Synthesis of 3-substituted and 2,3-disubstituted-4H-1,4-benzoxazines

Article abstract of DOI:10.1016/S0040-4020(99)01023-6

Two new and efficient synthetic routes towards substituted 4H-1,4- benzoxazine derivatives were reported. The first one involves the synthesis in four steps of the 4-Boc-4H-1,4-benzoxazine and its regioselective substitution on C-3 following a lithiation-

Full text of DOI:10.1016/S0040-4020(99)01023-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 605–614
Synthesis of 3-Substituted and
2
,3-Disubstituted-4H-1,4-Benzoxazines
*
C. Buon, L. Chacun-Lef e` vre, R. Rabot, P. Bouyssou and G. Coudert
Institut de Chimie Organique et Analytique associ e´ au CNRS, Universit e´ d’Orl e´ ans, BP 6759, 45067 Orl e´ ans Cedex 02, France
Received 23 September 1999; accepted 23 November 1999
Abstract—Two new and efficient synthetic routes towards substituted 4H-1,4-benzoxazine derivatives were reported. The first one involves
the synthesis in four steps of the 4-Boc-4H-1,4-benzoxazine and its regioselective substitution on C-3 following a lithiation–electrophilic
substitution sequence. The second route involves palladium-catalyzed coupling reactions between organostannanes and a vinylphosphate
obtained from a benzoxazin-3-one derivative. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Scheme 1.
Introduction
derivatives, except phenoxazines of course, only very
particular derivatives have been prepared via cycloaddition
reactions which are far from being generally applicable.
2,3
In the course of our studies related to the synthesis of bio-
active compounds containing a 1,4-benzoxazine unit we
were confronted with the lack of a general and efficient
method allowing easy access to this kind of derivative.
Indeed, 4H-1,4-benzoxazines constitute a little studied
heterocyclic system and few of them have been described
in the literature. For instance, to the best of our knowledge,
We have very recently reported two complementary
methods allowing the synthesis of 3-substituted ben-
4,5
zoxazines. The present paper concerns the extension of
this preliminary work and moreover the preparation of
2,3-disubstituted benzoxazines.
only one example of
zoxazine has been reported. Concerning 2,3-disubstituted
a 3-substituted 4H-1,4-ben-
1
Results and Discussion
Synthesis of 3-substituted-4H-1,4-benzoxazines via the
regioselective formation of the 3-lithio-4-Boc-4H-1,4-
benzoxazines
Keywords: 4H-1,4-benzoxazine; metallation; lithiation–electrophilic
substitution.
*
7
Corresponding author. Tel.: ϩ33-02-38-49-45-89; fax: ϩ33-02-38-41-
2-81; e-mail: gerard.coudert@univ-orleans.fr
The past decade has seen the growing utility of Directed
0
040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01023-6

6
06
C. Buon et al. / Tetrahedron 56 (2000) 605–614
7
8
Table 1.
described by Muchowski and Beak as an excellent
directing activator for both the ortho-lithiation of anilines
and tetrahydroquinolines as well as the a-lithiation of
secondary amines. We postulated that this group could
direct the metallation of the C-3 site of the unsaturated
benzoxazine 3 thus allowing the regiospecific functional-
isation of this position (Scheme 1).
We prepared carbamate 2 in two steps from commercially
available 2-aminophenol. Treatment of 2-aminophenol with
di-tert-butyl dicarbonate in dry tetrahydrofuran at room
temperature led to N-Boc phenolic compounds 1 in 96%
yield. The 2,3-dihydrobenzoxazine 2 was then obtained in
a
4
Electrophile
Mel
Y
Yield (%)
a
b
c
d
e
f
Me
Me
I
75
83
81
82
85
65
83
65
3
Me SiCl
3
Si
I
2
Cl
CO
ClCOOEt
Me SnCl
Bu SnCl
2
BrCCBrCl
2
Br
7
5% yield by heating 1 and 1,2-dibromoethane in refluxing
2
CO
COOEt
Me Sn
Bu Sn
2
H
acetone for 20 h in the presence of an excess of potassium
carbonate. This reaction could be advantageously
performed under microwave irradiation for 1 h in refluxing
pentan-3-one (yield: 76%). The required unsaturated
carbamate 3 was finally obtained in 76% yield by using a
bromination–debromination sequence previously described
g
h
3
3
3
3
a
Isolated yield.
9
4
Metallation Groups (DMGs) for the regiospecific construc-
tion of polysubstituted aromatic and heteroaromatic
compounds. The Directed Ortho Metallation (DOM)
reaction involves the deprotonation of a site ortho to a
for the synthesis of benzodioxines and benzoxazines. The
brominated intermediate was not isolated.
As expected, the deprotonation occurred regio-specifically on
the heterocyclic ring at carbon C-3, adjacent to the N-Boc
group, when 3 was reacted in dry tetrahydrofuran at low
temperature with lithium diisopropylamide. The reaction of
the 3-lithio intermediate with electrophiles led, according to
the nature of the latter, to the 3-substituted benzoxazines 4
6
heteroatom-containing DMG by a lithiated base. The
ortho-lithiated species treated with electrophilic species
lead to 1,2-disubstituted derivatives. Among numerous
DMGs the tert-butoxycarbonyl group (Boc) has been
(
Table 1) or 5 (Table 2). In the two cases, the required hetero-
Table 2.
cyclic compounds were obtained in satisfactory yields.
It could be advantageous to use easily available vinyl-
stannanes 4g and 4h or unsaturated halides 4c and 4d for
performing palladium-catalyzed cross-coupling reactions
(
Stille and Suzuki reactions). Benzoxazines bearing vinyl,
aryl and heteroaryl groups on C-3 could be easily obtained
in this way but we developed an alternative and more
convenient method.
0
0
5
RCOR
R
R
Yield
a
(
%)
When aldehydes or ketones were used as electrophiles, the
formation in situ of an alkoxide anion induced the cleavage
of the carbamic moiety and the formation of a new hetero-
cyclic system.
a
CH
3
COCH
3
Me
Me
90
70
b
2 5
–(CH ) –
Synthesis of 3-substituted-4H-1,4-benzoxazines via
palladium-catalyzed coupling reactions
c
3
CH CHO
Me
H
H
82
75
d
Palladium-catalyzed coupling reactions of organostannanes
with aryl and alkenyl halides or triflates, known as the Stille
reaction, are powerful tools for the construction of carbon–
11
10
carbon bonds. Comins and more recently Hiemstra
prepared lactam derived enol triflates as useful building
a
Isolated yield.
Scheme 2.

C. Buon et al. / Tetrahedron 56 (2000) 605–614
607
Table 3.
Scheme 3.
blocks in several palladium-catalyzed reactions. We postu-
lated that we could obtain in a similar way 3-substituted
benzoxazines from the benzoxazin-3-one 8 via the enol
triflate 6 (Scheme 2).
0
a
1
a
0
R
Yield (%)
87
b
82
Treatment of commercial 4H-1,4-benzoxazine-3-one 7 with
di-tert-butyldicarbonate in dry tetrahydrofuran at room
temperature in the presence of DMAP led to the N-Boc
derivative 8 in 96% yield (Scheme 3).
c
d
e
91
96
84
The corresponding lithium enolate obtained at Ϫ78ЊC in dry
tetrahydrofuran with LDA (1.2 equiv.) and TMEDA
(1.2 equiv.) was then reacted with the triflating agent
N-phenyltrifluoromethanesulfonimide. The required enol
triflate could not be isolated, as it decomposed when the
temperature exceeded Ϫ50 ЊC. Such a lack of stability
was previously observed by Nicolaou with cyclic ketene
acetal triflates and the problem was overcome using cyclic
1
2,13
ketene acetal phosphate.
We hoped that such a method-
f
93
ology would allow, in our case, access to the diphenyl
phosphate 9 and its further use in coupling reactions. The
lithium enolate of the lactam was prepared as previously
described and quenched at Ϫ78ЊC with diphenylchloro-
phosphate (1.2 equiv.). The phosphate 9 proved to be stable
enough at room temperature to be purified by flash chroma-
tography on silica gel; it was eventually obtained in 85%
yield (Scheme 4).
a
Isolated yield.
The reduction of vinyl phosphate 9 was performed in 67%
yield according to the procedure described by Cacchi et
al., and constitutes an attractive alternative to the method
15
previously described for the synthesis of 3 (Scheme 5).
