Synthesis of 3,4-dihydro-2H-1,3-benzoxazine-2-thiones via cyclization of 2-(1-isothiocyanatoalkyl)phenols

Article abstract of DOI:10.3987/COM-15-S(T)2

Convenient sequences for the preparation of 3,4-dihydro-2H-1,3-benzoxazine-2-thiones from 2-hydroxybenzaldehyde and 2-hydroxyphenyl ketones or 2-methylphenols have been developed, which both employ cyclization of 2-(1-isothiocyanatoalkyl)phenols generated

Full text of DOI:10.3987/COM-15-S(T)2

HETEROCYCLES, Vol. 93, No. 1, 2016, pp. -. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 3rd June, 2015, Accepted, 25, June, 2015, Published online, 15th July 2015
DOI: 10.3987/COM-15-S(T)2
SYNTHESIS OF 3,4-DIHYDRO-2H-1,3-BENZOXAZINE-2-THIONES VIA
CYCLIZATION OF 2-(1-ISOTHIOCYANATOALKYL)PHENOLS
Kazuhiro Kobayashi,* Hiroki Inouchi, Naoki Matsumoto, and Yuuki
Chikazawa
Division of Applied Chemistry, Department of Chemistry and Biotechnology,
Graduate School of Engineering, Tottori University, 4-101 Koyama-minami,
Tottori 680-8552, Japan; E-mail: kkoba@chem.tottori-u.ac.jp
Abstract
–
Convenient
sequences
for
the
preparation
of
3,4-dihydro-2H-1,3-benzoxazine-2-thiones from 2-hydroxybenzaldehyde and
2-hydroxyphenyl ketones or 2-methylphenols have been developed, which both
employ cyclization of 2-(1-isothiocyanatoalkyl)phenols generated in situ under
mild conditions.
INTRODUCTION
Some 3,4-dihydro-2H-1,3-benzoxazine-2-thione derivatives were reported to exhibit antidepressant
activity in 1969.1 In 1977 Arct et al. demonstrated that the synthesis of 4-nonsubstituted
3,4-dihydro-2H-1,3-benzoxazine-2-thiones
can
be
achieved
by
reacting
o-hydroxybenzyltrimethylammonium salts with potassium thiocyanate,2 and two years after these
3,4-dihydro-2H-1,3-benzoxazine-2-thione derivatives were shown to be potential fungicides.3 However,
few methods for the preparation of this class of heterocycles have been reported since then, though only
one method has been reported by Yadav et al., which utilizes montmorillonite catalyzed cyclization of
salicylaldehyde 4-arylsemicarbazone.4 On the other hand, we recently reported a convenient synthesis of
1-acyl-3,4-dihydroquinazoline-2(1H)-thiones
via
cyclization
of
N-[2-(isothiocyanatomethyl)phenyl]carboxamides generated in situ.5 In respect to this method, we
envisioned that the achievement of the generation of 2-(1-isothiocyanatoalkyl)phenols would lead to
development of new methods for the preparation of 3,4-dihydro-2H-1,3-benzoxazine-2-thiones. We now
wish to report our investigations which reveal that the isothiocyanatophenols (6) can be generated from
commercially available 2-hydroxybenzaldehyde and 2-hydroxyphenyl ketones (1) utilizing a simply
operated sequence and that they cyclized cleanly under mild conditions to give the desired

3,4-dihydro-2H-1,3-benzoxazine-2-thiones (7). An alternative sequence starting with 2-methylphenols (8),
via cyclization of the corresponding 2-(1-isothiocyanatoalkyl)phenols, is also described.
RESULTS AND DISCUSSION
The synthesis of 7 from 1 was conducted according to the sequence illustrated in Scheme 1. The reaction
of 1 with formamide and formic acid at 120 ˚C afforded the corresponding formylaminophenols (2) in
reasonable yields. O-tert-Butoxycarbonylation of 2 with di-tert-butyl dicarbonate in dichloromethane
could be shortly achieved at 0 ˚C using a catalytic amount of 4-(dimethylamino)pyridine (DMAP) to
provide formylamino carbonates (3) in excellent yields. Conversion of these formamides (3) into the
corresponding isothiocyanates (5), via isocyanides (4), was carried out by applying the reported
procedures.6,7 Thus, compounds (3) were allowed to react with phosphoryl chloride in THF in the
presence of triethylamine at 0 ˚C to result in the formation of 4, which, without any purification after
usual aqueous workup, were further treated with sulfur in THF in the presence of a catalytic amount of
selenium and excess triethylamine at room temperature to afford 5 in good overall yields. These results
are summarized in Table 1.
R3
R3
O
R1
R2
R1
R2
R1
R2
HCONH2, HCO2H
120 ˚C
R3
OH
(Boc)2O, cat. DMAP
CH2Cl2, 0 ˚C
NHCHO
OH
NHCHO
OBoc
2
3
1
R3
R3
R1
R2
R1
S8, Cat. Se, Et3N, THF, rt
POCl3, Et3N, THF, 0 ˚C
NCS
OBoc
NC
OBoc
R2
4
5
R3
R3
R1
R1
R2
Et3N, 0 ˚C
NH
TFA, CH2Cl2, 0 ˚C
NCS
OH
R2
O
S
7
6
Scheme 1
The isothiocyanatocarbonate (5), thus obtained, were treated with trifluoroacetic acid in dichloromethane
at 0 ˚C to generate 2-(1-isothiocyanatoalkyl)phenol intermediates (6), which on treatment with excess
triethylamine at the same temperature underwent clean cyclization by intramolecular attack of the
hydroxy oxygen on the isothiocyanato carbon to afford, after aqueous workup followed by purification of

