Synthesis of dihydrobenzo[1,4]oxazines using copper catalyzed intramolecular ring closure reaction

Article abstract of DOI:10.1016/j.tetlet.2013.04.090

The synthesis of dihydrobenzo[1,4]oxazines has been accomplished efficiently by copper catalyzed intramolecular cyclization of the adducts formed by the treatment of 1,2-cyclic sulfamidates with 2-halo phenols. The products (except two) are new and their yields are high. The catalyst is easily available and less expensive.

Full text of DOI:10.1016/j.tetlet.2013.04.090

Tetrahedron Letters 54 (2013) 3453–3456
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of dihydrobenzo[1,4]oxazines using copper catalyzed
intramolecular ring closure reaction q
⇑
Paramesh Jangili, Jajula Kashanna, Biswanath Das
Organic Chemistry Division—I, CSIR – Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of dihydrobenzo[1,4]oxazines has been accomplished efficiently by copper catalyzed intra-
molecular cyclization of the adducts formed by the treatment of 1,2-cyclic sulfamidates with 2-halo phe-
nols. The products (except two) are new and their yields are high. The catalyst is easily available and less
expensive.
Received 28 March 2013
Revised 18 April 2013
Accepted 20 April 2013
Available online 28 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Dihydrobenzo[1,4]oxazines
Copper catalyzed cyclization
Adduct
1,2-Cyclic sulfamidate
2-Halo phenol
Dihydrobenzo[1,4]oxazines are highly important for their inter-
esting biological properties.1 They are used as neuroprotectants
and inhibitors of nitric oxide synthases.2 They are also applied
for the synthesis of fungicides and herbicides.1 In addition, they
have been utilized for construction of different bioactive natural
products.3 Chiral dihydrobenzo[1,4]oxazines are also employed
as catalysts for the asymmetric transfer-hydrogenation of
a,b-
unsaturated aldehydes.4 Consequently, several methods have been
XH
Y
Boc
N
Y
CuI,
2
NaH
DMF
then HCl
R
DMEDA
Cs2CO3,
THF, 80°C
Boc NH
X
X
R
3
4
X = O, NH
Y= Br, I
O
N
R
O
S
Boc
O
COOH
I
1
Boc
N
R
CuI,
I
5
DMEDA
Et3N, Dry DMF
Boc NH
R
O
Cs2CO3,
THF, 80°C
O
55°C, 18 h
then THF/H2O,
H2SO4, rt, 3 h
O
6
O
7
(not observed)
Scheme 1. Copper-catalyzed synthesis of dihydrobenzo[1,4]oxazines from 1,2-cyclic sulfamidates.
q
Part 226 in the series ‘Studies on novel synthetic methodologies’.
⇑
Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.090

