A new application of the Pictet-Spengler reaction to the preparation of 4-substituted 1H-2,3-benzoxazines

Article abstract of DOI:10.1055/s-2006-951564

Intramolecular coupling reaction of benzylic O-hydroxamates and aldehydes was investigated to afford a variety of 4-substituted 1H-2,3-benzoxazine ring systems in good to excellent yields. The reaction involved an intramolecular C-C bond formation between

Full text of DOI:10.1055/s-2006-951564

LETTER
3277
A New Application of the Pictet–Spengler Reaction to the Preparation of
4-Substituted 1H-2,3-Benzoxazines
S
ynthesis of 4-Sub
i
stituted
u
1
H
-2,3-Ben
f
zoxazin
a
a
College of Pharmaceuticals and Biotechnology, Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27890968; E-mail: kangzhao@tju.edu.cn
b
School of Pharmaceuticals, Xinxiang Medical College, Xinxiang 453003, P. R. of China
Received 2 August 2006
bu reaction6,7 and base-catalyzed cyclization5,8
(Scheme 2). However, these methods require 1,2-disub-
stituted substrates, and the geometry of the oxime is re-
stricted to the syn-isomer. Additionally, these reaction
Abstract: Intramolecular coupling reaction of benzylic O-hydrox-
amates and aldehydes was investigated to afford a variety of 4-sub-
stituted 1H-2,3-benzoxazine ring systems in good to excellent
yields. The reaction involved an intramolecular C–C bond forma-
tion between an N-acyl- or N-sulfonyl-oxoiminium ion with the aryl conditions are carefully chosen to avoid the formation of
nitrone by intramolecular N-alkylation.9 Herein a conve-
ring. Under the studied conditions, electron-donating groups in the
aryl ring are essential for the desired coupling reactions.
nient method to construct 2 from 1 by Lewis acid induced
Pictet–Spengler reaction10 is described (Scheme 1). This
Key words: 1H-2,3-benzoxazine, Pictet–Spengler reaction, oxo-
iminium ion, hydroxamate, aldehyde
strategy allows 4-substituted 1H-2,3-benzoxazines to be
synthesized from hydroxamates directly and avoids the
formation of a five-membered ring. Thus, some of the pri-
The Pictet–Spengler reaction is an acid-catalyzed in- mary limitations are overcome in this new reaction proto-
tramolecular cyclization of the intermediate imine of 2- col.
arylethylamine formed by condensation with a carbonyl
compound.1 It has been widely used in the formation of
OH
N
tetrahydroisoquinolines and tetrahydrocarbolines, which
are present in numerous natural products and synthetic
medical compounds possessing biological activities.2
This reaction has found wide application in the following
three amine prototypes: dopamine/tyramine,3 tryptophan/
tryptamine,3 histidine/histamine.4 However, to the best of
our knowledge, the Pictet–Spengler cyclization has never
been applied to the related benzyloxyamine derivatives 1
(Scheme 1). This prompted us to explore the use of hy-
droxamates 1 as possible substrates for the Pictet–Spen-
gler reaction to give N–O fused 1H-2,3-benzoxazines 2.
Additionally, the heterocycle itself may be a useful scaf-
fold for the development of drug leads, among which
some compounds possess CNS depressant activity5 and
herbicidal activity.6
DEAD
Ph3P
OH
N
O
N
OH
N
1. MeI
THF
2. n-BuLi
THF
Ph
Ph
Ph
3
5
4
Scheme 2
The required hydroxamates 1 for this approach were con-
veniently prepared in high yields according to a reported
process in three steps from commercial materials.11
Initial attention was focused on the use of N-aroylhydrox-
amate 1a, employing its cyclization with n-butyraldehyde
as a model reaction, to produce compound 2a. The con-
version was further explored by looking at the use of dif-
ferent Lewis acids (ZnCl2, BF3·OEt2, FeCl3, TiCl4, AlCl3
and TMSCl) and different solvent systems (CH2Cl2,
Traditionally, 1H-2,3-benzoxazines 2 can be made from
5, which have been prepared from 3 and 4 by the Mitsuno-
O
N
O
N
R1
R1
O
R3-CHO
R1
R2
R2
HN
R2
R3
R3
1
2
R1 = H, OMe
R
R
2 = acyl, aroyl, COOMe, Ms
3 = H, alkyl, aryl
Scheme 1
SYNLETT 2006, No. 19, pp 3277–3283
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951564; Art ID: W16106ST
© Georg Thieme Verlag Stuttgart · New York