the crude products by column chromatography on silica gel, the desired products (7). The yields of the
products were fair to good as compiled in Table 1 as well.
Table 1. Preparation of 3,4-dihydro-2H-1,3-benzoxazine-2-thiones (7)
Entry
1
2
Yielda
64
3
Yielda
94
5
Yielda,b
86
74
7
Yielda,c
81
67
1
2
3
4
5
6
7
8
1a (R1 = R2 = R3 = H)
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
5a
5b
5c
5d
5e
5f
7a
7b
7c
7d
7e
7f
1b (R1 = R2 = H, R3 = Me)
1c (R1 = R2 = H, R3 = Et)
1d (R1 = R2 = H, R3 = Ph)
1e (R1 = H, R2 = R3 = Me)
1f (R1 = R3 = Me, R2 = H)
1g (R1 = Cl, R2 = H, R3 = Me)
72
61
84
64
63
65
62
87
97
89
85
94
85
85
79
72
85
78
87
87
67
71
61
70
64
70
2g
3g
3h
5g
5h
7g
7h
1h (R1 = MeO, R2 = H, R3 = Me) 2h
a Yields/% of isolated products. b Yields from 3. c Yields from 5.
Me
Me
(Boc)2O, cat. DMAP, CH2Cl2, 0 ˚C for 8a
R
OH
R
OR'
AcCl, Py, THF, rt, for 8b
a R = H, R' = Boc
b R = Cl, R' = Ac
8
9a 92%
9b 87%
CH2N3
OR'
CH2Br
NaN3, DMF, rt
NBS, cat. AIBN
MeCO2t-Bu, reflux
R
R
OR'
10
11a 57%
11b 53%
CH2N3
OH
TFA, CH2Cl2, 0 ˚C for 11a
10% aq. HCl, THF, reflux for 11b
1. PPh3, CH2Cl2, rt
NH
2. CS2, MeCN, reflux
R
O
S
R
12a 70%
12b 88%
13a (= 7a) 70%
13b 74%
Scheme 2
We then decided to carry out exploration of an alternative method using 2-methylphenols as simpler
starting materials and tert-butoxycarbonyl and acetyl groups as protecting groups. We have found that
3,4-dihydro-2H-1,3-benzoxazine-2-thione (13a = 7a) and 7-chloro-3,4-dihydro-2H-1,3-benzoxazine-2-
thione (13b) can be prepared from 2-methylphenol (8a) and 5-chloro-2-methylphenol (8b), respectively,
via six-step operationally simple sequences (Schemes 2). Thus, the hydroxy groups of 8a and 8b were
protected as the tert-butyl carbonate (9a) on treatment with di-tert-butyl dicarbonate in dichloromethane
in the presence of a catalytic amount of 4-(dimethylamino)pyridine (DMAP) at 0 ˚C and as the acetate
(9b) on treatment with acetyl chloride in THF in the presence of pyridine at room temperature. Benzylic
bromination of compounds (9) was then achieved with N-bromosuccinimide (NBS) in the presence of a

catalytic amount of azobisisobutyronitrile (AIBN) in refluxing tert-butyl acetate. The resulting bromides
(10) were used without purification in the next reaction with sodium azide in DMF at room temperature
to afford benzyl azides (11) in reasonable yields from 9. Treatment of 11a with trifluoroacetic acid (TFA)
in dichloromethane at 0 ˚C gave 2-(azidomethyl)phenol (12a). Hydrolysis of 11b with 10% hydrochloric
acid in refluxing THF gave 2-(azidomethyl)-5-chlorophenol (12b). The reaction of compounds (12) with
triphenylphosphine in dichloromethane at room temperature was followed by treatment with excess
carbon disulfide in refluxing acetonitrile to generate the corresponding 2-(isothiocyanatomethyl)phenols,
cyclization of which occurred immediately under the reaction conditions to result in the formation of
3,4-dihydro-2H-1,3-benzoxazine-2-thiones (13) in satisfactory yields. Unfortunately, however, this
method is only applicable to the synthesis of 4-nonsubstituted derivatives. Starting from 2-ethylphenol,
the transformation of the corresponding azide into isothiocyanate did not proceed cleanly to give the
desired product in very low yield.
In conclusion, the results detailed herein demonstrate that 3,4-dihydro-2H-1,3-benzoxazine-2-thiones can
be conveniently prepared from commercially available starting materials. These methods may be of value
in organic synthesis because of their usefulness in the simple manipulations.
EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are
1
uncorrected. IR spectra were recorded with a Perkin–Elmer Spectrum65 FTIR spectrophotometer. H
13
NMR and C NMR spectra were recorded using TMS as an internal reference with a JEOL ECP500 FT
NMR spectrometer operating at 500 and 125 MHz, respectively. High-resolution MS spectra (DART,
positive) were measured by a Thermo Scientific Exactive spectrometer. Elemental analyses were
performed with an Elementar Vario EL II instrument. TLC was carried out on Merck Kieselgel 60 PF254.
Column chromatography was performed 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.
Starting Materials. All chemicals used in this study were commercially available.
Typical
Procedure
for
the
Preparation
of
Formamides
(2).
N-[(2-Hydroxyphenyl)methyl]formamide (2a).8 A mixture of 2-hydroxybenzaldehyde (2.4 g, 20 mmol),
HCONH2 (11 g, 0.23 mol), and HCO2H (7.5 g, 0.16 mol) was heated at 120 ˚C for 6 h. After cooling to rt,
the mixture was diluted with H2O (100 mL) and extracted with AcOEt (3 × 25 mL). The combined
extracts were washed with saturated aqueous NaHCO3 (4 × 20 mL) and brine (20 mL), dried (Na2SO4),
and concentrated by evaporation. The residue was purified by column chromatography on SiO2
(AcOEt/CH2Cl2 1:2) to afford 2a (1.9 g, 64%); a white solid; mp 87–90 ˚C (hexane/CH2Cl2) (lit.,8 mp
92–93 ˚C); IR (KBr) 3223, 1644, 1607 cm–1; 1H NMR (CDCl3) δ 4.40 (d, J = 6.3 Hz, 2H), 6.58 (br s, 1H),

