dd, 1H, H-8, J = 7.7, 1.4 Hz). 13C
NMR (DMSO-d6): d 21.83 (Me), 31.13 (C-2), 46.03 (C-3), 113.48
(C-8a), 114.68 (C-5), 116.14 (C-7), 125.18 and 126.69 (C-6 and C-
8), 142.60 (C-4a). HRMS (ESI) calcd for C9H12NS [M+H]+:
166.0685; found: 166.0686.
4.9. 3,4-Dihydro-3-phenyl-4-(N0-phthaloyl-(S)-leucyl)-2H-
[1,4]benzothiazine 6b (diastereomeric mixture)
The mother liquor, after recrystallization of amide (S,S)-6b (see
above), was evaporated to dryness, and the residue was purified by
flash column chromatography (eluent hexane–EtOAc 9:1). Yield
0.17 g (23%). Amorphous yellowish solid. R,S/S,S 65:35; HPLC (Phe-
nomenex Luna C18; MeCN–H2O 7:3): s(R,S)-6b 15.7 min, s(S,S)-6b
1
26.6 min. H NMR (DMSO-d6, 100 °C): d 0.31 (d, 1.05H, Me-40
(S,S), J = 6.6 Hz), 0.63 (d, 1.05H, Me-40 (S,S), J = 6.7 Hz), 0.92 (d,
1.95H, Me-40 (R,S), J = 6.6 Hz), 0.99 (ddd, 0.35H, H-30B (S,S),
J = 13.8, 9.9, 3.5 Hz), 1.22–1.32 (m, 0.35H, H-40 (S,S)), 1.41–1.49
(m, 0.65H, H-40 (R,S)), 1.84 (ddd, 0.65H, H-30B (R,S), J = 14.1, 9.2,
5.1 Hz), 2.07 (ddd, 0.65H, H-30A (R,S), J = 14.1, 8.7, 5.2 Hz), 2.60
(ddd, 0.35H, H-30A (S,S), J = 13.8, 12.0, 3.9 Hz), 3.07–3.13 (m, 1H,
H-2B), 3.58 (dd, 0.65H, H-2A (R,S), J = 12.9, 6.5 Hz), 3.70 (dd,
0.35H, H-2A (S,S), J = 13.2, 7.2 Hz), 5.25 (dd, 0.65H, H-20 (R,S),
J = 9.2, 5.1 Hz), 5.45 (dd, 0.35H, H-20 (S,S), J = 12.0, 3.5 Hz), 5.95–
6.00 (m, 1H, H-3), 6.68 (dd, 0.65H, H-8 (R,S), J = 7.8, 1.3 Hz), 6.83
(ddd, 0.65H, H-6 (R,S), J = 7.6, 7.6, 1.3 Hz), 7.02–7.09 (m, 1.3H, H-
7 (R,S) and Ph (R,S)), 7.12–7.17 (m, 1.65H, Ph), 7.20–7.25 (m,
2.7H, Ph), 7.26–7.44 (m, 1.35H, H-5 (R,S), H-6 (S,S) and H-7 (S,S)),
7.46 (dd, 0.35H, H-8 (S,S), J = 7.7, 1.5 Hz), 7.59–7.63 (m, 1.65H, H-
5 (S,S) and Phth (R,S)), 7.70–7.74 (m, 1.3H, Phth (R,S)), 7.83–7.87
(m, 1.4H, Phth (S,S)); Anal. Calcd for C28H26N2O3S: C, 71.46; H,
5.57; N, 5.95; S, 6.81. Found: C, 71.38; H, 5.69; N, 5.93; S, 6.80.
