Convenient synthesis of 1,4-dihydro-2H-3,1-benzoxazin-2-ones by iodocyclization of t-butyl 2-vinylphenylcarbamates

Article abstract of DOI:10.3987/COM-07-11186

It has been found that t-butyl 2-vinylphenylcarbamate derivatives underwent iodocyclization on treatment with iodine in the presence of sodium hydrogencarbonate to afford 4-iodomethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives in generally good yields. The reduction of these 4-iodomethyl derivatives with tributyltin hydride gave the corresponding 4-methyl derivatives in good yields.

Full text of DOI:10.3987/COM-07-11186

HETEROCYCLES, Vol. 75, No. 1, 2008
95
HETEROCYCLES, Vol. 75, No. 1, 2008, pp. 95 – 105. © The Japan Institute of Heterocyclic Chemistry
Received, 26th July, 2007, Accepted, 14th September, 2007, Published online, 20th September, 2007. COM-07-11186
CONVENIENT SYNTHESIS OF 1,4-DIHYDRO-2H-3,1-BENZOXAZIN-
2-ONES
BY
IODOCYCLIZATION
OF
t-BUTYL
2-VINYLPHENYLCARBAMATES
Kazuhiro Kobayashi,* Shuhei Fukamachi, Daizo Nakamura, Osamu Morikawa,
and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Abstract - It has been found that t-butyl 2-vinylphenylcarbamate derivatives
underwent iodocyclization on treatment with iodine in the presence of sodium
hydrogencarbonate to afford 4-iodomethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one
derivatives in generally good yields. The reduction of these 4-iodomethyl
derivatives with tributyltin hydride gave the corresponding 4-methyl derivatives
in good yields.
We previously demonstrated that the preparation of 4H-1,3-benzodioxin-2-one derivatives could be
achieved by iodocyclization of t-butyl 2-vinylphenyl carbonate derivatives, derived from
t-butoxycarbonylation of 2-vinylphenol derivatives.1 As an extension of this cyclization reaction, we
anticipated that a similar sequence starting with 2-aminostyrene derivatives should lead to formation of
1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives. We report here on details concerning the results of our
investigation which provide a new and simple method for constructing the 1,4-dihydro-2H-3,1-
benzoxazin-2-one skeleton.2 Compounds having this skeleton have attracted considerable attention of
medicinal and synthetic organic chemists, because some of them have been reported to exhibit a variety
of biological activities,3 such as HIV-1 reverse transcriptase inhibitory3a and progesterone receptor
antagonistic activities.3b,e 1-Substituted 1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives have been used
as precursors for the generation of the corresponding aza-o-quinodimethane intermediates.4 Most of the
previous syntheses of 1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives have been based on the reaction
of 2-aminobenzyl alcohol derivatives with phosgene,3,5,6 though Nishiyama, Naitoh, and Sonoda have
recently reported a synthesis of 4-nonsubstituted derivatives by selenium-catalyzed carbonylation of
2-nitrobenzyl alcohols.7
We conducted reactions of t-butyl 2-vinylphenylcarbamates (2), which were easily prepared by
t-butoxycarbonylation of 2-aminostyrene derivatives (1) with di-t-butyl dicarbonate under the conditions

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HETEROCYCLES, Vol. 75, No. 1, 2008
reported by Misawa et al,8 with iodine in the presence of sodium hydrogencarbonate in acetonitrile at 0
˚C, as outlined in Scheme 1. The iodocyclization reaction proceeded very smoothly (within 5 min) to
afford the expected 4-iodomethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives (3) in excellent
yields. Attempts to obtain the products (3) in one-pot were unsuccessful. Addition of iodine to the
reaction mixtures of 1 and di-t-butyl dicarbonate resulted in the formation of intractable mixtures of
products, from which only very low yields of the desired products were isolated. In order to displace the
iodine of 3 with hydrogen, compounds (3) were allowed to react with tributyltin hydride in benzene.
Although the reaction needed heating at reflux temperature for the times given in Experimental section
due to low solubility of 3 in the solvent, the corresponding 4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-
one derivatives (4) were obtained in good to excellent yields. These results are also summarized in
Scheme 1.
R3
R3
R3
I
R1
R2
R1
R2
R1
R2
O
(Boc)2O, aq. NaOH
1,4-dioxane, 50 ˚C
I2, NaHCO3
MeCN, 0 ˚C
N
H
O
NH2
NHBoc
1
2a 91%
3a 97%
3b 97%
3c 91%
3d 95%
3e 91%
2b 89%
2c 43%
2d 85%
2e 81%
a R1 = R2 = H, R3 = Me
b R1 = R2 = H, R3 = Ph
c R1 = H, R2 = F, R3 = Me
d R1 = OMe, R2 = H, R3 = Ph
e R1 = R2 = OMe, R3 = Me
Me
R3
R1
R2
n-Bu3SnH
O
benzene, reflux
N
H
O
4a 98%
4b 98%
4c 78%
4d 96%
4e 84%
Scheme 1
We found that preparation of 1-methyl-4-iodomethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one derivatives
(6) could be carried out in one-pot from 2-(N-methylamino)styrene derivatives (5), as illustrated in
Scheme 2. Thus, compounds (5) were treated with di-t-butyl dicarbonate in the presence of sodium
hydrogencarbonate in acetonitrile at reflux temperature for the times given in Experimental section.