6.85 (ddd, J = 7.4, 6.3, 1.1 Hz, 1H), 6.95 (dd, J = 8.0, 1.1 Hz, 1H), 7.11 (dd, J = 7.4, 1.7 Hz, 1H), 7.23
(ddd, J = 8.0, 6.3, 1.7 Hz, 1H), 8.15 (s, 1H), 8.74 (s, 1H).
N-[1-(2-Hydroxyphenyl)ethyl]formamide (2b): a colorless oil; Rf 0.16 (AcOEt/hexane 1:1); IR (neat)
3276, 1657, 1608 cm–1; 1H NMR (CDCl3) δ 1.59 and 1.60 (2d, J = 7.4 and 6.9 Hz, respectively, combined
3H), 4.62–4.68 and 5.33–5.39 (2m, combined 1H), 6.28 (br s, 1H), 6.82–6.94 (m, 2H), 7.06–7.22 (m, 2H),
8.07–8.57 (m, 2H). Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.18; H, 6.70; N,
8.31.
N-[1-(2-Hydroxyphenyl)propyl]formamide (2c): a pale-yellow oil; Rf 0.23 (AcOEt/hexane 1:1); IR
1
(neat) 3272, 1660, 1608 cm–1; H NMR (CDCl3) δ 0.92 and 0.98 (2t, J = 7.4 Hz, each, combined
3H),1.95–2.01 (m, 2H), 4.97 and 6.05 (2q, J = 7.4 Hz each, combined 1H), 6.25 (br s, 1H), 6.83–6.94 (m,
2H), 7.12–7.22 (m, 2H), 8.12–9.00 (m, 2H). Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82.
Found: C, 66.95; H, 7.41; N, 7.68.
N-[(2-Hydroxyphenyl)(phenyl)methyl]formamide (2d): a pale-yellow solid; mp 152–154 ˚C
1
(hexane/CH2Cl2); IR (KBr) 3327, 1652, 1635 cm–1; H NMR (CDCl3) δ 6.04 and 6.42 (2d, J = 9.2 Hz
each, combined 1H), 6.75–9.62 (m, 12H). Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found:
C, 73.93; H, 5.87; N, 6.07.
N-[1-(2-Hydroxy-4-methylphenyl)ethyl]formamide (2e): a yellow oil; Rf 0.22 (AcOEt/hexane 1:1); IR
1
(neat) 3300, 1663, 1632 cm–1; H NMR (CDCl3) δ 1.51 and 1.57 (2d, J = 7.4 Hz each, combined 3H),
2.24 and 2.26 (2s, combined 3H), 4.61 and 5.30 (2 quint, J = 7.4 Hz each, combined 1H), 6.45 (br s, 1H),
6.63–7.35 (m, 3H), 8.04–8.79 (m, 2H). Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C,
73.93; H, 5.87; N, 6.07.
N-[1-(2-Hydroxy-5-methylphenyl)ethyl]formamide (2f): a pale-yellow solid; mp 161–163 ˚C
1
(hexane/CH2Cl2); IR (KBr) 3291, 1659, 1627 cm–1; H NMR (CDCl3) δ 1.57 and 1.60 (2d, J = 6.9 Hz
each, combined 3H), 2.25 and 2.27 (2s, combined 3H), 4.62–4.66 and 5.30–5.36 (2m, combined 1H),
6.19 (br, 1H), 6.72–8.18 (m, 5H). Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82 Found: C, 67.02;
H, 7.45; N, 7.61.
N-[1-(5-Chloro-2-hydroxyphenyl)ethyl]formamide (2g): a pale-yellow solid; mp 169–172 ˚C
1
(hexane/CH2Cl2); IR (KBr) 3295, 1667, 1634 cm–1; H NMR (CDCl3) δ 1.26 and 1.33 (2d, J = 6.9 Hz
each, combined 3H)), 4.86 and 5.17 (2quint, J = 6.9 Hz each, combined 1H), 6.78–9.85 (m, 6H). Anal.
Calcd for C9H10ClNO2: C, 54.15; H, 5.05; N, 7.02. Found: C, 54.03; H, 5.25; N, 6.88.
N-[1-(2-Hydroxy-5-methoxyphenyl)ethyl]formamide (2h): a yellow solid; mp 134–137 ˚C
1
(hexane/CH2Cl2); IR (KBr) 3261, 1637 cm–1; H NMR (CDCl3) δ 1.25 and 1.32 (2d, J = 6.9 Hz, each,
combined 3H), 4.86 and 5.18 (2quint, J = 6.9 Hz each, combined 1H), 3.64 and 3.65 (2s, combined 3H),

