Synthesis of 2-(2-Dialkylamino-4 H -3,1-benzothiazin-4-yl)acetic acid derivatives and 2-(2-Thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetic Acid derivatives

Article abstract of DOI:10.1055/s-0029-1218746

An efficient method for the preparation of 2-(4H-3,1-benzothiazin-4-yl) acetic acid derivatives and 2-(2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetic acid derivatives has been developed. The reaction of 3-(2-isothiocyanatophenyl) propenoic acid derivatives with secondary amines in methanol at room temperature gave the corresponding thiourea intermediates, which on heating at reflux temperature cyclized by an attack of the sulfur atom on the propenoic moiety in a 1,4-addition manner, to give 2-(2-dialkylamino-4H-3,1-benzothiazin-4-yl)acetic acid derivatives in one pot. A similar sequence using primary amines in place of secondary amines afforded 2-[3-alkyl(or aryl)-2-thioxo-1,2,3,4- tetrahydroquinazolin-4-yl]acetic acid derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218746

PAPER
1593
Synthesis of 2-(2-Dialkylamino-4H-3,1-benzothiazin-4-yl)acetic Acid
Derivatives and 2-(2-Thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetic Acid
Derivatives
Shuhei Fukamachi, Hisatoshi Konishi, Kazuhiro Kobayashi*
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 5 January 2010; revised 8 March 2010
preparation of this class of quinazoline derivatives have
been reported.5 Although Richter et al. have reported the
synthesis of 3,4-disubstituted 2-thioxo-1,2,3,4-tetrahy-
droquinazoline derivatives by the reaction of 2-aminoben-
Abstract: An efficient method for the preparation of 2-(4H-3,1-
benzothiazin-4-yl)acetic acid derivatives and 2-(2-thioxo-1,2,3,4-
tetrahydroquinazolin-4-yl)acetic acid derivatives has been devel-
oped. The reaction of 3-(2-isothiocyanatophenyl)propenoic acid de-
rivatives with secondary amines in methanol at room temperature zyl alcohols with isothiocyanates, this method suffers
from drastic reaction conditions.5a,b
gave the corresponding thiourea intermediates, which on heating at
reflux temperature cyclized by an attack of the sulfur atom on the
propenoic moiety in a 1,4-addition manner, to give 2-(2-dialkylami-
The starting materials for our synthesis, 3-(2-isothiocy-
anatophenyl)propenoic acid derivatives 4, were prepared
by the process illustrated in Scheme 1. Thus, Heck reac-
tion of N-(2-iodophenyl)formamides 1 with propenoic
acid derivatives afforded 3-(2-formylaminophenyl)prop-
enoic acid derivatives 2, which were dehydrated with
phosphorous oxychloride in the presence of triethylamine
to afford 3-(2-isocyanophenyl)propenoic acid derivatives
3. These isocyanides were converted into the correspond-
ing isothiocyanate 4 on treatment with sulfur in the pres-
ence of a catalytic amount of selenium and triethylamine
under Fujiwara’s conditions.6
no-4H-3,1-benzothiazin-4-yl)acetic acid derivatives in one pot. A
similar sequence using primary amines in place of secondary
amines afforded 2-[3-alkyl(or aryl)-2-thioxo-1,2,3,4-tetrahydro-
quinazolin-4-yl]acetic acid derivatives.
Key words: 4H-3,1-benzothiazines, 2-thioxo-1,2,3,4-tetrahydro-
quinazolines, 3-(2-isothiocyanatophenyl)propenoic acids, thio-
ureas, 1,4-addition
Compounds having the 4H-3,1-benzothiazine skeleton
have recently attracted much attention because of their
biological activities,1 and a number of efficient methods
for their preparation have been reported.2 In 2000, Miller
et al. reported a synthesis of 2-[2-alkyl(or aryl)amino-4H-
3,1-benzothiazin-4-yl]acetic acid derivatives based on tri-
fluoroacetic acid mediated cyclization of thioureas, pre-
pared by treating 3-(2-aminophenyl)propenoic acid
derivatives with isothiocyanates.2d We found that 2-(2-di-
alkylamino-4H-3,1-benzothiazin-4-yl)acetic acid deriva-
tives could be obtained by simply heating the respective
thiourea intermediates, generated in situ by treating 3-(2-
isothiocyanatophenyl)propenoic acid derivatives with
secondary amines, in methanol.3 We describe here the re-
sults of our work, which provide an efficient one-pot pro-
cedure for the preparation of this type of 4H-3,1-
benzothiazines. We also found that the use of primary
amines in place of secondary amines provided an ap-
proach for the construction of a new class of quinazoline
derivatives, 2-(2-thioxo-1,2,3,4-tetrahydroquinazolin-4-
yl)acetic acid derivatives. The 1,2,3,4-tetrahydroquinazo-
line skeleton is found in many biologically active
compounds.4 Therefore, 2-thioxo-1,2,3,4-tetrahydro-
quinazoline derivatives are also of potential biological im-
portance. However, few practical methods for the
R1
I
NHCHO
R1
COY
1
Pd(OAc)2
+
Et3N, reflux
COY
NHCHO
2a R1 = H, Y = OMe 76%
2b R1 = H, Y = Ot-Bu 76%
2c R1 = H, Y = NMe2 87%
2d R1 = Cl, Y = OMe 85%
2e R1 = CO2Et, Y = OMe 51%
R1
COY
POCl3, Et3N, THF, 0 °C
NC
3a R1 = H, Y = OMe 67%
3b R1 = H, Y = Ot-Bu 75%
3c R1 = H, Y = NMe2 66%
3d R1 = Cl, Y = OMe 59%
3e R1 = CO2Et, Y = OMe 52%
R1
COY
sulfur, selenium (cat.)
Et3N, THF, r.t.
