Two-pot synthesis of N,N-disubstituted 4H-3,1-benzothiazin-2-amines from aryl(2-isothiocyanatophenyl)methanones and secondary amines

Article abstract of DOI:10.1016/j.tet.2011.10.045

A convenient synthesis of N,N-disubstituted 4H-3,1-benzothiazin-2-amines from aryl(2-isothiocyanatophenyl)methanones using a two-pot procedure has been developed. Thus, treatment of these isothiocyanato ketones with secondary amines gave the corresponding

Full text of DOI:10.1016/j.tet.2011.10.045

Tetrahedron 67 (2011) 9680e9684
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Two-pot synthesis of N,N-disubstituted 4H-3,1-benzothiazin-2-amines from
aryl(2-isothiocyanatophenyl)methanones and secondary amines
*
Kazuhiro Kobayashi , Yuuki Kanbe
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 August 2011
Received in revised form 11 October 2011
Accepted 12 October 2011
Available online 19 October 2011
A convenient synthesis of N,N-disubstituted 4H-3,1-benzothiazin-2-amines from aryl(2-isothiocyana-
tophenyl)methanones using a two-pot procedure has been developed. Thus, treatment of these iso-
thiocyanato ketones with secondary amines gave the corresponding keto thioureas, which were allowed
to react with sodium borohydride or methylmagnesium bromide to afford 1,1-dialkyl-3-{2-[aryl
(hydroxy)methyl]phenyl}thioureas or 1,1-dialkyl-3-[2-(1-aryl-1-hydroxyethyl)phenyl]thioureas, respec-
tively, in one pot. Hydrobromic acid-mediated cyclization of these hydroxy thiourea precursors provided
the desired 4H-3,1-benzothiazin-2-amines.
Keywords:
4H-3,1-Benzothiazin-2-amines
2-Isothiocyanatophenyl ketones
Secondary amines
Thioureas
Ó 2011 Elsevier Ltd. All rights reserved.
Hydrobromic acid
1. Introduction
2. Results and discussion
Some compounds having the 4H-3,1-benzothiazin-2-amine
structure have recently been reported to exhibit biological activi-
ties,1 and several efficient routes to 4H-3,1-benzothiazin-2-amine
derivatives have been published.2 As a part of our studies on the
synthesis of heterocyclic compounds utilizing o-functionalized
phenyl isothiocyanates,3 we recently described the synthesis of 2-
(2-dialkylamino-4H-3,1-benzothiazin-2-yl)acetic acid derivatives
by the reaction of 3-(2-isothiocyanatophenyl)prop-2-enoic acid
derivatives with secondary amines.3d In this paper we wish to re-
port that a new class of 4H-3,1-benzothiazin-2-amines, N,N-di-
substituted 4-aryl-4H-3,1-benzothiazin-2-amines, can be prepared
by easily operated hydrobromic acid-mediated cyclization of
1,1-dialkyl-3-[2-(1-aryl-1-hydroxyalkyl)phenyl]thioureas, readily
available from aryl(2-isothiocyanatophenyl)methanones and sec-
ondary amines. After completion of this work, we were aware of
a report on the synthesis of N,N-disubstituted 5-aryl-1,5-dihydro-
2,4-benzothiazepine-3-amines hydrochlorides by cyclization of
1,1-dialkyl-3-{2-[hydroxy(phenyl)methyl]phenylmethyl}thioureas
mediated by dry hydrogen chloride,4 which is hazardous and te-
dious to handle.
The synthesis of N,N-disubstituted 4-aryl-4H-3,1-benzothiazin-
2-amines from aryl(2-isothiocyanatophenyl)methanones
4
1
has been accomplished according to the sequence illustrated in
Scheme 1. The precursors for 4, 1,1-dialkyl-3-{2-[aryl(hydroxy)
methyl]phenyl}thioureas 3aec, 3eeg, and 3iek, or 1,1-dialkyl-3-
[2-(1-aryl-1-hydroxyethyl)phenyl]thioureas 3d and 3h, were pre-
pared in one pot by an easy two-step sequence. Thus, compounds 1
were first treated with secondary amines in EtOH (for 3aec, 3eeg,
and 3iek) or THF (for 3d and 3h) to generate the corresponding
keto thiourea derivatives 2, which were then allowed to react with
sodium borohydride or methylmagnesium bromide, respectively,
to afford, after aqueous workup followed by purification using
column chromatography on silica gel, the desired hydroxy thiourea
precursors 3 in good to excellent yields from 1 as summarized in
Table 1. It should be noted that an attempt was made to convert 2a
into 1,1-diethyl-3-[2-[1-hydroxy-1-phenylpropyl]phenyl]thiourea
(3; R1¼R2¼H, R3¼R4¼R5¼Et) on treatment with ethylmagnesium
bromide, but it resulted in the formation of 3a.
We envisaged that the desired products 4 could be accessible
through an acid-mediated cyclization of 3. First, 1,1-diethyl-3-{2-
[hydroxy(phenyl)methyl]phenyl}thiourea (3a) was treated with an
equimolar amount of concentrated hydriodic acid. However, a con-
siderably complicated mixture of products was obtained, and only
low yield (15%) of the desired product, N,N-diethyl-4-phenyl-4H-
3,1-benzothiazin-2-amine (4a), could be isolated. Subsequently,
treatment of the precursors 3 with an equimolar amount of
* Corresponding author. Tel./fax: þ81 857 31 5263; e-mail address: kkoba@
chem.tottori-u.ac.jp (K. Kobayashi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.045

K. Kobayashi, Y. Kanbe / Tetrahedron 67 (2011) 9680e9684
9681
and N,N0-dimethyl-1,3-propanediamine to 2 M amounts of the ap-
propriate aryl(2-isothiocyanatopheny)methanones 1a and 1e, re-
spectively, followed by sodium borohydride reduction proceeded
uneventfully, affording the corresponding bisthiourea precursors 5a
and 5b in good yields. The cyclization of 5 mediated by an equivalent
of concentrated hydrobromic acid completed within 1 h for 5a and
5 min for 5b at room temperature and the desired bis(benzothia-
zinyl)alkanediamines 6a and 6b could be obtained in fair yields as
a mixture of diastereomers (ca. 1:1) in each case.