6.60–9.14 (m, 6H). Anal. Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.18. Found: C, 61.47; H, 6.78; N,
7.06.
Typical
Procedure
for
the
Preparation
of
Carbonates
(3).
1,1-Dimethylethyl
2-[(Formylamino)methyl]phenyl Carbonate (3a). To a stirring solution of 2a (0.35 g, 2.3 mmol),
4-(dimethylamino)pyridine (DMAP) (29 mg, 0.23 mmol) in CH2Cl2 (4 mL) at 0 ˚C was added dropwise
(Boc)2O (0.56 g, 2.6 mmol). After 5 min, the mixture was diluted with AcOEt (30 mL), washed with H2O
(2 × 10 mL) and brine (10 mL), dried (Na2SO4), and concentrated by evaporation. The residue was
purified by column chromatography on SiO2 to afford 3a (0.48 g, 78%); a pale-yellow oil; Rf 0.43
1
(AcOEt/CH2Cl2 1:2); IR (neat) 3287, 1758, 1666, 1147 cm–1; H NMR (CDCl3) δ 1.56 (s, 9H), 4.37 and
4.45 (2d, J = 5.7 Hz each, combined 2H), 5.99 (br, 1H), 7.15 (dd, J = 8.0, 1.1 Hz, 1H), 7.24 (ddd, J = 7.4,
6.3, 1.1 Hz, 1H), 7.34 (ddd, J = 8.0, 6.3, 1.7 Hz, 1H), 7.40 (dd, J = 7.4, 1.7 Hz, 1H), 8.18 and 8.20 (2s,
combined 1H). Anal. Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 62.11; H, 7.05; N, 5.57.
1,1-Dimethylethyl 2-[1-(Formylamino)ethyl]phenyl Carbonate (3b): a pale-yellow oil; Rf 0.45
1
(AcOEt/hexane 2:1); IR (neat) 3285, 1759, 1667, 1148 cm–1; H NMR (CDCl3) δ 1.50 and 1.53 (2d, J =
6.9 and 7.4 Hz, respectively, combined 3H), 1.56 (s, 9H), 4.88 and 5.37 (2quint, J = 7.4 and 6.9 Hz,
respectively, combined 1H), 5.90 and 5.98 (2br s, combined 1H), 7.16–7.25 (m, 2H), 7.31–7.36 (m, 2H),
8.13–8.17 (m, 1H). Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.28; H, 7.44; N,
5.28.
1,1-Dimethylethyl 2-[1-(Formylamino)propyl]phenyl Carbonate (3c): a pale-yellow oil; Rf 0.45
1
(AcOEt/CH2Cl2 1:3); IR (neat) 3284, 1759, 1662, 1148 cm–1; H NMR (CDCl3) δ 0.88 and 0.95 (2t, J =
7.4 Hz each, combined 3H), 1.56 (s, 9H), 1.74–1.92 (m, 2H), 4.54 and 5.14 (2q, J = 7.4 Hz each,
combined 1H), 5.95 and 6.05 (2br s, combined 1H), 7.16–7.25 (m, 2H), 7.30–7.35 (m, 2H), 8.11–8.36 (m,
1H). Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.50; H, 7.70; N, 4.91.
1,1-Dimethylethyl 2-[(Formylamino)(phenyl)methyl]phenyl Carbonate (3d): a pale-yellow solid; mp
1
143–145 ˚C (hexane/CH2Cl2); IR (KBr) 3320, 1761, 1660, 1146 cm–1; H NMR (CDCl3) δ 1.36 and 1.37
(2s, combined 9H), 5.93 and 6.51 (2d, J = 8.6 Hz each, combined 1H), 6.33 and 6.45 (br, combined 1H),
7.18–7.39 (m, 9H), 8.22–8.33 (m, 1H). Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C,
69.64; H, 4.63; N, 3.98.
1,1-Dimethylethyl 2-[1-(Formylamino)ethyl]-5-methylphenyl Carbonate (3e): a colorless oil; Rf 0.40
1
(AcOEt/hexane 1:1); IR (neat) 3273, 1759, 1664, 1241 cm–1; H NMR (CDCl3) δ 1.49 and 1.51 (2d, J =
6.9 Hz each, combined 3H), 1.56 (s, 9H), 2.345 and 2.352 (2s, combined 3H), 4.83 and 5.31 (2quint, J =
6.9 Hz each, combined 1H), 6.97–8.16 (m, 5H). Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01.
Found: C, 64.46; H, 7.60; N, 4.81.