Scheme 4.
Vinyl phosphate 9 was then tested in palladium-catalyzed
coupling reactions with vinyl, aryl and heteroaryl organ-
ostannanes (3 equiv.) (Table 3).
Scheme 5.
Synthesis of 2,3-disubstituted-4H-1,4-benzoxazines
All experiments were run under an argon atmosphere, in
refluxing tetrahydrofuran with a catalytic amount of
Pd(PPh ) (0.05 equiv.) in the presence of lithium chloride
Next, we focused our interest on the synthesis of ben-
zoxazines bearing two distinct substituents on C-2 and
C-3, with the further aim of constructing polycyclic nitrogen
containing analogs of natural products. We postulated that
the presence of a withdrawing group on C-3 could greatly
facilitate deprotonation on the nearby atom C-2. A methyl
ester group appeared as a good candidate for this purpose
because it may be further easily converted to other
functional groups. Treatment of benzoxazinic acid 4e with
methyl iodide in dimethylacetamide for 24 h at room
temperature afforded the required methyl ester 11 in 85%
yield. The lithiation of 11 with LDA (3 equiv.) at Ϫ78ЊC in
3
4
(
3 equiv.) according to the procedure previously described
12
by Nicolaou. Most of the organostannanes were commer-
cially available (entries a–e); the benzodioxine derivative
(
entry f) was easily obtained by condensation of Bu SnCl
3
1
4
and 2-lithio-1,4-benzodioxine.
The 3-substituted benzoxazines were obtained in high yields
and the procedure could be extended to many organ-
ostannanes providing easy access to a wide range of new
heterocyclic systems.

6
08
C. Buon et al. / Tetrahedron 56 (2000) 605–614
Table 4.
Table 6.
a
14
Electrophile
Y
Yield (%)
0
a
1
a
2
Electrophile
CH COCH
R
R
Yield (%)
a
b
c
ClSiMe
ClSnBu
CO
3
Me
Bu
3
CO H
2
3
Si
Sn
80
83
81
3
3
Me
Me
78
72
3
b
2 5
–(CH ) –
2
a
Isolated yield.
c
Me
Ph
70
Conclusion
We have developed two new versatile methods allowing
easy access to a little known heterocyclic system, the
4H-1,4-benzoxazines. A large number of derivatives can
be obtained using either procedures: the unsubstituted
product or 3-substituted and 2,3-disubstituted heterocycles.
a
Isolated yield.
dry tetrahydrofuran was followed by reaction with electro-
philic reagents to give disubstituted benzoxazines 12 or 13
The coupling reaction involving vinyl phosphate will allow
the introduction of vinyl, aryl or heteroaryl groups
depending on the available organostannanes.
(Tables 4 and 5).
When the 2-lithio intermediate was quenched with ketones
3 equiv.), the in situ formation of alkoxy species induced an
intramolecular cyclisation leading to lactone derivatives 12
Table 4).
On the other hand, the lithiation–electrophilic substitution
sequence should be preferentially used for the synthesis of
derivatives bearing substituents such as iodine and bromine,
alkyl, trialkylsilyl, trialkylstannyl or carboxyl groups.
(
(
Other electrophiles (3 equiv.) reacted as expected with the
lithiated species leading to the desired 2,3-disubstitued-4H-
Moreover these methods could probably be extended to the
synthesis and functionalization of several types of nitrogen
or oxygen-containing heterocycles.
1,4-benzoxazines 13 in good yields (Table 5).
As shown in Table 6, the presence of a withdrawing group
on C-3 is not essential to observe deprotonation on C-2.
Experimental
General
The typical procedure previously used also affords
2,3-disubstituted benzoxazines 14 in high yield from the
3
-phenyl substituted derivative 10e.
Melting points were determined with a B u¨ chi SMP-20 melt-
ing point apparatus and are uncorrected. IR spectra were
1
recorded on a Perkin–Elmer FT PARAGON 1000 PC. H
13
and C NMR were recorded on a Bruker Avance DPX250
Table 5.
1
13
spectrometer (250.19 MHz H, 62.89 MHz C), multiplici-
ties were determined by the DEPT 135 sequence. MS were
recorded on a Perkin–Elmer SCIEX API 3000 spectro-
meter. For microwave heating, reactives were placed in a
quartz tube introduced into the Synthewave S402 Prolabo
microwave reactor (power 300 W, microwave frequency
2
450 MHz). All reactions were carried out in flame-
dried glassware under an argon atmosphere. Thin layer
chromatography (TLC) was carried out on Merck silica
gel 60F254 precoated plates. “Usual workup” means
a
1
3
Electrophile
ClSiMe
Y
Yield (%)
extraction with EtOAc, drying with MgSO , filtration and
4
a
b
c
3
Me
I
Me
3
Si
72
70
78
82
evaporation.
I
2
ClSnMe
CO
3
3
Sn
d
2
CO
2
H
N-(tert-butoxycarbonyl)-2-aminophenol (1). A mixture of
2
-aminophenol (4.91 g, 45 mmol) and di-tert-butyldicarbo-
a
Isolated yield.
nate (19.64 g, 90 mmol) in THF (70 mL) was stirred at room

C. Buon et al. / Tetrahedron 56 (2000) 605–614
609
1
3
temperature for 2 h. After concentration and hydrolysis, the
reaction mixture was treated according to usual workup and
gave colorless crystals that were washed with carbon tetra-
6.89–7.01 (m, 2H), 7.78 (m, 1H). C NMR (CDCl ): d ppm
3
28.2 (3CH ), 82.1 (C), 110.4 (CH), 116.3 (CH), 121.4 (CH),
3
123.5 (CH), 125.5 (CH), 127.7 (C), 130.9 (CH), 147.3 (C),
150.1 (C). MS: m/zˆ234 (Mϩ1). Anal. Calcd for
C H NO : C, 66.94, H, 6.48, N, 6.00. Found C, 67.05,
chloride, filtered and dried in vacuo (9.2 g, 96%). Mp: 140–
Ϫ1
1
(
1
41ЊC. IR (KBr): n cm 3426 (OH), 3292 (NH), 1691
13
15
3
1
CyO). H NMR (CDCl ): d ppm 1.53 (s, 9H), 6.66 (bs,
H, 6.57 N, 6.15.
3
1
3
H), 6.81–7.08 (m, 4H), 8.12 (bs, 1H). C NMR (CDCl ): d
3
ppm 28.2 (3CH ), 82.1 (C), 118.9 (CH), 120.7 (CH), 121.4
4-(tert-Butoxycarbonyl)-3-methyl-4H-1,4-benzoxazine
(4a). To a cold (Ϫ78ЊC) solution of 3 (466 mg, 2 mmol) in
dry THF (15 mL) was added a solution of LDA 2 M in
heptane/THF (1.2 mL, 2.4 mmol). The reaction solution
was stirred at Ϫ78ЊC for 35 min and iodomethane
(851 mg, 6 mmol) was added, then the mixture was treated
with a solution of saturated ammonium chloride solution,
and allowed to warm to room temperature. After usual
workup and chromatography with petroleum ether/EtOAc
(95/5), 4a was obtained as a white solid (371 mg, 75%). Mp:
3
(
CH), 125.5 (CH), 125.6 (C), 147.5 (C), 155.0 (C). MS:
m/zˆ210 (Mϩ1). Anal. Calcd for C H NO C, 63.14,
1
1
15
3:
H, 7.23, N, 6.69. Found C, 63.19, H, 7.26, N, 6.72.
