One-pot synthesis of 4-substituted 4-alkoxy-1,4-dihydro-3,1-benzoxazine-2- thiones by the reaction of 2-isothiocyanatobenzoates with organolithiums

Article abstract of DOI:10.1016/j.tet.2011.04.088

An efficient one-pot procedure for the preparation of 4-substituted 4-alkoxy-1,4-dihydro-3,1-benzoxazine-2-thiones from 2-isothiocyanatobenzoates has been developed. Thus, 2-isothiocyanatobenzoates were reacted with organolithiums including lithium enolat

Full text of DOI:10.1016/j.tet.2011.04.088

Tetrahedron 67 (2011) 4535e4538
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One-pot synthesis of 4-substituted 4-alkoxy-1,4-dihydro-3,1-benzoxazine-2-
thiones by the reaction of 2-isothiocyanatobenzoates with organolithiums
*
Kazuhiro Kobayashi , Hiroo Hashimoto, Yuuki Kanbe, Hisatoshi Konishi
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:
An efficient one-pot procedure for the preparation of 4-substituted 4-alkoxy-1,4-dihydro-3,1-benzox-
azine-2-thiones from 2-isothiocyanatobenzoates has been developed. Thus, 2-isothiocyanatobenzoates
were reacted with organolithiums including lithium enolates of acetates and tertiary acetamides in THF
at ꢀ78 ꢁC to give the desired products in generally good yields.
Received 15 March 2011
Received in revised form 22 April 2011
Accepted 22 April 2011
Available online 5 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Dihydro-3,1-benzoxazine-2-thiones
2-Isothiocyanatobenzoates
Organolithiums
Lithium eater enolates
Lithium tertiary amide enolates
1. Introduction
methoxybenzoate (1c) and ethyl 5-chloro-2-isothiocyanatobenzoate
(1d) could be obtained in a three-step sequence from methyl 2-
Compounds having the 1,4-dihydro-3,1-benzoxazine-2-thione
skeleton have recently attracted much attention, because some of
these derivatives exhibit biological activities.1 1,4-Dihydro-3,
1-benzoxazine-2-thione derivatives have been synthesized by the
treatment of the respective 1,4-dihydro-3,1-benzoxazin-2-one with
Lawesson reagent at rather higher temperatures.1a,b,d Therefore, we
have recently reported a facile method for the preparation of
4-monosubstituted and 4,4-disubstituted derivatives by the reaction
of 2-lithiophenyl isothiocyanates with aldehydes, ketones, or
butanolide.2 Literature searching revealed that there have been no
reports on the synthesis of derivatives carrying an alkoxy sub-
stituent at the 4-position. In this paper, we wish to describe the
results of our study on the reaction of 2-isothiocyanatobenzoates 1
with organolithiums including lithium enolates of acetates and
tertiary acetamides, which provide facile access to 4-substituted
4-alkoxy-1,4-dihydro-3,1-benzoxazine-2-thiones 3.
amino-5-methoxybenzoate3 and ethyl-2-amino-5-chlorobenzoate,4
respectively, utilizing the easily conducted reactions reported
previously.5ꢀ7
First, we found that 2-isothiocyanatobenzoates 1 were allowed
to react with various alkyl- or aryllithiums, including (thiophen-2-
yl)lithium, in THF at ꢀ78 ꢁC to give 4-substituted 4-alkoxy-1,
4-dihydro-3,1-benzoxazines 3. Probably almost completely selec-
tive addition of an organolithium to the ester carbonyl of 1 occurred
to lead to formation of lithium 1-alkoxy-1-(isothiocyanatophenyl)
alkan-1-yloxide intermediates 2, which underwent cyclization by
the attack of the alkanyloxide on the isothiocyanate carbon to give,
after aqueous work up, products 3, as illustrated in Scheme 1. These
results are listed in Table 1, which indicates the yields of the
products are relatively good. It is interesting to note that the ad-
dition of lithium 1-alkoxy-1-(isothiocyanatophenyl)alkan-1-ylox-
ide to isothiocyanato functional group occurs before elimination of
lithium alkoxide. This reaction sequence proceeded cleanly and
was complete within 10 min. The structures of the products were
determined on the basis of IR, 1H and 13C NMR, and MS spectros-
copies and elemental analyses. For example, mass spectrometry
and elemental analysis of the product 3a indicated its molecular
formula to be C14H19NO2S. The IR spectrum showed no evidence for
the presence of both the carbonyl and isothiocyanato groups but
showed absorption bands at 3185 and 1186 cmꢀ1 due to NeH and
C]S groups, respectively. The 13C NMR spectrum exhibited 14
2. Results and discussion
The starting isothiocyanates 1 were easily accessible. Methyl
2-isothiocyanatobenzoate (1a) and ethyl 2-isothiocyanatobenzoate
(1b) were commercially available. Methyl 2-isothiocyanato-5-
* Corresponding author. Tel./fax: þ81 857 31 5263; e-mail address: kkoba@
signals including a signal at d 183.26 assignable to the thiocarbonyl
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.2011.04.088

4536
K. Kobayashi et al. / Tetrahedron 67 (2011) 4535e4538
carbon. The 1H NMR spectrum exhibited a signal at
d 9.73 assign-
Table 2
Preparation of 2-(4-alkoxy-2-thioxo-1,4-dihydro-3,1-benzoxazin-4-yl)acetic acid
derivatives 4
able to the NeH proton and the other signals were in good agree-
ment with the structure of 3a. The spectra for products 3bef
uniformly showed the above characteristic signals in the same re-
gions (see Experimental section).