After cooling to 0 ˚C, iodine was added to the resulting reaction mixtures. The iodocyclization reactions
went to completion within 30 min to afford the desired products (6). The t-butoxycarbonylation of less
reactive starting materials (5d) and (5e) proceeded much more sluggishly than 5a-c and required
considerably prolonged reaction times. As the result of the low reactivity in the t-butoxycarbonylation

HETEROCYCLES, Vol. 75, No. 1, 2008
97
step, rather decreased yields of the desired 4-iodomethyl derivatives (6d) and (6e), respectively, were
obtained after iodocylization. The reduction of 4-iodomethyl derivatives (6) using tributyltin hydride
proceeded very smoothly even at room temperature to afford the corresponding 4-methyl derivatives (7)
in fair to good yields. These results are also shown in Scheme 2. Attempts at one-pot production of 3
from 1 under conditions similar to those for the preparation of 6 were all in vain, because
t-butoxycarbonylation of 1 proceeded very sluggishly.
R4
R4
R4
I
Me
O
1) (Boc)2O, NaHCO3,
MeCN, reflux
R1
R2
R1
R2
R1
R2
n-Bu3SnH
O
benzene, rt
2) I2, 0 ˚C
N
Me
O
NHMe
N
Me
O
R3
R3
R3
5
7a 71%
7b 67%
7c 85%
7d 71%
7e 66%
6a 84%
6b 68%
6c 80%
6d 50%
6e 53%
a R1 = R2 = R3 = H, R4 = Me
b R1 = R2 = R3 = H, R4 = Ph
c R1 = R2 = OMe, R3 = H, R4 = Me
d R1 = R3= H, R2 = Cl, R4 = Me
e R1 = H, R2 = H, R3 = R4 = Me
Scheme 2
In conclusion, a convenient route for the preparation of 1,4-dihydro-2H-3,1-benzoxazin-2-one
derivatives has been developed. The method may have some potential utility for heterocycle synthesis
because of its simplicity and the ready availability of the starting materials.
EXPERIMENTAL
The melting points were determined on a Laboratory Devices MEL-TEMP II melting-point apparatus
1
and are uncorrected. The IR spectra were recorded on a Shimadzu FTIR-8300 spectrometer. The H
NMR spectra were determined using SiMe4 as an internal reference with a JEOL ECP500 FT NMR
spectrometer operating at 500 MHz. Low-resolution mass spectra (EI) were recorded on a JEOL
AUTOMASS 20 spectrometer (Center for Joint Research and Development, this University). Thin-layer
chromatography (TLC) was carried out on Merck Kieselgel 60 PF254. Column chromatography was
performed using Merck Kieselgel 60 (0.063–0.200 mm). All of the solvents used were dried over
appropriate drying agents and distilled under argon prior to use.
Starting Materials. Ethyl 2-amino-4-fluorobenzoate,9 2-(1-phenylethenyl)benzenamine (1b),10
4-methoxy-2-(1-phenylethenyl)benzenamine (1d),11 4,5-dimethoxy-2-(1-methylethenyl)benzenamine
(1e),12 N-methyl-2-(1-methylethenyl)benzenamine (5a),13 N-methyl-2-(1-phenylethenyl)benzenamine
(5b),11
5-chloro-2-(1-methylethenyl)benzenamine,12 and ethyl 2-amino-3-methylbenzoate14 were

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HETEROCYCLES, Vol. 75, No. 1, 2008
prepared by the appropriate reported methods. All other chemicals used in this study were commercially
available.