4.12. (3R)-3,4-Dihydro-3-methyl-2H-[1,4]benzothiazine (R)-4a
A solution of amide (R,S)-7 (1.06 g, 2.54 mmol) in a mixture of
AcOH (10 mL) and concentrated HCl (10 mL) was heated at 95–
100 °C for 28 h, then concentrated under reduced pressure to a
half-volume and poured into water (100 mL). The resulting mix-
ture was alkalized with Na2CO3 and extracted with benzene
(3 ꢁ 15 mL). The organic layers were washed with water
(2 ꢁ 20 mL), dried over MgSO4, and evaporated. The residue was
purified by flash column chromatography on silica gel using hex-
ane–benzene 3:7 mixture as an eluent. Yield 0.30 g (70%). Colorless
oil. [
hexane–iPrOH–MeOH 100:1.5:1.5):
a]
20 = +78.7 (c 1.2, CHCl3). Ee 99.2%; HPLC (Chiralcel OD-H;
D
s
12.6 min. 1H and 13C NMR
spectra were identical to those of (S)-4a. HRMS (ESI) calcd for
C9H12NS [M+H]+: 166.0685; found: 166.0686.
4.13. (3S)-3,4-Dihydro-3-phenyl-2H-[1,4]benzothiazine (S)-4b
4.10. Diastereoisomers of 3,4-dihydro-3-methyl-4-(N0-
tosylprolyl)-2H-[1,4]benzothiazine 7
The title compound was obtained as described for amine (S)-4a
(Method A) starting from amide (S,S)-5b (97 mg, 0.22 mmol), AcOH
(3 mL), and concentrated HCl (3 mL). Yield 30.6 mg (61%). Yellow-
A solution of N-tosyl-(S)-prolyl chloride 3 (2.55 g, 8.87 mmol) in
toluene (85 mL) was added to a solution of amine 4a (2.93 g,
17.74 mmol) in toluene (90 mL) at +20 °C. The reaction mixture
was kept at +20 °C for 24 h, then the organic solution was succes-
sively washed with 4 M HCl (3 ꢁ 70 mL), saturated NaCl
(4 ꢁ 100 mL), 5% NaHCO3 (2 ꢁ 100 mL), water (2 ꢁ 100 mL), dried
over MgSO4, and evaporated. Amides (S,S)-7 (fast eluting diastereo-
isomer) and (R,S)-7 (slow eluting diastereoisomer) were isolated by
flash column chromatography using a hexane–EtOAc mixture as an
eluent. The analytical data for amides (S,S)-7 and (R,S)-7 were pub-
lished previously.5g
ish oil. [
hexane–iPrOH 5:1):
a]
20 = +55.9 (c 1.0, CHCl3). Ee 92.6%, HPLC (Chiralcel OD-H;
D
s
15.0 min. Anal. Calcd for C14H13NS: C, 73.97;
H, 5.76; N, 6.16; S, 14.11. Found: C, 73.79; H, 5.94; N, 5.87; S, 14.22.
NMR spectra were identical to those of racemic compound 4b.
4.14. Oxidation of racemic 3-substituted 3,4-dihydro-2H-
[1,4]benzothiazines
30% aqueous H2O2 solution (2.83 mL, 24.8 mmol) was added to
a solution of amine 4a or 4b (6.2 mmol) in AcOH (18 mL). The reac-
tion mixture was refluxed for 40 min, then cooled, concentrated
under reduced pressure to a volume of 7 mL and poured into water
(100 mL). The solution was alkalized with Na2CO3 and extracted
with CH2Cl2 (3 ꢁ 15 mL). The organic layers were washed with
water (2 ꢁ 20 mL), dried over MgSO4, and evaporated. The product
was purified by flash column chromatography using a benzene–
EtOAc mixture as an eluent.
4.11. (3S)-3,4-Dihydro-3-methyl-2H-[1,4]benzothiazine [(S)-4a]
Method A: A solution of amide (S,S)-5a (0.276 g, 0.73 mmol) in a
mixture of AcOH (5 mL) and concentrated HCl (5 mL) was heated
at 92–96 °C for 10 h, then concentrated under reduced pressure to
half-volume and poured into water (50 mL). The precipitate was fil-
tered off and washed with water (2 mL). The combined filtrate was
alkalized with Na2CO3 to pH 8–9 and then extracted with benzene
(3 ꢁ 3 mL). The organic layers were washed with water
(2 ꢁ 5 mL), dried over MgSO4, and evaporated. The residue was puri-
fied by flash column chromatography on silica gel using hexane–
benzene 3:7 mixture as an eluent. Yield 0.09 g (75%), colorless oil.