Entry
1
Y
4
Yielda/%
1
2
3
4
5
6
7
1a (R1¼H, R2¼Et)
NMe2
NEt2
Pyrrolidin-1-yl
OEt
Piperidin-1-yl
OMe
4a
4b
4c
4d
4e
4f
63
70
64
76
62
77
91
1a
1a
1a
R2O
O
R3
OLi
NCS
R1
R1
1b (R1¼H, R2¼Me)
1c (R1¼OMe, R2¼Me)
1d (R1¼Cl, R2¼Et)
R3Li
OR2
NCS
THF, – 78 C
Ot-Bu
4g
a
Isolated yields.
2
1
addition
then H3O+
more than a trace amount of the corresponding 4-ethoxy-1,
4-dihydro-3,1-benzoxazine-2-thione was obtained (Scheme 3). It
may be speculated that a softer organometal, ethylmagnesium
bromide, compared to organolithiums attacks preferentially the
isothiocyanato group, which is a softer electrophilic group than the
R3
O
R2O
R1
carbonyl group.
O
N
H
S
EtMgBr, THF, – 78 C
OEt
1a
3
N C Et
H
S
Scheme 1.
5 36%
Table 1
Preparation of 4-alkoxy-1,4-dihydro-3,1-benzoxazine-2-thiones 3
Scheme 3.
Entry
1
R3
3
Yielda/%
In conclusion, the results reported above demonstrate that an
efficient one-pot procedure has been developed for the preparation
of 4-substituted 4-alkoxy-1,4-dihydro-3,1-benzoxazine-2-thiones
by the reaction of 2-isothiocyanatobenzoates with organolithiums
including lithium enolates of acetates and tertiary acetamides. It is
unlikely that this type of 1,4-dihydro-3,1-benzoxazine-2-thiones
can be prepared by previous methods.1,2 The present method may
find some value in organic synthesis, because it is operationally
very simple and the starting materials are readily available.
1
2
3
4
5
6
1a (R1¼H, R2¼Et)
1b (R1¼H, R2¼Me)
1c (R1¼OMe, R2¼Me)
1c
n-Bu
Ph
Me
t-Bu
Thiophen-2-yl
n-Bu
3a
3b
3c
3d
3e
3f
76
75
75
72
82
81
1c
1d (R1¼Cl, R2¼Et)
a
Isolated yields.
We next turned our attention to the use of lithium enolates of
acetates and tertiary acetamides, which were generated from the
respective acetates and tertiary acetamides using LDA under the
standard conditions, in place of alkyl- or aryllithiums to obtain
2-methoxy-2-(2-thioxo-1,4-dihydro-3,1-benzoxazin-4-yl)acetic acid
derivatives 4. We found that the addition of lithium enolates to the
ester carbonyl of 1 also occurred selectively and a reaction sequence
similar to that described for the formation of 3 proceeded cleanly to
give the desired products 4 as outlined in Scheme 2. Structure
determination of the products 4 was carried out in a manner similar
to that for the products 3 as mentioned above. The yields of the
products were also relatively good as summarized in Table 2. An
attempted use of 2-lithioacetonitrile proved unsuccessful, giving
only a considerably intractable mixture of products.
Subsequently, the reaction of ethyl 2-isothiocyanatobenzoate
(1a) and ethylmagnesium bromide under the same conditions as
described for the reaction of 1a with organolithiums was examined
in order to explore the difference of the reactivities between these
two organometals. The reaction resulted only in the formation of
a rather intractable mixture of products, from which a 36% yield of
ethyl 2-(thiopropanoylamino)benzoate (5) was obtained and no
3. Experimental
3.1. General
All melting points were obtained on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were
determined with a Shimadzu FTIR-8300 spectrophotometer as
KBr disks. 1H NMR spectra were determined in CDCl3 using TMS as
an internal reference with a Bruker Biospin AVACNE II 600 spec-
trometer operating at 600 MHz, a JEOL ECP500 FT NMR spec-
trometer operating at 500 MHz, or a JEOL LA400 FT NMR
spectrometer operating at 400 MHz. 13C NMR spectra were de-
termined in CDCl3 using TMS as an internal reference with
a Bruker Biospin AVACNE II 600 spectrometer operating at
150 MHz or a JEOL ECP500 FT NMR spectrometer operating at
125 MHz. Low-resolution MS spectra (EI, 70 eV) were measured
with a JEOL JMS AX505 HA spectrometer. TLC was carried out on
a Merck Kieselgel 60 PF254. Column chromatography was per-
formed using Wako Gel C-200E. All of the organic solvents used in
this study were dried over appropriate drying agents and distilled
prior to use.