4
(
-(tert-Butoxycarbonyl)-3,4-dihydro-2H-1,4-benzoxazine
2). Oil bath heating: A solution of 1 (2.09 g, 10 mmol),
dibromoethane (15.03 g, 80 mmol) and potassium carbonate
27.64 g, 200 mmol) in acetone (200 mL) were refluxed for
8 h. The reaction mixture was cooled, then filtered through
(
1
Ϫ1
1
Celite. After the usual workup and chromatography with
petroleum ether/EtOAc (95/5), 2 was obtained as a white
solid (1.76 g, 75%). Microwave heating: A solution of 1
Ͻ25ЊC. IR (KBr): n cm 1724 (CyO). H NMR (CDCl ):
3
d ppm 1.53 (s, 9H), 2.01 (d, 3H, Jˆ1 Hz), 6.22 (d, 1H,
Jˆ1 Hz), 6.83–6.89 (m, 1H), 7.00–7.08 (m, 2H), 7.43–
13
(
2.09 g, 10 mmol), dibromoethane (15.03 g, 80 mmol) and
potassium carbonate (27.64 g, 200 mmol) in pentan-3-one
100 mL) were refluxed under microwave irradiation for
h. The reaction mixture was cooled, then filtered through
7.49 (m, 1H). C NMR (CDCl ): d ppm 15.6 (CH ), 29.7
3 3
(3CH ), 81.9 (C), 116.3 (CH), 121.8 (C), 122.8 (CH), 124.6
3
(
1
(CH), 125.6 (CH), 129.1 (C), 134.9 (CH), 150.9 (C), 152.3
(C). MS: m/zˆ248 (Mϩ1). Anal. Calcd for C H NO : C,
14
17
3
Celite. After the usual workup and chromatography with
68.00, H, 6.93, N, 5.66. Found C, 68.15, H, 7.12, N, 5.75.
petroleum ether/EtOAc (95/5), 2 was obtained as a white
Ϫ1
solid (1.79 g, 76%): mp: 78–79ЊC. IR (KBr): n cm 1722
4-(tert-Butoxycarbonyl)-3-trimethylsilyl-4H-1,4-benzoxa-
zine (4b). The reaction was carried out as described above
for the synthesis of compound 4a with chlorotrimethylsilane
(652 mg, 6 mmol) as an electrophile. Chromatography with
petroleum ether/EtOAc (95/5) gave 4b (507 mg, 83%) as a
1
(
CyO). H NMR (CDCl ): d ppm 1.54 (s, 9H), 3.83–3.88
3
(
m, 2H), 4.22–4.27 (m, 2H), 6.80–7.01 (m, 3H), 7.76 (d, 1H,
1
3
Jˆ7.8 Hz). C NMR (CDCl ): d ppm 28.3 (3CH ), 42.1
3
3
(CH ), 65.6 (CH ), 81.6 (C), 116.9 (CH), 120.2 (CH),
2 2
Ϫ1
1
23.5 (CH), 124.3 (CH), 126.2 (C), 145.9 (C), 152.6 (C).
white solid. Mp: 71–72ЊC. IR (KBr): n cm 1695 (CyO).
1
MS: m/zˆ236 (Mϩ1). Anal. Calcd for C H NO : C,
H-NMR (CDCl ): d ppm 0.23 (s, 9H), 1.53 (s, 9H), 6.23
1
3
17
3
3
66.36, H, 7.28, N, 5.95. Found C, 66.15, H, 7.43, N, 5.90.
(s, 1H), 6.83–6.88 (m, 1H), 6.96–7.09 (m, 2H), 7.36–7.41
13
(
m, 1H). C NMR (CDCl ): d ppm 0.3 (3CH ), 28.3
3
3
4
-(tert-Butoxycarbonyl)-4H-1,4-benzoxazine (3). Method
(3CH ), 82.1 (C), 116.3 (CH), 123.5 (CH), 123.7 (CH),
3
A: To a solution of compound 2 (940 mg, 4 mmol) in dry
carbon tetrachloride (50 mL) was added N-bromosuccini-
mide (1.56 g, 8.8 mmol) and a catalytic amount of benzoyl
peroxide. The resulting mixture was stirred and heated with
a bulb lamp (60 W) at reflux for 45 min. The mixture was
allowed to cool and the succinimide was filtered off. The
filtrate was evaporated to yield an oil sufficiently pure to be
used directly in the next step of the reaction. The crude
product was stirred in acetone (50 mL) at room temperature
for 2 h with sodium iodide (2.99 g, 20 mmol). The acetone
was removed from the greenish slurry under reduced
pressure then water, EtOAC and 1 M sodium thiosulfate
solution were added to the resulting brown residue. After
the usual workup and chromatography with petroleum
ether/EtOAc (95/5), 3 was obtained as a colorless oil
125.7 (CH), 125.5 (C), 129.1 (C), 143.0 (CH), 149.9 (C),
151.8 (C). MS: m/zˆ306 (Mϩ1). Anal. Calcd for
C H NO Si: C, 62.92, H, 7.59, N, 4.59. Found C, 63.11,
16
23
3
H, 7.68, N, 4.71.
4-(tert-Butoxycarbonyl)-3-iodo-4H-1,4-benzoxazine (4c).
To a cold (Ϫ78ЊC) solution of 3 (466 mg, 2 mmol) in dry
THF (15 mL) was added a solution of LDA 2 M in heptane/
THF (1.2 mL, 2.4 mmol). The reaction solution was stirred
at Ϫ78ЊC for 35 min and iodine (1.01 g, 4 mmol) in cold
(Ϫ78ЊC) THF (5 mL) was added, then the mixture was trea-
ted with a solution of sodium thiosulfate 1 M, allowed to
warm to room temperature. The phases were separated, the
aqueous phase was extracted with EtOAc ꢀ3×10 mL†; and
the combined organic phases were dried over MgSO and
4
(
1.88 g, 86%). Method B: A solution of formic acid
concentrated. Chromatography with toluene gave 4c
Ϫ1
(
184 mg, 4 mmol) and triethylamine (607 mg, 6 mmol) in
(582 mg, 81%) as a colorless oil. IR (neat): n cm 1721
1
DME (3 mL) was stirred for 5 min at room temperature and
a solution of triphenylphosphine (42 mg, 0.16 mmol),
palladium(II) acetate (19 mg, 0.08 mmol) and compound 9
(CyO). H NMR (CDCl ): d ppm 1.55 (s, 9H), 6.57 (s, 1H),
3
6.86–6.91 (m, 1H), 7.07–7.11 (m, 2H), 7.40–7.44 (m, 1H).
13
C NMR (CDCl ): d ppm 28.1 (3CH ), 70.3 (C), 83.5 (C),
3
3
(
963 mg, 2 mmol) in DME (3 mL) was added. The mixture
115.9 (CH), 123.8 (CH), 124.7 (CH), 126.7 (CH), 128.0 (C),
143.7 (CH), 150.6 (C), 151.4 (C). MS: m/zˆ360 (Mϩ1).
Anal. Calcd for C H INO : C, 43.47, H, 3.93, N, 3.90.
was stirred at reflux for 1 h. After the usual workup and
chromatography on silica gel of the residue with petroleum
13
14
3
ether/EtOAc (95/5), 3 was obtained as a colorless oil
Found C, 43.50, H, 3.99, N, 4.01.
Ϫ1
(
1
312 mg, 67%). IR (neat): n cm 1712 (CyO), 1587 and
1
495 (CyC). H NMR (CDCl ): d ppm 1.54 (s, 9H), 5.97 (d,
3-Bromo-4-(tert-butoxycarbonyl)-4H-1,4-benzoxazine
(4d). The reaction was carried out as described above for the
3
1H, Jˆ4.4 Hz), 6.18 (d, 1H, Jˆ4.4 Hz), 6.70–6.77 (m, 1H),

6
10
C. Buon et al. / Tetrahedron 56 (2000) 605–614
1
3
synthesis of compound 4a with 1,2-dibromotetrachloro-
ethane (1.95 g, 6 mmol) in solution in THF (5 mL) as an
electrophile. Chromatography with petroleum ether/EtOAc
7.42–7.46 (m, 1H). C NMR (CDCl ): d ppm Ϫ6.3 (3CH ),
3 3
28.2 (3CH ), 82.2 (C), 116.3 (CH), 122.3 (CH), 122.9 (CH),
125.3 (CH), 123.5 (C), 128.6 (C), 138.3 (CH), 148.9
3
116
(
95/5) gave 4d (624 mg, 82%) as a colorless oil. IR (neat): n
(C), 152.1 (C). MS: m/zˆ394 (Mϩ1) ( Sn), 396
Ϫ1
1
118
120
cm 1732 (CyO). H NMR (CDCl ): d ppm 1.55 (s, 9H),
(Mϩ1) ( Sn), 398 (Mϩ1) ( Sn). Anal. Calcd for
3
6
.61 (s, 1H), 6.91–6.95 (m, 1H), 7.07–7.16 (m, 2H), 7.44–
C H NO Sn: C, 48.52, H, 5.85, N, 3,54. Found C,
48.48, H, 5.89, N, 3.51.