NCS
4a R1 = H, Y = OMe 89%
4b R1 = H, Y = Ot-Bu 93%
4c R1 = H, Y = NMe2 98%
4d R1 = Cl, Y = OMe 63%
4e R1 = CO2Et, Y = OMe 83%
SYNTHESIS 2010, No. 10, pp 1593–1598
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Advanced online publication: 15.04.2010
DOI: 10.1055/s-0029-1218746; Art ID: F00110SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Preparation of 3-(2-isothiocyanatophenyl)propenoic acid
derivatives

1594
S. Fukamachi et al.
PAPER
The one-pot synthesis of 2-(2-dialkylamino-4H-3,1-ben- amines under conditions similar to those described for the
zothiazin-4-yl)acetic acid derivatives 6 from 3-(2-isothio- preparation of 6 to afford 8. The results are summarized in
cyanatophenyl)propenoic acid derivatives
4
was Table 2, which indicates that the yields are also generally
conducted as illustrated in Scheme 2. Thus, compounds 4 high.
were treated with secondary amines in methanol at room
temperature to generate the corresponding thiourea inter-
mediates 5, which on heating at reflux temperature cy-
clized by an attack of the sulfur atom on the propenoic
COY
S
R1
H2NR2, MeOH, r.t.
4
moiety in a 1,4-addition manner. The completion of each
N
H
NHR2
step of the sequence could be confirmed by TLC (silica
gel) analyses. After cooling, the solutions were concen-
trated by evaporation and subsequent purification of the
residues by column chromatography on silica gel to afford
the desired products 6. The results are summarized in
Table 1, which indicates that the yields are generally high,
independent of the starting materials 4 and secondary
amines used.
7
COY
R2
COY
S
R1
R1
reflux
N
not
N
H
S
N
NHR2
8
9
Scheme 3 Preparation of 2-thioxo-1,2,3,4-tetrahydroquinazoline
COY
derivatives
R1
HNR2R3, MeOH, r.t.
S
4
Table 2 2-(2-Thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)aceticAcid
Derivatives 8
N
NR2R3
H
R2
Y
8 (Yield, %)a
8a (96)
5
Entry
4
COY
1
2
3
4
5
6
4b
4c
4c
4c
4d
4d
Bn
Ot-Bu
NMe2
NMe2
NMe2
OMe
OMe
R1
Me
8b (95)
8c (92)
reflux
S
n-Pr
N
NR2R3
6
4-MeOC6H4
8d (85)
8e (86)
Scheme 2 Preparation of 4H-3,1-benzothiazine derivatives
Et
Table 1 2-(2-Dialkylamino-4H-3,1-benzothiazin-4-yl)acetic Acid
Derivatives 6
Ph
8f (80)
a Isolated yields.
Entry
4
HNR2R3
Y
6 (Yield, %)a
6a (87)
6b (89)
6c (85)
6d (93)
6e (98)
6f (93)
In each of the reactions using primary amines, only one of
the two possible structural isomers was exclusively ob-
tained. We assigned the structure of the products as
quinazoline-2-thiones 8 rather than the isomeric 2-amino-
4H-benzothiazines 9 on the basis of their spectral data
(see Experimental). The assignment was further con-
firmed by NOE experiments. Thus, for example, an en-
hancement (10.3%) of the signal at d = 4.97 assignable to
4-H of compound 8e was observed when the signal at
d = 2.69 assignable to 3-methylene protons was irradiat-
ed.
1
2
3
4
5
6
7
8
9
4a
4a
4a
4b
4c
4c
4c
4d
4e
pyrrolidine
piperidine
morpholine
i-Pr2NH
OMe
OMe
OMe
Ot-Bu
NMe2
NMe2
Et2NH
pyrrolidine
4-methylpiperazine NMe2
6g (88)
6h (89)
6i (85)
pyrrolidine
PhNHMe
OMe
OMe
In conclusion, we have demonstrated that 2-(2-dialkyl-
amino-4H-3,1-benzothiazin-4-yl)acetic acid derivatives
or
2-(3-alkyl(or
aryl)-2-thioxo-1,2,3,4-tetrahydro-
a Isolated yields.
quinazolin-4-yl)acetic acid derivatives could be prepared
efficiently using one-pot addition/cyclization sequences
Next, we found that 2-(2-thioxo-1,2,3,4-tetrahydro- between 3-(2-isothiocyanatophenyl)acrylic acid deriva-
quinazolin-4-yl)acetic acid derivatives 8 were produced tives and secondary or primary amines, respectively. The
in one pot by a similar treatment of 3-(2-isothiocy- present method must be useful in organic synthesis, be-
anatophenyl)propenoic acid derivatives 4 with primary cause it is operationally very simple and the starting ma-
amines in place of secondary amines as illustrated in terials are readily available.
Scheme 3. Thus, compounds 4 were treated with primary
Synthesis 2010, No. 10, 1593–1598 © Thieme Stuttgart · New York

PAPER
Synthesis of 4H-3,1-Benzothiazine Derivatives
1595
IR (KBr): 3219, 1713, 1682, 1657 cm–1.
1H NMR: d = 3.821 and 3.824 (2 s, total 3 H), 6.40–6.45 (m, 1 H),
7.16–8.47 (m, 6 H).
All melting points were obtained on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were de-
termined with a Shimadzu FTIR-8300 spectrophotometer. The H
1
NMR spectra were determined in CDCl3 using TMS as an internal
reference with a JEOL ECP500 FT NMR spectrometer operating at
500 MHz. The 13C NMR spectra were determined in CDCl3 using
TMS as an internal reference with a JEOL ECP500 FT NMR spec-
trometer operating at 125 MHz. Low-resolution MS spectra (EI, 70
eV) were measured by a JEOL JMS AX505 HA spectrometer. TLC
was carried out on a Merck Kieselgel 60 PF254. Column chromatog-
raphy was performed using Wakogel C-200E. All of the organic
solvents used in this study were dried over appropriate drying
agents and distilled prior to use. Ethyl 4-amino-3-iodobenzoate7 and
N-(2-iodophenyl)formamide (1a)8 were prepared according to the
reported procedures. All other chemicals used in this study were
commercially available.
