1
126
Y. Lu, B. Hu, M. Prashad, S. Kabadi, O. Repiꢀ, T. Blacklock
Vol 43
EXPERIMENTAL
Reaction of N-(tert-Butoxycarbonyl)-2,3-dihydro-1,4-benzoxa-
zine (1) with Butyllithium.
To a cold (ꢀ20 °C) solution of TMEDA (tetramethylethyl-
enediamine) (1.16 g, 10 mmol) in dry THF (20 mL), was added
a solution of 1.6 M BuLi in hexane (6.25 mL, 10 mmol). The
mixture was stirred at ꢀ20 °C for 10 min. Then a solution of N-
(tert-butoxycarbonyl)-2,3-dihydro-1,4-benzoxazine (1; 1.175 g;
5
.0 mmol) in THF (3 mL) was added at ꢀ20 °C. The reaction
mixture was stirred at ꢀ20 °C for 1 h and then at 20 °C for 2 h.
The reaction mixture was cooled to ꢀ20 °C and quenched with
aqueous NH Cl (3.0 mL). THF was removed and isopropyl
4
acetate (30 mL) and water (10 mL) were added to the mixture.
This solution was washed with 20% citric acid (15 mL), water
(
20 mL), sat. aqueous NaHCO (20 mL) and water (20 mL).
3
Figure 1. ORTEP representation of the crystal structure of compound 3.
The organic layer was dried over anhydrous sodium sulfate,
concentrated and chromatographed over silica gel (some
decomposition of the product was observed on silica gel) using
i-PrOAc/heptane mixture as the eluant to afford pure 2-N-(tert-
butoxycarbonyl)-N-vinyl-amino)phenol (3): 0.7 g (60%). mp:
1
9
We then decided to study the lithiation with N-methyl-
2
,3-dihydro-1,4-benzoxazine (4) [14].
The desired
compound 4 was obtained in quantitative yield in two
steps by the treatment of compound 1 with conc. HCl in
MeCN (to deprotect the N-Boc group), followed by N-
methylation of the resulting intermediate with BuLi/MeI.
The lithiation in 4 occurred at the oxygen-adjacent ortho-
position of the aromatic ring. Thus, when 4 was treated
with 4.0 equiv of BuLi/TMEDA, followed by treatment of
the resulting lithiated species 5 with MeI afforded 6 in
1
14-116 °C. H NMR (600 MHz, CDCl ): ꢁ 7.31 (dd, J = 15.8 &
3
.0 Hz, 1H), 7.28-7.23 (m, 2H), 7.07 (d, J = 9.0 Hz, 1H), 7.02
(d, J = 9.0 Hz, 1H), 6.99-6.93 (m, 1H), 5.16 (br s, 1H), 4.29 (d, J
13
= 9.0 Hz, 1H), 3.96 (d, J = 15.8 Hz, 1H), 1.43 (s, 9H); C NMR
(150 MHz, CDCl ): ꢁ 152.65, 151.78, 133.25, 129.59, 129.48,
24.58, 121.12, 117.00, 94.05, 82.22, 28.07; m/z 221 [(M+1) -
3
+
1
+
Me], 136 [(M+1) -BOC].
Anal. Calcd for C H NO : C, 66.36; H, 7.28; N, 5.95. Found:
1
3
17
2
C, 66.24; H, 6.95; N, 6.02.
5
0% yield (Scheme 2). Similar results were obtained with
Reaction of N-Methyl-2,3-dihydro-1,4-benzoxazine (4) with
sec-BuLi/TMEDA. The structure of 6 was confirmed by
comparison of the spectral data with those of an authentic
sample that was prepared starting from 2-amino-6-
methylphenol using the same method as used for the
preparation of compound 4. Similarly, treatment of the
lithiated species 5 with bis(trimethylsilyl)peroxide [15]
afforded the phenol 7 in 30-40% yield (due to incomplete
reaction). These results demonstrated that the lithiation in
N-methyl-2,3-dihydro-1,4-benzoxazine (4) was directed
by the O-CH group over CH -N-CH .
Butyllithium and Iodomethane.
To a cold (ꢀ20 °C) solution of TMEDA (2.32 g, 20 mmol) in
dry THF (20 mL), was added a solution of 1.6 M BuLi in hexane
(12.5 mL, 20 mmol). The mixture was stirred at ꢀ20 °C for 10
min. Then a solution of N-methyl-2,3-dihydro-1,4-benzoxazine
(4; 0.745 g; 5.0 mmol) in THF (3 mL) was added at ꢀ20 °C.
The reaction mixture was stirred at ꢀ20 °C for 1 h and then at 20
°
C for 2 h. The reaction mixture was cooled to ꢀ20 °C and
iodomethane (22.5 mmol) was added. THF was removed and
isopropyl acetate (30 mL) and water (10 mL) were added to the
mixture. This solution was washed with 20% aqueous citric acid
2
3
2
(
15 mL), water (20 mL), sat. aqueous NaHCO (20 mL) and
3
Scheme 2
water (20 mL). The organic layer was dried over anhydrous
sodium sulfate, concentrated and chromatographed over silica
gel using i-PrOAc/heptane mixture as the eluant to afford the
CH
N
3
CH
N
3
pure 4,8-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (6): 0.41 g
BuLi / TMEDA
THF
1
(
50%). H NMR (600 MHz, CDCl ): ꢁ 6.85-6.70 (m, 1H), 6.65-
3
O
O
6.50 (m, 2H), 4.40-4.25 (m, 2H), 3.35-3.20 (m, 2H), 2.87 (s,
1
3
3
1
1
H), 2.17 (s, 3H); C NMR (150 MHz, CDCl ): ꢁ 142.40,
Li
3
4
36.25, 125.19, 120.47, 120.21, 110.53, 64.80, 49.35, 39.13,
5.93; m/z 164 [(M+1) ].
5
+
El+
Anal. Calcd for C H NO: C, 73.59; H, 8.03; N, 8.58. Found:
1
0
13
C, 73.61; H, 8.03; N, 8.38.
CH
N
3
Reaction of N-Methyl-2,3-dihydro-1,4-benzoxazine (4) with
Butyllithium and Bis(trimethylsilyl)peroxide.
6
7
: El = CH
3
: El = OH
O
An analogous reaction was performed employing N-methyl-
2,3-dihydro-1,4-benzoxazine (4; 0.745 g; 5.0 mmol) and
El