16
23
3
1
3
7.48 (m, 1H). C NMR (CDCl ): d ppm 28.1 (3CH ), 83.5
3
3
(
C), 87.8 (C), 115.9 (CH), 123.8 (CH), 124.9 (CH), 126.7
CH), 128.7 (C), 138.2 (C), 138.9 (CH), 150.7 (C). MS:
(
4-(tert-Butoxycarbonyl)-3-tributyltin-4H-1,4-benzoxazine
(4h). The reaction was carried out as described above for the
synthesis of the compound 4a with tributyltin chloride
(1.30 g, 4 mmol) as an electrophile. Chromatography with
petroleum ether/EtOAc (98/2) gave 4g (679 mg, 65%) as a
7
9
81
m/zˆ312 ( Br) (Mϩ1), 314 ( Br) (Mϩ1). Anal. Calcd
for C H BrNO : C, 50.02, H, 4.52, N, 4.49. Found C,
1
3
14
3
5
0.11, H, 4.60, N, 4.53.
Ϫ1
1
4
-(tert-Butoxycarbonyl)-4H-1,4-benzoxazine-3-carboxylic
colorless oil. IR (neat): n cm 1675 (CyO). H NMR
acid (4e). To a cold (Ϫ78ЊC) solution of 3 (466 mg,
mmol) in dry THF (15 mL) was added a solution of
(CDCl ): d ppm 0.84–1.55 (m, 36H), 5.86 (s, 1H), 6.75–
3
13
2
6.79 (m, 1H), 6.90–7.01 (m, 2H), 7.32–7.36 (m, 1H).
C
LDA 2 M in heptane/THF (1.2 mL, 2.4 mmol). The reaction
solution was stirred at Ϫ78ЊC for 35 min then carbon
dioxide from dry ice, dried over sulfuric acid, was intro-
duced above the surface of the rapidly stirred solution
during 10 min, then the mixture was treated with a sodium
hydroxide solution (20%) and allowed to warm to room
temperature. The mixture was extracted with dichloro-
methane ꢀ2×10 mL†; the aqueous phase was acidified with
hydrochloric acid solution (10%) and extracted with
dichloromethane ꢀ3×10 mL†: The organic phases were
NMR (CDCl ): d ppm 12.2 (3CH ), 13.7 (3CH ), 27.3
3
2
3
(3CH ), 28.2 (3CH ), 28.9 (3CH ), 82.0 (C), 116.2 (CH),
2
3
2
122.4 (CH), 122.8 (CH), 123.2 (C), 125.2 (CH), 128.7 (C),
138.4 (CH), 149.2 (C), 152.0 (C). MS: m/zˆ520 (Mϩ1)
116
118
120
(
Sn), 522 (Mϩ1) ( Sn), 524 (Mϩ1) ( Sn). Anal.
Calcd for C H NO Sn: C, 57.49, H, 7.91, N, 22.68.
25
41
3
Found C, 57.62, H, 8.05, N, 22.85.
3,3-Dimethyl-3H-benzo [b][1,3]oxazolo [3,4-d][1,4]oxazin-
1-one (5a). The reaction was carried out as described above
for the synthesis of compound 4a with acetone (348 mg,
6 mmol) as an electrophile. Chromatography with petro-
leum ether/EtOAc (95/5) gave 5a (391 mg, 90%) as white
dried over MgSO , concentrated and 4e (471 mg, 85%) was
4
obtained as a crude product. Mp: 154–155ЊC. IR (KBr): n
Ϫ1
1
cm 3400–2600 (OH), 1726 (CyO), 1702 (CyO). H NMR
Ϫ1
(
(
CDCl ): d ppm 1.49 (s, 9H), 6.92–6.96 (m, 1H), 7.06–7.16
m, 2H), 7.40 (s, 1H), 7.61–7.65 (m, 1H), 10.03 (bs, 1H). C
crystals. Mp: 125–126ЊC. IR (KBr): n cm 1757 (CyO).
3
13
1
H NMR (CDCl ): d ppm 1.59 (s, 6H), 5.78 (s, 1H), 6.66–
3
13
NMR (CDCl ): d ppm 27.9 (3CH ), 83.2 (C), 116.1 (CH),
6.71 (m, 1H), 6.89–6.98 (m, 2H), 7.89–7.95 (m, 1H).
C
3
3
1
16.8 (C), 124.7 (CH), 126.3 (2CH), 127.9 (C), 147.2
NMR (CDCl ): d ppm 27.8 (2CH ), 79.4 (C), 116.1 (CH),
3
3
(
(
CH), 148.6 (C), 151.5 (C), 168.7 (C). MS: m/zˆ278
116.5 (CH), 119.7 (CH), 124.1 (CH), 124.4 (CH), 126.5 (C)
126.3 (C), 143.3 (C), 151.5 (C). MS: m/zˆ218 (Mϩ1).
Anal. Calcd for C H NO : C, 66.35, H, 5.10, N, 6.45.
Mϩ1). Anal. Calcd for C H NO : C, 60.65, H, 5.45,
1
4
15
5
N, 5.05. Found C, 60.68, H, 5.50, N, 5.07.
12
11
3
Found C, 66.24, H, 5.21, N, 6.45.