R2O
CH2COY
O
R1
MeCOY–LDA, THF, –78 C
1
3.2. Starting materials
N
H
S
Methyl 2-amino-5-methoxybenzoate3 and ethyl 2-amino-5-
chlorobenzoate4 were prepared by the reported procedure. All
chemicals used in this study were commercially available.
4
Scheme 2.

K. Kobayashi et al. / Tetrahedron 67 (2011) 4535e4538
4537
3.2.1. 2-Formylaminobenzoates. The following formamides were
prepared by the N-formylation of the respective 2-aminobenzoates
with HCO2H under the previously reported conditions.5
131e133 ꢁC; IR (KBr) 3185, 1624, 1603, 1186 cmꢀ1; 1H NMR (500 MHz)
d
0.84 (t, J¼7.4 Hz, 3H), 1.18e1.46 (m, 7H), 2.03e2.09 (m,1H), 2.14e2.20
(m, 1H), 3.37e3.43 (m, 1H), 3.59e3.65 (m, 1H), 6.90 (d, J¼8.0 Hz, 1H),
7.20 (dd, J¼8.0, 7.4 Hz, 1H), 7.25 (d, J¼8.0 Hz, 1H), 7.35 (ddd, J¼8.0, 7.4,
3.2.1.1. Methyl 2-formylamino-5-methoxybenzoate. Yield: 88%;
a white solid; mp 61e64 ꢁC (hexaneeCH2Cl2); IR (KBr) 3287, 1705,
1.1 Hz, 1H), 9.73 (br s, 1H); 13C NMR (150 MHz, CDCl3)
d 13.78, 14.94,
22.38, 25.01, 40.96, 60.06, 110.62, 114.08, 119.87, 125.30, 125.42, 130.29,
133.12, 183.26; MS m/z 265 (Mþ, 33), 208 (100). Anal. Calcd for
C14H19NO2S: C, 63.36; H, 7.22; N, 5.28. Found: C, 63.18; H, 7.06; N, 5.20.
1686,1667 cmꢀ1; 1H NMR (500 MHz)
d 3.83 (s, 3H), 3.94 (s, 3H), 7.13
(dd, J¼9.2, 3.4 Hz, 1H), 7.53 (d, J¼3.4 Hz, 1H), 8.46 (d, J¼1.7 Hz, 1H),
8.64 (d, J¼9.2 Hz, 1H), 10.70 (br s, 1H). Anal. Calcd for C10H11NO4: C,
57.41; H, 5.30; N, 6.70. Found: C, 57.30; H, 5.40; N, 6.88.
3.3.2. 4-Methoxy-4-phenyl-1,4-dihydro-3,1-benzoxazine-2-thione
(3b). A white solid; mp 160e162 ꢁC (hexaneeCHCl3); IR (KBr) 3173,
3.2.1.2. Ethyl
a white solid; mp 119e120 ꢁC (hexaneeCH2Cl2); IR (KBr) 3282, 1702,
1686 cmꢀ1 1H NMR (400 MHz)
5-chloro-2-formylaminobenzoate. Yield:
92%;
1620, 1603, 1157 cmꢀ1 1H NMR (400 MHz)
; d 3.47 (s, 3H), 6.96 (d,
J¼7.8 Hz, 1H), 7.06 (dd, J¼7.8, 1.0 Hz, 1H), 7.13 (ddd, J¼7.8, 7.3, 1.0 Hz,
;
d
1.43 (t, J¼7.3 Hz, 3H), 4.30 (q,
1H), 7.36 (ddd, J¼7.8, 7.3, 1.0 Hz, 1H), 7.40e7.45 (m, 3H), 7.52(dd, J¼7.8,
J¼7.3Hz, 2H), 7.50 (dd, J¼8.8,2.4Hz,1H), 8.02(d, J¼2.4Hz,1H), 8.50(d,
J¼1.5 Hz, 1H), 8.70 (d, J¼8.8 Hz, 1H), 10.96 (br s, 1H). Anal. Calcd for
C10H10ClNO3:C, 52.76; H, 4.43;N, 6.15. Found:C, 52.61;H, 4.71; N, 6.11.