1,1-Dimethylethyl 2-[1-(Formylamino)ethyl]-4-methylphenyl Carbonate (3f): a pale-yellow oil; Rf
0.36 (AcOEt/hexane 1:1); IR (neat) 3281, 1756, 1664 cm–1; 1H NMR (CDCl3) δ 1.47 and 1.49 (2d, J = 6.9
Hz each, combined 3H), 1.54 and 1.55 (2s, combined 9H), 2.05 and 2.33 (2s, combined 3H), 4.82 and
5.31 (2quint, J = 6.9 Hz each, combined 1H), 6.05 (br, 1H), 7.02–8.15 (m, 4H). Anal. Calcd for
C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.31; H, 7.70; N, 4.90.
4-Chloro-2-[1-(Formylamino)ethyl]phenyl 1,1-Dimethylethyl Carbonate (3g): a yellow oil; Rf 0.48
(AcOEt/hexane 1:1); IR (neat) 3279, 1760, 1663 cm–1; 1H NMR (CDCl3) δ 1.48 and 1.52 (2d, J = 6.9 Hz
each, 3H), 1.56 (s, 9H), 4.84 and 5.33 (2quint, J = 6.9 Hz each, combined 1H), 5.94 (br, 1H), 7.11–8.16
(m, 4H). Anal. Calcd for C14H18ClNO4: C, 56.10; H, 6.05; N, 4.67. Found: C, 56.07; H, 6.06; N, 4.61.
1,1-Dimethylethyl 2-[1-(Formylamino)ethyl]-4-methoxyphenyl Carbonate (3h): a beige oil; Rf 0.27
(AcOEt/hexane 2:1); IR (neat) 3280, 1757, 1663 cm–1; 1H NMR (CDCl3) δ 1.48 and 1.51 (2d, J = 6.9 Hz
each, combined 3H), 1.55 (s, 9H), 3.80 (s, 3H), 4.81 and 5.23 (2quint, J = 6.9 Hz each, combined 1H),
5.98 (br s, 1H), 6.80–8.16 (m, 4H). Anal. Calcd for C15H21NO5: C, 61.00; H, 7.17; N, 4.74. Found: C,
60.94; H, 7.28; N, 4.60.
General Procedure for the Preparation of Isothiocyanates (5). Compounds (3) (1.0 mmol) were
treated with POCl3 (0.22 g, 1.5 mmol) in the presence of Et3N (0.71 g, 7.0 mmol) under conditions
reported previously.6 After aqueous workup, the crude isocyanides 4 were, without any purification,
subjected to the treatment with S8 (32 mg, 1.0 mmol) in the presence of a catalytic amount of Se (4.7 mg,
0.060 mmol) and excess Et3N (0.35 mL) at rt.7 The crude products were purified by column
chromatography on SiO2 to give 5.
1,1-Dimethylethyl 2-(Isothiocyanatomethyl)phenyl Carbonate (5a): a pale-yellow oil; Rf 0.12
1
(CH2Cl2/hexane 1:2); IR (neat) 2173, 2094, 1760 cm–1; H NMR (CDCl3) δ 1.57 (s, 9H), 4.74 (s, 2H),
7.22 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), 7.38 (dd, J = 8.0, 7.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H).
Anal. Calcd for C13H15NO3S: C, 58.85; H, 5.70; N, 5.28. Found: C, 58.53; H, 5.81; N, 5.24.
1,1-Dimethylethyl 2-(1-Isothiocyanatoethyl)phenyl Carbonate (5b): a yellow oil; Rf 0.32
(AcOEt/hexane 1:10); IR (neat) 2124, 2093, 1760 cm–1; 1H NMR (CDCl3) δ 1.56 (s, 9H), 1.65 (d, J = 6.8
Hz, 3H), 5.18 (q, J = 6.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.30 (dd, J = 7.8, 7.4 Hz, 1H), 7.35 (dd, J =
7.8, 7.4 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H). Anal. Calcd for C14H17NO3S: C, 60.19; H, 6.13; N, 5.01.
Found: C, 60.06; H, 6.44; N, 4.85.
1,1-Dimethylethyl 2-(1-Isothiocyanatopropyl)phenyl Carbonate (5c): a yellow oil; Rf 0.28
1
(AcOEt/hexane 1:10); IR (neat) 2084, 1760 cm–1; H NMR (CDCl3) δ 1.04 (t, J = 7.4 Hz, 3H), 1.56 (s,
9H), 1.93 (qd, J = 7.4, 6.3 Hz, 2H), 4.99 (t, J = 6.3 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.29 (t, J = 7.4 Hz,
1H), 7.35 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H). Anal. Calcd for C15H19NO3S: C, 61.41; H, 6.53; N,
4.77. Found: C, 61.30; H, 6.67; N, 4.71.