Scheme 1.
Table 1
Preparation of N,N-disubstituted 4H-3,1-benzothiazin-2-amines 4
Entry 1a
R2R3NH
R4
3
Yieldb HBr
(%) (equiv)
Time
4
Yieldb
(%)
1
2
3
4
5
6
7
8
1a Et2NH
H
H
H
3a 88
3b 76
3c 93
1
1
1
1
2
2
1
1
1
1
1
2.5 h
2 h
2 h
4a 85
4b 69
4c 73
4d 59
4e 78
1a Piperidine
1a Morpholine
1a Pyrrolidine
1b Et2NH
1b PhNHMe
1c Et2NH
1c Piperidine
1d Et2NH
1d PhNHMe
1e Et2NH
Me 3d 82
5 h
c
H
H
H
3e 87
3f 86
3g 97
c
4f
70
Scheme 2.
1.5 h
5 h
5 min 4i
5 min 4j
4g 70
4h 53
Me 3h 86
9
10
11
H
H
H
3i
3j
98
96
80
66
In summary, the results reported above demonstrate that ad-
dition of secondary amines to the isothiocyanato carbon of aryl(2-
isothiocyanatophenyl)methanones, followed by treatment with
sodium borohydride or methylmagnesium bromide, provides the
corresponding hydroxy thiourea precursors in one pot, which can
be easily transformed into N,N-disubstituted 4H-3,1-benzothiazin-
2-amines on treatment with concentrated hydrobromic acid under
mild conditions. The method is of use, because the starting mate-
rials are readily available and the manipulations are very easy,
compared to the previous methods for the preparation of 4H-3,1-
benzothiazin-2-amines2 and related derivatives.4
3k 88
5 min 4k 76
a
1a (R1¼R2¼H, Ar¼Ph), 1b (R1¼Cl, R2¼H, Ar¼Ph), 1c (R1¼R2¼H, Ar¼4-ClC6H4),
1d (R1¼R2¼H, Ar¼4-MeOC6H4), 1e (R1¼R2¼OMe, Ar¼Ph).
b
Yields of isolated products.
Overnight.
c
concentrated hydrobromic acid at room temperature proved to af-
ford the desired N,N-dialkyl-4H-3,1-benzothiazin-2-amines 4 in
satisfactory yields. Similarly, the other 10 products 4bek were ob-
tained. All products 4 have IR, 1H and 13C NMR, and mass spectra,
which are consistent with the assigned structures and all gave sat-
isfactory analytical data (see Experimental section). Table 1 also
summarizes the yields of the products 4 along with reaction con-
ditions for the formation of 4. The hydrobromic mediated cyclization
proceeded smoothly in general. Especially, the precursors derived
from (2-isothiocyanatophenyl)(4-methoxyphenyl)methanone (1d)
3. Experimental
3.1. General
and
(2-isothiocyanato-4,5-dimethoxyphenyl)phenylmethanone
The melting points were obtained on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were
recorded with a PerkineElmer Spectrum65 FTIR spectrophotome-
ter. The 1H NMR spectra were recorded in CDCl3 using TMS as an
internal reference with a Bruker Biospin AVANCE II 600 spec-
trometer operating at 600 MHz, a JEOL ECP500 FT NMR spec-
trometer operating at 500 MHz, or JEOL LA400FT NMR
spectrometer operating at 400 MHz. The 13C NMR spectra were
recorded in CDCl3 using TMS as an internal reference with a Bruker
Biospin AVANCE II 600 spectrometer operating at 150 MHz, a JEOL
ECP500 FT NMR spectrometer operating at 125 MHz, or JEOL
LA400FT NMR spectrometer operating at 100 MHz. Low-resolution
MS spectra (EI, 70 eV, or CI) were measured by a JEOL JMS AX505
(1e) proved to be very reactive to provide the corresponding desired
products 4iek (entries 9e11). However, the precursors from (5-
chloro-2-isothiocyanatophenyl)phenylmethanone (1b) did pro-
ceed very sluggishly under the same conditions. Increasing the
equivalents of concentrated hydrobromic acid from 1.0 to 2.0 and
extending the reaction time overnight gave satisfactory yields of the
desired products 4e and 4f (entries 5 and 6).
In order to demonstrate the usefulness of the present procedure,
the synthesis of an N,N0-bis(4H-3,1-benzothiazin-4-yl)-1,2-
ethanediamine derivative 6a and an N,N0-bis(4H-3,1-benzothiazin-
4-yl)-1,3-propanediamine derivative 6b was carried out as illus-
trated in Scheme 2. Addition of N,N0-dimethyl-1,2-ethanediamine

9682
K. Kobayashi, Y. Kanbe / Tetrahedron 67 (2011) 9680e9684
HA spectrometer. TLC was carried out on a Merck Kieselgel 60 PF254
.
6H), 3.55e3.64 (m, 5H), 5.95 (s, 1H), 7.23e7.24 (m, 3H), 7.28 (t,
J¼7.4 Hz, 1H), 7.32e7.37 (m, 5H), 7.53 (d, J¼8.0 Hz, 1H). Anal. Calcd
for C18H22N2OS: C, 68.75; H, 7.05; N, 8.91. Found: C, 68.74; H, 7.05;
N, 8.73.
Column chromatography was performed using WAKO GEL C-200E.