Anal. Calcd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84. Found: C,
55.23; H, 4.35; N, 5.83.
Methyl (E)-3-(5-Ethoxycarbonyl-2-formylaminophenyl)pro-
penoate (2e)
Pale-yellow solid; mp 96–98 °C (hexane–CH2Cl2).
IR (KBr): 3295, 1715, 1696, 1681, 1639 cm–1.
1H NMR: d = 1.41, 1.43 (2 t, J = 7.3 Hz each, total 3 H), 3.62 and
3.84 (2 s, total 3 H), 4.39 and 4.40 (2 q, J = 7.3 Hz each, total 2 H),
6.51–8.69 (m, 7 H).
Anal. Calcd for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C,
60.43; H, 5.63; N, 4.83.
N-(2-Iodophenyl)formamides 1b–e
(E)-3-(2-Isocyanophenyl)propenoic Acid Derivatives 3
These compounds were prepared by treating 3-(2-formylaminophe-
nyl)propenoic acid derivatives 2 with POCl3 in the presence of Et3N
in THF at 0 °C.12
These compounds were prepared by the treatment of the respective
2-iodoaniline with formic acid in toluene at reflux temperature.9
N-(4-Chloro-2-iodophenyl)formamide (1d)
Yield: 97%; pale-yellow needles; mp 139–140 °C (hexane–
CH2Cl2),
IR (KBr): 3273, 1668 cm–1.
Methyl 3-(2-Isocyanophenyl)propenoate (3a)
This is a known compound.11
1H NMR: d = 7.13–8.63 (m, 5 H).
1,1-Dimethylethyl (E)-3-(2-Isocyanophenyl)propenoate (3b)
Pale-yellow solid; mp 59–60 °C (hexane).
IR (KBr): 2118, 1713, 1640 cm–1.
Anal. Calcd for C7H5ClINO: C, 29.87; H, 1.79; N, 4.98. Found: C,
29.89; H, 1.84; N, 4.97.
1H NMR: d = 1.55 (s, 9 H), 6.47 (d, J = 15.6 Hz, 1 H), 7.39 (td,
J = 7.3, 1.4 Hz, 1 H), 7.40–7.44 (m, 2 H), 7.65–7.66 (m, 1 H), 7.99
(d, J = 15.6 Hz, 1 H).
Ethyl 4-Formylamino-3-iodobenzoate (1e)
Yield: 90%; beige solid; mp 157–159 °C (hexane–THF).
IR (KBr): 3256, 1713, 1670 cm–1.
1H NMR: d = 1.40 (t, J = 7.3 Hz, 3 H), 4.37 (q, J = 7.3 Hz, 2 H),
7.64–8.38 (m, 5 H).
Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C,
73.24; H, 6.65; N, 6.23.
(E)-3-(2-Isocyanophenyl)-N,N-dimethylpropenamide (3c)
White solid; mp 132–134 °C (hexane–CH2Cl2).
IR (KBr): 2124, 1653, 1611 cm–1.
Anal. Calcd for C10H10INO3: C, 37.64; H, 3.16; N, 4.39. Found: C,
37.58; H, 3.18; N, 4.68.
(E)-3-(2-Formylaminophenyl)propenoic Acid Derivatives 2
These compounds were prepared by the treatment of N-(2-iodophe-
nyl)formamides 1 with propenoic acid derivatives in the presence of
a catalytic amount of Pd(OAc)2 in Et3N at reflux temperature.10
1H NMR: d = 3.09 (s, 3 H), 3.19 (s, 3 H), 7.06 (d, J = 15.6 Hz, 1 H),
7.37 (td, J = 7.8, 1.4 Hz, 1 H), 7.40–7.44 (m, 2 H), 7.61 (dd, J = 7.8,
1.4 Hz, 1 H), 7.83 (d, J = 15.6 Hz, 1 H).
Anal. Calcd for C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C,
71.80; H, 6.05; N, 13.85.
Methyl 3-(2-Formylaminophenyl)propenoate (2a)
This is a known compound.11
Methyl (E)-3-(5-Chloro-2-isocyanophenyl)propenoate (3d)
Pale-yellow solid; mp 121–123 °C (hexane).
IR (KBr): 2114, 1715, 1640 cm–1.
1H NMR: d = 3.85 (s, 3 H), 6.53 (d, J = 16.0 Hz, 1 H), 7.385–7.388
(m, 2 H), 7.64 (s, 1 H), 7.90 (d, J = 16.0 Hz, 1 H).
1,1-Dimethylethyl (E)-3-(2-Formylaminophenyl)propenoate
(2b)
White solid; mp 111–112 °C (hexane–Et2O).
IR (KBr): 3244, 1705, 1668, 1634 cm–1.
1H NMR: d = 1.529 and 1.535 (2 s, total 9 H), 6.33–6.37 (m, 1 H),
7.19–8.53 (m, 7 H).
Anal. Calcd for C11H8ClNO2: C, 59.61; H, 3.64; N, 6.32. Found: C,
59.55; H, 3.89; N, 6.21.
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C,
67.94; H, 7.18; N, 5.51.
Methyl (E)-3-(5-Ethoxycarbonyl-2-isocyanophenyl)propen-
oate (3e)
White solid; mp 92–93 °C (hexane–Et2O).
IR (KBr): 2118, 1719, 1637, 1609 cm–1.
1H NMR: d = 1.42 (t, J = 7.3 Hz, 3 H), 3.86 (s, 3 H), 4.42 (q, J = 7.3
Hz, 2 H), 6.65 (d, J = 16.0 Hz, 1 H), 7.51 (d, J = 8.2 Hz, 1 H), 7.98
(d, J = 16.0 Hz, 1 H), 8.08 (dd, J = 8.2, 1.8 Hz, 1 H), 8.35 (d, J = 1.8
Hz, 1 H).