2-(2-Amino-4-fluorophenyl)propan-2-ol. This compound was prepared by the reaction of ethyl
2-amino-4-fluorobenzoate9 with excess MeMgBr in 84% yield; a yellow liquid; Rf 0.53 (THF–hexane,
1:3); IR (neat) 3460, 3367, 1622 cm–1; 1H NMR (CDCl3): δ = 1.65 (s, 6H), 1.73 (s, 1H), 4.82 (br s, 2H),
6.32–6.36 (m, 2H), 7.04 (ddd, J = 8.2, 6.4, 1.4 Hz, 1H). Anal. Calcd for C9H12FNO: C, 63.89; H, 7.15; N,
8.28. Found: C, 63.65; H, 7.23, N, 8.25.
5-Fluoro-2-(1-methylethenyl)benzenamine (1c). This compound was prepared by thermal dehydration
(neat, 10 min at 130 ˚C) of 2-(2-amino-4-fluorophenyl)propan-2-ol in 75% yield; a yellow liquid; Rf
0.50 (THF–hexane, 1:5); IR (neat) 3479, 3387, 1620 cm–1; 1H NMR (CDCl3) δ 2.04 ( d, J = 0.9 Hz, 3H),
3.93 (br s, 2H), 5.03 (quint, J = 0.9 Hz, 1H), 5.29 (quint, J = 0.9 Hz, 1H), 6.38–6.44 (m, 2H), 6.96 (dd, J
= 8.2, 6.2 Hz, 1H). Anal. Calcd for C9H10FN: C, 71.50; H, 6.67; N, 9.26. Found: C, 71.48; H, 6.74; N,
9.37.
t-Butyl N-[2-(1-Methylethenyl)phenyl]carbamate (2a).15 2-(1-Methylethenyl)benzenamine (0.27 g,
2.0 mmol) was treated with di-t-butyl dicarbonate (0.96 g, 4.4 mmol) in 20% aqueous
NaOH–1,4-dioxane (3 mL each) at 50 ˚C10 for 2 h to give 2a (0.42 g, 91%); a colorless oil; Rf 0.70
1
(THF–hexane, 1:3); IR (neat): 3422, 1732 cm–1; H NMR (CDCl3) δ 1.51 (s, 9H), 2.06 (d, J = 1.4 Hz,
3H), 5.01 (q, J = 0.9 Hz, 1H), 5.36 (td, J = 1.4, 0.9 Hz, 1H), 6.82 (br s, 1H), 7.00 (ddd, J = 7.8, 7.3, 1.4
Hz, 1H), 7.10 (dd, J = 7.3, 1.4 Hz, 1H), 7.23 (td, J = 7.3, 1.4 Hz, 1H), 8.04 (br d, J = 7.8 Hz, 1H).
t-Butyl N-[2-(1-Phenylethenyl)phenyl]carbamate (2b). This compound was prepared by
t-butoxycarbonylation of 1b10 as described for the preparation of 2a (reaction time: 8 h); a pale-yellow
oil; Rf 0.52 (THF–hexane, 1:10); IR (neat) 3423, 1732 cm–1; 1H NMR (CDCl3) δ 1.38 (s, 9H), 5.34 (d, J
= 1.4 Hz, 1H), 5.90 (d, J = 1.4 Hz, 1H), 6.44 (br s, 1H), 7.06 (ddd, J = 7.8, 7.3, 1.4 Hz, 1H), 7.17 (dd, J
= 7.8, 1.4 Hz, 1H), 7.30–7.36 (m, 6H), 8.01 (br d, J = 8.2 Hz, 1H). Anal. Calcd for C19H21NO2: C, 77.26;
H, 7.17; N, 4.74. Found: C, 76.99; H, 7.28, N, 4.88.
t-Butyl N-[5-Fluoro-2-(1-methylethenyl)phenyl]carbamate (2c). This compound was prepared by
t-butoxycarbonylation of 1c as described for the preparation of 2a (reaction time: 3 d): a pale-yellow oil;
Rf 0.63 (THF–hexane, 1:10); IR (neat): 3418, 1732 cm–1; 1H NMR (CDCl3) δ 1.52 (s, 9H), 2.04 (s, 3H),
5.00 (s, 1H), 5.39 (s, 1H), 6.69 (td, J = 8.7, 2.7 Hz, 1H), 6.91 (br s, 1H), 7.03 (dd, J = 8.7, 6.4 Hz, 1H),
7.91 (br d, J = 11.0 Hz, 1H). Anal. Calcd for C14H18FNO2: C, 66.91; H, 7.22; N, 5.57. Found: C, 66.90;
H, 7.28, N, 5.53.
t-Butyl N-[4-Methoxy-2-(1-phenylethenyl)phenyl]carbamate (2d). This compound was prepared by
t-butoxycarbonylation of 1d11 as described for the preparation of 2a (reaction time: 1.5 h); a yellow oil;
1
Rf 0.69 (THF–pentane, 1:4); IR (neat) 3427, 1732 cm–1; H NMR (CDCl3) δ 1.35 (s, 9H), 3.79 (s, 3H),
5.33 (d, J = 1.4 Hz, 1H), 5.87 (d, J = 1.4 Hz, 1H), 6.15 (br s, 1H), 6.76 (d, J = 3.2 Hz, 1H), 6.90 (dd, J =

HETEROCYCLES, Vol. 75, No. 1, 2008
99
8.7, 3.2 Hz, 1H), 7.29–7.32 (m, 5H), 7.80 (br s, 1H). Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N,