All of the organic solvents used in this study were dried over ap-
propriate drying agents and distilled prior to use.
3.2. Starting materials
3.3.2. N-{2-[Hydroxy(phenyl)methyl]phenyl}piperidine-1-
carbothioamide (3b). A colorless oil; Rf 0.31 (1:2 AcOEtehexane); IR
Aryl(2-isocyanophenyl)methanones were prepared by the
method reported previously by us.3,5 All other chemicals used in
this study were commercially available.
(neat) 3431, 1619, 1527, 1491, 1157 cmꢀ1 1H NMR (500 MHz)
;
d
1.54e1.64 (m, 6H), 3.23 (br s, 1H), 3.64e3.66 (m, 4H), 5.92 (s, 1H),
7.20 (t, J¼7.4 Hz, 1H), 7.26e7.28 (m, 3H), 7.31e7.35 (m, 5H), 7.42 (d,
J¼8.6 Hz, 1H). Anal. Calcd for C19H22N2OS: C, 69.90; H, 6.79; N, 8.58.
Found: C, 69.90; H, 6.81; N, 8.52.
3.2.1. Aryl(2-isothiocyanatophenyl)methanones
1. These
com-
pounds were prepared by reacting aryl(2-isocyanophenyl)meth-
anones with sulfur in the presence of a catalytic amount of
selenium under conditions reported by Fujiwara et al.6
3.3.3. N-{2-[Hydroxy(phenyl)methyl]phenyl}morpholine-4-
carbothioamide (3c). A colorless oil; Rf 0.50 (2:1 AcOEtehexane); IR
(neat) 3425, 1620, 1524, 1490, 1159 cmꢀ1; 1H NMR (500 MHz)
d 3.10
3.2.1.1. (2-Isothiocyanatophenyl)phenylmethanone (1a)7. Yield:
94%; a yellow oil; Rf 0.49 (1:5 THFehexane); IR (neat) 2099,
(br s, 1H), 3.59e3.63 (m, 8H), 5.91 (s, 1H), 7.22 (t, J¼7.4 Hz, 1H),
7.28e7.30 (m, 2H), 7.34e7.37 (m, 5H), 7.50 (d, J¼8.0 Hz, 1H), 7.67 (br
s,1H). Anal. Calcd for C18H20N2O2S: C, 65.83; H, 6.14; N, 8.53. Found:
C, 65.78; H, 6.15; N, 8.52.
1662 cmꢀ1; 1H NMR (500 MHz)
d 7.35e7.39 (m, 2H), 7.48e7.54 (m,
4H), 7.62 (t, J¼7.3 Hz, 1H), 7.81 (dd, J¼7.8, 1.4 Hz, 2H).
3.2.1.2. (5-Chloro-2-isothiocyanatophenyl)phenylmethanone
3.3.4. N-[2-(1-Hydroxy-1-phenylethyl)phenyl]pyrrolidine-1-
(1b)8. Yield: 90%; a yellow solid; mp 63e64 ꢁC (hexane); IR (KBr)
carbothioamide (3d). A pale-yellow oil; Rf 0.15 (1:5
2076, 1667 cmꢀ1
;
1H NMR (500 MHz)
d
7.29 (d, J¼8.6 Hz, 1H),
AcOEtehexane); IR (neat) 3349, 1619, 1531, 1451, 1172 cmꢀ1 1H
;
7.46e7.49 (m, 2H), 7.52 (t, J¼7.4 Hz, 2H), 7.65 (t, J¼7.4 Hz, 1H), 7.81
NMR (500 MHz) d 1.87e1.88 (m, 4H), 1.91 (s, 3H), 3.27 (m, 1H), 3.54
(dd, J¼7.4, 1.1 Hz, 2H).
(br s, 4H), 7.22 (t, J¼7.4 Hz, 1H), 7.26e7.30 (m, 4H), 7.33 (d, J¼7.6 Hz,
2H), 7.38 (td, J¼7.6, 1.9 Hz, 1H), 7.59 (d, J¼7.6 Hz, 1H), 7.69 (d,
J¼7.6 Hz, 1H). Anal. Calcd for C19H22N2OS: C, 69.90; H, 6.79; N, 8.58.
Found: C, 69.82; H, 6.73; N, 8.32.
3.2.1.3. (4-Chlorophenyl)(2-isothiocyanatophenyl)methanone
(1c). Yield: 82%; a pale-yellow solid; mp 73e74 ꢁC (hexaneeEt2O);
IR (KBr) 2137, 1661 cmꢀ1; 1H NMR (400 MHz)
d 7.35e7.40 (m, 2H),
7.47e7.56 (m, 4H), 7.76 (d, J¼8.3 Hz, 2H). Anal. Calcd for
C14H8ClNOS: C, 61.43; H, 2.95; N, 5.12. Found: C, 61.32; H, 2.96; N,
5.12.
3.3.5. 3-[4-Chloro-2-hydroxy(phenyl)methyl]phenyl-1,1-diethyl-
thiourea (3e). A yellow oil; Rf 0.36 (1:2 AcOEtehexane); IR (neat)
3289, 1613, 1521, 1489, 1159 cmꢀ1 1H NMR (500 MHz)
; d 1.20 (t,
J¼6.9 Hz, 6H), 3.43 (br s,1H), 3.57e3.64 (m, 4H), 5.89 (s,1H), 7.20 (d,
J¼2.3 Hz, 1H), 7.25 (d, J¼8.0 Hz, 1H), 7.29e7.38 (m, 6H), 7.52 (d,
J¼8.0 Hz, 1H). Anal. Calcd for C18H21ClN2OS: C, 61.97; H, 6.07; N,
8.03. Found: C, 61.95; H, 6.09; N, 8.02.
3.2.1.4. (2-Isothiocyanatophenyl)(4-methoxyphenyl)methanone
(1d). Yield: 86%; a yellow oil; Rf 0.35 (1:5 AcOEtehexane); IR (neat)
2086, 1656 cmꢀ1 1H NMR (500 MHz)
; d 3.89 (s, 3H), 6.96 (d,
J¼9.2 Hz, 2H), 7.33 (d, J¼7.4 Hz, 1H), 7.36 (td, J¼7.4, 1.1 Hz, 1H), 7.46
(dd, J¼7.4, 1.7 Hz, 1H), 7.49 (td, J¼7.4, 1.7 Hz, 1H), 7.80 (d, J¼9.2 Hz,
2H). Anal. Calcd for C15H11NO2S: C, 66.89; H, 4.12; N, 5.20. Found: C,
66.63; H, 4.14; N, 5.03.