Method B: A solution of amide (S,S)-6a (1.30 g, 3.21 mmol) in a
mixture of AcOH (12 mL) and concentrated HCl (12 mL) was
4.14.1. (3RS)-3,4-Dihydro-3-methyl-2H-[1,4]benzothiazine-1,1-
dioxide (RS)-9a
Yield 0.22 g (18%). Colorless solid, mp 159 °C. HPLC (Chiralcel
OD-H; hexane–iPrOH 5:1): s(R)-9a 19.1 min, s(S)-9a 22.5 min. 1H
NMR (DMSO-d6): d 1.34 (d, 3H, Me-3, J = 6.5 Hz), 3.12 (dd, 1H, H-
2B, J = 13.4, 12.6 Hz), 3.46 (ddd, 1H, H-2A, J = 13.4, 2.4, 1.2 Hz),
3.90 (dqd, 1H, H-3, J = 12.6, 6.5, 2.4 Hz), 6.68 (ddd, 1H, H-7,
J = 8.0, 7.0, 1.0 Hz), 6.78 (dd, 1H, H-5, J = 8.5, 1.0 Hz), 6.92 (s, 1H,

D. A. Gruzdev et al. / Tetrahedron: Asymmetry 26 (2015) 186–194
193
NH), 7.27 (ddd, 1H, H-6, J = 8.5, 7.0, 1.5 Hz), 7.48 (dd, 1H, H-8,
J = 8.0, 1.5 Hz). 13C NMR (DMSO-d6): d 20.16 (Me), 46.53 (C-3),
53.30 (C-2), 115.73 and 115.82 (C-6 and C-7), 120.58 (C-8a),
C28H26N2O5S: C, 66.91; H, 5.21; N, 5.57; S, 6.38. Found: C, 66.95;
H, 5.44; N, 5.24; S, 6.30.
123.04 (C-8), 133.23 (C-6), 144.56 (C-4a). Anal. Calcd for C9H11
-
4.15.3. (3R,20S)-3,4-Dihydro-3-methyl-4-(N0-tosylprolyl)-2H-[1,4]
benzothiazine-1,1-dioxide (R,S)-10
NO2S: C, 54.80; H, 5.62; N, 7.10; S, 16.26. Found: C, 54.81; H,
5.46; N, 6.97; S, 16.08.
Yield 0.54 g (78%) after flash column chromatography (eluent
benzene–EtOAc). Yellowish solid, mp 182–184 °C (dec).
4.14.2. (3RS)-3,4-Dihydro-3-phenyl-2H-[1,4]benzothiazine-1,1-
dioxide (RS)-9b
[
a
]
20 = ꢀ294 (c 1.1, CHCl3); 1H NMR (DMSO-d6, 100 °C): d 1.30 (d,
D
3H, Me-3, J = 6.9 Hz), 1.64 (m, 1H, H-40B), 1.98 (m, 1H, H-40A),
2.08–2.13 (m, 2H, 2 ꢁ H-30), 2.36 (s, 3H, Me-Tos), 3.30 (ddd, 1H,
H-50B, J = 9.8, 7.3, 6.6 Hz), 3.43 (ddd, 1H, H-50A, J = 9.8, 7.2,
5.7 Hz), 3.45 (dd, 1H, H-2B, J = 14.1, 5.2 Hz), 3.96 (dd, 1H, H-2A,
J = 14.1, 6.2 Hz), 4.38 (t, 1H, H-20, J = 6.5 Hz), 5.28 (qdd, 1H, H-3,
J = 6.9, 6.2, 5.2 Hz), 7.26 (d, 2H, Hm-Tos, J = 8.4 Hz), 7.29 (dd, 1H,
H-5, J = 7.9, 1.0 Hz), 7.40 (d, 2H, Ho-Tos, J = 8.4 Hz), 7.57 (td, 1H,
H-7, J = 7.7, 1.0 Hz), 7.65 (ddd, 1H, H-6, J = 7.9, 7.6, 1.6 Hz), 7.91
(dd, 1H, H-8, J = 7.9, 1.6 Hz). 13C NMR (DMSO-d6, 100 °C): d 17.28,
20.25, 23.76, 30.62, 47.44, 48.49, 56.71, 57.38, 123.47, 126.34
(2C), 126.81, 127.09, 128.97 (2C), 132.51, 133.57, 134.48, 134.52,
142.67, 170.39. Anal. Calcd for C21H24N2O5S2: C, 56.23; H, 5.39;
N, 6.25; S, 14.30. Found: C, 56.36; H, 5.64; N, 6.28; S, 14.22.