3278
X. Zheng et al.
LETTER
MeCN, THF and PhMe). Among these conditions, addi- Hydroxamates bearing no or just one electron-donating
tion of BF3·OEt2 to the mixture of 1a and n-butyraldehyde group, such as 1h and 1i, respectively, remained unreac-
at –78 °C, followed by warming to room temperature over tive towards the cyclization even in the presence of excess
a period of one hour provided the best results. In every BF3·OEt2 and n-butyraldehyde at 110 °C (Table 1, entries
case, the product was easily purified by silica gel flash 9, 10). The reaction also worked with other aliphatic alde-
chromatography.
hydes such as iso-butyraldehyde, and the corresponding
benzoxazine 2h was isolated in 70% yield (Table 1, entry
8).16,18 However, paraformaldehyde and aromatic alde-
hydes did not react under similar conditions (Table 1, en-
tries 11, 12).
These optimized conditions were subsequently applied to
the reactions of n-butyraldehyde with different hydrox-
amates 1 (Table 1). Generally, electron-rich aromatic
rings bearing at least two electron-donating groups are
needed in order to promote the next cyclization to furnish
the desired 1H-2,3-benzoxazines 2 (Table 1, entries 1–7).
a
Table 1 Pictet–Spengler Cyclization Induced by BF3·OEt2
Entry
Hydroxamate
Aldehyde
Product (yield, %)b
Time (h)
H
N
O
MeO
MeO
O
MeO
OMe
O
N
1
1
CHO
MeO
Pr
O
2a (98)
OMe
1a
MeO
MeO
O
O
HN
N
2
3
1
1
CHO
MeO
MeO
O
Pr
O
1b
MeO
2b (99)
O
HN
O
MeO
NO2
MeO
O
N
CHO
MeO
Ph
O
2c (98)
NO2
1c
MeO
MeO
O
O
HN
O
N
O
4
5
1
1
CHO
CHO
MeO
MeO
Pr
1d
2d (84)
MeO
MeO
O
O
HN
O
N
O
MeO
MeO
Pr
Cl
Cl
1e
2e (89)
MeO
MeO
O
O
O
O
HN
N
6
7
1
1
CHO
CHO
MeO
S
MeO
S
Me
Me
O
O
Pr
Pr
1f
2f (97)
MeO
MeO
O
O
N
HN
O
O
MeO
MeO
OMe
OMe
1g
2g (86)
Synlett 2006, No. 19, 3277–3283 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Substituted 1H-2,3-Benzoxazines
3279
Table 1 Pictet–Spengler Cyclization Induced by BF3·OEt2a (continued)
Entry
Hydroxamate
Aldehyde
Product (yield, %)b
Time (h)
MeO
OMe
O
CHO
N
8
1a
1
MeO
O
2h (70)
(0)
O
HN
O
9
24
24
CHO
OMe
1h
(0)
O
HN
O
10
CHO
MeO
OMe
1i
11
12
1a
(HCHO)n
(0)
(0)
4
CHO
1a
24
a Reaction conditions: BF3·OEt2, CH2Cl2, –78 °C to r.t.
b Isolated yields.
To further extend the applicability of this Pictet–Spengler 1g was utilized. Furthermore, the reaction rate was also
cyclization of hydroxamates 1 with aromatic aldehydes, significantly accelerated (Table 2, entries 6–10).
several Lewis acids were examined. To our delight, 1a un-
The importance of the electron-donating group in control-
derwent cyclization with benzaldehyde in the presence of
ling the outcome of the reaction was also noted. Hence,
TMSCl and NaI in MeCN at room temperature to provide
both the unsubstituted 1h and the p-methoxy-substituted
1i were unreactive towards the cyclization reaction
(Table 2, entries 12, 13). In contrast, the m-methoxy-sub-
stituted derivative 1j produced the desired product 2s in
2i in 36% yield (Table 2, entry 1).17,18 Controlled experi-
ments showed that TMSCl itself was not responsible for
the cyclization. Various solvents were also examined, and
MeCN appeared to be the best. It was believed that a facile
excellent yield (Table 2, entry 11). This was consistent
transformation from TMSCl/NaI to TMSI occur in
with the mechanism of the cyclization (Scheme 1), in
which the m-methoxy substitutent was correctly posi-
MeCN.12 This result led us to explore the potential of TM-
SCl/NaI-catalyzed Pictet–Spengler reaction. To our de-
tioned to facilitate the nucleophilic attack of the oxoimin-
light, this catalyst system worked well with a variety of
ium ion via the carbon atom para to the methoxy
substituent.