3.3.6. 1-[4-Chloro-2-hydroxy(phenyl)methyl]phenyl-3-methyl-3-
phenylthiourea (3f). A pale-yellow solid; mp 55e59 ꢁC (hex-
aneeEt2O); IR (KBr) 3395, 1510, 1343, 1102 cmꢀ1
;
1H NMR
(500 MHz)
d
2.05 (br s,1H), 3.70 (s, 3H), 5.77 (s,1H), 7.09 (d, J¼2.3 Hz,
3.2.1.5. (4,5-Dimethoxy-2-isothiocyanatophenyl)phenylmethanone
1H), 7.18e7.22 (m, 4H), 7.26e7.34 (m, 5H), 7.38 (tt, J¼7.4, 1.1 Hz, 1H),
7.44 (t, J¼7.4 Hz, 2H), 7.56 (d, J¼8.6 Hz, 1H). C21H19ClN2OS: C, 65.87;
H, 5.00; N, 7.32. Found: C, 65.84; H, 5.04; N, 7.16.
(1e). Yield: 72%; a yellow solid; mp 108e108.5 ꢁC (hexaneeEt2O); IR
(KBr) 2099,1644 cmꢀ1; 1H NMR (400 MHz)
d 3.89 (s, 3H), 3.95 (s, 3H),
6.78 (s, 1H), 7.03 (s, 1H), 7.50 (t, J¼7.3 Hz, 2H), 7.61 (t, J¼7.3 Hz, 1H),
7.79 (d, J¼7.3 Hz, 2H). Anal. Calcd for C16H13NO3S: C, 64.20; H, 4.38;
N, 4.68. Found: C, 64.18; H, 4.44; N, 4.62.
3.3.7. 1-{2-[(4-Chlorophenyl)hydroxymethyl]phenyl}-3,3-diethyl-
thiourea (3g). A pale-yellow oil; Rf 0.21 (1:3 AcOEtehexane); IR
(neat) 3307, 1524, 1352, 1091 cmꢀ1 1H NMR (400 MHz)
; d 1.24 (t,
3.3. General procedure for the preparation of thiourea
derivatives 3 and 5
J¼7.3 Hz, 6H), 3.62e3.67 (m, 5H), 5.92 (s, 1H), 7.17e7.38 (m, 8H),
7.49 (d, J¼7.8 Hz, 1H). Anal. Calcd for C18H21ClN2OS: C, 61.97; H,
6.07; N, 8.03. Found: C, 61.75; H, 6.12; N, 8.11.
To a stirred solution of 1 (0.24 g,1.0 mmol) in EtOH (for NaBH4) or
THF (for MeMgBr) (5 mL) at room temperature was added a sec-
ondary amine (1.0 mmol; for diamines 0.5 mmol) dropwise. After
confirmation of complete consumption of 1 by TLC (silica gel)
analyses, NaBH4 or MeMgBr (2.0 mmol) was added and stirring was
continued for 1 h at the same temperature. Saturated aqueous NH4Cl
(10 mL) was added and organic materials were extracted with AcOEt
(3ꢂ10 mL). The combined extracts were washed with brine, dried
(Na2SO4), and concentrated by evaporation. The residue was puri-
fied by column chromatography on silica gel to give 3 or 5.
3.3.8. N-{2-[(4-Chlorophenyl)hydroxymethyl]phenyl}piperidine-1-
carbothioamide (3h). A pale-yellow solid; mp 215e217 ꢁC (hex-
aneeTHF); IR (KBr) 3333, 1522, 1328, 1088 cmꢀ1
;
1H NMR
(400 MHz)
d 1.40e1.49 (m, 6H), 1.90 (s, 3H), 3.17 (br s, 1H),
3.38e3.54 (m, 4H), 7.20e7.41 (m, 7H), 7.54 (d, J¼7.3 Hz,1H), 7.70 (br
s, 1H). Anal. Calcd for C20H23ClN2OS: C, 64.07; H, 6.18; N, 7.47.
Found: C, 64.07; H, 6.19; N, 7.46.
3.3.9. 1,1-Diethyl-3-{2-[hydroxy(4-methoxyphenyl)methyl]phenyl}
thiourea (3i). A colorless viscous oil; Rf 0.32 (1:2 AcOEtehexane);
3.3.1. 1,1-Diethyl-3-{2-[hydroxy(phenyl)methyl]phenyl}thiourea
IR (neat) 3380, 1520, 1353, 1172 cmꢀ1; 1H NMR (500 MHz)
d 1.21 (t,
(3a). A pale-yellow oil; Rf 0.42 (1:2 AcOEtehexane); IR (neat) 3457,
J¼7.4 Hz, 6H), 3.38 (br s,1H), 3.60e3.67 (m, 4H), 3.80 (s, 3H), 5.91 (s,
1616, 1524, 1486, 1164 cmꢀ1; 1H NMR (500 MHz)
d
1.20 (t, J¼7.4 Hz,
1H), 6.87 (d, J¼8.6 Hz, 2H), 7.18e7.22 (m, 2H), 7.27 (d, J¼8.6 Hz, 2H),

K. Kobayashi, Y. Kanbe / Tetrahedron 67 (2011) 9680e9684
9683
7.34 (ddd, J¼8.0, 7.4, 2.3 Hz, 1H), 7.47 (br s, 1H), 7.63 (d, J¼8.0 Hz,
1H). Anal. Calcd for C19H24N2O2S: C, 66.25; H, 7.02; N, 8.13. Found:
C, 66.23; H, 7.06; N, 7.88.