4
-(tert-Butoxycarbonyl)-3-ethyl-4H-1,4-benzoxazine-3-
carboxylate (4f). The reaction was carried out as described
above for the synthesis of compound 4a with ethyl chloro-
formate (651 mg, 6 mmol) as an electrophile. Chroma-
3-Spiro [4,5]-3H-benzo[b][1,3]oxazolo[3,4-d][1,4]oxazin-
1-one (5b). The reaction was carried out as described above
for the synthesis of compound 4a with cyclohexanone
(589 mg, 6 mmol) as an electrophile. Chromatography
with petroleum ether/EtOAc (95/5) gave 5b (360 mg,
70%) as white crystals. Mp: 152–153ЊC. IR (KBr): n
tography with petroleum ether/EtOAc (80/20) gave 4f
Ϫ1
(
1
397 mg, 65%) as a colorless oil. IR (neat): n cm 1725,
1
665 (CyO). H NMR (CDCl ): d ppm 1.33 (t, 3H,
3
Ϫ1
1
Jˆ7.2 Hz), 1.49 (s, 9H), 4.28 (q, 2H, Jˆ7.2 Hz), 6.90–
cm 1749 (CyO). H NMR (CDCl ): d ppm 1.42–2.09
3
6
.93 (m, 1H), 7.07–7.20 (m, 2H), 7.26 (s, 1H), 7.62–7.66
(m, 10H), 5.72 (s, 1H), 6.58–6.66 (m, 1H), 6.85–6.94 (m,
1
3
13
(m, 1H). C NMR (CDCl ): d ppm 15.1 (CH ), 28.3
2H), 7.88–7.96 (m, 1H). C NMR (CDCl ): d ppm 21.4
3
3
3
(
1
(
(
3CH ), 61.9 (CH ), 83.1 (C), 116.3 (CH), 118.2 (C),
24.5 (CH), 124.8 (CH), 126.6 (CH), 128.4 (C), 139.1
(2CH ), 24.4 (CH ), 36.8 (2CH ), 81.3 (C), 116.0 (CH),
3
2
2
2
2
116.5 (CH), 120.4 (CH), 124.1 (CH), 124.5 (C), 126.4
(CH), 129.9 (C), 143.5 (C), 150.4 (C). MS: m/zˆ258
(Mϩ1). Anal. Calcd for C H NO : C, 70.02, H, 5.88, N,
CH), 150.3 (C), 153.6 (C), 163.4 (C). MS: m/zˆ306
Mϩ1). Anal. Calcd for C H NO : C, 62.94, H, 6.27, N,
1
6
19
5
15 15
3
4.59. Found C, 63.06, H, 6.33, N, 4.69.
5.44. Found C, 69.99, H, 5.91, N, 5.39.
4
-(tert-Butoxycarbonyl)-3-trimethyltin-4H-1,4-benzoxa-
3-Methyl-3H-benzo [b][1,3]oxazolo [3,4-d][1,4]oxazin-1-
one (5c). The reaction was carried out as described above
for the synthesis of compound 4a with acetaldehyde
(264 mg, 6 mmol) as an electrophile. Chromatography
with petroleum ether/EtOAc (95/5) gave 5c (333 mg,
zine (4g). The reaction was carried out as described above
for the synthesis of the compound 4a with trimethyltin
chloride (797 mg, 4 mmol) as an electrophile. Chroma-
tography with petroleum ether/EtOAc (99/1) gave 4g
Ϫ1
(
657 mg, 83%) as white crystals. Mp: 78–79ЊC. IR (KBr):
82%) as white crystals. Mp: 90–91ЊC. IR (KBr): n cm
Ϫ1
1
1
n cm 1676 (CyO), 1583, 1497 (CyC). H NMR (CDCl ):
1755 (CyO). H NMR (CDCl ): d ppm 1.58 (d, 3H,
3
3
1
19
117
d ppm 0.25 (s, 9H, J ( Sn,CH )ˆ57 Hz, J ( Sn,CH3)
Jˆ6.3 Hz), 5.10–5.18 (qd, 1H, Jˆ6.3 Hz, Jˆ2.2 Hz), 5.74
3
1
19
ˆ
54 Hz), 1.58 (s, 9H), 5.94 (s, 1H, J ( Sn,H )ˆ19 Hz, J
(d, 1H, Jˆ2.2 Hz), 6.63–6.66 (m, 1H), 6.86–6.96 (m, 2H),
2
1
17
13
(
Sn,H )ˆ18 Hz), 6.80–6.84 (m, 1H), 6.94–7.06 (m, 2H),
7.86–7.90 (m, 1H). C NMR (CDCl ): d ppm 21.8 (CH ),
2
3
3

C. Buon et al. / Tetrahedron 56 (2000) 605–614
611
7
1.3 (CH), 116.1 (CH), 116.4 (CH), 120.4 (CH), 124.2
4-(tert-Butoxycarbonyl)-3-vinyl-4H-1,4-benzoxazine
(10a). Phosphate 9 (481 mg, 1 mmol) and tributyl(vinyl)tin
(634 mg, 2 mmol) were dissolved in THF (3 mL). Tetrakis-
(triphenylphosphine)palladium (0) (58 mg, 0.05 mmol) and
lithium chloride (127 mg, 3 mmol) were added and the reac-
tion was refluxed for 2 h. After usual workup, extraction
with acetonitrile/pentane and chromatography with petro-
leum ether/EtOAc (95/5), 10a was obtained as a colorless
(
(
CH), 122.4 (C), 124.1 (C), 126.6 (CH), 143.4 (C), 151.5
C). MS: m/zˆ204 (Mϩ1). Anal. Calcd for C H NO :
1
1
9
3
C, 65.02, H, 4.46, N, 6.89. Found C, 64.99, H, 4.50, N,
6
.78.
3-(3,4-Dimethoxyphenyl)-3H-benzo [b][1,3]oxazolo [3,4-d]-
[
1,4]oxazin-1-one (5d). The reaction was carried out as
described above for the synthesis of compound 4a with
,4-dimethoxybenzaldehyde (997 mg, 6 mmol) as an
electrophile. Chromatography with petroleum ether/EtOAc
Ϫ1
oil (225 mg, 87%). IR (neat): n cm 1716 (CyO), 1662
1
3
(CyC). H NMR (CDCl ): d ppm 1.47 (s, 9H), 5.06 (d, 1H,
3
Jˆ10.9 Hz), 5.25 (d, 1H, Jˆ17.2 Hz), 6.18 (dd, 1H,
(
1
80/20) gave 5d (488 mg, 75%) as yellow crystals. Mp:
20–121ЊC. IR (KBr): n cm 1762 (CyO). H NMR
Jˆ10.9 Hz, Jˆ17.2 Hz), 6.65 (s, 1H), 6.90–6.96 (m, 1H),
Ϫ1
1
13
7.07–7.12 (m, 2H), 7.46–7.53 (m, 1H). C NMR (CDCl ): d
3
(
CDCl ): d ppm 3.91 (s, 3H), 3.93 (s, 3H), 5.63 (d, 1H,
ppm 27.9 (3CH ), 81.9 (C), 115.7 (CH ), 118.8 (CH), 123.2
3
3
2
Jˆ2 Hz), 5.93 (d, 1H, Jˆ2 Hz), 6.66–6.70 (m, 1H), 6.87–
(CH), 125.2 (C), 125.3 (CH), 125.8 (CH), 128.1 (CH), 128.8
(C), 138.8 (CH), 150.6 (C), 152.2 (C). MS: m/zˆ260 (Mϩ1).
Anal. Calcd for C H NO : C, 69.48, H, 6.61, N, 5.40. Found
1
3
7
5
1
1
1
.03 (m, 5H), 7.92–7.97 (m, 1H). C NMR (CDCl ): d ppm
3
6.4 (CH ), 56.5 (CH ), 77.1 (CH), 110.4 (CH), 111.4 (CH),
3
3
15 17
3
16.6 (CH), 116.9 (CH), 120.7 (CH), 121.1 (C), 122.9 (CH),
24.7 (CH), 124.1 (C), 127.1 (CH), 128.1 (C), 143.8 (C),
49.9 (C), 150.8 (C), 150.9 (C). MS: m/zˆ326 (Mϩ1).
C, 69.45, H, 6.68, N, 5.34.
4-(tert-Butoxycarbonyl)-3-(1-ethoxyvinyl)-4H-1,4-benzox-
azine (10b). The reaction was carried out as described above
for the synthesis of compound 10a with tributyl(1-ethoxy-
vinyl)tin (722 mg, 2 mmol). Chromatography with petro-
leum ether/EtOAc (95/5) gave 10b (249 mg, 82%) as a
Anal. Calcd for C H NO : C, 66.46, H, 4.65, N, 4.31.
1
8
15
3
Found C, 66.52, H, 4.67, N, 4.41.
4
3
(
-(tert-Butoxycarbonyl)-3,4-dihydro-2H-1,4-benzoxazin-
-one (8). To a solution of 7 (1.49 g, 10 mmol) in THF
20 mL) were added di-tert-butyldicarbonate (2.62 g,
Ϫ1
colorless oil. IR (neat): n cm 1715 (CyO), 1587, 1492
1
(CyC). H NMR (CDCl ): d ppm 1.34 (t, 3H, Jˆ7 Hz), 1.47
3
1
2 mmol) and 4-dimethylaminopyridine (1.46 g, 12 mmol).
(s, 9H), 3.84 (q, 2H, Jˆ7 Hz), 4.07 (d, 1H, Jˆ2.5 Hz), 4.31
The mixture was stirred at room temperature for 3 h. After
concentration, the residue was diluted with EtOAc and
washed with a solution of hydrochloric acid 3 M
(d, 1H, Jˆ2.5 Hz), 6.86 (s, 1H), 6.88–6.92 (m, 1H), 7.04–
13
7.09 (m, 2H), 7.53–7.57 (m, 1H). C NMR (CDCl ): d ppm
3
14.4 (CH ), 28.0 (3CH ), 63.2 (CH ), 81.5 (CH ), 82.1 (C),
3
3
2
2
ꢀ
2×10 mL†: After the usual workup and chromatography
115.8 (CH), 123.0 (C), 123.3 (CH), 125.0 (CH), 125.9 (CH),
129.1 (C), 137.9 (CH), 150.9 (C), 152.2 (C), 154.8 (C). MS:
m/zˆ304 (Mϩ1). Anal. Calcd for C H NO : C, 67.31, H,
with petroleum ether/EtOAc (95/5), 8 was obtained as
white crystals (2.39 g, 96%). Mp: 72–73ЊC. IR (KBr): n
1
7
21
4
Ϫ1
1
cm 1779–1702 (CyO). H NMR (CDCl ): d ppm 1.62
6.98, N, 4.62. Found C, 67.39, H, 7.02, N, 4.52.
3
1
3
(s, 9H), 4.56 (s, 2H), 7.03–7.17 (m, 4H). C NMR (CDCl ):
3
d ppm 27.6 (3CH ), 68.3 (CH ), 85.6 (C), 117.3 (CH), 118.4
4-(tert-Butoxycarbonyl)-3-(2-thienyl)-4H-1,4-benzoxazine
(10c). The reaction was carried out as described above for
the synthesis of compound 10a with 2-(tributylstannyl)-
thiophene (746 mg, 2 mmol). Chromatography with petro-
leum ether/EtOAc (95/5) gave 10c (287 mg, 91%) as a
3
2
(
CH), 122.8 (CH), 125.3 (CH), 126.2 (C), 145.4 (C), 149.5
(
C), 164.2 (C). MSˆ250 (Mϩ1). Anal. Calcd for
C H NO : C, 62.64, H, 6.07, N, 5.62. Found C, 62.71,
13
15
4
H, 6.18, N, 5.73.
