Efficient synthesis of 2,3-dihydro-1,4-benzoxazines via intramolecular copper-catalyzed O-arylation

Article abstract of DOI:10.1016/j.tetlet.2009.04.055

A highly efficient synthetic approach to 2,3-dihydro-1,4-benzoxazines is described. The method involves a mild intramolecular copper-catalyzed O-arylation of β aminoalcohol, which works well without N-protection.

Full text of DOI:10.1016/j.tetlet.2009.04.055

Tetrahedron Letters 50 (2009) 3790–3793
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Efficient synthesis of 2,3-dihydro-1,4-benzoxazines via intramolecular
copper-catalyzed O-arylation
Zhangqin Liu a,b, Yuanwei Chen a,
*
a Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, PR China
b Graduate School of Chinese Academy of Sciences, Beijing 100039, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient synthetic approach to 2,3-dihydro-1,4-benzoxazines is described. The method involves
a mild intramolecular copper-catalyzed O-arylation of b aminoalcohol, which works well without
N-protection.
Received 5 December 2008
Revised 31 March 2009
Accepted 3 April 2009
Available online 18 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Benzoxazine
O-Arylation
Intramolecular
Ullmann coupling
2,3-Dihydro-1,4-benzoxazines are an important class of mole-
cules, which are a common heterocyclic scaffold in biologically ac-
tive and medicinally significant compounds. For example,
levofloxacin that exhibits excellent activities against Gram-posi-
tive and Gram-negative bacteria, possesses 2,3-dihydro-1,4-ben-
zoxazine moiety. In addition, some benzoxazines are central
nervous system depressants, antipsychotic agents, calcium antago-
nists, and antibacterial agents; moreover, some are potential drugs
for neuroprotective, antitumor, antithrombotic, antihypertensive
agents, and cardiovascular drugs.1 Due to the importance of 1,4-
benzoxazines, several synthetic methods for 2,3-dihydro-1,4-ben-
zoxazines have been reported over the past few decades.1a,2 How-
ever, these methods suffered some limitations in the generation of
molecular diversity.2 The recent developments of metal-catalyzed
intramolecular O-arylation and N-arylation provide efficient meth-
ods for benzoxazines synthesis. Buchwald reported benzoxazines
synthesis via palladium-catalyzed intramolecular etherification.3
More recently, synthesis of 2,3-dihydro-1,4-benzoxazines through
palladium-catalyzed intramolecular N-arylation has been re-
ported.4 However; these methods have some limitations with re-
spect to the toxic catalysts and N-protection. Thus, there is
clearly a demand for more general and environment friendly en-
tries to this interesting class of substances.
bonds. However, traditional copper-catalyzed Ullmann coupling
reaction5 was conducted under harsh conditions, including high
temperature, stoichiometric amount of copper agent, and extended
period of time which limited the scope of the reaction. Since Buch-
wald’s and Taillefer’s pioneering work, exhaustive efforts have
been made to explore efficient copper/ligand systems and signifi-
cant progresses have been achieved.6 The achievements have been
widely used in heterocycle synthesis.7 Moreover, Buchwald re-
ported control of the chemoselectivity of N-arylation versus O-ary-
lation of 1,2-aminoalcohols with different copper/base
combinations or other aminoalcohols with copper/ligand/base
combinations.8 Herein, we would like to describe an efficient
methodology for the synthesis of 2,3-dihydro-1,4-benzoxazine by
CuI/1, 10-phenanthroline system catalyzed intramolecular O-ary-
lation of b-aminoalcohols without N-protection.
As reported, the chemoselectivity of intermolecular O-arylation
was low with copper/ligand systems and moderate with ligand-
free system when b-aminoalcohol was employed.8a However, un-
der the ligand free condition, the intramolecular coupling of 1a
was the minor reaction.9,10 Then, we performed the intramolecular
coupling of 1a in the presence of CuI/1, 10-phenanthroline with
various bases in different solvents (Table 1). The reaction was first
carried out in toluene mediated by K3PO4; however, no desired
coupling product was obtained with starting material quantita-
tively recovered (entry 1). To our surprise, when a stronger base,
NaOt-Bu was used, the O-arylation product 2a was obtained with
75% yield (entry 2). Encouraged by this finding, the optimal
cyclization conditions were screened. Several solvents including
Since the discovery, the copper-mediated Ullmann coupling
reaction is the straightforward method to form carbon–heteroatom
* Corresponding author. Tel./fax: +86 28 85232730.
E-mail address: chenyw@cioc.ac.cn (Y. Chen).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.055