Yield 0.39 g (24%). Colorless solid, mp 134 °C (lit. mp 184 °C,15a
184–186 °C15b). HPLC (Chiralcel OD-H, hexane–iPrOH 2:1): s(R)-9b
9.3 min (R), s(S)-9b 14.4 (S). 1H NMR (CDCl3, 25 °C): d 3.31–3.34
(m, 1H, H-2B), 3.47–3.52 (m, 1H, H-2A), 4.51 (s, 1H, NH), 5.16
(dd, 1H, H-3, J = 12.7, 2.4 Hz), 6.68 (m, 1H, H-5), 6.88 (m, 1H, H-
7), 7.33 (ddd, 1H, H-6, J = 7.3, 7.3, 1.3 Hz), 7.40–7.48 (m, 5H, Ph),
7.78 (dd, 1H, H-8, J = 8.0, 1.3 Hz). 13C NMR (CDCl3, 25 °C): d
54.99, 56.11, 116.17, 118.39, 122.01, 124.07, 126.84 (2C), 129.37
(3C), 133.87, 138.84, 143.29. Anal. Calcd for C14H13NO2S: C,
64.84; H, 5.05; N, 5.40; S, 12.36. Found: C, 64.77; H, 4.92; N,
5.32; S, 12.56.
4.15. Oxidation of amides (S,S)-6a,b and (R,S)-7
4.16. (3S)-3,4-Dihydro-3-methyl-2H-[1,4]benzothiazine-1,1-
dioxide (S)-9a
30% aqueous H2O2 (0.6 mL, 5.3 mmol) was added to a solution
of amide (S,S)-6a, (S,S)-6b, or ,(R,S)-7 (1.54 mmol) in AcOH
(3 mL). The reaction mixture was refluxed for 20 min, then cooled
to room temperature, and poured into water (70 mL). The solution
was neutralized with Na2CO3 and extracted with CHCl3
(3 ꢁ 15 mL). Organic layers were washed with water (2 ꢁ 20 mL),
dried over MgSO4, and evaporated to give amides (S,S)-8a, (S,S)-
8b, or (R,S)-10, respectively.