Ϫ1
colorless oil. IR (neat): n cm 1712 (CyO), 1588, 1491
1
4
4
-(tert-Butoxycarbonyl)-3-[(diphenoxyphosphoryl)oxo]-
H-1,4-benzoxazine (9). To a cold (Ϫ78ЊC) solution of 8
(CyC). H NMR (CDCl ): d ppm 1.35 (s, 9H), 6.73 (s, 1H),
3
6.95–6.99 (m, 2H), 7.04–7.06 (m, 1H), 7.09–7.13 (m, 2H),
0
0
13
(2.49 g, 10 mmol) in dry THF (50 mL) and N,N,N ,N -tetra-
7.18 (dd, 1H, Jˆ1.2 Hz, Jˆ5 Hz), 7.61–7.69 (m, 1H).
C
methylenediamine (1.28 g, 11 mmol) was added a solution
of LDA 2 M in heptane/THF (6 mL, 12 mmol). The reaction
mixture was stirred at Ϫ78ЊC for 1 h and 30 min and freshly
distilled diphenyl chlorophosphate (3.22 mL, 12 mmol) was
added, then the mixture was stirred for 20 min, and allowed
to warm to room temperature. The volatiles were removed
and the residue was hydrolyzed. After the usual workup and
chromatography on silica gel with petroleum ether/EtOAc
NMR (CDCl ): d ppm 27.7 (3CH ), 82.2 (C), 115.8 (CH),
3
3
121.8 (C), 123.2 (CH), 123.4 (CH), 123.5 (CH), 125.0 (CH),
125.8 (C), 126.1 (CH), 126.2 (CH), 128.9 (C), 135.5 (CH),
151.0 (C), 152.2 (C). MS: m/zˆ316 (Mϩ1). Anal. Calcd for
C H NO S: C, 64.74, H, 5.43, N, 4.44. Found C, 64.86, H,
17
17
3
5.49, N, 4.40.
4-(tert-Butoxycarbonyl)-3-(2-furyl)-4H-1,4-benzoxazine
(10d). The reaction was carried out as described above for
the synthesis of compound 10a with 2-(tributylstannyl)furan
(714 mg, 2 mmol). Chromatography with petroleum ether/
EtOAc (95/5) gave 10d (287 mg, 96%) as a colorless oil. IR
(
6
(
(
90/10), 9 was obtained as white crystals (4.09 g, 85%). Mp:
Ϫ1
4–65ЊC. IR (KBr): n cm 1732 (CyO), 1591, 1489
1
CyC), 1315 (PyO). H NMR (CDCl ): d ppm 1.46
3
13
s, 9H), 6.70 (d, 1H, JH,Pˆ4 Hz), 6.91–7.41 (m, 14H).
C
Ϫ1
1
NMR (CDCl ): d ppm 27.9 (3CH ), 83.2 (C), 115.9 (CH),
(neat): n cm 1726 (CyO), 1589, 1491 (CyC). H NMR
3
3
19.8 (4CH, JC,Pˆ4.6 Hz), 123.5 (CH), 124.9 (CH), 125.6
(CDCl ): d ppm 1.35 (s, 9H), 6.30 (dd, 1H, Jˆ0.6 Hz,
3
Jˆ3.2 Hz), 6.39 (dd, 1H, Jˆ1.7 Hz, Jˆ3.2 Hz), 6.86 (s,
C,P
1H), 6.92–6.95 (m, 1H), 7.07–7.11 (m, 2H), 7.35 (dd, 1H,
13
Jˆ0.6 Hz, Jˆ1.7 Hz), 7.61–7.65 (m, 1H). C NMR
(CDCl ): d ppm 27.7 (3CH ), 82.0 (C), 105.6 (CH), 110.9
2
5
24
7
3
3
Found C, 62.46, H, 5.05, N, 2.88.
(CH), 115.8 (CH), 118.7 (C), 123.4 (CH), 125.0 (CH), 126.1

6
12
C. Buon et al. / Tetrahedron 56 (2000) 605–614
CH), 128.7 (C), 136.2 (CH), 140.8 (CH), 147.9 (C), 150.8
usual workup and chromatography with petroleum ether/
EtOAc (95/5), 12a was obtained as white crystals
Ϫ1
(494 mg, 78%). Mp: 120–121ЊC. IR (KBr): n cm 1780,
17
17
4
1
1724 (CyO). H NMR (CDCl ): d ppm 1.53 (s, 9H), 1.59
3
(
s, 6H), 6.91–6.99 (m, 1H), 7.05–7.19 (m, 2H), 7.73–7.81
13
4
(
-(tert-Butoxycarbonyl)-3-phenyl-4H-1,4-benzoxazine
10e). The reaction was carried out as described above for
the synthesis of compound 10a with tributylphenyltin
734 mg, 2 mmol). Chromatography with petroleum ether/
(m, 1H). C NMR (CDCl ): d ppm 24.3 (2CH ), 27.9
(3CH ), 78.7 (C), 83.7 (C), 108.9 (C), 116.7 (CH), 124.8
(CH), 125.5 (CH), 126.4 (CH), 127.5 (C), 147.8 (C), 151.3
(C), 163.1 (C), 168.3 (C). MS: m/zˆ318 (Mϩ1). Anal.
Calcd for C H NO : C, 64.34, H, 6.03, N, 4.41. Found
3
3
3
(
EtOAc (95/5) gave 10e (260 mg, 84%) as white crystals.
17
19
5
Ϫ1
Mp: 115–116ЊC. IR (KBr): n cm 1710 (CyO), 1588,
C, 64.37, H, 6.07, N, 4.39.
1
1493 (CyC). H NMR (CDCl ): d ppm 1.15 (s, 9H), 6.59
3
(
(
(
s, 1H), 6.90–6.96 (m, 1H), 7.08–7.12 (m, 2H), 7.24–7.37
9-(tert-Butoxycarbonyl)-3-spiro[4,5]-3,9-dihydro-1H-
benzo[b]furo[3,4-e][1,4]oxazin-1-one (12b). The reaction
was carried out as described above for the synthesis of
compound 12a with cyclohexanone (589 mg, 6 mmol) as
an electrophile. Chromatography with petroleum ether/
EtOAc (95/5) gave 12b (514 mg, 72%) as white crystals.
1
3
m, 5H), 7.69–7.71 (m, 1H). C NMR (CDCl ): d ppm 27.6
3
3CH ), 81.9 (C), 115.8 (CH), 123.4 (CH), 124.5 (CH),
3
1
24.6 (CH), 125.8 (CH), 126.0 (CH), 126.7 (C), 127.2
CH), 128.3 (2CH), 129.0 (C), 135.4 (CH), 135.5 (C),
51.0 (C), 152.0 (C). MS: m/zˆ310 (Mϩ1). Anal. Calcd
for C H NO : C, 73.77, H, 6.19, N, 4.53. Found C,
(
1
Ϫ1
1
Mp: 145–146ЊC. IR (KBr): n cm 1780, 1725 (CyO). H
1
9
19
3
7
3.79, H, 6.18, N, 4.50.
NMR (CDCl ): d ppm 1.52 (s, 9H), 1.54–1.89 (m, 10H),
3
6
.90–6.96 (m, 1H), 7.02–7.13 (m, 2H), 7.71–7.80 (m, 1H).
C NMR (CDCl ): d ppm 21.6 (2CH ), 24.3 (CH ), 27.9
13
3-[2-(1,4-Benzodioxino)]-4-(tert-butoxycarbonyl)-4H-1,4-
3
2
2
benzoxazine (10f). The reaction was carried out as
described above for the synthesis of the compound 10a
with 2-trimethyltin-1,4-benzodioxine (846 mg, 2 mmol).
(3CH ), 33.2 (2CH ), 80.3 (C), 83.6 (C), 109.2 (C), 116.7
3 2
(CH), 124.8 (CH), 125.5 (CH), 126.4 (CH), 127.6 (C), 147.8
(C), 151.3 (C), 163.5 (C), 168.9 (C). MS: m/zˆ358 (Mϩ1).
Anal. Calcd for C H NO : C, 67.21, H, 6.49, N, 3.92.