4.30. Found: C, 73.79; H, 6.98, N, 4.68.
t-Butyl N-[4,5-Dimethoxy-2-(1-methylethenyl)phenyl]carbamate (2e). This compound was prepared
by t-butoxycarbonylation of 1e12 as described for the preparation of 2a (reaction time: 14 h); a white
1
solid; mp 82–84 ˚C (hexane–THF); IR (KBr) 3354, 1699, 1607 cm–1; H NMR (CDCl3) δ 1.48 (s, 9H),
2.05 (s, 3H), 3.84 (s, 3H), 3.91 (s, 3H), 4.99 (d, J = 0.9 Hz, 1H), 5.34 (d, J = 0.9 Hz, 1H), 6.62 (s, 1H),
6.70 (br s, 1H), 7.70 (br, 1H). Anal. Calcd for C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C, 65.48;
H, 7.94, N, 4.76.
Typical Procedure for the Preparation of 3. 4-Iodomethyl-4-methyl-1,4-dihydro-2H-3,1-
benzoxazin-2-one (3a). To a stirred mixture of 2a (0.24 g, 1.0 mmol) and NaHCO3 (0.26 g, 3.1 mmol)
in MeCN (3 mL) at 0 ˚C was added iodine (0.78 g, 3.1 mmol) by portions. After 5 min, 10% aqueous
Na2S2O3 was added until the color of iodine disappeared, and the organic materials were extracted with
Et2O three times (10 mL each). The combined extracts were washed with brine, dried over anhydrous
Na2SO4, and evaporated. The residual solid was recrystallized from hexane–THF to give 3a (0.29 g,
1
97%): a white solid; mp 193 ˚C (decomp) (hexane–THF); IR (KBr) 3215, 1705 cm–1; H NMR
(DMSO-d6) δ 1.73 (s, 3H), 3.70 (d, J = 11.0 Hz, 1H), 3.85 (d, J = 11.0 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H),
7.01 (dd, J = 7.8, 7.3 Hz, 1H), 7.24 (ddd, J = 7.8, 7.3, 1.4 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 10.25 (s,
1H); MS m/z 303 (M+, 25), 162 (100). Anal. Calcd for C10H10INO2: C, 39.63; H, 3.33; N, 4.62. Found: C,
39.52; H, 3.32; N, 4.60.
4-Iodomethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (3b): a pale-yellow solid; mp 177–179
˚C (hexane–THF); IR (KBr): 3208, 1709 cm–1; 1H NMR (DMSO-d6) δ 4.02 (d, J = 11.5 Hz, 1H), 4.37 (d,
J = 11.5 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 7.16 (dd, J = 7.8, 7.3 Hz, 1H), 7.29–7.38 (m, 6H), 7.59 (d, J
= 7.8 Hz, 1H), 10.34 (br s, 1H); MS m/z 365 (M+, 15), 224 (100). Anal. Calcd for C15H12INO2: C, 49.34;
H, 3.31; N, 3.84. Found: C, 49.38; H, 3.29; N, 3.80.
7-Fluoro-4-iodomethyl-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (3c): a white solid; mp
1
169–171 ˚C (hexane–CH2Cl2).; IR (KBr) 3227, 1713, 1616 cm–1; H NMR (CDCl3) δ 1.91 (s, 3H), 3.58
(d, J = 11.0 Hz, 1H), 3.62 (d, J = 11.0 Hz, 1H), 6.61 (dd, J = 10.2, 2.3 Hz, 1H), 6.80 (td, J = 8.7, 2.3 Hz,
1H), 7.10 (dd, J = 8.7, 5.5 Hz, 1H), 8.71 (br s, 1H); MS m/z 321 (M+, 14), 180 (100). Anal. Calcd for
C10H9FINO2: C, 37.41; H, 2.83; N, 4.36. Found: C, 37.30; H, 2.80; N, 4.11.
4-Iodomethyl-6-methoxy-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (3d): a white solid; mp 150
1
˚C (decomp) (Et2O–THF); IR (KBr) 3206, 1713 cm–1; H NMR (DMSO-d6) δ 3.77 (s, 3H), 3.99 (d, J =
11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.91 (dd, J = 8.7, 2.7 Hz, 1H), 7.21 (d,
J = 2.7 Hz, 1H), 7.29–7.37 (m, 5H), 10.13 (br s, 1H); MS m/z 395 (M+, 31), 224 (100). Anal. Calcd for
C16H14INO2: C, 48.63; H, 3.57; N, 3.54. Found: C, 48.41; H, 3.73; N, 3.42.