1,1-Dimethylethyl 2-[(Isothiocyanato)(phenyl)methyl]phenyl Carbonate (5d): a yellow oil; Rf 0.37
(CH2Cl2/hexane 1:2); IR (neat) 2068, 1760 cm–1; 1H NMR (CDCl3) δ 1.47 (s, 9H), 6.28 (s, 1H), 7.20 (d, J
= 8.0 Hz, 1H), 7.26–7.39 (m, 7H), 7.46 (dd, J = 7.4, 1.7 Hz, 1H). Anal. Calcd for C19H19NO3S: C, 66.84;
H, 5.61; N, 4.10. Found: C, 66.72; H, 5.63; N, 4.02.
1,1-Dimethylethyl 2-(1-Isothiocyanatoethyl)-5-methylphenyl Carbonate (5e): a beige oil; Rf 0.29
(CH2Cl2/hexane 1:3); IR (neat) 2132, 2086, 1759 cm–1; 1H NMR (CDCl3) δ 1.56 (s, 9H), 1.63 (d, J = 6.3
Hz, 3H), 2.36 (s, 3H), 5.12 (q, J = 6.3 Hz, 1H), 6.98 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz,
1H). Anal. Calcd for C15H19NO3S: C, 61.41; H, 6.53; N, 4.77. Found: C, 61.34; H, 6.51; N, 4.69.
1,1-Dimethylethyl 2-(1-Isothiocyanatoethyl)-4-methylphenyl Carbonate (5f): a yellow oil; Rf 0.36
1
(CH2Cl2/hexane 1:3); IR (neat) 2088, 1759 cm–1; H NMR (CDCl3) δ 1.55 (s, 9H), 1.63 (d, J = 6.3 Hz,
3H), 2.37 (s, 3H), 5.14 (q, J = 6.3 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 7.13 (dd, J = 8.6, 2.3 Hz, 1H), 7.26
(d, J = 2.3 Hz, 1H). Anal. Calcd for C15H19NO3S: C, 61.41; H, 6.53; N, 4.77. Found: C, 61.29; H, 6.68; N,
4.60.
4-Chloro-2-(1-isothiocyanatoethyl)phenyl 1,1-Dimethylethyl Carbonate (5g): a reddish-yellow oil; Rf
1
0.40 (CH2Cl2/hexane 1:3); IR (neat) 2083, 1762 cm–1; H NMR (CDCl3) δ 1.56 (s, 9H), 1.64 (d, J = 6.9
Hz, 3H), 5.15 (q, J = 6.9 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.46 (d, J = 2.3
Hz, 1H). Anal. Calcd for C14H16ClNO3S: C, 53.59; H, 5.14; N, 4.46. Found: C, 53.53; H, 5.18; N, 4.31.
1,1-Dimethylethyl 2-(1-Isothiocyanatoethyl)-4-methoxyphenyl Carbonate (5h): a yellow oil; Rf 0.23
(CH2Cl2/hexane 1:2); IR (neat) 2084, 1757, 1610 cm–1; 1H NMR (CDCl3) δ 1.55 (s, 9H), 1.63 (d, J = 6.9
Hz, 3H), 3.83 (s, 3H), 5.12 (q, J = 6.9 Hz, 1H), 6.85 (dd, J = 9.2, 2.9 Hz, 1H), 6.98 (d, J = 2.9 Hz, 1H),
7.07 (d, J = 9.2 Hz, 1H). Anal. Calcd for C15H19NO4S: C, 58.23; H, 6.19; N, 4.53. Found: C, 58.10; H,
6.18; N, 4.29.
Typical Procedure for the Preparation of 3,4-Dihydro-2H-1,3-benzoxazine-2-thiones (7).
3,4-Dihydro-2H-1,3-benzoxazine-2-thione (7a). To a stirred solution of 5a (0.28 g, 1.1 mmol) in CH2Cl2
(3 mL) at 0 ˚C was added CF3CO2H (0.5 mL). After 1 h, Et3N (1.2 mL) was added and the mixture was
poured into cold water (30 mL). The mixture was extracted with CH2Cl2 (3 × 10 mL) and the combined
extracts were washed with 1% aqueous HCl (2 × 10 mL) and brine (10 mL), dried (Na2SO4), and
concentrated by evaporation. The residue was purified by column chromatography on SiO2 (CH2Cl2) to
afford 7a (0.17 g, 97%); colorless needles; mp 163–165 ˚C (hexane/CH2Cl2); IR (KBr) 3185, 1627, 1197
cm–1; 1H NMR (DMSO-d6) δ 4.41 (s, 2H), 7.08 (d, J = 7.4 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.24 (d, J =
7.4 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 10.29 (br s, 1H);13C NMR (DMSO-d6) δ 41.46, 115.43, 117.02,
125.14, 126.57, 128.99, 148.28, 181.88. HR-MS. Calcd for C8H8NOS (M+H): 166.0326. Found: m/z
166.0325. Anal. Calcd for C8H7NOS: C, 58.16; H, 4.27; N, 8.48. Found: C, 58.06; H, 4.38; N, 8.50.

4-Methyl-3,4-dihydro-2H-1,3-benzoxazine-2-thione (7b): colorless needles; mp 107–108 ˚C
(hexane/CH2Cl2); IR (KBr) 3161, 1626, 1183 cm–1; 1H NMR (CDCl3) δ 1.60 (d, J = 6.9 Hz, 3H), 4.73 (qd,
J = 6.9, 2.3 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.32 (t, J
13
= 7.4 Hz, 1H), 8.83 (br s, 1H); C NMR (DMSO-d6) δ 24.04, 49.08, 116.42, 120.94, 125.33, 125.57,
129.31, 147.85, 182.72. HR-MS. Calcd for C9H10NOS (M+H): 180.0483. Found: m/z 180.0474. Anal.
Calcd for C9H9NOS: C, 60.31; H, 5.06; N, 7.81; S, 17.89. Found: C, 60.04; H, 4.90; N, 7.72; S, 17.69.
4-Ethyl-3,4-dihydro-2H-1,3-benzoxazine-2-thione (7c): colorless needles; mp 135–136 ˚C
1
(hexane/CH2Cl2); IR (KBr) 3169, 1623, 1194 cm–1; H NMR (CDCl3) δ 0.92 (t, J = 7.4 Hz, 3H),
1.83–2.00 (m, 2H), 4.64 (td, J = 7.4, 2.3 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.20
13
(t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 9.11 (br s, 1H); C NMR (DMSO-d6) δ 8.04, 30.91, 54.24,
116.25, 119.21, 125.53, 125.69, 129.17, 148.54, 183.25. HR-MS. Calcd for C10H12NOS (M+H): 194.0639.
Found: m/z 194.0635. Anal. Calcd for C10H11NOS: C, 62.15; H, 5.74; N, 7.25. Found: C, 62.03; H, 5.79;
N, 7.19.
4-Phenyl-3,4-dihydro-2H-1,3-benzoxazine-2-thione (7d):
a
white solid; mp 191–193 ˚C
1
(hexane/CH2Cl2); IR (KBr) 3183, 1620, 1195 cm–1; H NMR (DMSO-d6) δ 5.72 (s, 1H), 7.15–7.19 (m,
13
3H), 7.28 (d, J = 7.4 Hz, 2H), 7.30–7.35 (m, 2H), 7.38 (t, J = 7.4 Hz, 2H), 10.86 (s, 1H); C NMR
(DMSO-d6) δ 55.65, 115.74, 120.95, 125.52, 126.62, 127.92, 128.20, 129.01, 129.40, 142.35, 147.58,
181.28. HR-MS. Calcd for C14H12NOS (M+H): 242.0639. Found: m/z 242.0632. Anal. Calcd for
C14H11NOS: C, 69.68; H, 4.59; N, 5.80. Found: C, 69.68; H, 4.72; N, 5.59.
4,7-Dimethyl-3,4-dihydro-2H-1,3-benzoxazine-2-thione (7e): a white solid; mp 144–146 ˚C
(hexane/CH2Cl2); IR (KBr) 3182, 1636, 1168 cm–1; 1H NMR (CDCl3) δ 1.56 (d, J = 6.3 Hz, 3H), 2.35 (s,
13
3H), 4.67 (q, J = 6.3 Hz, 1H), 6.94 (s, 1H), 7.00 (s, 2H), 8.18 (br s, 1H); C NMR (DMSO-d6) δ 20.99,
24.08, 49.00, 116.70, 121.64, 125.00, 126.47, 139.78, 147.71, 183.02. HR-MS. Calcd for C10H12NOS
(M+H): 194.0639. Found: m/z 194.0634. Anal. Calcd for C10H11NOS: C, 62.15; H, 5.74; N, 7.25. Found:
C, 62.09; H, 5.83; N, 7.23.
4,6-Dimethyl-3,4-dihydro-2H-1,3-benzoxazine-2-thione (7f): a white solid; mp 161–163 ˚C
(hexane/CH2Cl2); IR (KBr) 3194, 1625, 1186 cm–1; 1H NMR (CDCl3) δ 1.58 (d, J = 6.9 Hz, 3H), 2.33 (s,
3H), 4.68 (q, J = 6.9 Hz, 1H), 6.91 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 8.73 (br,
1H);13C NMR (DMSO-d6) δ 20.81, 24.20, 49.09, 116.11, 120.64, 125.57, 129.77, 135.36, 145.88, 182.75.
HR-MS. Calcd for C10H12NOS (M+H): 194.0639. Found: m/z 194.0632. Anal. Calcd for C10H11NOS: C,
62.15; H, 5.74; N, 7.25. Found: C, 62.08; H, 5.80; N, 7.20.
6-Chloro-4-methyl-3,4-dihydro-2H-1,3-benzoxazine-2-thione (7g): a white solid; mp 188–191 ˚C
(hexane/CH2Cl2); IR (KBr) 3200, 1618, 1199 cm–1; 1H NMR (CDCl3) δ 1.60 (d, J = 6.9 Hz, 3H), 4.68 (q,