1.5 Hz, 2H), 9.89 (br s,1H); 13C NMR (150 MHz, CDCl3)
d 52.31, 107.95,
114.14, 121.46, 125.27, 126.68, 126.91, 128.51, 129.40, 130.56, 132.87,
137.67, 182.82; MS m/z 271 (Mþ, 100). Anal. Calcd for C15H13NO2S: C,
66.40; H, 4.83; N, 5.16. Found: C, 66.32; H, 4.83; N, 5.10.
3.2.2. 2-Isocyanobenzoates. The following isocyanides were pre-
pared by the dehydration of the above formamides with POCl3
under the previously reported conditions.6
3.3.3. 4,6-Dimethoxy-4-methyl-1,4-dihydro-3,1-benzoxazine-2-thi-
one (3c). A pale-yellow solid; mp 157e158 ꢁC (hexaneeCH2Cl2); IR
(KBr) 3181,1622,1184 cmꢀ1; 1H NMR (500 MHz)
d 1.90 (s, 3H), 3.67 (s,
3.2.2.1. Methyl
a yellow solid; mp 58e59 ꢁC (hexaneeCH2Cl2); IR (KBr) 2131, 1732,
1607 cmꢀ1; 1H NMR (500 MHz)
3.87 (s, 3H), 3.98 (s, 3H), 7.05 (dd,
J¼8.6, 2.9 Hz, 1H), 7.40 (d, J¼8.6 Hz, 1H), 7.47 (d, J¼2.9 Hz, 1H). Anal.
Calcd for C10H9NO3: C, 62.82; H, 4.74; N, 7.33. Found: C, 62.61; H,
4.61; N, 7.14.
2-isocyano-5-methoxybenzoate. Yield: 99%;
3H), 3.82 (s, 3H), 6.82(d, J¼2.3 Hz,1H), 6.89 (d, J¼8.6 Hz,1H), 6.92 (dd,
J¼8.6, 2.3 Hz, 1H), 9.85 (br s, 1H); 13C NMR (125 MHz, CDCl3)
d 26.25,
d
51.46, 55.72, 107.18, 109.88, 115.62, 116.15, 122.32, 126.27, 157.36,
181.87; MS m/z 239 (Mþ, 28) 224 (100). Anal. Calcd for C11H13NO3S: C,
55.21; H, 5.48; N, 5.85. Found: C, 55.03; H, 5.44; N, 5.52.
3.3.4. 4,6-Dimethoxy-4-(1,1-dimethylethyl)-1,4-dihydro-3,1-benzox-
3.2.2.2. Ethyl 5-chloro-2-isocyanobenzoate. Yield: 89%; a pale-
yellow solid; mp 85e86 ꢁC (hexaneeEt2O); IR (KBr) 2136,
azine-2-thione (3d). A white solid; mp 173e178 ꢁC (hex-
aneeCH2Cl2); IR (KBr) 3188, 1612, 1172 cmꢀ1 1H NMR (500 MHz)
;
1736 cmꢀ1
;
1H NMR (400 MHz)
d
1.44 (t, J¼7.3 Hz, 3H), 4.46 (q,
d
1.03 (s, 9H), 3.26 (s, 3H), 3.81 (s, 3H), 6.74 (d, J¼2.9 Hz,1H), 6.86 (d,
J¼7.3 Hz, 2H), 7.42 (d, J¼8.3 Hz, 1H), 7.53 (dd, J¼8.3, 2.4 Hz, 1H), 7.98
(d, J¼2.4 Hz, 1H). Anal. Calcd for C10H8ClNO2: C, 57.30; H, 3.85; N,
6.68. Found: C, 57.13; H, 3.87; N, 6.53.
J¼9.2 Hz, 1H), 6.91 (dd, J¼9.2, 2.9 Hz, 1H), 9.74 (br s, 1H); 13C NMR
(125 MHz, CDCl3)