4-Iodomethyl-6,7-dimethoxy-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (3e): a white solid; mp

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HETEROCYCLES, Vol. 75, No. 1, 2008
143 ˚C (decomp) (hexane–THF); IR (KBr) 3223, 1717, 1627, 1612 cm–1; 1H NMR (DMSO-d6) δ 1.63 (s,
3H), 3.60 (d, J = 11.5 Hz, 1H), 3.62 (s, 6H), 3.76 (d, J = 11.5 Hz, 1H), 6.37 (s, 1H), 6.79 (s, 1H), 9.89
(br s, 1H); MS m/z 363 (M+, 45), 222 (100). Anal. Calcd for C12H14INO2: C, 39.69; H, 3.89; N, 3.86.
Found: C, 39.32; H, 3.87; N, 3.85.
Typical Procedure for the Reduction of 3 to 4. 4,4-Dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one
(4a). A solution of 3a (0.12 g, 0.40 mmol) in benzene (3 mL) containing n-Bu3SnH (0.22 g, 0.80 mmol)
was heated at reflux temperature for 2 h. After evaporation of the solvent, the precipitate was collected
by filtration and recrystallization from hexane–Et2O to give 4a (69 mg, 98%); a pale-yellow solid; mp
111–113 ˚C (lit.,4 115–116 ˚C); IR (KBr) 3231, 1711, 1601 cm–1; 1H NMR (CDCl3) δ 1.72 (s, 6H), 6.82
(d, J = 7.8 Hz, 1H), 7.06 (ddd, J = 7.8, 7.3, 0.9 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.24 (ddd, J = 7.8, 7.3,
1.4 Hz, 1H), 8.20 (br s, 1H); MS m/z 177 (M+, 87), 133 (100).
4-Methyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (4b): reflux time: 8h; colorless needles; mp
219–221 ˚C (THF); IR (KBr) 3206, 1724 cm–1; 1H NMR (CDCl3) δ 1.85 (s, 3H), 6.80 (d, J = 7.8 Hz, 1H),
7.03 (dd, J = 7.8, 7.3 Hz, 1H), 7.13 (d, J = 7.3 Hz, 2H), 7.18–7.26 (m, 4H), 7.35 (d, J = 7.3 Hz, 1H),
10.13 (br s, 1H); MS m/z 239 (M+, 11), 194 (100). Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48; N,
5.85. Found: C, 75.12; H, 5.37; N, 5.73.
7-Fluoro-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (4c): reflux time: 1 h; colorless needles;
mp 140–142 ˚C (hexane–Et2O); IR (KBr) 3300, 1742, 1616 cm–1; 1H NMR (CDCl3) δ 1.71 (s, 6H), 6.59
(dd, J = 9.2, 2.3 Hz, 1H), 6.76 (td, J = 8.7, 2.3 Hz, 1H), 7.10 (dd, J = 8.7, 5.5 Hz, 1H), 8.72 (br s, 1H);
MS m/z 195 (M+, 53,), 180 (100). Anal. Calcd for C10H10FNO2: C, 61.53; H, 5.16; N, 7.18. Found: C,
61.13; H, 5.23; N, 7.07.
6-Methoxy-4-methyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (4d): reflux time: 24 h; a
colorless needles; mp 164–166 ˚C (hexane–CHCl3); IR (KBr) 3204, 1728 cm–1; 1H NMR (CDCl3) δ 2.02
(s, 3H), 3.82 (s, 3H), 6.75 (d, J = 7.3 Hz, 1H), 6.84–6.87 (m, 2H), 7.26–7.30 (m, 5H), 7.79 (br s, 1H);
MS m/z 269 (M+, 44), 224 (100). Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C,
71.03; H, 5.70; N, 5.10.
6,7-Dimethoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (4e): reflux time: 36 h;
1
pale-yellow needles; mp 136–138 ˚C (hexane–CH2Cl2); IR (KBr) 3265, 1705, 1614 cm–1; H NMR
(CDCl3) δ 1.75 (s, 6H), 3.865 (s, 3H), 3.867 (s, 3H), 6.39 (s, 1H), 6.63 (s, 1H), 8.88 (br s, 1H); MS m/z
237 (M+, 100). Anal. Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C, 60.57; H, 6.37; N,
5.84.
N-[4,5-Dimethoxy-2-(1-methylethenyl)phenyl]formamide. This compound was prepared by treating
4,5-dimethoxy-2-(1-methylethenyl)benzenamine12 with formic acid in toluene at reflux temperature
under azeotropic conditions in 78 yield; a light-brown oil; Rf 0.39 (AcOEt–hexane, 1:1); IR (neat) 3320,
1
1682, 1611 cm–1; H NMR (CDCl3): δ 2.03 and 2.06 (2s, combined 3H), 3.86, 3.88, 3.90, and 3.91 (4s,

HETEROCYCLES, Vol. 75, No. 1, 2008
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combined 6H), 4.98 and 5.02 (2s, combined 1H), 5.32 and 5.39 (2s, combined 1H), 6.65 (s, 1H), 6.69
and 6.71 (2s, combined 1H), 7.36–8.54 (m, 2H). Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33.