J = 6.9 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.6, 2.3 Hz, 1H), 7.96 (br
13
s, 1H); C NMR (DMSO-d6) δ 23.52, 47.94, 117.48, 124.19, 125.96 (2 overlapped Cs), 128.96, 146.36,
180.61. HR-MS. Calcd for C9H9ClNOS (M+H): 214.0093. Found: m/z 214.0090. Anal. Calcd for
C9H8ClNOS: C, 50.59; H, 3.77; N, 6.56. Found: C, 50.46; H, 3.87; N, 6.40.
4-Methyl-6-methoxy-3,4-dihydro-2H-1,3-benzoxazine-2-thione (7h): a white solid; mp 166–168 ˚C
(hexane/CH2Cl2); IR (KBr) 3192, 1631, 1197 cm–1; 1H NMR (CDCl3) δ 1.58 (d, J = 6.3 Hz, 3H), 3.80 (s,
3H), 4.67 (q, J = 6.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 6.83 (dd, J = 8.6, 2.3 Hz, 1H), 7.08 (d, J = 8.6 Hz,
1H), 7.75 (br s, 1H); 13C NMR (DMSO-d6) δ 23.71, 48.27, 55.58, 110.60, 114.52, 116.49, 122.94, 141.57,
156.38, 181.10. HR-MS. Calcd for C10H12NO2S (M+H): 210.0588. Found: m/z 210.0579. Anal. Calcd for
C10H11NO2S: C, 57.39; H, 5.30; N, 6.69. Found: C, 57.15; H, 5.36; N, 6.40.
1,1-Dimethylethyl 2-Methylphenyl Carbonate (9a).9 To a stirred solution of 2-methylphenol (8a) (0.54
g, 5.0 mmol) in CH2Cl2 (7 mL) containing DMAP (61 mg, 0.5 mmol) at 0 ˚C was added (Boc)2O (1.2 g,
5.5 mmol) dropwise. After 10 min, the mixture was diluted with AcOEt (50 mL) and washed with H2O (2
× 15 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated by evaporation. The
residue was purified by column chromatography on SiO2 to give 9a (0.96 g, 92%); a colorless liquid; Rf
1
0.66 (AcOEt/hexane 1:10). IR and H NMR data of this compound was identical to those reported
previously.9b
5-Chloro-2-methylphenyl Acetate (9b).10 To a stirred solution of 5-chloro-2-methylphenol (8b) (1.0 g,
7.0 mmol) and pyridine (0.55 g, 7.0 mmol) in THF (10 mL) at 0 ˚C was added AcCl (0.55 g, 7.0 mL)
dropwise. The mixture was warmed to rt and stirring was continued overnight. Water (30 mL) was added
and the mixture was extracted with AcOEt (3 × 20 mL). The combined extracts were washed with water
(3 × 15 mL) and brine (15 mL), dried (Na2SO4), and concentrated by evaporation. The residue was
purified by column chromatography on silica gel to afford 9b (1.1 g, 87%); a colorless liquid; Rf 0.57
1
(AcOEt/hexane 1:5); IR (neat) 1773, 1604 cm–1; H NMR (CDCl3) δ 2.14 (s, 3H), 2.32 (s, 3H), 7.04 (s,
1H), 7.12 (dd, J = 8.0, 1.7 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H).
Typical Procedure for the Preparation of Benzyl Azides (11). 2-(Azidomethyl)phenyl
1,1-Dimethylethyl Carbonate (11a). A solution of 9a (0.95 g, 4.6 mmol), NBS (0.81 g, 4.6 mmol) in
t-BuOAc (14 mL) containing AIBN (45 mg, 0.27 mmol) was heated at reflux temperature for 2.5 h. After
cooling to rt, saturated aqueous NaHCO3 (30 mL) was added and the mixture was extracted with AcOEt
(3 × 20 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4), and concentrated
by evaporation. The residue was dissolved in DMF (15 mL) and NaN3 (0.30 g, 4.6 mmol) was added
under stirring. After 2 h, H2O (30 mL) was added and the mixture was extracted with AcOEt (3 × 20 mL).
The combined extracts were washed with H2O (3 × 10 mL) and brine (15 mL), dried (Na2SO4), and