Z. Liu, Y. Chen / Tetrahedron Letters 50 (2009) 3790–3793
3791
Table 1
Optimization of reaction conditionsa
10% mol CuI, base, solvent
Cl
I
Cl
O
10% mol 1,10-phenanthroline
OH
N
H
100°C
N
H
1a
2a
Entry
Base
Solvent
Toluene
Toluene
o-Xylene
Dioxane
DMF
MeCN
Dioxane
Dioxane
Yieldb (%)
1
2
3
4
5
6
7
8
K3PO4
NR
75
71
86
Trace
Trace
Trace
Trace
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
Cs2CO3
KOt-Bu
a
Reaction conditions: 1a (0.5 mmol); CuI (10 mol %); 1,10-phenanthroline (20 mol %); base (1 mmol); dry solvent (2 ml); reaction time 12–24 h; under N2 atmosphere.
Isolated yield.
b
toluene, o-xylene, dioxane, DMF, and MeCN were tested (entries
Having established the preferred reaction condition, we applied
this methodology to synthesize a series of 2,3-dihydro-1,4-benzox-
azine derivatives. The representative results are summarized in
Table 2.11 Substituent variations such as chloro- and methyl groups
on the iodoaryl moiety of 1 were tolerated and 2 was obtained in
excellent yields (entries 1 and 2).12 It should be noted that the
2–6). It turned out that dioxane was superior to the other solvents
(entry 4). It was found that NaOt-Bu was the most efficient base.
When stronger base such as KOt-Bu or weaker base such as Cs2CO3
was employed, only trace cyclization product was obtained (en-
tries 7 and 8).
Table 2
Cu catalyzed intramolecular O-arylation to form 2,3-dihydro-1,4-benzoxazines
R1
I
CuI
R1
O
R3
R2
R2
1,10-phenanthroline
OH
N
H
N
H
NaOt-Bu/dioxane
100°C
R3
2
1
Entry
1
1
2
Yield of 2a (%)
Cl
I
Cl
O
86
OH
N
H
N
H
2a
1a
I
O
2
95
92
OH
N
H
N
H
2b
1b
I
O
3b
N
H
N
H
2c
OH
1c
Cl
I
Cl
O
4
91
N
N
H
H
2d
OH
1d
(continued on next page)

3792
Z. Liu, Y. Chen / Tetrahedron Letters 50 (2009) 3790–3793
Table 2 (continued)
Entry
1
2
Yield of 2a (%)
Cl
I
OH
OH
OH
OH
Cl
O
5
6
84
N
H
N
H
1e
2e
Cl
Cl
Cl
I
Cl
Cl
O
85
86
87
81
82
91
94
89
N
H
N
H
2f
1f
O
I
7
N
H
N
H
2g
2h
1g
1h
1i
F
F
I
Cl
O
8
N
H
N
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
I
OH
OH
Cl
Cl
O
9
Cl
Cl
N
H
N
H
2i
I
O
Cl
Cl
10
11
12
13
14
N
H
N
H
2j
1j
I
Cl
Cl
Cl
Cl
O
O
O
O
Ph
N
H
O
O
O
Ph
N
H
1k
1l
2k
OH
OH
OH
I
O
N
H
N
H
2l
I
O
N
H
N
H
1m
2m
2n
O
Cl
I
87
OH
N
H
N
H
1n
(continued on next page)