aromatic aldehydes to give the corresponding benzox-
azines (Table 2, entries 1–11). Remarkably, the yields of
these reactions were higher when carbalkoxyhydroxamate
Table 2 Pictet–Spengler Cyclization Induced by TMSCl/NaIa
Entry
Hydroxamate
Aldehyde
Product (yield, %)b
Time
6 h
MeO
OMe
O
CHO
N
1
1a
MeO
Ph
O
O
2i (36)
MeO
CHO
O
N
2
1b
7 h
MeO
Ph
2j (32)
Synlett 2006, No. 19, 3277–3283 © Thieme Stuttgart · New York

3280
X. Zheng et al.
LETTER
Table 2 Pictet–Spengler Cyclization Induced by TMSCl/NaIa (continued)
Entry
3
Hydroxamate
Aldehyde
Product (yield, %)b
Time
MeO
NO2
O
CHO
N
1c
24 h
MeO
Ph
O
2k (17)
MeO
O
CHO
CHO
CHO
4c
1e
1f
6 h
N
O
MeO
Ph
2l (44)
MeO
O
O
N
5
10 h
MeO
S
Me
O
Ph
Ph
2m (54)
MeO
O
N
O
6
1g
5 min
MeO
OMe
2n (99)
MeO
O
N
CHO
O
MeO
Cl
7
8
1g
1g
5 min
Cl
OMe
2o (94)
MeO
O
N
CHO
O
MeO
5 min
OMe
Cl
Cl
2p (98)
MeO
O
N
CHO
Cl
O
MeO
OMe
9
1g
5 min
Cl
2q (94)
MeO
O
N
CHO
O
MeO
OMe
10
11
1g
5 min
MeO
OMe
MeO
OMe
OMe
OMe
2r (73)
MeO
MeO
O
N
O
CHO
O
HN
O
5 min
Ph
OMe
OMe
2s (98)
1j
Synlett 2006, No. 19, 3277–3283 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Substituted 1H-2,3-Benzoxazines
3281
Table 2 Pictet–Spengler Cyclization Induced by TMSCl/NaIa (continued)
Entry
Hydroxamate
Aldehyde
Product (yield, %)b
Time
CHO
12
1h
(0)
24 h
24 h
CHO
13
1i
(0)
a Reaction conditions: TMSCl/NaI, MeCN, r.t.
b Isolated yields.
c Dechlorinated product was obtained.13
Interestingly, a dechlorinated product 2l was obtained
when compound 1e was employed in the reaction
(Table 2, entry 4). During the course of the reaction, both
the cyclized benzoxazine 2t and dechlorinated hydroxam-
ate 1k could be detected (Scheme 3). In another experi-
ment, 2t was also obtained from the oxime 6 in the
presence of chloroacetyl chloride and KI in 1,2-dichloro-
ethane at room temperature.14 These findings also con-
firmed the formation of oxoiminium ion15 during these
reactions.
References and Notes
(1) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44,
2030.
(2) Bentley, K. W. Nat. Prod. Rep. 2004, 21, 395; and
references cited therein.
(3) For reviews, see: (a) Royer, J.; Bonin, M.; Micouin, L.
Chem. Rev. 2004, 104, 2311. (b) Nielsen, T. E.; Diness, F.;
Meldal, M. Curr. Opin. Drug. Discovery Dev. 2003, 6, 801.
(c) Cox, E. D.; Cook, J. Chem. Rev. 1995, 95, 1797.
(d) Whaley, W. M.; Govindachari, T. R. Org. React. 1951,
6, 151.