47.80, 122.59, 122.97, 124.84, 126.33, 127.56, 128.01, 128.28, 128.55,
140.59, 146.31, 154.37; MS m/z 308 (Mþ, 100). Anal. Calcd for
C19H20N2S: C, 73.99; H, 6.54; N, 9.08. Found: C, 73.92; H, 6.74; N,
9.07.
3.3.10. 1-{2-[Hydroxy(4-methoxyphenyl)methyl]phenyl}-3-methyl-
3-phenylthiourea (3j). A pale-yellow viscous oil; Rf 0.29 (1:3,
3.4.3. 2-(Morpholin-4-yl)-4-phenyl-4H-3,1-benzothiazine
colorless oil; Rf 0.34 (1:5, AcOEtehexane); IR (neat) 1601,
1551 cmꢀ1 1H NMR (500 MHz)
3.61e3.78 (m, 8H), 5.26 (s, 1H),
6.92 (d, J¼7.4 Hz, 1H), 7.01 (td, J¼7.4, 1.1 Hz, 1H), 7.19 (dd, J¼7.8,
1.1 Hz, 1H), 7.22e7.32 (m, 6H); 13C NMR (125 MHz)
47.18, 47.30,
66.71, 122.54, 123.73, 125.04, 126.49, 127.75, 127.94, 128.45, 128.65,
140.34, 145.61, 154.80; MS m/z 310 (Mþ, 100). Anal. Calcd for
C18H18N2OS: C, 69.65; H, 5.84; N, 9.02. Found: C, 69.60; H, 5.94; N,
8.75.
(4c). A
AcOEtehexane); IR (neat) 3325, 1512, 1345, 1173 cmꢀ1 1H NMR
;
(500 MHz)
d
2.66 (br s, 1H), 3.72 (s, 3H), 3.81 (s, 3H), 5.78 (s, 1H),
;
d
6.83 (d, J¼8.6 Hz, 2H), 7.10e7.20 (m, 6H), 7.31 (td, J¼7.4, 1.1 Hz, 1H),
7.36e7.39 (m, 2H), 7.43 (dd, J¼8.0, 7.4 Hz, 2H), 7.62 (d, J¼8.0 Hz,1H).
Anal. Calcd for C22H22N2O2S: C, 69.81; H, 5.86; N, 7.40. Found: C,
69.70; H, 6.05; N, 7.16.
d
3.3.11. 3-[2-Hydroxy(phenyl)methyl-4,5-dimethoxy]phenyl-1,1-
diethylthiourea (3k). A white solid; mp 54e56 ꢁC (hexaneeEt2O);
IR (KBr) 3418, 1615, 1520, 1354, 1222 cmꢀ1
;
1H NMR (400 MHz)
3.4.4. 4-Methyl-4-phenyl-2-(pyrrolidin-1-yl)-4H-3,1-benzothiazine
d
1.21 (t, J¼7.3 Hz, 6H), 3.58 (br, 4H), 3.74 (br s, 1H), 3.81 (s, 3H), 3.87
(4d). A colorless oil; Rf 0.21 (1:10 AcOEtehexane); IR (neat) 1601,
(s, 3H), 5.88 (s, 1H), 6.78 (s, 1H), 6.85 (s, 1H), 6.94 (s, 1H), 7.25e7.38
(m, 5H). Anal. Calcd for C20H26N2O3S: C, 64.14; H, 7.00; N, 7.48.
Found: C, 63.96; H, 6.98; N, 7.45.
1551 cmꢀ1
;
1H NMR (400 MHz)
d
1.89e1.92 (m, 4H), 1.99 (s, 3H),
3.59 (br s, 4H), 6.95e6.96 (m, 2H), 7.17e7.29 (m, 5H), 7.42 (dd, J¼7.3,
1.5 Hz, 2H); 13C NMR (125 MHz)
24.99, 28.25, 47.58, 52.08, 122.51,
d
124.05, 125.10, 127.19, 127.60, 127.94, 128.01, 128.56, 144.57, 146.16,
153.22; MS m/z 308 (Mþ, 100). Anal. Calcd for C19H20N2S: C, 73.99;
H, 6.54; N, 9.08. Found: C, 73.92; H, 6.57; N, 9.02.
3.3.12. 1,10-(Ethane-1,2-diyl)bis(3-{2-[hydroxy(phenyl)methyl]phe-
nyl}-1-methylthiourea) (5a). A mixture of diastereomers (ca. 1:1);
a white solid; Rf 0.26 (1:1, AcOEtehexane); mp 119e131 ꢁC; IR (KBr)
3425, 3234, 1533, 1344 cmꢀ1; 1H NMR (500 MHz)
d
1.68 (br s, 2H),
3.4.5. 6-Chloro-N,N-diethyl-4-phenyl-4H-3,1-benzothiazin-2-amine
(4e). A white solid; mp 91e93 ꢁC (hexane); IR (KBr) 1597,
3.11e3.28 (m, 10H), 5.92 (s, 1H), 5.94 (s, 1H), 6.98e7.59 (m, 20H).
Anal. Calcd for C32H34N4O2S2: C, 67.34; H, 6.00; N, 9.82. Found: C,
67.31; H, 6.00; N, 9.80.