Chromatography with petroleum ether/EtOAc (95/5) gave
20
23
5
Ϫ1
1
(
0f (340 mg, 93%) as a colorless oil. IR (neat): n cm 1722
Found C, 67.37, H, 6.44, N, 3.82.
1
CyO), 1491 (CyC). H NMR (CDCl ): d ppm 1.48 (s, 9H),
3
6
7
2
1
.11 (s, 1H), 6.70–6.75 (m, 3H), 6.83–6.93 (m, 3H,), 7.07–
9-(tert-Butoxycarbonyl)-3-methyl-3-phenyl-3,9-dihydro-
1H-benzo[b]furo[3,4-e][1,4]oxazin-1-one (12c). The reac-
tion was carried out as described above for the synthesis of
compound 12a with acetophenone (721 mg, 6 mmol) as an
electrophile. Chromatography with petroleum ether/EtOAc
(95/5) gave 12c (514 mg, 72%) as white crystals. Mp: 145–
1
3
.11 (m, 2H), 7.55–7.59 (m, 1H). C NMR (CDCl ): d ppm
3
8.2 (3CH ), 83.8 (C), 116.1 (CH), 116.3 (CH), 116.4 (CH),
3
18.9 (C), 123.5 (CH), 123.7 (CH), 124.3 (2CH), 125.3
(
1
(
CH), 126.4 (CH), 128.7 (C), 132.3 (C), 136.6 (CH),
42.3 (C), 142.5 (C), 151.0 (C), 152.2 (C). MS: m/zˆ366
Mϩ1). Anal. Calcd for C H NO : C, 69.03, H, 5.24, N,
Ϫ1
146ЊC. IR (KBr): n cm 1785, 1725 (CyO), 1488 (CyC).
2
1
19
3
1
3.83. Found C, 69.09, H, 5.28, N, 3.79.
H NMR (CDCl ): d ppm 1.54 (s, 9H), 1.95 (s, 3H), 6.96–
3
13
7
.14 (m, 3H), 7.36–7.54 (m, 5H), 7.77–7.80 (m, 1H).
C
4
3
-(tert-Butoxycarbonyl)-3-methyl-4H-1,4-benzoxazine-
-carboxylate (11). To a solution of 4e (2.7 g, 10 mmol) in
NMR (CDCl ): d ppm 24.7 (CH ), 27.8 (3CH ), 81.0 (C),
3
3
3
83.8 (C), 109.0 (C), 116.8 (CH), 124.7 (CH), 124.8 (2CH),
125.6 (CH), 126.4 (CH), 127.4 (C), 128.8 (3CH), 137.6 (C),
147.7 (C), 151.1 (C), 163.2 (C), 167.2 (C). MS: m/zˆ380
(Mϩ1). Anal. Calcd for C H NO : C, 69.65, H, 5.58, N,
N,N-dimethylacetamide (50 mL) was added iodomethane
4.48 g, 33 mmol) and sodium hydrogencarbonate (4.2 g,
0 mmol). The resulting mixture was stirred at room
(
5
22
21
5
temperature for 24 h. After usual workup and chroma-
tography on silica gel with petroleum ether/EtOAc (90/
3.69. Found C, 69.78, H, 5.67, N, 3.80.
1
0), 11 was obtained as an inert solid (2.47 g, 85%). IR
4-(tert-Butoxycarbonyl)-2-trimethylsilyl-3-methyl-4H-
1,4-benzoxazine-3-carboxylate (13a). The reaction was
carried out as described above for the synthesis of
compound 12a with chlorotrimethylsilane (652 mg,
6 mmol) as an electrophile. Chromatography with petro-
Ϫ1
1
(
KBr): n cm 1742, 1707 (CyO). H NMR (CDCl ): d
3
ppm 1.49 (s, 9H), 3.84 (s, 3H), 6.84–6.94 (m, 1H), 7.08–
1
3
7
.12 (m, 2H), 7.24 (s, 1H), 7.62–7.66 (m, 1H). C NMR
(
(
(
CDCl ): d ppm 28.9 (3CH ), 51.9 (CH ), 82.8 (C), 116.0
CH), 117.6 (C), 124.5 (CH), 124.7 (CH), 126.2 (CH), 128.1
C), 145.0 (CH), 148.8 (C), 151.5 (C), 163.6 (C). MS:
3
3
3
leum ether/EtOAc (95/5) gave 13a (523 mg, 72%) as a
Ϫ1
white solid. Mp: 62–63ЊC. IR (KBr): n cm
1724
1
m/zˆ292 (Mϩ1). Anal. Calcd for C H NO : C, 61.85, H,
(CyO). H NMR (CDCl ): d ppm 0.29 (s, 9H), 1.51
1
5
17
5
3
5
.88, N, 4.81. Found C, 61.91, H, 5.93, N, 4.83.
(s, 9H), 3.78 (s, 3H), 6.85–6.91 (m, 1H), 7.01–7.11
13
(
m, 2H), 7.50–7.59 (m, 1H). C NMR (CDCl ): d ppm
3
9
-(tert-Butoxycarbonyl)-3,3-dimethyl-3,9-dihydro-1H-
Ϫ1.5 (3CH ), 27.9 (3CH ), 51.5 (CH ), 82.3 (C), 115.7
3 3 3
benzo[b]furo[3,4-e][1,4]oxazin-1-one (12a). A solution of
1 (582 mg, 2 mmol) in dry THF (15 mL) was cooled at
Ϫ78ЊC and LDA 2 M in solution in THF/heptane (3 mL,
mmol) was added slowly by syringe. The solution was
stirred for 35 min at Ϫ78ЊC and acetone (348 mg,
(CH), 123.7 (CH), 123.8 (CH), 125.0 (CH), 125.8 (C),
128.7 (C), 150.1 (C), 151.0 (C), 163.5 (C), 164.7 (C). MS:
m/zˆ364 (Mϩ1). Anal. Calcd for C H NO Si: C, 59.48,
1
18
25
5
6
H, 6.93, N, 3.85. Found C, 59.50, H, 6.93, N, 3.76.
6
1
mmol) was added. The mixture was stirred at Ϫ78ЊC for
0 min and the reaction was quenched by the addition of
4-(tert-Butoxycarbonyl)-2-iodo-3-methyl-4H-1,4-benz-
oxazine-3-carboxylate (13b). The reaction was carried out
as described above for the synthesis of compound 12a with
water and allowed to warm to room temperature. After the

C. Buon et al. / Tetrahedron 56 (2000) 605–614
613
iodine (1,52 mg, 6 mmol) as an electrophile. After hydro-
lysis and warming to room temperature, the organic layer
was washed with a sodium thiosulfate solution (1 M) then
(98/2), 14a was obtained as white crystals (618 mg, 81%).
Ϫ1 1
Mp: 127–128ЊC. IR (KBr): n cm 1709 (CyO). H NMR
(CDCl ): d ppm Ϫ0.01 (s, 9H), 1.14 (s, 9H), 6.90–6.94 (m,
3
dried over MgSO and concentrated. Chromatography with
1H), 7.06–7.11 (m, 2H), 7.29–7.35 (m, 5H), 7.71–7.75 (m,
4
13
toluene/EtOAc (95/5) gave 13b (584 mg, 70%) as a white
1H). C NMR (CDCl ): d ppm Ϫ0.9 (3CH ), 27.7 (3CH ),
3 3 3
Ϫ1
solid. Mp 99–100ЊC. IR (KBr): n cm 1742, 1730 (CyO).
81.7 (C), 115.5 (CH), 122.7 (CH), 123.5 (CH), 125.6 (CH),
127.7 (2CH), 127.9 (CH), 129.0 (2CH),130.7 (C), 136.7 (C),
137.3 (C), 150.5 (C), 151.4 (C), 152.7 (C). MS: m/zˆ382
(Mϩ1). Anal. Calcd for C H NO Si: C, 69.26, H, 7.13, N,
1
H NMR (CDCl ): d ppm 1.49 (s, 9H), 3.84 (s, 3H), 6.96–
3
13
7
.03 (m, 1H), 7.08–7.22 (m, 2H), 7.59–7.67 (m, 1H).