(4) (a) Beke, G.; Szabo, L. F.; Podanyi, B. J. Nat. Prod. 2002,
65, 649. (b) Hutchins, S. M.; Chapman, K. T. Tetrahedron
Lett. 1996, 37, 4865. (c) Kametani, T.; Koizumi, M.; Okui,
K.; Nishii, Y.; Ono, M. J. Med. Chem. 1972, 15, 203.
(d) Stocker, F. B.; Fordice, M. W.; Larson, J. K.;
Thorstenson, J. H. J. Org. Chem. 1966, 31, 2380. (e) Heyl,
D.; Harris, S. A.; Folkers, K. J. Am. Chem. Soc. 1948, 70,
3429. (f) Kametani, T.; Fukumoto, K. Heterocycles 1975, 3,
311.
In summary, we have developed the Pictet–Spengler reac-
tion by using hydroxamates as a new amine prototype.
Both aromatic and aliphatic aldehydes can be used to pre-
pare a variety of 4-substituted 1H-2,3-benzoxazines. The
success of these reactions strongly depended on the pres-
ence of electron-donating substituents on the aromatic
ring.
(5) Pifferi, G.; Consonni, P.; Banfi, S.; Diena, A. J. Med. Chem.
1969, 12, 261.
(6) Kai, H.; Tomida, M.; Nakal, T.; Horita, Y.; Ueyama, Y.;
Mizuiani, A. J. Pesticide Sci. 2002, 27, 53.
(7) Kai, H.; Nakai, T. Tetrahedron Lett. 2001, 42, 6895.
(8) Barnish, I. T.; Hauser, C. R. J. Org. Chem. 1968, 33, 1372.
(9) Knight, D. W.; Leesea, M. P.; Kimpeb, N. D. Tetrahedron
Lett. 2001, 42, 2597.
(10) For recent Lewis acid mediated Pictet–Spengler reaction,
see: Youn, S. W. J. Org. Chem. 2006, 71, 2521; and
references therein.
Acknowledgment
K.Z. acknowledges the Tianjin Municipal Science and Technology
Commission, the Outstanding Young Scholarship from NSFC
(#30125043), the Basic Research Project (#2002CCA01500) of the
MOST, and the Cheung Kong Scholars Program for financial sup-
port. J.B. Chang acknowledges the Program of New Century Excel-
lent Talent, the Ministry of Education of China (NCET 050613).
The authors thank Prof. Gregory Linn for his modification of the
manuscript.
MeO
MeO
O
O
N
Ph-CHO
ClCOCH2Cl
KI, r.t.
N
O
1e
MeO
TMSCl, NaI
MeO
Ph
Ph
Cl
6
2t
TMSCl, NaI
TMSCl, NaI
MeO
MeO
MeO
MeO
O
N
O
Ph-CHO
O
HN
O
TMSCl, NaI
Ph
1k
21
Scheme 3
Synlett 2006, No. 19, 3277–3283 © Thieme Stuttgart · New York

3282
X. Zheng et al.
LETTER
(11) (a) Schumann, E. L.; Heinzelman, R. V.; Greig, M. E.;
Veldkamp, W. J. Med. Chem. 1964, 7, 329. (b) Pégurier,
C.; Morellato, L.; Chahed, E.; Andrieux, J.; Nicolas, J. P.;
Boutin, J. A.; Bennejean, C.; Delagrange, P.; Langlois, M.;
Mathé-Allainmat, M. Bioorg. Med. Chem. 2003, 11, 789.
(12) Olah, G. A.; Narang, S. C.; Balaram Gupta, B. G.; Malhotra,
R. J. Org. Chem. 1979, 44, 1247.
(13) Olah, G. A.; Arvanaghi, M.; Vankar, Y. D. J. Org. Chem.
1980, 45, 3531.
(14) Venkov, A. P.; Lukanov, L. K. Synthesis 1989, 59.
(15) For some similar oxoiminium salts that can be isolated, see:
Saad, G. D.; Shalom, E.; Shatzmiler, S. J. Org. Chem. 1982,
47, 2192.
J = 9.6, 4.0 Hz, 1 H), 6.48 (s, 1 H), 6.63 (s, 1 H). 13C NMR
(125 MHz, CDCl3): d = 9.16, 14.18, 19.73, 25.66, 38.38,
52.22, 56.14, 56.22, 71.64, 107.10, 109.76, 122.70, 127.33,
148.19, 148.43, 172.80.