d 24.16, 43.40, 52.66, 55.70, 112.73, 115.24 (two
overlapped Cs), 115.85, 118.15, 128.34, 156.48, 182.87; MS m/z 281
(Mþ, 34), 224 (100). Anal. Calcd for C14H19NO3S: C, 59.76; H, 6.81; N,
4.98. Found: C, 59.67; H, 6.82; N, 4.92.
3.2.3. 2-Isothiocyanatobenzoates. The following isothiocyanates
were prepared by treating the above isocyanides with sulfur in the
presence of a catalytic amount of selenium according to the pro-
cedure previously reported by Fujiwara et al.7
3.3.5. 4,6-Dimethoxy-4-(thiophen-2-yl)-1,4-dihydro-3,1-benzox-
azine-2-thione (3e). A pale-yellow solid; mp 121e123 ꢁC (hex-
aneeCH2Cl2); IR (KBr) 3185, 1616, 1165 cmꢀ1 1H NMR (500 MHz)
;
3.2.3.1. Methyl 2-isothiocyanato-5-methoxybenzoate (1c). Yield:
72%; a pale-yellow solid; mp 53e55 ꢁC (hexane); IR (KBr) 2140,
d
3.51 (s, 3H), 3.77 (s, 3H), 6.84 (d, J¼2.8 Hz, 1H), 6.91 (d, J¼8.6 Hz,
1H), 6.94 (dd, J¼8.6, 2.8 Hz,1H), 6.98 (dd, J¼5.1, 3.4 Hz,1H), 7.05 (dd,
1726 cmꢀ1; 1H NMR (500 MHz)
d 3.85 (s, 3H), 3.98 (s, 3H), 7.03 (dd,
J¼3.4,1.1 Hz,1H), 7.40 (dd, J¼5.1,1.1 Hz,1H), 9.88 (br s,1H); 13C NMR
J¼8.6, 2.9 Hz, 1H), 7.22 (d, J¼8.6 Hz, 1H), 7.47 (d, J¼2.9 Hz, 1H). Anal.
Calcd for C10H9NO3S: C, 53.80; H, 4.06; N, 6.27. Found: C, 53.54; H,
4.28; N, 6.38.
(125 MHz, CDCl3) d 52.66, 55.74, 106.14, 110.84, 115.58, 116.84,
121.93, 126.70 (two overlapped Cs), 127.41, 127.84, 141.68, 157.29,
181.39; MS m/z 307 (Mþ, 100). Anal. Calcd for C14H13NO3S2: C,
54.70; H, 4.26; N, 4.56. Found: C, 54.57; H, 4.48; N, 4.41.
3.2.3.2. Ethyl 5-chloro-2-isothiocyanatobenzoate (1d).8 Yield:
81%; a white solid; mp 62e63 ꢁC (hexaneeEt2O); IR (KBr) 2139,
3.3.6. 4-Butyl-6-chloro-4-ethoxy-1,4-dihydro-3,1-benzoxazine-2-
1719 cmꢀ1
;
1H NMR (400 MHz)
d
1.44 (t, J¼7.3 Hz, 3H), 4.23 (q,
thione (3f). A white solid; mp 180e181 ꢁC (hexaneeTHF); IR (KBr)
J¼7.3 Hz, 2H), 7.24 (d, J¼8.3 Hz, 1H), 7.47 (dd, J¼8.3, 2.4 Hz, 1H), 7.96
3186, 1623, 1185 cmꢀ1; 1H NMR (400 MHz)
d
0.86 (t, J¼7.3 Hz, 3H),
(d, J¼2.4 Hz, 1H).
1.21 (t, J¼7.3 Hz, 3H),1.24e1.36 (m, 4H),1.99e2.06 (m,1H), 2.11e2.19
(m,1H), 3.40e3.47 (m,1H), 3.59e3.67 (m,1H), 6.87 (d, J¼8.8 Hz,1H),
7.23 (d, J¼2.0 Hz, 1H), 7.32 (dd, J¼8.8, 2.0 Hz,1H), 9.86 (br s, 1H); 13C
3.3. Typical procedure for the preparation of 4-alkoxy-
4-alkyl(or aryl)-1,4-dihydro-3,1-benzoxazine-2-thiones 3
NMR (125 MHz, CDCl3)
d 13.80, 14.96, 22.38, 24.93, 40.70, 60.26,
109.99, 115.47, 121.72, 125.37, 130.47, 130.51, 131.70, 182.96; MS m/z
299 (Mþ, 34), 242 (100). Anal. Calcd for C14H18ClNO2S: C, 56.08; H,
6.05; N, 4.67. Found: C, 55.83; H, 6.02; N, 4.67.