Found: C, 64.59; H, 6.84; N, 6.23.
N-Methyl-4,5-dimethoxy-2-(1-methylethenyl)benzenamine (5c). This compound was prepared by the
LAH reduction of the above formamide in Et2O at room temperature in 79% yield; a light-brown oil; Rf
0.26 (THF–hexane, 1:7); IR (neat) 3416, 1611 cm–1; 1H NMR (CDCl3) δ 2.04 (s, 3H), 2.83 (s, 3H), 3.81
(s, 3H), 3.90 (s, 3H), 3.96 (br, 1H), 5.01 (s, 1H), 5.27 (s, 1H), 6.28 (s, 1H), 6.65 (s, 1H). Anal. Calcd for
C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.48; H, 8.60; N, 6.78.
N-[5-Chloro-2-(1-methylethenyl)]phenylformamide. This compound was prepared by treating
5-chloro-2-(1-methylethenyl)benzenamine12 with formic acid in toluene at reflux temperature under
azeotropic conditions in 77% yield; a pale-yellow oil; Rf 0.31 (AcOEt–hexane, 1:3); IR (neat) 3312,
1
1682 cm–1; H NMR (CDCl3) δ 2.05 and 2.06 (s and d, J = 1.4 Hz, combined 3H), 5.00 and 5.04 (2s,
combined 1H), 5.43 and 5.44 (s, and d, J = 1.4 Hz, combined 1H), 7.08–7.22 (m, 3H), 7.58–8.71 (m,
2H). Anal. Calcd for C10H10ClNO: C, 61.39; H, 5.15; N, 7.16. Found: C, 61.08; H, 4.96; N, 7.56.
5-Chloro-N-methyl-2-(1-methylethenyl)benzenamine (5d). This compound was prepared by the LAH
reduction of N-[5-chloro-2-(1-methylethenyl)]phenylformamide in Et2O at room temperature in 64%
1
yield; a pale-yellow liquid; Rf 0.42 (benzene–hexane, 1:10); IR (neat) 3429, 1636 cm–1; H NMR
(CDCl3) δ 2.01 (t, J = 1.4 Hz, 3H), 2.81 (d, J = 4.6 Hz, 3H), 4.24 (br s, 1H), 5.00 (q, J = 1.4 Hz, 1H),
5.29 (q, J = 1.4 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 6.63 (dd, J = 7.8, 2.3 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H).
Anal. Calcd for C10H12ClN: C, 66.12; H, 6.66; N, 7.71. Found: C, 65.92; H, 6.68; N, 7.71.
2-(2-Amino-3-methylphenyl)propan-2-ol. This compound was prepared by the reaction of ethyl
2-amino-3-methylbenzoate6 with excess MeMgBr in Et2O at 0 ˚C in 83% yield; a pale-yellow needle;
1
mp 66–68 ˚C (hexane); IR (KBr) 3385, 3254 cm–1; H NMR (CDCl3) δ 1.69 (s, 7H), 2.18 (s, 3H), 4.50
(br s, 2H), 6.62 (dd, J = 7.8, 7.3 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H). Anal. Calcd
for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.49; H, 9.19; N, 8.48.
2-Methyl-6-(1-methylethenyl)benzenamine.16 This compound was prepared by thermal dehydration
(neat, 2h at 220 ˚C) of 2-(2-amino-3-methylphenyl)propan-2-ol in 59% yield; a pale-yellow liquid; Rf
0.33 (Et2O–hexane, 1:10); IR (neat) 3474, 3383, 1614 cm–1; 1H NMR (CDCl3) δ 2.07 (dd, J = 1.4, 0.9 Hz.
3H), 2.19 (s, 3H), 3.81 (br s, 2H), 5.05 (q, J = 0.9 Hz, 1H), 5.30 (q, J = 1.4 Hz, 1H), 6.80 (dd, J = 7.8,
7.3 Hz, 1H), 6.92 (dd, J = 7.8, 1.4 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H).
N-[2-Methyl-6-(1-methylethenyl)]phenylformamide. This compound was prepared by treating
2-methyl-6-(1-methylethenyl)benzeneamine7 with formic acid in toluene at reflux temperature under
azeotropic conditions in 49% yield; white needle; mp 80–83 ˚C (hexane–CH2Cl2); IR (KBr) 3202, 1674,
1
1661, 1636 cm–1; H NMR (CDCl3) δ 2.02 (d, J = 0.9 Hz, 3H), 2.29 and 2.33 (2s, combined 3H), 4.91
and 4.50 (2q, J = 0.9 Hz each, combined 1H), 5.20 and 5.26 (2q, J = 0.9 Hz each, combined 1H),

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6.92–7.20 (m, 4H), 8.17–8.35 (m, 1H). Anal. Calcd for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C,
75.46; H, 7.54; N, 7.89.