Z. Liu, Y. Chen / Tetrahedron Letters 50 (2009) 3790–3793
3793
Table 2 (continued)
Entry
1
2
Yield of 2a (%)
Cl
I
Cl
O
15
82
N
H
1o
N
OH
H
2o
a
Isolated yield.
b
The configuration of 2c is determined by comparison of the data with the literature (see Ref. 2f).
Albanese, D.; Landini, D.; Lupi, V.; Penso, M. Ind. Eng. Chem. Res. 2003, 42, 680–
686; (g) Brown, D. W.; Ninan, A.; Sainsbury, M. Synthesis 1997, 895–898.
3. Kuwabe, S.; Torraca, K. F.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202–
12206.
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5. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–2384; (b) Bacon, R. G. R.;
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1984, 40, 1433–1456. and references therein.
trans-cyclohexyl amino alcohol moiety was also tolerated well to
give corresponding trans-benzoxazine with excellent yield (entries
3 and 4).2f,9 Substrates with aryl substituents on the amino alcohol
moiety were examined as well (entries 5–10 and 15). The phenyl
ring could be substituted in 2, 3, or 4 positions and the substituents
can be electron-withdrawing or electron-donating groups. When
4-methyl, 4-fluoro, and 4-chloro phenyl moiety were employed,
good yields of 2 were obtained (entries 6–8). 2-Chloro phenyl moi-
ety and 3-chloro phenyl moiety could cyclize smoothly to give ben-
zoxazine with 82% and 81% yields, respectively (entries 9 and 10).
The compound that has bulky substituent on the alcohol moiety
could also give cyclization product with good yield (entry 15).
Methyl and ether groups on amino alcohol moiety were also well
tolerated under these conditions (entries 11–14).
In conclusion, we have developed a general, more sustainable
methodology for the copper-catalyzed intramolecular O-arylation
to synthesize benzoxazines, which is a valuable framework with
interesting therapeutic properties. In addition, the process toler-
ates variation of both aryl iodide and amino alcohol portions of
the substrate. Furthermore, this methodology allows free N–H
group which was protected in other benzoxazines synthesis
methods.8
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Acknowledgment
We are grateful for financial support from National Nature Sci-
ence Foundation of China (Project No. 20872138).
References and notes
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10. Typical procedure for the preparation of 1a: The reactor was charged with 4-
chloro-2-iodobenzenamine (2 mmol), 2-methyloxirane (6 mmol), LiBr
(2 mmol), and 3 ml dry THF, and the resultant mixture was stirred at
35 °C for 72 h. Addition of water, extraction with CH2Cl2, drying with
Na2SO4, filtration, and solvent removal in vacuo gave a residue that was
purified by column chromatography using ethyl acetate/petroleum ether as
eluent to give 1a (410 mg, 66%). 1H NMR (300 MHz, CDCl3):
d 1.29 (d,
J = 6 Hz, 3H), 1.90 (br s, 1H), 3.00–3.07 (m, 1H), 3.19–3.25 (m, 1H), 4.01–4.11
(m, 1H), 4.46 (br s, 1H), 6.49 (d, J = 8 Hz, 1H), 7.14–7.18 (m, 1H), 7.62 (d,
J = 2 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 145.9, 137.8, 129.1, 122.0, 111.0,
85.1, 65.9, 51.5, 20.9.
11. Typical representative experimental procedure: NaOt-Bu (96 mg, 1 mmol), CuI
(9.5 mg, 0.05 mmol), 1,10-phenanthroline (18 mg, 0.1 mmol), and 1a (155 mg,
0.5 mmol) were taken in
a 10 ml round-bottomed flask. The flask was
evacuated and back-filled with nitrogen three times. Dry dioxane (2 ml) was
added to the mixture at room temperature. The resulting mixture was placed
at oil base, and heated for 24 h at 100 °C. after complete disappearance of 1a
(TLC), the reaction mixture was allowed to cool to room temperature and the
solvent was evaporated. The mixture was purified by flash chromatography on
silica gel using ethyl acetate/petroleum ether as eluent to give white solid 2a
(79 mg, 86%).
12. Analytical data for 2a: 1H NMR (300 MHz, CDCl3): d 1.35 (d, J = 6 Hz, 3H), 3.03–
3.10 (m, 1H), 3.30–3.35 (m, 1H), 3.74 (br s, 1H), 4.16–4.23 (m, 1H), 6.49 (d,
J = 8 Hz, 1H), 6.69–6.73 (m, 1H), 6.78 (d, J = 2 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d 18.4, 46.6, 70.4, 115.7, 116.8, 120.8, 122.8, 131.7, 144.4; ESI-MS: m/z
calcd for C9H10NOCl: 183.0529; found: 184.0518 [M+H].
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