(E)-3-(2-Formylaminophenyl)-N,N-dimethylpropenamide (2c)
Colorless needles; mp 111–113 °C (hexane–CH2Cl2).
IR (KBr): 3210, 1674, 1645, 1605 cm–1.
1H NMR: d = 3.07 (s, 3 H), 3.18 (s, 3 H), 6.81–8.54 (m, 8 H).
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.04; H, 6.52; N, 12.74.
Anal. Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C,
64.83; H, 5.19; N, 5.32.
Methyl (E)-3-(5-Chloro-2-formylaminophenyl)propenoate (2d)
Pale-yellow solid; mp 168–170 °C (hexane–CH2Cl2).
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(E)-3-(2-Isothiocyanatophenyl)propenoic Acid Derivatives 4
These compounds were prepared by treating 3-(2-isocyanophe-
nyl)propenoic acid derivatives 3 with sulfur in the presence of a cat-
alytic amount of selenium and Et3N in THF at reflux temperature.6
analyses. After cooling to r.t., the resulting mixture was concentrat-
ed by evaporation. The residue was purified by column chromatog-
raphy on silica gel to afford 6a as a colorless oil; yield: 0.12 g
(87%); Rf = 0.58 (THF–hexane, 1:2).
IR (neat): 1738, 1549 cm–1.
Methyl (E)-3-(2-Isothiocyanatophenyl)propenoate (4a)
1H NMR: d = 1.95 (br s, 4 H), 2.71 (dd, J = 16.0, 6.4 Hz, 1 H), 2.80
(dd, J = 16.0, 9.1 Hz, 1 H), 3.56 (br s, 2 H), 3.68 (s, 3 H), 3.70 (br
s, 2 H), 4.43 (dd, J = 9.1, 6.4 Hz, 1 H), 6.96 (t, J = 7.8 Hz, 1 H), 7.07
(d, J = 7.8 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 1 H), 7.22 (t, J = 7.8 Hz, 1
H).
13C NMR: d = 25.01, 39.98, 41.66, 47.87, 51.80, 121.29, 122.65,
124.91, 126.07, 128.53, 145.36, 151.25, 170.99.
White solid; mp 46–47 °C (hexane).
IR (KBr): 2053, 1701, 1593 cm–1.
1H NMR: d = 3.84 (s, 3 H), 6.50 (d, J = 16.0 Hz, 1 H), 7.28 (td,
J = 7.8, 1.4 Hz, 1 H), 7.33 (dd, J = 7.8, 1.4 Hz, 1 H), 7.37 (td,
J = 7.8, 1.4 Hz, 1 H), 7.59 (d, J = 7.8, 1.4 Hz, 1 H), 7.93 (d, J = 16.0
Hz, 1 H).
Anal. Calcd for C11H9NO2S: C, 60.26; H, 4.14; N, 6.39. Found: C,
60.28; H, 4.28; N, 6.09.
MS: m/z (%) = 290 (51, [M+]), 217 (100).
Anal. Calcd for C15H18N2O2S: C, 62.04; H, 6.25; N, 9.65. Found: C,
61.87; H, 6.47; N, 9.51.
1,1-Dimethylethyl (E)-3-(2-Isothiocyanatophenyl)propenoate
(4b)
Methyl 2-[2-(Piperidin-1-yl)-4H-3,1-benzothiazin-4-yl]acetate
(6b)
Colorless oil; Rf = 0.67 (THF–hexane, 1:3).
IR (neat): 1738, 1549 cm–1.
1H NMR: d = 1.60–1.70 (m, 6 H), 2.68 (dd, J = 16.0, 6.4 Hz, 1 H),
2.80 (dd, J = 16.0, 8.7 Hz, 1 H), 3.68 (s, 3 H), 3.73–3.76 (m, 4 H),
4.47 (dd, J = 8.7, 6.4 Hz, 1 H), 6.99 (td, J = 7.8, 1.4 Hz, 1 H), 7.09–
7.11 (m, 2 H), 7.23 (td, J = 7.8, 1.8 Hz, 1 H).
White solid; mp 35–36 °C (hexane).
IR (KBr): 2085, 1707, 1618 cm–1.
1H NMR: d = 1.55 (s, 9 H), 6.41 (d, J = 16.0 Hz, 1 H), 7.25–7.31 (m,
2 H), 7.35 (ddd, J = 7.8, 7.3, 1.4 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H),
7.84 (d, J = 16.0 Hz, 1 H).
Anal. Calcd for C14H15NO2S: C, 64.34; H, 5.79; N, 5.36. Found: C,
64.20; H, 6.07; N, 5.15.
13C NMR: d = 25.01, 25.97, 40.12, 41.29, 47.86, 51.76, 121.78,
(E)-3-(2-Isothiocyanatophenyl)-N,N-dimethylpropenamide (4c)
White solid; mp 103–104 °C (hexane–Et2O).
IR (KBr): 2112, 1651, 1605 cm–1.
123.07, 124.98, 125.88, 128.42, 145.16, 153.19, 170.96.
MS: m/z (%) = 304 (57, [M+]), 231 (100).
1H NMR: d = 3.09 (s, 3 H), 3.19 (s, 3 H), 7.00 (d, J = 15.6 Hz, 1 H),
7.25–7.29 (m, 1 H), 7.31–7.33 (m, 2 H), 7.55 (d, J = 8.2 Hz, 1 H),
7.82 (d, J = 15.6 Hz, 1 H).
Anal. Calcd for C16H20N2O2S: C, 63.13; H, 6.62; N, 9.20. Found: C,
63.08; H, 6.28; N, 9.47.