Compound 2e: white solid, mp 115–117 °C. 1H NMR (500
MHz, CDCl3): d = 0.94 (t, J = 7.0 Hz, 3 H), 1.34–1.52 (m, 2
H), 1.73–1.80 (m, 1 H), 1.88–1.96 (m, 1 H), 3.86 (s, 3 H),
3.86 (s, 3 H), 4.27, 4.33 (AB, J = 13.0 Hz, 2 H), 4.89 (d,
J = 13.5 Hz, 1 H), 5.14 (d, J = 13.5 Hz, 1 H), 5.33 (dd,
J = 9.5, 4.0 Hz, 1 H), 6.48 (s, 1 H), 6.61 (s, 1 H). 13C NMR
(125 MHz, CDCl3): d = 14.17, 19.61, 38.42, 40.92, 53.20,
56.22, 56.30, 72.42, 107.05, 109.63, 122.16, 126.35, 148.46,
148.64, 165.01.
Compound 2f: white solid, mp 121–123 °C. 1H NMR (500
MHz, CDCl3): d = 0.97 (t, J = 7.0 Hz, 3 H), 1.48–1.56 (m, 2
H), 1.75–1.82 (m, 1 H), 1.92–1.99 (m, 1 H), 3.12 (s, 3 H),
3.85 (s, 3 H), 3.87 (s, 3 H), 4.83 (dd, J = 9.0, 5.0 Hz, 1 H),
4.84, 5.43 (AB, J = 14.0 Hz, 2 H), 6.49 (s, 1 H), 6.60 (s, 1
H). 13C NMR (125 MHz, CDCl3): d = 14.07, 19.85, 38.27,
39.30, 54.82, 56.15, 56.26, 69.37, 107.01, 109.63, 122.25,
125.63, 148.21, 148.61.
(16) General Procedure for the Synthesis of Benzoxazines
2a–h.
To a solution of hydroxamate 2 (0.6 mmol) in dry CH2Cl2 (4
mL) was added aldehyde (0.6 mmol) in one portion. The
resulting mixture was chilled to –78 °C and BF3·OEt2 (1.2
mmol) was added dropwise under N2. The reaction mixture
was allowed to warm to r.t. and quenched with Et3N. The
solvent was evaporated under reduced pressure and the
residue was isolated by chromatography on silica gel to
afford the desired benzoxazines 2a–h.
Compound 2g: white solid, mp 60–61 °C. 1H NMR (500
MHz, CDCl3): d = 0.89 (t, J = 7.5 Hz, 3 H), 1.39–1.46 (m, 2
H), 1.60–1.67 (m, 1 H), 1.86–1.93 (m, 1 H), 3.71 (s, 3 H),
3.76 (s, 3 H), 3.80 (s, 3 H), 4.67, 4.88 (AB, J = 14.0 Hz, 2
(17) General Procedure for the Synthesis of Benzoxazines
2i–s.
H), 5.06 (d, J = 14.0 Hz, 1 H), 6.42 (s, 1 H), 6.54 (s, 1 H). 13
NMR (125 MHz, CDCl3): d = 14.02, 19.82, 38.06, 53.29,
C
To the solution of hydroxamate 2 (0.6 mmol) in dry MeCN
(6 mL) was added aldehyde (0.9 mmol) in one portion
followed by NaI (1.8 mmol) under N2. Then, TMSCl (1.8
mmol) was added dropwise. The resulting mixture was
stirred until all the hydroxamate was consumed. The
resulting mixture was treated with 20% NaHSO3 (6 mL) and
extracted with EtOAc (3 × 10 mL). The organic phases were
collected, washed (sat. NaHCO3 and brine), dried (Na2SO4)
and evaporated under reduced pressure. The residue was
isolated by chromatography on silica gel to afford the
desired benzoxazines 2i–s.
55.83, 56.14, 56.22, 69.96, 107.28, 109.52, 123.18, 127.07,
148.23, 148.29, 155.95.