A solution of amide (S,S)-8a (0.575 g, 1.31 mmol) in MeOH
(30 mL) was added to a solution of sodium methoxide (4.78 mmol)
in MeOH (30 mL). The reaction mixture was stirred for 4 h at room
temperature, and then poured into 0.5 N NaOH (200 mL). The
resulting solution was extracted with CHCl3 (3 ꢁ 25 mL). Organic
layers were washed with water (3 ꢁ 50 mL), dried over MgSO4,
and evaporated to give sulfone (S)-9a (0.243 g, 94%) as a colorless
4.15.1. (3S,20S)-3,4-Dihydro-3-methyl-4-(N0-phthaloylleucyl)-2H-
[1,4]benzothiazine-1,1-dioxide (S,S)-8a
solid, mp 144–146 °C. [
(Chiralcel OD-H; hexane–iPrOH 5:1):
a
]
20 = ꢀ177 (c 1.1, CHCl3). Ee 99%; HPLC
D
s
22.5 min. 1H and 13C NMR
Yield 0.65 g (96%). Colorless foam. [
a
]
D
20 = +415 (c 1.3, CHCl3). 1H
spectra were identical to those of racemic amine (RS)-9a. HRMS
NMR (DMSO-d6, 100 °C): d 0.32 (d, 3H, Me-40, J = 6.6 Hz), 0.63 (d,
3H, Me-40, J = 6.6 Hz), 1.17 (ddd, 1H, H-30B,, J = 14.2, 9.8, 3.4 Hz),
1.18 (d, 3H, Me-3, J = 6.7 Hz), 1.26 (m, 1H, H-40), 2.54 (ddd, 1H,
H-30A, J = 14.2, 12.0, 3.6 Hz), 3.20 (dd, 1H, H-2B, J = 14.6, 7.4 Hz),
4.04 (dd, 1H, H-2A, J = 14.5, 7.9 Hz), 5.09 (ddq, 1H, H-3, J = 7.9,
7.4, 6.7 Hz), 5.39 (dd, 1H, H-20, J = 12.0, 3.4 Hz), 7.67 (td, 1H, H-7,
J = 7.6, 1.0 Hz), 7.76 (dd, 1H, H-5, J = 8.0, 1.0 Hz), 7.85–7.89 (m,
5H, H-6 and Phth), 7.95 (dd, 1H, H-8, J = 7.7, 1.5 Hz). 13C NMR
(DMSO-d6, 100 °C): d 18.80, 19.50, 21.81, 24.14, 33.70, 48.38,
51.61, 57.05, 122.59 (2C), 124.20, 127.56, 127.79, 130.82 (2C),
133.87, 134.11 (2C), 134.41, 135.43, 167.56 (2C), 168.43. Anal.
Calcd for C23H24N2O5S: C, 62.71; H, 5.49; N, 6.36; S, 7.28. Found:
C, 62.80; H, 5.48; N, 6.42; S, 7.03.
(ESI) calcd for C9H12NO2S [M+H]+: 198.0583; found: 198.0584.
4.17. (3R)-3,4-Dihydro-3-methyl-2H-[1,4]benzothiazine-1,1-
dioxide (R)-9a
A solution of amide (R,S)-10 (0.476 g, 1.06 mmol) in MeOH–
CH2Cl2 5:1 mixture (25 mL) was added to a solution of sodium
methoxide (3.56 mmol) in MeOH (25 mL). The reaction mixture
was stirred for 4 h at room temperature, and then poured into
0.5 M NaOH (200 mL) and the resulting solution was extracted
with CHCl3 (3 ꢁ 25 mL). The organic layers were washed with
water (3 ꢁ 50 mL), dried over MgSO4, and evaporated. The residue
was purified by flash column chromatography using benzene–
EtOAc 8:2 mixture as an eluent. Yield 0.182 g (87%). Colorless solid,
4.15.2. (3S,20S)-3,4-Dihydro-3-phenyl-4-(N0-phthaloylleucyl)-2H-
[1,4]benzothiazine-1,1-dioxide (S,S)-8b
mp 143–146 °C. [
OD-H; hexane–iPrOH 5:1):
a]
20 = +170 (c 1.0, CHCl3). Ee 97%; HPLC (Chiralcel
D
s
19.1 min. 1H and 13C NMR spectra
Obtained starting from amide (S,S)-6b (0.25 g, 0.53 mmol) as
described above. Yield 0.248 g (93%). Colorless solid, mp 123–
were identical to those of racemic amine (RS)-9a. Anal. Calcd for
C9H11NO2S: C, 54.80; H, 5.62; N, 7.10; S, 16.26. Found: C, 55.00;
H, 5.46; N, 6.89; S, 16.30.