Methyl2-[2-(Morpholin-4-yl)-4H-3,1-benzothiazin-4-yl]acetate
(6c)
Pale-yellow oil; Rf = 0.77 (THF–hexane, 1:3).
Anal. Calcd for C12H12N2OS: C, 62.04; H, 5.21; N, 12.06. Found:
C, 61.99; H, 5.24; N, 12.04.
IR (neat): 1738, 1553 cm–1.
Methyl (E)-3-(5-Chloro-2-isothiocyanatophenyl)propenoate
(4d)
Yellow needles; mp 121–123 °C (hexane–Et2O).
IR (KBr): 2131, 1713, 1634 cm–1.
1H NMR: d = 3.84 (s, 3 H), 6.48 (d, J = 16.0 Hz, 1 H), 7.27 (d,
J = 8.2 Hz, 1 H), 7.35 (dd, J = 8.2, 2.3 Hz, 1 H), 7.56 (d, J = 2.3 Hz,
1 H), 7.85 (d, J = 16.0 Hz, 1 H).
1H NMR: d = 2.68 (dd, J = 16.0, 6.4 Hz, 1 H), 2.74 (dd, J = 16.0, 8.7
Hz, 1 H), 3.68 (s, 3 H), 3.74–3.81 (m, 8 H), 4.50 (dd, J = 8.7, 6.4
Hz, 1 H), 7.04 (t, J = 7.8 Hz, 1 H), 7.11 (d, J = 7.8 Hz, 2 H), 7.24 (t,
J = 7.8 Hz, 1 H).
13C NMR: d = 25.59, 41.37, 47.17, 51.84, 66.71, 121.76, 123.81,
125.16, 125.98, 128.58, 144.44, 153.71, 170.76.
MS: m/z (%) = 306 (61, [M+]), 233 (100).
Anal. Calcd for C11H8ClNO2S: C, 52.08; H, 3.18; N, 5.52. Found:
C, 52.15; H, 3.15; N, 5.47.
Anal. Calcd for C15H18N2O3S: C, 58.80; H, 5.92; N, 9.14. Found: C,
58.72; H, 5.96; N, 8.86.
Methyl (E)-3-(5-Ethoxycarbonyl-2-isothiocyanatophenyl)prop-
enoate (4e)
Pale-yellow solid; mp 54–55 °C (hexane–Et2O).
IR (KBr): 2064, 1722, 1640, 1600 cm–1.
1H NMR: d = 1.41 (t, J = 7.3 Hz, 3 H), 3.85 (s, 3 H), 4.40 (q, J = 7.3
Hz, 2 H), 6.59 (d, J = 16.0 Hz, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 7.93
(d, J = 16.0 Hz, 1 H), 8.02 (dd, J = 8.7, 1.8 Hz, 1 H), 8.28 (d, J = 1.8
Hz, 1 H).
1,1-Dimethylethyl 2-[2-Bis(1-methylethyl)amino-4H-3,1-ben-
zothiazin-4-yl]acetate (6d)
Yellow oil; Rf = 0.35 (Et2O–hexane, 1:10).
IR (neat): 1732, 1553 cm–1.
1H NMR: d = 1.38 (d, J = 6.4 Hz, 6 H), 1.41 (d, J = 6.4 Hz, 6 H),
1.44 (s, 9 H), 2.60 (dd, J = 15.6, 6.4 Hz, 1 H), 2.66 (dd, J = 15.6, 8.7
Hz, 1 H), 4.16–4.22 (m, 2 H), 4.38 (dd, J = 8.7, 6.4 Hz, 1 H), 6.95
(td, J = 7.8, 0.9 Hz, 1 H), 7.08 (d, J = 7.8 Hz, 2 H), 7.21 (td, J = 7.8,
0.9 Hz, 1 H).
13C NMR: d = 20.89, 28.07, 40.56, 42.05, 48.95, 80.97, 122.23,
122.49, 124.68, 125.74, 128.13, 145.24, 150.98, 169.87.
Anal. Calcd for C14H13NO4S: C, 57.72; H, 4.50; N, 4.81. Found: C,
57.92; H, 4.32; N, 4.60.
Methyl 2-[2-(Pyrrolidin-1-yl)-4H-3,1-benzothiazin-4-yl]acetate
(6a); Typical Procedure
A mixture of 4a (0.10 g, 0.46 mmol) and pyrrolidine (32 mg, 0.46
mmol) in MeOH (3 mL) was stirred at r.t. for 5 min. The mixture
was then heated at reflux temperature for 10 min. The completion
of each step of the sequence could be confirmed by TLC (silica gel)
MS: m/z (%) = 362 (25, [M+]), 306 (79), 247 (100).
Anal. Calcd for C20H30N2O2S: C, 66.26; H, 8.34; N, 7.73. Found: C,
66.25; H, 8.37; N, 7.65.
Synthesis 2010, No. 10, 1593–1598 © Thieme Stuttgart · New York

PAPER
Synthesis of 4H-3,1-Benzothiazine Derivatives
1597
N,N-Dimethyl-2-(2-diethylamino-4H-3,1-benzothiazin-
4-yl)acetamide (6e)
Pale-yellow oil; Rf = 0.41 (THF–hexane, 1:2).
Methyl 2-[6-Ethoxycarbonyl-2-methyl(phenyl)amino-4H-3,1-
benzothiazin-4-yl]acetate (6i)
Pale-yellow solid; mp 124–125 °C (hexane–CH2Cl2).
IR (neat): 1645, 1549 cm–1.
IR (KBr): 1732, 1713, 1531 cm–1.