concentrated by evaporation. The residue was purified by column chromatography on SiO2 to afford 11a
1
(0.65 g, 57% from 9a); a colorless liquid; Rf 0.17 (AcOEt/hexane 1:20); IR (neat) 2100, 1759 cm–1; H
NMR (CDCl3) δ 1.56 (s, 9H), 4.36 (s, 2H), 7.14 (ddd, J = 8.0, 7.4, 1.7 Hz, 1H), 7.26 (td, J = 7.4, 1.1 Hz,
1H), 7.36 (dd, J = 8.0, 1.1 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H). Anal. Calcd for C12H15N3O3: C, 57.82; H,
6.07; N, 16.86. Found: C, 57.70; H, 6.16; N, 16.87.
2-(Azidomethyl)-5-chlorophenyl Acetate (11b): a colorless liquid; Rf 0.29 (AcOEt/hexane 1:20); IR
1
(neat) 2104, 1771, 1604 cm–1; H NMR (CDCl3) δ 2.34 (s, 3H), 4.26 (s, 2H), 7.19 (d, J = 1.7 Hz, 1H),
7.25 (dd, J = 8.0, 1.7 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H). Anal. Calcd for C9H8ClN3O2: C, 47.91; H, 3.57; N,
18.62. Found: C, 47.89; H, 3.68; N, 18.40.
2-(Azidomethyl)phenol (12a).11 To a stirred solution of 11a (0.42 g, 1.7 mmol) in CH2Cl2 (5 mL) at 0 ˚C
was added TFA (1 mL). After 30 min, H2O (20 mL) was added and the mixture was extracted with
AcOEt (3 × 15 mL). The combined extracts were washed with H2O (2 × 10 mL) and brine (15 mL), dried
(Na2SO4), and concentrated by evaporation. The residue was purified by column chromatography on SiO2
to afford 12a (0.17 mg, 70%); a pale-yellow liquid; Rf 0.21 (AcOEt/hexane 1:10). IR and 1H NMR data of
this compound was identical to those reported previously.11b
2-(Azidomethyl)-5-chlorophenol (12b). A solution of 11b (0.47 g, 2.1 mmol) in THF (7 mL) containing
10% aqueous HCl (1.8 mL) was heated at reflux temperature for 4.5 h. After cooling to rt, the mixture
was worked up and purified in a manner similar to that described for the preparation of 12a to give 12b
1
(0.34 g, 88%); a white solid; mp 80–83 ˚C (hexane/CH2Cl2); IR (neat) 3269, 2140, 1604 cm–1; H NMR
(CDCl3) δ 4.39 (s, 2H), 5.67 (s, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.92 (dd, J = 8.0, 2.3 Hz, 1H), 7.12 (d, J =
8.0 Hz, 1H). Anal. Calcd for C7H6ClN3O: C, 45.79; H, 3.29; N, 22.89. Found: C, 45.80; H, 3.39; N, 22.90.
Typical Procedure for the Preparation of 3,4-Dihydro-2H-1,3-benzoxazine-2-thiones (13).
3,4-Dihydro-2H-1,3-benzoxazine-2-thione (13a = 7a). A solution of 12a (80 mg, 0.53 mmol) and PPh3
(0.14 g, 0.53 mmol) in CH2Cl2 (5 mL) was stirred for 4 h at rt. The solvent was removed by evaporation
and the residue was dissolved in MeCN (3 mL). To this solution was added CS2 (0.5 mL) and the
resulting solution was heated at reflux temperature for 30 min. After cooling to rt, the mixture was
concentrated by evaporation and the residue was purified by column chromatography on SiO2 (CH2Cl2) to
give 13a (= 7a) (61 mg, 70%).
7-Chloro-3,4-dihydro-2H-1,3-benzoxazine-2-thione (13b):
a
white solid; mp 195–197 ˚C
1
(hexane/CH2Cl2); IR (KBr) 3204, 1624, 1192 cm–1; H NMR (DMSO-d6) δ 4.40 (s, 2H), 7.24–7.30 (m,
13
3H), 10.38 (br s, 1H); C NMR (DMSO-d6) δ 41.25, 115.58, 116.20, 125.04, 128.08, 132.72, 148.76,
181.27. HR-MS. Calcd for C8H7ClNOS (M+H): 199.9937. Found: m/z 199.9932. Anal. Calcd for
C8H6ClNOS: C, 48.13; H, 3.03; N, 7.02. Found: C, 48.01; H, 3.01; N, 6.90.

ACKNOWLEDGEMENTS
Financial support from JSPS (KAKENHI Grant No. 26410051) is gratefully acknowledged. We thank
Mrs. Miyuki Tanmatsu of our university for recording mass spectra and performing combustion analyses.
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