3.3.1. 4-Butyl-4-ethoxy-1,4-dihydro-3,1-benzoxazine-2-thione
(3a). To a stirred solution of 1a (0.21 g, 1.0 mmol) in THF (4 mL) at
ꢀ78 ꢁC was added n-BuLi (1.6 M in hexane; 1.0 mmol) dropwise. Stir-
ring was continued at the same temperature for 10 min before satu-
rated aqueous NH4Cl (10 mL) was added. The mixture was extracted
with AcOEt three times (10 mL each), and the combined extracts were
washed with brine (10 mL) and dried over anhydrous Na2SO4. Evapo-
ration of the solvent gave a residual solid, which was recrystallized
from hexaneeCH2Cl2 to give 3a (0.20 g, 76%); a white solid; mp
3.4. Typical procedure for the preparation of 2-(2-thioxo-1,
4-dihydro-3,1-benzoxazin-4-yl)acetic acid derivatives 4
3.4.1. N,N-Dimethyl-2-(4-ethoxy-2-thioxo-1,4-dihydro-3,1-benzox-
azin-4-yl)acetamide (4a). To a stirred solution of LDA (1.2 mmol),
generated by the standard method, in THF (5 mL) at ꢀ78 ꢁC was

4538
K. Kobayashi et al. / Tetrahedron 67 (2011) 4535e4538
added AcNMe2 (0.11 g, 1.2 mmol). After 15 min a solution of 1a
(0.25 g, 1.2 mmol) in THF (2 mL) was added and the stirring was
continued for 30 min before saturated aqueous NH4Cl (15 mL) was
added. The mixture was extracted with AcOEt three times (10 mL
each), and the combined extracts were washed with brine (10 mL)
and dried over anhydrous Na2SO4. After evaporation of the solvent
the residual solid was purified by recrystallization from hex-
aneeCHCl3 to give 4a (0.22 g, 63%); a pale-yellow solid; mp
179e180 ꢁC; IR (KBr) 3167,1618,1602,1169 cmꢀ1; 1H NMR(500 MHz)
(KBr) 3198, 1740, 1631, 1609, 1163 cmꢀ1; 1H NMR (600 MHz)
d 3.18 (d,
J¼16.0 Hz,1H), 3.25 (s, 3H), 3.30 (d, J¼16.0 Hz,1H), 3.59 (s, 3H), 3.81 (s,
3H), 6.77 (d, J¼2.9 Hz,1H), 6.87 (d, J¼8.6 Hz,1H), 6.92 (dd, J¼8.6, 2.9 Hz,
1H), 9.79 (br s, 1H); 13C NMR (125 MHz, CDCl3)
d 45.75, 51.35, 51.96,
55.70,106.23,110.11,115.47,116.69,118.98,127.31,157.26,167.99,181.45;
MS m/z 297 (Mþ, 5.8), 266 (100). Anal. Calcd for C13H15NO5S: C, 52.51;
H, 5.09; N, 4.71. Found: C, 52.33; H, 5.19; N, 4.49.
3.4.7. 1,1-Dimethylethyl 2-(6-chloro-4-ethoxy-2-thioxo-1,4-dihydro-
d
1.18 (t, J¼7.4 Hz, 3H), 2.84 (s, 3H), 3.05 (s, 3H), 3.20 (d, J¼15.5 Hz,
3,1-benzoxazin-4-yl)acetate (4g). A white solid; mp 158e159 ꢁC
1H), 3.24e3.29 (m, 1H), 3.38 (d, J¼15.5 Hz, 1H), 3.54e3.59 (m, 1H),
6.81 (d, J¼8.0 Hz,1H), 7.15 (td, J¼7.4,1.1 Hz,1H), 7.23 (dd, J¼7.4,1.1 Hz,
1H), 7.29 (ddd, J¼8.0, 7.4, 1.1 Hz, 1H), 9.56 (br s, 1H); 13C NMR
(hexaneeCH2Cl2); IR (KBr) 3185, 1724, 1619, 1170 cmꢀ1 1H NMR
;
(500 MHz)
d
1.19 (t, J¼6.9 Hz, 3H), 1.29 (s, 9H), 3.09 (d, J¼15.5 Hz, 1H),
3.26 (d, J¼15.5 Hz, 1H), 3.33e3.39 (m,1H), 3.55e3.61 (m,1H), 6.87 (d,
J¼8.6Hz,1H), 7.27(d,J¼2.3Hz,1H),7.33(dd,J¼8.6,2.3Hz,1H),9.99(br
(150 MHz, DMSO-d6)
d 14.73, 34.49, 36.65, 43.43, 58.00, 105.62,
113.71, 119.42, 124.20, 125.02, 129.67, 133.88, 166.64, 181.28; MS m/z
(%) 294 (Mþ, 6.0), 249 (100). Anal. Calcd for C14H18N2O3S: C, 57.12; H,
6.16; N, 9.52. Found: C, 56.95; H, 6.21; N, 9.48.
s, 1H); 13C NMR (125 MHz, CDCl3)
d 14.79, 27.75, 47.50, 59.94, 82.01,
105.82,115.25,120.54,125.50,130.37,130.76,131.86,166.41,182.14;MS
m/z 357 (Mþ, 7.0), 312 (24), 301 (100). Anal. Calcd for C16H20ClNO4S: C,
53.70; H, 5.63; N, 3.91. Found: C, 53.68; H, 5.69; N, 3.87.