1H NMR: d = 1.20 (t, J = 7.3 Hz, 6 H), 2.64 (dd, J = 15.1, 6.4 Hz, 1
H), 2.72 (s, 3 H), 2.78 (dd, J = 15.1, 8.2 Hz, 1 H), 2.92 (s, 3 H), 3.57
(dq, J = 14.2, 7.3 Hz, 2 H), 3.69 (dq, J = 14.2, 7.3 Hz, 2 H), 4.60
(dd, J = 8.2, 6.4 Hz, 1 H), 6.96 (td, J = 7.8, 1.4 Hz, 1 H), 7.08 (dd,
J = 7.8, 1.4 Hz, 1 H), 7.10 (dd, J = 7.8, 1.4 Hz, 1 H), 7.22 (td,
J = 7.8, 1.4 Hz, 1 H).
1H NMR: d = 1.39 (t, J = 7.3 Hz, 3 H), 4.35 (dd, J = 15.5, 6.4 Hz, 1
H), 4.73 (dd, J = 15.5, 9.1 Hz, 1 H), 3.59 (s, 3 H), 3.62 (s, 3 H), 4.35
(q, J = 7.3 Hz, 2 H), 4.41 (dd, J = 9.1, 6.4 Hz, 1 H), 7.21–7.23 (m,
3 H), 7.34 (tt, J = 7.3, 1.4 Hz, 1 H), 7.40 (dd, J = 7.8, 7.3 Hz, 2 H),
7.82 (d, J = 1.8 Hz, 1 H), 7.95 (dd, J = 8.2, 1.8 Hz, 1 H).
13C NMR: d = 14.38, 39.75, 40.50, 41.29, 51.81, 60.68, 121.70,
124.99, 125.09, 127.80, 127.87, 128.00, 129.27, 129.99, 144.10,
149.01, 154.96, 166.41, 170.35.
13C NMR: d = 14.03, 35.45, 37.07, 39.48, 40.43, 43.27, 122.19,
122.68, 124.68, 126.10, 128.27, 145.54, 153.12, 169.88.
MS: m/z (%) = 305 (53, [M+]), 219 (100).
MS: m/z (%) = 398 (39, [M+]), 325 (100).
Anal. Calcd for C16H23N3OS: C, 62.92; H, 7.59; N, 13.76. Found:
C, 62.73; H, 7.72; N, 13.53.
Anal. Calcd for C21H22N2O4S: C, 63.30; H, 5.56; N, 7.03. Found: C,
63.29; H, 5.67; N, 6.94.
N,N-Dimethyl-2-[2-(pyrrolidin-1-yl)-4H-3,1-benzothiazin-4-
yl]acetamide (6f)
Pale-yellow solid; mp 105–107 °C (hexane–Et2O).
1,1-Dimethylethyl 2-(3-Phenylmethyl-2-thioxo-1,2,3,4-tetrahy-
droquinazolin-4-yl)acetate (8a)
Colorless crystals; mp 175–177 °C (hexane–CH2Cl2).
IR (KBr): 1645, 1549 cm–1.
IR (KBr): 3185, 1722, 1481, 1148 cm–1.
1H NMR: d = 1.95–1.97 (m, 4 H), 2.71 (s, 3 H), 2.72 (dd, J = 15.6,
6.4 Hz, 1 H), 2.78 (dd, J = 15.6, 8.2 Hz, 1 H), 2.91 (s, 3 H), 3.55–
3.75 (m, 4 H), 4.57 (dd, J = 8.2, 6.4 Hz, 1 H), 6.95 (t, J = 7.8 Hz, 1
H), 7.08 (d, J = 7.8 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 1 H), 7.21 (t,
J = 7.8 Hz, 1 H).
13C NMR: d = 25.03, 30.29, 35.47, 37.06, 40.33, 47.80, 121.80,
122.66, 124.70, 126.38, 128.38, 145.43, 152.54, 169.88.
1H NMR: d = 1.37 (s, 9 H), 2.56 (dd, J = 15.1, 8.7 Hz, 1 H), 2.62
(dd, J = 15.1, 5.0 Hz, 1 H), 4.59 (d, J = 15.1 Hz, 1 H), 4.92 (dd,
J = 8.7, 5.0 Hz, 1 H), 6.07 (d, J = 15.1 Hz, 1 H), 6.85 (d, J = 8.2 Hz,
1 H), 6.96–6.99 (m, 2 H), 7.21–7.36 (m, 6 H), 8.69 (s, 1 H).
13C NMR: d = 27.93, 40.33, 54.91, 55.63, 81.57, 113.53, 121.07,
123.69, 125.74, 127.86 (2 C), 128.76, 128.96, 134.11, 135.91,
169.12, 177.54.
MS: m/z (%) = 303 (32, [M+]), 217 (100).
MS: m/z (%) = 368 (38, [M+]), 312 (41), 253 (100).
Anal. Calcd for C16H21N3OS: C, 63.33; H, 6.98; N, 13.85. Found:
C, 63.26; H, 7.13; N, 13.76.
Anal. Calcd for C21H24N2O2S: C, 68.45; H, 6.56; N, 7.60. Found: C,
68.18; H, 6.79; N, 7.48.
N,N-Dimethyl-2-[2-(4-methylpiperazin-1-yl)-4H-3,1-benzo-
thiazin-4-yl]acetamide (6g)
Yellow viscous oil; Rf = 0.18 (THF).
N,N-Dimethyl-2-(3-methyl-2-thioxo-1,2,3,4-tetrahydro-
quinazolin-4-yl)acetamide (8b)
Pale-yellow solid; mp 172–173 °C (hexane–CH2Cl2).
IR (neat): 1643, 1549 cm–1.
IR (KBr): 3233, 1616, 1485, 1125 cm–1.
1H NMR: d = 2.32 (s, 3 H), 2.44 (t, J = 5.0 Hz, 4 H), 2.65 (dd,
J = 15.6, 6.4 Hz, 1 H), 2.73 (s, 3 H), 2.78 (dd, J = 15.6, 8.2 Hz, 1 H),
2.92 (s, 3 H), 3.74–3.87 (m, 4 H), 4.64 (dd, J = 8.2, 6.4 Hz, 1 H),
7.01 (td, J = 7.3, 1.4 Hz, 1 H), 7.10 (dd, J = 7.3, 1.4 Hz, 1 H) 7.12
(dd, J = 7.3, 1.4 Hz, 1 H), 7.23 (td, J = 7.3, 1.4 Hz, 1 H).