2,N-Dimethyl-6-(1-methylethenyl)benzenamine (5e). This compound was prepared by the LAH
reduction of N-[2-methyl-6-(1-methylethenyl)]phenylformamide in Et2O at room temperature in 63%
1
yield; a pale-yellow liquid; Rf 0.53 (THF–hexane, 1:7); IR (neat) 3377, 1634 cm–1; H NMR (CDCl3) δ
2.07 (d, J = 1.4 Hz, 3H), 2.31 (s, 3H), 2.78 (s, 3H), 3.56 (br, 1H), 4.97 (d, J = 0.9 Hz, 1H), 5.22 (q, J =
1.4 Hz, 1H), 6.82 (dd, J = 7.8, 7.3 Hz, 1H), 6.93 (dd, J = 7.8, 0.9 Hz, 1H), 7.04 (dd, J = 7.3, 0.9 Hz, 1H).
Anal. Calcd for C11H15N: C, 81.94; H, 9.38; N, 8.69. Found: C, 81.81; H, 9.30; N, 8.52.
Typical Procedure for the preparation of 6. 4-Iodomethyl-1,4-dimethyl-1,4-dihydro-2H-3,1-
benzoxazin-2-one (6a). A mixture of 5a (0.30 g, 2.0 mmol), (Boc)2O (1.1 g, 5.0 mmol), and NaHCO3
(1.3 g, 15 mmol) in MeCN (10 mL) was heated at reflux temperature for 2.5 h. The mixture was cooled
to 0 ˚C and iodine (1.5 g, 6.0 mmol) was added. After stirring for 30 min, 10% aqueous Na2S2O3 was
added until the color of iodine disappeared. The precipitate was collected by filtration and recrystallized
from hexane–CH2Cl2 gave 6a (0.52 g, 84%); a white solid; mp 133 ˚C (hexane–CH2Cl2); IR (KBr) 1699
cm–1; 1H NMR (CDCl3) δ 1.88 (s, 3H), 3.41 (s, 3H), 3.56 (d, J = 11.0 Hz, 1H), 3.60 (d, J = 11.0 Hz, 1H),
6.96 (d, J = 7.8 Hz, 1H), 7.14 (ddd, J = 7.8, 7.3, 0.9 Hz, 1H), 7.18 (dd, J = 7.8, 1.4 Hz, 1H), 7.38 (ddd, J
= 7.8, 7.3, 1.4 Hz, 1H); MS m/z 317 (M+, 9.7), 176 (100). Anal. Calcd for C11H12INO2: C, 41.66; H, 3.81;
N, 4.42. Found: C, 41.58; H, 3.85; N, 4.15.
4-Iodomethyl-1-methyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (6b): pale-yellow needles;
mp 185 ˚C (decomp) (hexane–CH2Cl2); IR (KBr) 1715 cm–1; 1H NMR (CDCl3) δ 3.26 (s, 3H), 3.86 (d, J
= 11.4 Hz, 1H), 3.89 (d, J = 11.4 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 7.25 (td, J = 7.3, 0.9 Hz, 1H), 7.32 (s,
5H), 7.36 (dd, J = 7.3, 1.4 Hz, 1H), 7.44 (ddd, J = 8.2, 7.3, 1.4 Hz, 1H); MS m/z 379 (M+, 15), 238 (100).
Anal. Calcd for C16H14INO2: C, 50.68; H, 3.72; N, 3.69. Found: C, 50.63; H, 3.62; N, 3.59.
4-Iodomethyl-6,7-dimethoxy-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (6c): a pale-yellow
solid; mp 110–112 ˚C (hexane–Et2O); IR (KBr): 1712, 1616 cm–1; 1H NMR (CDCl3) δ 1.86 (s, 3H), 3.40
(s, 3H), 3.53 (d, J = 11.0 Hz, 1H), 3.57 (d, J = 11.0 Hz, 1H), 3.89 (s, 3H), 3.93 (s, 3H), 6.49 (s, 1H), 6.67
(s, 1H). MS m/z 377 (M+, 16), 236 (100). Anal. Calcd for C13H16INO4: C, 41.40; H, 4.28; N, 3.71.
Found: C, 41.30; H, 4.19; N, 3.41.
7-Chloro-4-iodomethyl-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (6d): reaction time of 5d
with (Boc)2O: 2 days; a pale-yellow solid; mp 103–105 ˚C (hexane–Et2O); IR (KBr) 1715, 1601 cm–1;
1H NMR (CDCl3) δ 1.87 (s, 3H), 3.39 (s, 3H), 3.55 (d, J = 11.0 Hz, 1H), 3.56 (d, J = 11.0 Hz, 1H), 6.95
(d, J = 1.8 Hz, 1H), 7.08–7.13 (m, 2H). MS m/z 351 (M+, 16), 210 (100). Anal. Calcd for C11H11ClINO2:
C, 37.58; H, 3.15; N, 3.98. Found: C, 37.21; H, 3.15; N, 3.92.