3.4.2. 2-(4-Ethoxy-2-thioxo-1,4-dihydro-3,1-benzoxazin-4-yl)-N,
N-diethylacetamide (4b). A white solid; mp 151e152 ꢁC (hex-
3.5. Ethyl 2-(thiopropanoylamino)benzoate (5)9
aneeCH2Cl2); IR (KBr) 3196, 1624, 1604, 1172 cmꢀ1 1H NMR (500
;
MHz3)
d
1.01 (t, J¼7.4 Hz, 3H), 1.18 (t, J¼6.9 Hz, 6H), 3.18 (d, J¼15.5 Hz,
To a stirred solution of 1a (0.21 g, 1.0 mmol) in THF (4 mL) at
ꢀ78 ꢁC was added EtMgBr (3 M in Et2O; 1.0 mmol) dropwise. After
20 min saturated aqueous NH4Cl (10 mL) was added and the
mixture was extracted with AcOEt three times (10 mL each). The
combined extracts were washed with brine (10 mL), dried over
anhydrous Na2SO4, and concentrated by evaporation. The residue
was purified by preparative TLC on silica gel to give 5 (86 mg,
36%); a yellow oil; Rf 0.16 (hexane); IR (neat) 3250, 1694, 1609,
1H), 3.18e3.35 (m, 4H), 3.35 (d, J¼15.5 Hz, 1H), 3.39e3.46 (m, 1H),
3.54e3.60 (m, 1H), 6.79 (d, J¼8.0 Hz, 1H), 7.16 (ddd, J¼8.0, 7.4, 1.1 Hz,
1H), 7.24 (d, J¼8.0 Hz, 1H), 7.30 (ddd, J¼8.0, 7.4, 1.1 Hz, 1H), 9.41 (br s,
1H); 13C NMR (150 MHz, CDCl3)
d 12.83, 14.24, 14.79, 40.23, 42.36,
45.19, 59.64,107.49,114.11,119.16,124.77,125.23,130.20,133.63,165.97,
182.38; MS m/z 322 (Mþ, 8.2), 277 (100). Anal. Calcd for C16H22N2O3S:
C, 59.60; H, 6.88; N, 8.69. Found: C, 59.54; H, 6.95; N, 8.59.
1263 cmꢀ1
;
1H NMR (500 MHz)
d
1.428 and 1.433 (2t, J¼7.8 and
3.4.3. 2-(4-Ethoxy-2-thioxo-1,4-dihydro-3,1-benzoxazin-4-yl)-1-
(pyrrolidin-1-yl)ethanone (4c). A white solid; mp 158e161 ꢁC (hex-
aneeCH2Cl2); IR (KBr) 3171, 1614, 1601, 1165 cmꢀ1; 1H NMR (500 MHz,
6.8, respectively, combined 6H), 2.92 (q, J¼7.8 Hz, 2H), 4.41 (q,
J¼6.8 Hz, 2H), 7.23 (dd, J¼8.8, 7.8 Hz, 1H), 7.60 (ddd, J¼8.8, 7.8,
2.0 Hz, 1H), 8.10 (d, J¼7.8 Hz, 1H), 9.54 (d, J¼8.8 Hz, 1H), 12.39 (br s,
CDCl3)
d
1.18 (t, J¼6.9 Hz, 3H),1.74e2.02 (m, 4H), 3.11 (d, J¼15.5 Hz, 1H),
1H); 13C NMR (150 MHz, CDCl3)
d 13.77, 14.14, 43.79, 61.74, 117.64,
3.27e3.44 (m, 5H), 3.55e3.61 (m, 2H), 6.78 (d, J¼8.0 Hz, 1H), 7.16 (td,
121.54, 124.63, 130.91, 133.72, 141.59, 168.08, 206.34; MS m/z 237
J¼7.4,1.1 Hz,1H), 7.26 (d, J¼7.4 Hz,1H), 7.30 (ddd, J¼8.0, 7.4,1.1 Hz,1H),
(Mþ, 100).
9.29 (br s, 1H); 13C NMR (125 MHz, CDCl3)
d 14.81, 24.28, 26.07, 45.83,
46.91, 47.16, 59.62,107.37,114.29,119.04,124.77,125.23,130.24,133.72,
165.36, 182.31; MS m/z 320 (Mþ, 6.5), 275 (100). Anal. Calcd for
C16H20N2O3S: C, 59.98; H, 6.29; N, 8.74. Found: C, 59.90; H, 6.40; N, 8.52.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scien-
tific Research (C) 22550035 from Japan Society Fro the Promotion of
Science. We thank Mrs. Miyuki Tanmatsu of this university for as-
sistance in recording mass spectra and performing combustion
analyses.
3.4.4. Ethyl 2-(4-ethoxy-2-thioxo-1,4-dihydro-3,1-benzoxazin-4-yl)
acetate (4d). A white solid; mp 84e87 ꢁC (hexaneeCH2Cl2); IR (KBr)
3194, 1738, 1622, 1605, 1161 cmꢀ1 1H NMR (500 MHz)
; d 1.11 (t,
J¼7.4 Hz, 3H), 1.18 (t, J¼7.4 Hz, 3H), 3.19 (d, J¼16.6 Hz, 1H), 3.28e3.34
(m, 2H), 3.55e3.61 (m, 1H), 3.97e4.03 (m, 2H), 6.91 (d, J¼7.4 Hz, 1H),
7.19 (td, J¼7.4,1.1 Hz,1H), 7.27 (dd, J¼8.0,1.1 Hz,1H), 7.36 (ddd, J¼8.0,
References and notes
7.4,1.1Hz,1H), 9.95(brs,1H); 13CNMR (150MHz,CDCl3)
d13.87, 14.78,
46.50, 59.83, 60.91, 106.22, 113.88, 118.59, 125.26, 125.40, 130.68,
133.37,167.57,182.53; MS m/z 295 (Mþ, 5.4), 250 (100). Anal. Calcd for
C14H17NO4S:C,56.93;H, 5.80;N,4.74.Found:C,56.82;H, 5.94;N,4.52.