Compound 2h: white solid, mp 113–114 °C. 1H NMR (500
MHz, CDCl3): d = 1.04 (d, J = 9.0 Hz, 3 H), 1.16 (d, J = 6.0
Hz, 3 H), 2.28–2.35 (m, 1 H), 3.82 (s, 3 H), 3.85 (s, 3 H),
3.88 (s, 3 H), 4.65, 4.71 (AB, J = 13.0 Hz, 2 H), 5.43 (br, 1
H), 6.42 (s, 1 H), 6.72 (s, 1 H), 6.92 (d, J = 8.5 Hz, 2 H), 7.83
(br d, J = 6.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d =
19.15, 20.34, 34.53, 55.55, 56.14, 56.24, 57.31, 71.31,
107.05, 110.46, 113.34, 123.24, 125.75, 125.96, 131.26,
148.15, 148.34, 161.86, 169.44.
(18) Compound 2a: white solid, mp 98–100 °C. 1H NMR (400
MHz, CDCl3): d = 0.96 (t, J = 7.2 Hz, 3 H), 1.52 (br, 2 H),
1.78 (br, 1 H), 2.10 (br, 1 H), 3.77 (s, 3 H), 3.80 (s, 3 H), 3.85
(s, 3 H), 4.66, 4.76 (AB, J = 13.2 Hz, 2 H), 5.53 (br, 1 H),
6.40 (s, 1 H), 6.64 (s, 1 H), 6.89 (d, J = 8.8 Hz, 2 H), 7.77 (br,
2 H). 13C NMR (125 MHz, CDCl3): d = 14.17, 19.86, 38.27,
52.80, 55.46, 56.11, 56.20, 71.45, 107.22, 109.81, 113.36,
122.61, 125.78, 127.24, 131.12, 148.27, 148.44, 161.93,
168.98.
Compound 2i: white solid, mp 115–117 °C. 1H NMR (400
MHz, CDCl3): d = 3.78 (s, 3 H), 3.84 (s, 3 H), 3.87 (s, 3 H),
4.84, 5.01 (AB, J = 13.6 Hz, 2 H), 6.54 (s, 1 H), 6.59 (s, 1
H), 6.66 (s, 1 H), 6.90 (dd, J = 9.2, 2.4 Hz, 2 H), 7.29–7.75
(m, 5 H), 7.77 (dd, J = 9.2, 2.4 Hz, 2 H). 13C NMR (125
MHz, CDCl3): d = 55.58, 56.21, 56.24, 56.53, 71.58, 106.91,
110.86, 113.40, 123.49, 124.78, 125.71, 128.15, 128.66,
129.16, 131.22, 140.99, 148.70, 148.73, 162.05, 168.46.
Compound 2j: white solid, mp 125–127 °C. 1H NMR (500
MHz, CDCl3): d = 3.77 (s, 3 H), 3.86 (s, 3 H), 4.86, 5.00
(AB, J = 14.0 Hz, 2 H), 6.54 (s, 1 H), 6.58 (s, 1 H), 6.65 (s,
1 H), 7.26–7.69 (m, 10 H). 13C NMR (125 MHz, CDCl3):
d = 55.97, 55.9, 56.36, 71.51, 106.70, 110.58, 123.20,
124.38, 127.91, 127.99, 128.45, 128.51, 128.88, 130.88,
133.58, 140.59, 148.51, 148.54, 168.64.
Compound 2b: white solid, mp 109–111 °C. 1H NMR (500
MHz, CDCl3): d = 1.01 (br, 3 H), 1.58 (br, 2 H), 1.84 (br, 1
H), 2.04–2.12 (m, 1 H), 3.81 (s, 3 H), 3.89 (s, 3 H), 4.67 (br,
1 H), 4.77 (br, 1 H), 5.57 (br, 1 H), 6.43 (s, 1 H), 6.67 (s, 1
H), 7.40–7.49 (m, 3 H), 7.75 (br, 2 H). 13C NMR (125 MHz,
CDCl3): d = 14.22, 19.91, 38.33, 52.75, 56.19, 56.29, 71.70,
107.20, 109.81, 122.56, 127.17, 128.17, 128.75, 130.98,
134.07, 148.37, 148.52, 169.49.