1H NMR: d = 2.68 (dd, J = 15.1, 8.2 Hz, 1 H), 2.75 (s, 3 H), 2.77
(dd, J = 15.1, 5.5 Hz, 1 H), 2.91 (s, 3 H), 3.51 (s, 3 H), 5.18 (dd,
J = 8.2, 5.5 Hz, 1 H), 6.86 (d, J = 7.8 Hz, 1 H), 7.03 (t, J = 7.8 Hz,
1 H), 7.20 (d, J = 7.8 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 8.87 (s, 1
H).
13C NMR: d = 30.29, 35.48, 40.02, 40.38, 46.07, 46.31, 53.94,
122.23, 123.56, 124.92, 126.25, 128.36, 144.79, 154.60, 169.70.
13C NMR: d = 35.59, 37.27, 37.34, 40.86, 59.55, 113.27, 121.32,
123.66, 126.02, 128.85, 134.25, 168.99, 176.91.
MS: m/z (%) = 332 (89, [M+]), 246 (100).
MS: m/z (%) = 263 (49, [M+]), 177 (100).
Anal. Calcd for C17H24N4OS: C, 61.41; H, 7.28; N, 16.85. Found:
C, 61.16; H, 7.41; N, 16.80.
Anal. Calcd for C13H17N3OS: C, 59.29; H, 6.51; N, 15.96. Found:
C, 59.28; H, 6.57; N, 15.90.
Methyl 2-[6-Chloro-2-(pyrrolidin-1-yl)-4H-3,1-benzothiazin-4-
yl]acetate (6h)
Yellow viscous oil; Rf = 0.47 (EtOAc–hexane, 1:3).
N,N-Dimethyl-2-(3-propyl-2-thioxo-1,2,3,4-tetrahydroquinazo-
lin-4-yl)acetamide (8c)
Pale-yellow solid; mp 164–165 °C (hexane–CH2Cl2).
IR (neat): 1738, 1549 cm–1.
IR (KBr): 3210, 1628, 1483, 1134 cm–1.
1H NMR: d = 1.93–1.98 (m, 4 H), 2.69 (dd, J = 16.0, 6.4 Hz, 1 H),
2.80 (dd, J = 16.0, 9.1 Hz, 1 H), 3.55 (br s, 2 H), 3.68 (br s, 2 H),
3.70 (s, 3 H), 4.38 (dd, J = 9.1, 6.4 Hz, 1 H), 7.02 (d, J = 8.7 Hz, 1
H), 7.07 (d, J = 2.3 Hz, 1 H), 7.16 (dd, J = 8.7, 2.3 Hz, 1 H).
13C NMR: d = 24.99, 39.63, 41.43, 47.96, 51.91, 122.60, 125.94,
126.13, 126.94, 128.50, 144.13, 151.37, 170.67.
1H NMR: d = 0.92 (t, J = 7.8 Hz, 3 H), 1.75 (sext, J = 7.8 Hz, 2 H),
2.68 (dd, J = 15.1, 5.0 Hz, 1 H), 2.71 (s, 3 H), 2.76 (dd, J = 15.1, 8.2
Hz, 1 H), 2.89 (s, 3 H), 3.29–3.35 (m, 1 H), 4.58–4.64 (m, 1 H), 5.15
(dd, J = 8.2, 5.0 Hz, 1 H), 6.88 (d, J = 7.8 Hz, 1 H), 7.03 (t, J = 7.8
Hz, 1 H), 7.22 (d, J = 7.8 Hz, 1 H), 7.24 (t, J = 7.8 Hz, 1 H), 8.92 (s,
1 H).
13C NMR: d = 11.01, 20.99, 35.53, 37.21, 37.51, 53.89, 57.45,
113.29, 121.56, 123.59, 125.99, 128.80, 134.41, 169.02, 176.60.
MS: m/z (%) = 291 (53, [M+]), 205 (100).
MS: m/z (%) = 324 (54, [M+]), 251 (100).
Anal. Calcd for C15H17ClN2O2S: C, 55.46; H, 5.28; N, 8.62. Found:
C, 55.41; H, 5.20; N, 8.82.
Synthesis 2010, No. 10, 1593–1598 © Thieme Stuttgart · New York

1598
S. Fukamachi et al.
PAPER
Anal. Calcd for C15H21N3OS: C, 61.82; H, 7.26; N, 14.42. Found:
C, 61.75; H, 7.39; N, 14.18.
References
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N,N-Dimethyl-2-[3-(4-methoxyphenyl)-2-thioxo-1,2,3,4-tetra-
hydroquinazolin-4-yl]acetamide (8d)
Pale-yellow solid; mp 224–226 °C (hexane–CH2Cl2).
IR (KBr): 3187, 1647, 1494, 1233 cm–1.
1H NMR: d = 2.65 (s, 3 H), 2.80 (s, 3 H), 2.84 (dd, J = 15.1, 3.7 Hz,
1 H), 3.04 (dd, J = 15.1, 10.1 Hz, 1 H), 3.83 (s, 3 H), 5.33 (dd,
J = 10.1, 3.7 Hz, 1 H), 6.94–6.96 (m, 3 H), 7.03 (td, J = 7.8, 1.4 Hz,
1 H), 7.22–7.27 (m, 2 H), 7.29–7.32 (m, 2 H), 9.45 (s, 1 H).
13C NMR: d = 35.40, 37.10, 37.21, 55.40, 61.49, 113.65, 114.51,
121.53, 123.61, 126.48, 128.92, 129.36, 134.46, 136.69, 158.98,
168.56, 177.56.