1551 cmꢀ1
;
1H NMR (500 MHz)
d
1.13 (t, J¼6.9 Hz, 6H), 3.51e3.63
(m, 4H), 5.15 (s, 1H), 6.85 (d, J¼2.3 Hz, 1H), 7.09 (d, J¼8.6 Hz, 1H),
7.19 (dd, J¼8.6, 2.3 Hz, 1H), 7.23e7.33 (m, 5H); 13C NMR (125 MHz)
3.3.13. 1,10-(Propane-1,3-diyl)bis(3-{2-[hydroxy(phenyl)methyl]-4,5-
dimethoxyphenyl}-1-methylthiourea) (5b). A mixture of di-
astereomers (ca. 1:1); a white solid; Rf 0.39 (AcOEt); mp 90e125 ꢁC;
d 14.01, 43.46, 47.11, 124.07, 125.91, 126.02, 127.08, 127.91, 127.99,
128.22, 128.73, 139.63, 145.34, 153.58; MS m/z 330 (Mþ, 100). Anal.
Calcd for C18H19ClN2S: C, 65.34; H, 5.79; N, 8.47. Found: C, 65.22; H,
5.83; N, 8.45.
IR (KBr) 3312, 1611, 1523, 1341 cmꢀ1; 1H NMR (500 MHz)
d 1.56 (br
s, 2H), 2.04 (br s, 2H), 3.03 (s, 6H), 3.79 (s, 6H), 3.82 (s, 6H),
3.85e3.90 (m, 4H), 5.85 (s, 2H), 6.71 (s, 1H), 6.72 (s, 1H), 6.99 (s, 1H),
7.00 (s, 1H), 7.25e7.36 (m, 12H). Anal. Calcd for C37H44N4O6S2: C,
63.04; H, 6.29; N, 7.95. Found: C, 62.99; H, 6.47; N, 7.90.
3.4.6. 6-Chloro-N-methyl-N,4-diphenyl-4H-3,1-benzothiazin-2-
amine (4f). A white solid; mp 85e88 ꢁC (hexane); IR (KBr) 1597,
1545 cmꢀ1; 1H NMR (500 MHz)
d
3.52 (s, 3H), 5.09 (s, 1H), 6.87 (d,
J¼2.3 Hz, 1H), 7.03e7.05 (m, 2H), 7.17 (dd, J¼8.6, 2.3 Hz, 1H),
7.21e7.33 (m, 9H); 13C NMR (125 MHz)
39.66, 47.60, 124.57,
3.4. Typical procedure for the preparation of N,N-
disubstituted 4H-3,1-benzothiazin-2-amine derivatives
4 and 6
d
126.28, 126.32, 127.29, 127.73, 127.92, 128.09, 128.27, 128.32, 128.68,
129.14, 139.20, 144.65, 144.73, 154.66; MS m/z 364 (Mþ, 100). Anal.
Calcd for C21H17ClN2S: C, 69.12; H, 4.70; N, 9.72. Found: C, 68.95; H,
4.81; N, 9.64.
3.4.1. N,N-Diethyl-4-phenyl-4H-3,1-benzothiazin-2-amine (4a). To
a stirred solution of 2a (0.10 g, 0.32 mmol) in MeCN (3 mL) was
added concentrated HBr (0.32 mmol, 55 mg). Stirring was continued
at the same temperature until TLC analyses had revealed complete
consumption of the starting material. Saturated aqueous NaHCO3
(10 mL) was added, and the organic solvent was removed by evap-
oration. The resulting mixture was extracted with AcOEt (3ꢂ10 mL)
and the combined extracts were washed with brine, dried (Na2SO4),
and concentrated by evaporation. The residue was purified by col-
umn chromatography on silica gel (1:10 AcOEtehexane) to give 4a
(80 mg, 85%); colorless crystals; mp 96e99 ꢁC (hexaneeTHF); IR
3.4.7. 4-(4-Chlorophenyl)-N,N-diethyl-4H-3,1-benzothiazin-2-amine
(4g). A colorless oil; Rf 0.49 (1:10 AcOEtehexane); IR (neat) 1602,
1550 cmꢀ1
;
1H NMR (400 MHz)
d
1.12 (t, J¼7.3 Hz, 6H), 3.56 (q,
J¼7.3 Hz, 4H), 5.16 (s, 1H), 6.90 (d, J¼7.3 Hz, 1H), 6.96 (t, J¼7.3 Hz,
1H), 7.14e7.29 (m, 6H); 13C NMR (100 MHz)
14.05, 43.43, 46.57,
d
121.73, 122.68, 124.92, 126.31, 128.51, 128.65, 129.25, 133.26, 139.53,
146.43, 152.62; MS m/z 330 (Mþ, 100). Anal. Calcd for C18H19ClN2S:
C, 65.34; H, 5.79; N, 8.47. Found: C, 65.23; H, 5.87; N, 8.40.
(KBr) 1602, 1543 cmꢀ1; 1H NMR (500 MHz)
d
1.13 (t, J¼7.4 Hz, 6H),
3.4.8. 4-(4-Chlorophenyl)-4-methyl-2-(piperidin-1-yl)-4H-3,1-
3.52e3.63 (m, 4H), 5.21 (s, 1H), 6.89 (dd, J¼7.4, 1.7 Hz, 1H), 6.94 (td,
benzothiazine (4h). A white solid; mp 99e101 ꢁC (hexane); IR (KBr)
J¼7.4, 1.1 Hz, 1H), 7.17 (dd, J¼8.0, 1.1 Hz, 1H), 7.23e7.30 (m, 6H); 13C
1600, 1547 cmꢀ1 1H NMR (600 MHz)
; d 1.49e1.54 (m, 4H), 1.97 (s,
NMR (125 MHz)
d
14.04, 43.40, 47.35, 122.55, 122.57, 124.75, 126.28,
3H), 1.58e1.64 (m, 2H), 3.68e3.70 (m, 4H), 7.04 (ddd, J¼7.7, 7.1,
1.3 Hz, 1H), 7.08 (dd, J¼7.7, 1.6 Hz, 1H), 7.18 (dd, J¼7.9, 1.3 Hz, 1H),
7.20 (d, J¼8.8 Hz, 2H), 7.26e7.29 (m, 3H); 13C NMR (150 MHz)
127.55, 128.04, 128.27, 128.55, 140.59, 146.57, 153.28; MS m/z 296
(Mþ, 100). Anal. Calcd for C18H20N2S: C, 72.93; H, 6.80; N, 9.45.