4-Iodomethyl-1,4,8-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (6e): reaction time of 5e with
1
(Boc)2O: 1 day; pale-yellow solid; mp 100–102 ˚C (hexane–CH2Cl2); IR (KBr): 1710 cm–1; H NMR

HETEROCYCLES, Vol. 75, No. 1, 2008
103
(CDCl3) δ 1.83 (s, 3H), 2.43 (s, 3H), 3.47 (s, 3H), 3.53 (d, J = 11.0 Hz, 1H), 3.57 (d, J = 11.0 Hz, 1H),
7.04 (d, J = 7.8 Hz, 1H), 7.07 (dd, J = 7.8, 7.3 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H); MS m/z 331 (M+, 39),
190 (100). Anal. Calcd for C12H14INO2: C, 43.52; H, 4.26; N, 4.23. Found: C, 43.38; H, 4.56; N, 4.18.
Typical Procedure for the Reduction of 6 to 7. 1,4,4-Trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-
one (7a).5 A solution of 6a (0.13 g, 0.41 mmol) and n-Bu3SnH (0.23 g, 0.83 mmol) in benzene (3 mL)
was stirred overnight at rt. After evaporation of the solvent, the precipitate was collected by filtration
and recrystallized from hexane–CH2Cl2 to give 7a (0.13 g, 71%); white solid; mp 92 ˚C; IR (KBr) 1701
1
cm–1; H NMR (CDCl3) δ 1.69 (s, 6H), 3.41 (s, 3H), 6.95 (d, J = 7.8 Hz, 1H), 7.10 (dd, J = 7.8, 7.3 Hz,
1H), 7.18 (dd, J = 7.8, 1.4 Hz, 1H), 7.33 (ddd, J = 7.8, 7.3, 1.4 Hz, 1H); MS m/z (%) 191 (M+, 25), 176
(25), 132 (100).
1,4-Dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (7b): a pale-yellow solid; mp 80–81 ˚C
1
(hexane–Et2O); IR (KBr) 1711 cm–1; H NMR (CDCl3) δ 2.01 (s, 3H), 3.25 (s, 3H), 6.95 (d, J = 7.8 Hz,
1H), 7.19 (t, J = 7.3 Hz, 1H), 7.27–7.31 (m, 5H), 7.35 (d, J = 7.3 Hz, 1H), 7.40 (dd, J = 7.8, 7.3 Hz, 1H).
MS m/z 253 (M+, 11), 208 (56), 194 (100). Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53.
Found: C, 75.65; H, 6.05; N, 5.46.
6,7-Dimethoxy-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (7c): a pale-yellow solid; mp
1
104–106 ˚C (hexane–Et2O); IR (KBr) 1699, 1618 cm–1; H NMR (CDCl3) δ 1.63 (s, 6H), 3.40 (s, 3H),
3.87 (s, 3H), 3.91 (s, 3H), 6.49 (s, 1H), 6.67 (s, 1H); MS m/z 252 (M+, 53), 236 (57), 192 (100). Anal.
Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 62.13; H, 6.80; N, 5.36.
7-Chloro-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (7d): a pale-yellow solid; mp 64–67
˚C (hexane–Et2O); IR (KBr) 1715, 1603 cm–1; 1H NMR (CDCl3) δ 1.67 (s, 6H), 3.39 (s, 3H), 6.93 (d, J =
1.8 Hz, 1H), 7.07 (dd, J = 8.2, 1.8 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H); MS m/z 225 (M+, 43,), 210 (64),
166 (100). Anal. Calcd for C11H12ClNO2: C, 58.54; H, 5.36; N, 6.21. Found: C, 58.53; H, 5.37; N, 6.17.
1,4,4,8-Tetramethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (7e): a pale-yellow solid; mp 99–102 ˚C
1
(hexane–Et2O); IR (KBr) 1709 cm–1; H NMR (CDCl3) δ 1.65 (s, 6H), 2.42 (s, 3H), 3.47 (s, 3H), 7.02
(dd, J = 7.3, 1.4 Hz, 1H), 7.04 (dd, J = 7.8, 7.3 Hz, 1H), 7.13 (dd, J = 7.8, 1.4 Hz, 1H); MS m/z 205 (M+,
22), 190 (58), 146 (100). Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.17; H,
7.53; N, 6.78.
ACKNOWLEDGEMENTS
We wish to acknowledge the helpful assistance of Mrs. Miyuki Tanmatsu of this Department in
determining mass spectra and performing combustion analyses.
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