MS: m/z (%) = 355 (47, [M+]), 269 (100).
(2) (a) Beilenson, B.; Hamer, F. M. J. Chem. Soc. 1942, 98.
(b) Besson, T.; Guillaumet, G.; Lamazzi, C.; Rees, C. W.;
Thiery, V. J. Chem. Soc., Perkin Trans. 1 1998, 4057.
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Schmidt, R. R. J. Heterocycl. Chem. 1999, 36, 153.
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(e) Femandes, M. A.; Reid, D. A. Synlett 2003, 2231.
(3) After completion of our work, we became aware of a report
by Gimbert and Vallribera, which describe a synthesis of 2-
[2-alkyl(or aryl)-4H-3,1-benzothiazin-4-yl]acetic acid
derivatives by the reaction of 3-(2-acylamino-
Anal. Calcd for C19H21N3O2S: C, 64.20; H, 5.95; N, 11.82. Found:
C, 64.22; H, 6.03; N, 11.73.
Methyl 2-(6-Chloro-3-ethyl-2-thioxo-1,2,3,4-tetrahydro-
quinazolin-4-yl)acetate (8e)
Yellow crystals; mp 140–141 °C (hexane–Et2O).
IR (KBr): 3179, 1734, 1487, 1234 cm–1.
1H NMR: d = 1.30 (t, J = 7.3 Hz, 3 H), 2.69 (dd, J = 15.6, 8.7 Hz, 1
H), 2.75 (dd, J = 15.6, 5.0 Hz, 1 H), 3.42–3.49 (m, 1 H), 3.68 (s, 3
H), 4.59–4.66 (m, 1 H), 4.97 (dd, J = 8.7, 5.0 Hz, 1 H), 6.75 (d,
J = 8.7 Hz, 1 H), 7.15 (d, J = 2.3 Hz, 1 H), 7.22 (dd, J = 8.7, 2.3 Hz,
1 H), 8.37 (s, 1 H).
13C NMR: d = 12.88, 39.10, 47.42, 52.15, 55.79, 114.79, 122.38,
125.65, 128.56, 129.16, 132.93, 170.18, 176.32.
phenyl)propenoic acid derivatives with Lawesson’s reagent
in refluxing toluene: Gimbert, C.; Vallribera, A. Org. Lett.
2009, 11, 269.
(4) (a) Hasegawa, H.; Muraoka, M.; Ohmori, M.; Matsui, K.;
Kojima, A. Bioorg. Med. Chem. 2005, 13, 3721. (b) Sarli,
V.; Huemmer, S.; Sunder-Plassmann, N.; Mayer, T. U.;
Giannis, A. ChemBioChem 2005, 6, 2005. (c) Peters, J.-
U.; Luebbers, T.; Alanine, A.; Kolczewski, S.; Blasco, F.;
Steward, L. Bioorg. Med. Chem. Lett. 2008, 18, 256.
(d) Peters, J.-U.; Luebbers, T.; Alanine, A.; Kolczewski, S.;
Blasco, F.; Steward, L. Bioorg. Med. Chem. Lett. 2008, 18,
262.
MS: m/z (%) = 298 (39, [M+]), 225 (100).
Anal. Calcd for C13H15ClN2O2S: C, 52.26; H, 5.06; N, 9.38. Found:
C, 52.26; H, 5.20; N, 9.33.
Methyl 2-(6-Chloro-3-phenyl-2-thioxo-1,2,3,4-tetrahydro-
quinazolin-4-yl)acetate (8f)
Pale-yellow needles; mp 99 °C (dec.) (hexane–Et2O).
(5) (a) Pflegel, P.; Kuehmstedt, C.; Richter, P. Pharmazie 1981,
36, 65. (b) Richter, P.; Oertel, F. Pharmazie 1990, 45, 721.
(c) Pfeiffer, W. D.; Pazdera, P.; Hetzheim, A.; Muecke, J.
Pharmazie 1995, 50, 21.
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Emmerling, M. R.; Michael, W.; Nadimpalli, R.; Nath, R.;
Raser, K. J.; Stafford, D.; Watson, D.; Wang, K.; Jaen, J. C.
J. Med. Chem. 1998, 41, 1060.
IR (KBr): 3173, 1732, 1495, 1229 cm–1.
1H NMR: d = 2.86 (dd, J = 15.6, 8.7 Hz, 1 H), 2.94 (dd, J = 15.6, 4.5
Hz, 1 H), 3.59 (s, 3 H), 5.21 (dd, J = 8.7, 4.5 Hz, 1 H), 6.84 (d,
J = 8.7 Hz, 1 H), 7.16 (d, J = 2.3 Hz, 1 H), 7.24 (dd, J = 8.7, 2.3 Hz,
1 H), 7.37–7.50 (m, 5 H), 8.99 (s, 1 H).
13C NMR: d = 39.24, 52.05, 60.43, 115.13, 122.29, 125.98, 128.48,
128.53, 128.83, 129.33, 129.58, 133.04, 143.48, 169.65, 177.21.
MS: m/z (%) = 346 (39, [M+]), 273 (100).
Anal. Calcd for C17H15ClN2O2S: C, 58.87; H, 4.36; N, 8.08. Found:
C, 58.84; H, 4.45; N, 8.16.
(9) Kobayashi, K.; Yoneda, K.; Miyamoto, K.; Morikawa, O.;
Konishi, H. Tetrahedron 2004, 60, 11639.
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Synthesis 2000, 429.
(12) Ito, Y.; Kobayashi, K.; Seko, N.; Saegusa, T. Bull. Chem.
Soc. Jpn. 1984, 54, 73.
Acknowledgment
We are grateful to Mrs. Miyuki Tanmatsu of this university for her
assistance in determining mass spectra and performing combustion
analyses.
Synthesis 2010, No. 10, 1593–1598 © Thieme Stuttgart · New York