Compound 2k: white solid, mp 191–197 °C. 1H NMR (500
MHz, CDCl3): d = 3.78 (s, 3 H), 3.88 (s, 3 H), 4.85, 4.95
(AB, J = 14.0 Hz, 2 H), 6.55 (s, 1 H), 6.58 (s, 1 H), 6.66 (s,
1 H), 7.34–7.43 (m, 5 H), 7.83 (dd, J = 7.0, 2.0 Hz, 2 H), 8.25
(dd, J = 7.0, 2.0 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d =
56.02, 56.04, 56.26, 71.99, 106.62, 110.49, 122.59, 123.17,
123.81, 128.33, 128.62, 128.90, 129.55, 139.55, 140.12,
148.71, 148.80, 148.98, 166.20.
Compound 2c: yellow solid, mp 61–63 °C. 1H NMR (500
MHz, CDCl3): d = 1.04 (t, J = 7.5 Hz, 3 H), 1.49–1.65 (m, 2
H), 1.85–1.91 (m, 1 H), 2.05–2.13 (m, 1 H), 3.83 (s, 3 H),
3.91 (s, 3 H), 4.70, 4.76 (AB, J = 13.5 Hz, 2 H), 5.57 (dd,
J = 10.0, 3.5 Hz, 1 H), 6.44 (s, 1 H), 6.69 (s, 1 H), 7.91 (d,
J = 8.5 Hz, 2 H), 8.29 (d, J = 8.5 Hz, 2 H). 13C NMR (125
MHz, CDCl3): d = 14.18, 19.89, 38.27, 53.03, 56.21, 56.31,
72.20, 107.11, 109.70, 121.89, 123.41, 126.53, 129.80,
140.04, 148.53, 148.75, 149.15, 167.08.
Compound 2l: white solid, mp 170–171 °C. 1H NMR (400
MHz, CDCl3): d = 2.16 (s, 3 H), 3.76 (s, 3 H), 3.89 (s, 3 H),
4.98, 5.14 (AB, J = 13.6 Hz, 2 H), 6.51 (s, 1 H), 6.53 (s, 1
H), 6.59 (s, 1 H), 7.28–7.35 (m, 5 H). 13C NMR (125 MHz,
CDCl3): d = 20.52, 55.34, 56.22, 71.84, 106.88, 110.78,
123.62, 124.74, 128.21, 128.63, 129.10, 140.93, 148.66,
148.78, 169.08.
Compound 2d: white solid, mp 72–75 °C. 1H NMR (400
MHz, CDCl3): d = 0.95 (t, J = 7.2 Hz, 3 H), 1.19 (t, J = 7.6
Hz, 3 H), 1.37–1.53 (m, 2 H), 1.70–1.79 (m, 1 H), 1.87–1.97
(m, 1 H), 2.39–2.48 (m, 1 H), 2.59–2.67 (m, 1 H), 3.84 (s, 3
H), 3.87 (s, 3 H), 4.84, 5.01 (AB, J = 13.6 Hz, 2 H), 5.38 (dd,
Synlett 2006, No. 19, 3277–3283 © Thieme Stuttgart · New York

LETTER
Compound 2m: white solid, mp 134–136 °C. 1H NMR (500
Synthesis of 4-Substituted 1H-2,3-Benzoxazines
3283
Compound 2q: white solid, mp 57–59 °C. 1H NMR (500
MHz, CDCl3): d = 3.76 (s, 3 H), 3.80 (s, 3 H), 3.88 (s, 3 H),
4.91, 5.21 (AB, J = 13.8 Hz, 2 H), 6.05 (s, 1 H), 6.48 (s, 1
H), 6.60 (s, 1 H), 7.26–7.31 (m, 4 H). 13C NMR (125 MHz,
CDCl3): d = 53.51, 56.20, 58.41, 70.98, 107.09, 110.46,
124.18, 124.32, 128.78, 130.47, 134.18, 139.11, 148.66,
148.81, 155.34.
MHz, CDCl3): d = 2.26 (s, 3 H), 3.73 (s, 3 H), 3.89 (s, 3 H),
5.06, 5.40 (AB, J = 13.5 Hz, 2 H), 5.78 (s, 1 H), 6.43 (s, 1
H), 6.62 (s, 1 H), 7.34–7.41 (m, 5 H). 13C NMR (125 MHz,
CDCl3): d = 35.79, 56.20, 56.21, 61.92, 72.71, 106.74,
110.69, 123.99, 125.81, 128.77, 129.10, 130.38, 137.78,
148.72, 148.74.