Found: C, 72.70; H, 6.81; N, 9.41.
d
25.01, 26.07, 27.93, 47.73, 51.55, 123.06, 123.49, 125.27, 128.07,
128.16, 128.37, 128.69, 132.92, 143.61, 145.20, 154.93; MS m/z 356
(Mþ, 100). Anal. Calcd for C20H21ClN2S: C, 67.30; H, 5.93; N, 7.85.
Found: C, 67.26; H, 5.99; N, 7.92.
3.4.2. 4-Phenyl-2-(piperidin-1-yl)-4H-3,1-benzothiazine
white solid; mp 59e62 ꢁC (hexane); IR (KBr) 1602, 1553 cmꢀ1
NMR (500 MHz) 1.46e1.63 (m, 6H), 3.67e3.74 (m, 4H), 5.23 (s,
1H), 6.90 (d, J¼7.4 Hz, 1H), 6.97 (t, J¼7.4 Hz, 1H), 7.18 (d, J¼8.0 Hz,
1H), 7.24e7.29 (m, 6H); 13C NMR (125 MHz)
24.98, 25.93, 47.35,
(4b). A
;
1H
d
3.4.9. N,N-Diethyl-4-(4-methoxyphenyl)-4H-3,1-benzothiazin-2-
amine (4i). A colorless oil; Rf 0.47 (1:5 AcOEtehexane); IR (neat)
d

9684
K. Kobayashi, Y. Kanbe / Tetrahedron 67 (2011) 9680e9684
1608, 1549 cmꢀ1
;
1H NMR (400 MHz)
d
1.14 (t, J¼7.3 Hz, 6H),
diastereomers (ca. 1:1); a pale-yellow viscous oil; Rf 0.39 (1:2
AcOEtehexane); IR (neat) 1609, 1557 cmꢀ1 1H NMR (400 MHz)
1.57e1.60 (m, 2H), 3.01 (s, 6H), 3.21e3.30 (m, 4H), 3.75 (s, 6H),
3.91 (s, 6H), 5.15 (s, 2H), 6.46 (s, 1H), 6.47 (s,1H), 6.79 (s, 1H), 6.80 (s,
1H), 7.14e7.21 (m, 10H); 13C NMR (125 MHz)
14.18, 21.03, 26.43,
26.46, 47.04, 48.53, 55.88, 56.18, 60.37, 108.50, 109.87, 112.66,
127.52, 127.70, 128.53, 140.42, 141.23, 141.27, 145.04, 149.11, 152.76;
MS (CI) m/z 669 ([Mþ1]þ, 100). Anal. Calcd for C37H40N4O4S2: C,
66.44; H, 6.03; N, 8.38. Found: C, 66.36; H, 6.26; N, 8.34.
3.51e3.65 (m, 4H), 3.78 (s, 3H), 5.18 (s, 1H), 6.82 (d, J¼8.8 Hz, 2H),
;
6.88 (d, J¼7.3 Hz, 1H), 6.94 (t, J¼7.3 Hz, 1H), 7.16e7.25 (m, 4H); 13C
d
NMR (125 MHz)
d 14.06, 43.36, 46.87, 55.26, 113.94, 122.54, 123.03,
124.71, 126.12, 128.16, 129.28, 132.44, 146.59, 153.57, 159.01; MS m/z
326 (Mþ,100). Anal. Calcd for C19H22N2OS: C, 69.90; H, 6.79; N, 8.58.
Found: C, 69.82; H, 6.99; N, 8.47.
d
3.4.10. 4-(4-Methoxyphenyl)-N-methyl-N-phenyl-4H-3,1-
benzothiazin-2-amine (4j). A colorless oil; Rf 0.42 (1:4
AcOEtehexane); IR (neat) 1607, 1547 cmꢀ1 1H NMR (400 MHz)
;
Acknowledgements
d
3.52 (s, 3H), 3.77 (s, 3H), 5.12 (s, 1H), 6.80 (d, J¼8.8 Hz, 2H), 6.89 (d,
J¼7.8 Hz, 1H), 6.99e7.11 (m, 5H), 7.23e7.33 (m, 5H); 13C NMR
This work was partially supported by a Grant-in-Aid for Scien-
tific Research (C) 22550035 from Japan Society for the Promotion of
Science. The authors thank Mrs. Miyuki Tanmatsu of this university
for recording mass spectra and performing combustion analyses.
(100 MHz)
d 39.62, 47.32, 55.26, 113.85, 123.43, 123.58, 125.10,
126.39, 127.00,127.74,128.23,129.03,129.32,132.05,144.80, 145.95,
154.52, 159.00; MS m/z 360 (Mþ, 100). Anal. Calcd for C22H20N2OS:
C, 73.30; H, 5.59; N, 7.77. Found: C, 73.10; H, 5.75; N, 7.70.
References and notes
3.4.11. N,N-Diethyl-6,7-dimethoxy-4-phenyl-4H-3,1-benzothiazin-2-
amine (4k). A white solid; mp 104e106 ꢁC (hexaneeEt2O); IR (KBr)
1. (a) Shridhar, D. R.; Rao, K. S.; Bhopale, K. K.; Tripathi, H. N.; Sai, G. S. T. Indian J.