125 °C. [a]
20 = +417 (c 0.64, CHCl3). 1H NMR (DMSO-d6, 100 °C): d
D
0.31 (d, 3H, Me-40, J = 6.4 Hz), 0.63 (d, 3H, Me-40, J = 6.5 Hz),
1.16–1.32 (m, 2H, H-30B and H-40), 2.57 (ddd, 1H, H-30A, J = 14.2,
12.0, 3.5 Hz), 3.15 (dd, 1H, H-2B, J = 14.7, 9.2 Hz,), 4.41 (dd, 1H,
H-2A, J = 14.7, 8.0 Hz), 5.43 (dd, 1H, H-20, J = 12.0, 3.4 Hz), 6.03
(m, 1H, H-3), 7.19–7.23 (m, 3H, Ph), 7.25–7.28 (m, 2H, Ph), 7.69
(ddd, 1H, H-7, J = 7.7, 7.6, 1.0 Hz), 7.83–7.85 (m, 5H, H-5 and Phth),
7.91 (ddd, 1H, H-6, J = 7.8, 7.6, 1.4 Hz), 7.99 (dd, 1H, H-8, J = 7.7,
1.4 Hz). 13C NMR (DMSO-d6, 100 °C): d 19.48, 21.79, 24.13, 33.59,
51.67, 55.64, 56.41, 122.59 (2C), 124.41, 125.70 (2C), 127.11,
127.67, 127.84, 128.01 (2C), 130.75 (2C), 134.10 (2C), 134.22,
134.73, 136.38, 138.61, 167.52 (2C), 169.02. Anal. Calcd for
4.18. (3R)-3,4-Dihydro-3-phenyl-2H-[1,4]benzothiazine-1,1-
dioxide (R)-9b
Obtained starting from amide (S,S)-8b (0.20 g, 0.40 mmol) in a
way similar to that described for compound (S)-9a. Yield 0.080 g
(77%). Colorless solid, mp 169–172 °C (subl.). [
a
]
20 = ꢀ54.8 (c 0.6,
D
CHCl3). Ee 82%; HPLC (Chiralcel OD-H, hexane–iPrOH 2:1): s(R)-9b
9.4 min, s(S)-9b 14.5 min. NMR spectra were identical to those of
racemic amine (RS)-9b. Anal. Calcd for C14H13NO2S: C, 64.84; H,
5.05; N, 5.40; S, 12.36. Found: C, 64.46; H, 5.23; N, 5.39; S, 12.43.

194
D. A. Gruzdev et al. / Tetrahedron: Asymmetry 26 (2015) 186–194
5. (a) Krasnov, V. P.; Levit, G. L.; Bukrina, I. M.; Andreeva, I. N.; Sadretdinova, L.
Acknowledgments
Sh.; Korolyova, M. A.; Kodess, M. I.; Charushin, V. N.; Chupakhin, O. N.
Tetrahedron: Asymmetry 2003, 14, 1985–1988; (b) Krasnov, V. P.; Levit, G. L.;
Kodess, M. I.; Charushin, V. N.; Chupakhin, O. N. Tetrahedron: Asymmetry 2004,
15, 859–862; (c) 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; (d) 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; (e) Gruzdev, D.
A.; Levit, G. L.; Kodess, M. I.; Krasnov, V. P. Chem. Heterocycl. Compd. 2012, 48,
748–757; (f) Gruzdev, D. A.; Levit, G. L.; Krasnov, V. P. Tetrahedron: Asymmetry
2012, 23, 1640–1646; (g) Gruzdev, D. A.; Vakarov, S. A.; Levit, G. L.; Krasnov, V.
P. Chem. Heterocycl. Compd. 2014, 49, 1795–1807; (h) Vakarov, S. A.; Gruzdev,
D. A.; Chulakov, E. N.; Sadretdinova, L. Sh.; Ezhikova, M. A.; Kodess, M. I.; Levit,
G. L.; Krasnov, V. P. Chem. Heterocycl. Compd. 2014, 50, 838–855.
The authors thank Dr. Pavel A. Slepukhin for performing X-ray
diffraction. The work was financially supported by the Russian Sci-
entific Foundation (grant 14-13-01077) in the part of studies on
3,4-dihydro-3-phenyl-2H-[1,4]benzothiazine and its derivatives,
and the Russian Foundation for Basic Research (grant 13-03-
00674) in the part of studies on 3,4-dihydro-3-methyl-2H-
[1,4]benzothiazine and its derivatives.
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