C
NMR (CDCl ): d ppm 27.9 (3CH ), 52.2 (CH ), 83.4 (C),
3
3
3
22 27
3
1
1
05.5 (C), 116.0 (CH), 120.7 (C), 124.5 (CH), 125.1 (CH),
26.2 (CH), 128.1 (C), 149.9 (C), 150.3 (C), 163.4 (C). MS:
3.67. Found C, 69.33, H, 7.08, N, 3.60.
m/zˆ418 (Mϩ1). Anal. Calcd for C H INO : C, 43.18, H,
4-(tert-Butoxycarbonyl)-3-phenyl-2-tributyltin-4H-1,4-
benzoxazine (14b). The reaction was carried out as
described above for the synthesis of compound 14a with
tributyltin chloride (1.95 g, 6 mmol) as an electrophile.
Chromatography with petroleum ether/EtOAc (95/5) gave
1
5
16
5
3
.87, N, 3.36. Found C, 43.25, H, 3.99, N, 3.49.
4
-(tert-Butoxycarbonyl)-2-trimethyltin-3-methyl-4H-1,4-
benzoxazine-3-carboxylate (13c). The reaction was carried
out as described above for the synthesis of compound 12a
with trimethyltin chloride (797 mg, 4 mmol) as an electro-
phile. Chromatography with petroleum ether/EtOAc (95/5)
gave 13c (708 mg, 78%) as white crystals. Mp: 87–88ЊC. IR
Ϫ1
13 (708 mg, 78%) as a colorless oil. IR (neat): n cm 1710
1
(CyO). H NMR (CDCl ): d ppm 0.82 (t, 9H, Jˆ7.2 Hz),
3
1.12–1.42 (m, 27H), 6.84–6.88 (m, 1H), 7.04–7.08 (m,
1
3
2H), 7.26–7.30 (m, 5H), 7.68–7.72 (m, 1H). C NMR
Ϫ1
1
(
KBr): n cm 1720, 1706 (CyO). H NMR (CDCl ): d
(CDCl ): d ppm 10.9 (3CH ), 13.5 (3CH ), 27.1 (3CH ),
3
3
2
3
2
1
19
117
ppm 0.32 (s, 9H, J( Sn,CH )ˆ58 Hz, J( Sn,CH )ˆ
27.7 (3CH ), 28.7 (3CH ,), 81.4 (C), 115.5 (CH), 122.6
3
3
3 2
5
7
6 Hz), 1.47 (s, 9H), 3.77 (s, 3H), 6.88–6.92 (m, 1H),
.05–7.09 (m, 2H), 7.55–7.59 (m, 1H).
(CH), 123.7 (CH), 125.5 (CH), 127.3 (CH), 127.5 (2CH),
128.0 (2CH), 130.4 (C), 136.3 (C), 138.2 (C), 151.4 (C),
1
3
C NMR
1
16
(
CDCl ): d ppm Ϫ7.6 (3CH ), 28.0 (3CH ), 51.6 (CH ),
2.1 (C), 115.9 (CH), 123.9 (CH), 124.0 (C), 124.4 (CH),
25.8 (CH), 129.0 (C), 150.0 (C), 151.4 (C), 165.6 (C),
152.1 (C), 155.3 (C). MS: m/zˆ496 (Mϩ1) ( Sn), 498
3
3
3
3
118
120
8
1
1
(Mϩ1) ( Sn), 500 (Mϩ1) ( Sn). Anal. Calcd for
C H NO Sn: C, 62.22, H, 7.58, N, 2.34. Found C, 62.17,
31
45
3
1
16
71.6 (C). MS: m/zˆ452 (Mϩ1) ( Sn), 454 (Mϩ1)
H, 7.61, N, 2.30.
1
18
120
(
Sn), 456 (Mϩ1)
(
Sn). Anal. Calcd for
C H NO Sn: C, 47.61, H, 5.55, N, 3.08. Found C, 47.70,
H, 5.59, N, 3.12.
4-(tert-Butoxycarbonyl)-3-phenyl-4H-1,4-benzoxazine-2-
carboxylic acid (14c). The reaction was carried out as
described above for the synthesis of compound 14a with
carbon dioxide from dry ice (dried over sulfuric acid) as
an electrophile. The mixture was treated with a sodium
hydroxide solution (20%) and allowed to warm to room
temperature. The mixture was extracted with dichloro-
methane ꢀ2×10 mL†; the aqueous phase was acidified with
hydrochloric acid solution (10%) and extracted with
dichloromethane ꢀ3×10 mL†: The organic phases were
18
25
5
4
-(tert-Butoxycarbonyl)-3-methoxycarbonyl-4H-1,4-benz-
oxazine-2-carboxylic acid (13d). The reaction was carried
out as described above for the synthesis of compound 12a
with carbon dioxide from dry ice, (dried over sulfuric acid)
as an electrophile. The mixture was treated with a sodium
hydroxide solution (20%) and allowed to warm to room
temperature. The mixture was extracted with dichloro-
methane ꢀ2×10 mL†; the aqueous phase was acidified with
hydrochloric acid solution (10%) and extracted with
dichloromethane ꢀ3×10 mL†: The organic phases were
dried over MgSO , concentrated and 14c (708 mg, 81%)
4
Ϫ1
was obtained as a colorless oil. IR (neat): n cm 3400–
1
3040 (OH), 1720, 1711 (CyO). H NMR (CDCl ): d ppm
3
dried over MgSO , concentrated and 13d (471 mg, 85%)
1.04 (s, 9H), 6.97–7.09 (m, 3H), 7.18–7.37 (m, 6H), 7.65–
4
13
was obtained as a crude product. Mp: Ͻ30ЊC. IR (neat): n
7.69 (m, 1H). C NMR (CDCl ): d ppm 27.5 (3CH ), 83.1
3 3
Ϫ1
1
cm
3704–3342 (OH), 1838–1675 (CyO). H NMR
(C), 116.1 (CH), 123.5 (CH), 124.0 (CH), 124.6 (C), 126.4
(CH), 127.5 (2CH), 128.3 (C), 128.9 (CH), 129.3 (2CH),
129.5 (C), 134.1 (C), 150.1 (C), 151.2 (C), 151.6 (C). MS:
m/zˆ354 (Mϩ1). Anal. Calcd for C H NO Sn: C, 67.98,
(
3
CDCl ): d ppm 1.51 (s, 9H), 3.90 (s, 3H), 7.05–7.11 (m,
3
1
3
H), 7.53–7.61 (m, 1H). C NMR (CDCl ): d ppm 28.0
3
(
(
(
3CH ), 53.6 (CH ), 84.5 (C), 116.7 (CH), 123.0 (C), 123.7
CH), 124.9 (CH), 126.9 (CH), 127.4 (C), 128.2 (C), 149.3
3 3
31 45
3
H, 5.42, N, 3.96. Found C, 67.92, H, 5.50, N, 4.02.
C), 150.5 (C), 162.8 (C), 165.7 (C). MS: m/zˆ336 (Mϩ1).
Anal. Calcd for C H NO : C, 57.31, H, 5.11, N, 4.18.
1
6
17
7
Found C, 57.49, H, 4.95, N, 4.12.
References
4
-(tert-Butoxycarbonyl)-3-phenyl-2-trimethylsilyl-4H-1,4-
1. Bartsch, H.; Ofner, M.; Schwarz, O.; Thomann, W.
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2. McKillop, A.; Sayer, T. S. B. J. Org. Chem. 1976, 41,
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4. Chacun-Lef e` vre, L.; Buon, C.; Bouyssou, P.; Coudert, G.
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dry THF (15 mL) was cooled at Ϫ78ЊC and LDA 2 M in
solution in THF/heptane (3 mL, 6 mmol) was added slowly
by syringe. The solution was stirred for 15 min at Ϫ78ЊC
and chlorotrimethylsilane (348 mg, 6 mmol) was added.
The mixture was stirred at Ϫ78ЊC for 10 min and the reac-
tion was quenched by the addition of water and allowed to
warm to room temperature. After the usual workup and
chromatography on silica gel with petroleum ether/EtOAc
5. Buon, C.; Bouyssou, P.; Coudert, G. Tetrahedron Lett. 1999,
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6
14
. Snieckus, V. Chem. Rev. 1990, 90, 879.
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12. Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; G a¨ rtner, P.; Yang,
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1
1
1
1
. Coudert, G.; Guillaumet, G.; Loubinoux, B. Tetrahedron Lett.
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0. Foti, C. J.; Comins, D. L. J. Org. Chem. 1995, 60, 2656.
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4
821.