1. (a) Fensome, A.; Bender, R.; Chopra, R.; Cohen, J.; Collins, M. A.; Hudak, V.;
Malakian, K.; Lockhead, S.; Olland, A.; Svenson, K.; Terefenko, E. A.; Unwalla, R. J.;
Wilhelm, J. M.; Wolform, S.; Zhu, Y.; Zhang, Z.; Zhang, P.; Winneker, R. C.;
Wrobel, J. J. Med. Chem. 2005, 48, 5092e5095; (b) Kern, J. C.; Terefenko, E. A.;
Fensome, A.; Unwallla, R.; Wrobel, J.; Zhu, Y.; Cohen, J.; Winneker, R.; Zhang, Z.;
Zhang, P. Bioorg. Med. Chem. Lett. 2007, 17, 189e192; (c) Nakagawa, A.; Uno, S.;
Makishima, M.; Miyachi, H.; Hashimoto, Y. Bioorg. Med. Chem. 2008, 16,
7046e7054; (d) Zhou, H.-B.; Lee, J. H.; Mayne, C. G.; Carson, K. E.; Katze-
nellenbogen, J. A. J. Med. Chem. 2010, 53, 3349e3360.
2. Kobayashi, K.; Yokoi, Y.; Komatsu, T.; Konishi, H. Tetrahedron 2010, 66,
9336e9339.
3. Theeraladanon, C.; Arisawa, M.; Nishida, A.; Nakagawa, M. Tetrahedron 2004, 60,
3017e3035.
3.4.5. 2-(4-Methoxy-2-thioxo-1,4-dihydro-3,1-benzoxazin-4-yl)-1-
(piperidin-1-yl)ethanone (4e). A pale-yellow solid; mp 154e156 ꢁC
(hexaneeCH2Cl2); IR (KBr) 3198, 1647, 1624, 1601, 1171 cmꢀ1 1H
;
NMR (600 MHz)
d
1.45e1.61 (m, 6H), 3.20 (s, 3H), 3.26 (d, J¼15.4 Hz,
1H), 3.38 (d, J¼15.4 Hz, 1H), 3.40e3.51 (m, 4H), 6.86 (d, J¼7.9 Hz,
1H), 7.15 (td, J¼7.5, 1.0 Hz, 1H), 7.25 (d, J¼7.5 Hz, 1H), 7.27 (ddd,
J¼7.9, 7.5, 1.0 Hz, 1H), 10.33 (br s, 1H); 13C NMR (125 MHz, CDCl3)
4. Kobayashi, K.; Takanohashi, A.; Hashimoto, K.; Morikawa, O.; Konishi, H. Tetra-
hedron 2006, 62, 3158e3161.
5. Kobayashi, K.; Yoneda, K.; Miyamoto, K.; Morikawa, O.; Konishi, H. Tetrahedron
d
24.36, 25.42, 26.31, 42.76, 44.66, 47.27, 51.22, 107.58, 114.27,
118.45, 124.84, 125.36, 130.37, 133.80, 165.11, 182.36; MS m/z 320
(Mþ, 5.8), 289 (100). Anal. Calcd for C16H20N2O3S: C, 59.98; H, 6.29;
N, 8.74. Found: C, 59.82; H, 6.40; N, 8.51.
2004, 60, 11639e11645.
6. Ito, Y.; Kobayashi, K.; Seko, N.; Saegusa, T. Bull. Chem. Soc. Jpn. 1984, 57, 73e84.
7. Fujiwara, S.; Shin-Ike, T.; Sonoda, N.; Aoki, M.; Okada, K.; Miyoshi, N.; Kambe, N.
Tetrahedron Lett. 1991, 32, 3503e3506.
8. Venugopalan, B.; Bapat, C. P.; Kaenik, P. J.; Chatterjee, D. K.; Iyer, N.; Lepcha, D.
J. Med. Chem. 1995, 38, 1922e1927.
9. Clausen, K.; Lawesson, S. O. Bull. Soc. Chim. Belg. 1979, 88, 305e311.
3.4.6. Methyl 2-(4,6-dimethoxy-2-thioxo-1,4-dihydro-3,1-benzoxazin-
4-yl)acetate (4f). A white solid; mp 171e173 ꢁC (hexaneeCH2Cl2); IR