Compound 2n: white solid, mp 113–115 °C. 1H NMR (500
MHz, CDCl3): d = 3.75 (s, 3 H), 3.80 (s, 3 H), 3.88 (s, 3 H),
4.92, 5.22 (AB, J = 14.0 Hz, 2 H), 6.09 (s, 1 H), 6.52 (s, 1
H), 6.60 (s, 1 H), 7.27–7.37 (m, 5 H). 13C NMR (125 MHz,
CDCl3): d = 53.45, 56.20, 59.08, 70.94, 107.02, 110.61,
124.16, 124.79, 128.24, 128.62, 129.05, 140.64, 148.55,
148.66, 155.40.
Compound 2r: white solid, mp 150–151 °C. 1H NMR (500
MHz, CDCl3): d = 3.79 (s, 6 H), 3.80 (s, 3 H), 3.82 (s, 3 H),
3.83 (s, 3 H), 3.89 (s, 3 H), 4.92–5.20 (AB, J = 13.8 Hz, 2 H),
6.02 (s, 1 H), 6.56 (s, 1 H), 6.58 (s, 2 H), 6.60 (s, 1 H). 13
C
NMR (125 MHz, CDCl3): d = 53.50, 56.18, 56.26, 56.34,
56.44, 59.10, 60.99, 70.91, 106.23, 107.00, 110.63, 124.09,
124.53, 136.34, 138.02, 148.52, 148.70, 153.27, 155.36.
Compound 2s: white solid, mp 98–99 °C. 1H NMR (500
MHz, CDCl3): d = 3.79 (s, 3 H), 3.80 (s, 3 H), 4.96, 5.25
(AB, J = 14.0 Hz, 2 H), 6.11 (s, 1 H), 6.64 (d, J = 2.5 Hz, 1
H), 6.79 (dd, J = 8.5, 2.5 Hz, 1 H), 6.99 (d, J = 8.5 Hz, 1 H),
7.26–7.36 (m, 5 H). 13C NMR (125 MHz, CDCl3): d = 53.47,
55.58, 59.14, 71.42, 109.18, 113.94, 125.13, 128.16, 128.59,
128.95, 129.38, 133.30, 140.95, 155.41, 158.77.
Compound 2o: white solid, mp 186–188 °C. 1H NMR (500
MHz, CDCl3): d = 3.77 (s, 3 H), 3.80 (s, 3 H), 3.87 (s, 3 H),
4.91, 5.23 (AB, J = 14.0 Hz, 2 H), 6.59 (s, 1 H), 6.60 (s, 1
H), 6.64 (s, 1 H), 7.15–7.43 (m, 4 H). 13C NMR (125 MHz,
CDCl3): d = 53.62, 55.34, 5.18, 56.19, 70.16, 107.14,
110.00, 123.72, 124.63, 127.38, 129.37, 129.71, 130.83,
133.55, 138.95, 148.78, 155.50.
Compound 2p: white solid, mp 127–129 °C. 1H NMR (500
MHz, CDCl3): d = 3.77 (s, 3 H), 3.81 (s, 3 H), 3.89 (s, 3 H),
4.92, 5.21 (AB, J = 14.0 Hz, 2 H), 6.04 (s, 1 H), 6.49 (s, 1
H), 6.60 (s, 1 H), 7.25–7.33 (m, 4 H). 13C NMR (125 MHz,
CDCl3): d = 53.56, 56.22, 56.25, 58.53, 70.92, 107.15,
110.50, 124.04, 124.18, 127.29, 128.50, 129.18, 129.87,
134.51, 142.53, 148.69, 148.90, 155.29.
Compound 2t: white solid, mp 180–182 °C. 1H NMR (400
MHz, CDCl3): d = 3.76 (s, 3 H), 3.90 (s, 3 H), 4.12, 4.34
(AB, J = 13.2 Hz, 2 H), 5.02, 5.28 (AB, J = 13.6 Hz, 2 H),
6.44 (s, 1 H), 6.52 (s, 1 H), 6.60 (s, 1 H), 7.30–7.37 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 41.30, 56.24, 56.48, 72.53,
106.80, 110.67, 123.21, 124.00, 128.52, 128.73, 129.18,
140.25, 148.83, 148.92, 164.87.
Synlett 2006, No. 19, 3277–3283 © Thieme Stuttgart · New York