Chem. 1981, 20B, 471e473; (b) Haecker, H.-G.; Brundmann, F.; Lohr, F.; Ottesbach,
P. A.; Zhou, J.; Schnakenburg, G.; Guetchow, M. Molecules 2009, 14, 378e402; (c)
Reynisson, J.; Court, W.; O’Neill, C.; Day, J.; Patterson, L.; McDonald, E.; Workman,
P.; Katan, M.; Eccles, S. A. Bioorg. Med. Chem. 2009, 17, 3169e3176.
2. (a) Gonda, J.; Kristian, P. Collect. Czech. Chem. Commun. 1986, 51, 2802e2809; (b)
Hari, A.; Miller, B. L. Org. Lett. 2000, 2, 3667e3670; (c) Schmittel, M.; Mahajan, A.;
Steffen, J.-P. Synthesis 2004, 415e418; (d) Fedotov, A. N.; Trofimova, E. V.; Ro-
manov, V. A.; Mochalov, S. S.; Shabarov, Y. S.; Zefirov, N. S. Chem. Heterocycl.
Compd. 2008, 44, 96e105; (e) Otani, T.; Katsurayama, S.; Ote, T.; Saito, T. J. Sulfur
Chem. 2009, 30, 250e263; (f) Tang, R. Y.; Luo, P.-S.; Zhang, X.-G.; Zhong, P.; Li, J.-
H. Synlett 2010, 1345e1350.
3. (a) Fukamachi, S.; Konishi, H.; Kobayashi, K. Synthesis 2009, 1786e1790; (b)
Kobayashi, K.; Fujita, S.; Fukamachi, S.; Konishi, H. Synthesis 2009, 3378e3382;
(c) Fukamachi, S.; Kobayashi, A.; Konishi, H.; Kobayashi, K. Synthesis 2010,
288e292; (d) Fukamachi, S.; Konishi, H.; Kobayashi, K. Synthesis 2010,
1593e1598; (e) Fukamachi, S.; Konishi, H.; Kobayashi, K. Synthesis 2010,
2985e2989; (f) Kobayashi, K.; Yokoi, Y.; Komatsu, T.; Konishi, H. Tetrahedron
2010, 66, 9336e9339; (g) Fukamachi, S.; Konishi, H.; Kobayashi, K. Helv. Chim.
Acta 2011, 94, 111e118; (h) Fukamachi, S.; Konishi, H.; Kobayashi, K. Heterocycles
2011, 83, 883e889; (i) Kobayashi, K.; Yokoi, Y.; Konishi, H. Synthesis 2011,
1526e1528.
1612, 1560 cmꢀ1
;
1H NMR (400 MHz)
d
1.11 (t, J¼7.3 Hz, 6H),
3.51e3.58 (m, 4H), 3.74 (s, 3H), 3.91 (s, 3H), 5.15 (s, 1H), 6.44 (s, 1H),
6.78 (s, 1H), 7.21e7.28 (m, 5H); 13C NMR (100 MHz)
14.00, 43.27,
d
47.08, 55.85, 56.21, 108.38, 109.86, 113.20, 127.48, 127.83, 128.51,
140.73, 141.17, 144.73, 149.06, 152.17; MS m/z 356 (Mþ, 100). Anal.
Calcd for C20H24N2O2S: C, 67.38; H, 6.79; N, 7.86. Found: C, 67.35; H,
6.91; N, 7.79.
3.4.12. N,N0-Dimethyl-N,N0-bis(4-phenyl-4H-3,1-benzothiazin-2-yl)
ethane-1,2-diamine (6a). A mixture of diastereomers (ca. 1:1);
a white solid; Rf 0.41 (1:3 AcOEtehexane); mp 143e172 ꢁC; IR (KBr)
1602, 1549 cmꢀ1 1H NMR (500 MHz)
; d 2.98 (s, 3H), 3.00 (s, 3H),
3.67 (br s, 4H), 5.19 (s, 2H), 6.90 (d, J¼7.4 Hz, 1H), 6.91 (d, J¼7.4 Hz,
1H), 6.97 (t, J¼7.4 Hz, 2H), 7.16e7.18 (m, 6H), 7.20e7.27 (m, 8H); 13C
NMR (125 MHz)
d 30.30, 37.46, 47.17, 121.53, 121.94, 122.01, 123.03,
124.86, 124.88, 126.48, 126.50, 127.60, 127.97, 128.01, 128.40, 128.56,
140.50, 140.62, 146.21, 146.25, 153.91; MS (CI) m/z 535 ([Mþ1]þ,
100). Anal. Calcd for C32H30N4S2: C, 71.87; H, 5.65; N, 10.48. Found:
C, 71.70; H, 5.65; N, 10.18.
4. Bream, J. B.; Schmutz, J. Helv. Chim. Acta 1977, 60, pp 2872e2880. The presence of
moisture is reported to cause the production of isoindolines as by-products.
5. Kobayashi, K.; Yoneda, K.; Miyamoto, K.; Morikawa, O.; Konishi, H. Tetrahedron
2004, 60, 11639e11645.
6. Fujiwara, S.; Shin-Ike, T.; Sonoda, N.; Aoki, M.; Okada, K.; Miyoshi, N.; Kambe, N.
Tetrahedron Lett. 1991, 32, 3503e3506.
7. Paraskewas, S. M.; Danopoulos, A. A. Synthesis 1983, 638e640.
8. Richter, P.; Buhrow, W. Pharmazie 1979, 34, 663.
3.4.13. N,N0-Bis(6,7-dimethoxy-4-phenyl-4H-benzo[d][1,3]thiazin-2-
yl)-N,N0-dimethylpropane-1,3-diamine
(6b). A
mixture
of