3454
P. Jangili et al. / Tetrahedron Letters 54 (2013) 3453–3456
developed for the synthesis of these heterocycles.1,4 Herein we re-
Table 1
Standardization of ligand, and basea
port an efficient method for the synthesis of these compounds
involving the copper mediated intramolecular ring closure
reaction.
CuI (5 mol%)
DMEDA (5 mol%)
Cs2CO3 (2 equiv.)
Boc
N
Br
In continuation of work5 on the development of useful synthetic
methodologies we have observed that the adducts (3) formed6 by
the reaction of 1,2-cyclic sulfamidate (1) and 2-halo phenols (2)
underwent copper catalyzed cyclization to form dihydro-
benzo[1,4]oxazines (4) in high yields (Scheme 1).
Me
Me
Boc
O
NH
Solvent (5 mL), 18 h
Temperature (T°C)
N
O
N
3c
4c
The cyclization was carried out by using CuI (as a catalyst) in
the presence of a ligand and a base. Initially several ligands
[N,N0-dimethylenediamine (DMEDA), 1,10-phenanthroline (Phen),
and 2,20-bipyridine (Bipy)] (Fig. 1) and bases (K2CO3 and Cs2CO3)
were used for standardization of the cyclization reaction (Table 1).
DMEDA was found to be the most efficient ligand and Cs2CO3 was
considered as the suitable base for the synthesis of dihydro-
benzo[1,4]oxazines. In absence of both the ligand and the base or
either of these no product was formed. The combination of the li-
gand, DMEDA and the base, Cs2CO3 was subsequently used for the
synthesis of various dihydrobenzo[1,4]oxazine derivatives.
The synthesis of 4c was also carried out using various solvents
(THF, DMF, DMSO, and MeCN) at variable temperatures (Table 2).
THF was chosen as the most suitable solvent at 80 °C to afford 4c
with highest yield (90%). The conversion was complete in 18 h.
When the time was decreased the yield was less but by increasing
the time the yield was not improved.
Entry
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
THF
THF
THF
THF
DMF
DMSO
CH3CN
rt
70
80
90
110
110
100
0
83
90
90
57
Trace
81
a
Reaction conditions: adduct 3c (1.0 mmol), CuI (5 mol %), DMEDA (5 mol %),
2.0 equiv of CS2CO3, 5.0 mL of THF at 80 °C for 18 h.
b
Isolated yield after column chromatography.
Table 2
Optimization of solvent and temperaturea
It may be mentioned here that during the synthesis of indolines
and their homologues starting from 2-iodophenethyl mesylates
and related compounds Minatti and Buchwald have carried out7
the similar cyclization reaction under similar reaction conditions
as we have performed here for the cyclization of the adducts 3.
We have expanded their methodology for the synthesis of
dihydrobenzo[1,4]oxazines.
CuI (5 mol%)
DMEDA (5 mol%)
Cs2CO3 (2 equiv.)
Boc
N
Br
Me
Me
O
Boc NH
Solvent (5 mL), 18 h
Temperature (T°C)
N
O
N
3c
4c
After standardization of the present intramolecular cyclization
several dihydrobenzo[1,4]oxazines (4) were synthesized from dif-
ferent adducts (3) (Table 3). All the dihydrobenzo[1,4]oxazine
derivatives except 4a8 and 4k9 are new. The adducts (3) were pre-
pared8 from various 1,2-cyclic sulfamidates (1) and bromo and iod-
ophenols (2). Both achiral and chiral sulfamidates have been
utilized. These compounds are known to be cleaved easily with
nucleophiles and recently they have been applied for the synthesis
of different bioactive compounds.10 Earlier we have also utilized
the cyclic sulfamidates for the preparation of b-amino phospho-
nates.11 In the present case, along with 2-halophenols, 2-hydro-
xy-3-bromo-5-methyl pyridine (2c) was also used as nucleophile
to form the adduct in excellent yield (99%). The adduct 3c formed
Entry
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
THF
THF
THF
THF
DMF
DMSO
CH3CN
rt
70
80
90
110
110
100
0
83
90
90
57
Trace
81
a
Reaction conditions: adduct 3c (1.0 mmol), CuI (5 mol %), DMEDA (5 mol %),
2.0 equiv of CS2CO3, 5.0 mL of THF at 80 °C for 18 h.
b
Isolated yield after column chromatography.
Table 3
Synthesis of 1,4-benzoxazines from 1,2-cyclic sulfamidatesa
S. No.
1,2-Cyclic sulfamidate (1)
Nucleophile (2)
Adduct (3) yielda (%)
Dihydrobenzo[1,4]oxazine (4) yielda (%)
O
N
O
O
OH
Br
Br
Boc
S
N
Boc
b
O
Boc NH
1
O
b
1a
4a
3a (99%)
(87%)
2a
OH
Br
Br
Boc
Me
Me
N
Me
Boc NH
O
2
3
O
4b (75%)
3b (98%)
Me
2b
OH
Br
Boc
N
Br
N
Boc
Me
NH
O
N
O
N
Me
2c
3c (99%)
4c
(90%)

P. Jangili et al. / Tetrahedron Letters 54 (2013) 3453–3456
3455
Table 3 (continued)
S. No.
1,2-Cyclic sulfamidate (1)
Nucleophile (2)
Adduct (3) yielda (%)
Dihydrobenzo[1,4]oxazine (4) yielda (%)
O
N
O
O
OH
Br
Br
Boc
N
S
Me
Boc
O
Boc NH
Me
4
5
O
Me
4d (83%)
1b
2a
3d (98%)
OH
I
I
Boc
N
Me
Me
NH
O
Boc
O
Me
4d (83%)
2d
3e (98%)
Br
OH
Br
Boc
N
Me
Me
O
Boc NH
Me
6
7
O
4e (72%)
Me
2b
3f (97%)
O
O
O
OH
Br
Br
O
Boc
N
S
Boc
N
Boc NH
O
2a
4f (88%)
1c
3g
(99%)
Br
OH
Br
Boc
N
Me
Me
Boc
Me
Me
NH
O
O
8
9
Me
4g (77%)
2b
3h (98%)
OH
Br
Boc
N
Br
N
Boc
NH
O
N
O
N
Me
2c
4h (90%)
3i (99%)
O
O
O
OH
Br
Br
Boc
N
S
Boc
N
Boc NH
O
O
4i (86%)
10
2a
1d
3j (98%)
OH
Br
Br
Boc
N
Me
Me
NH
O
Boc
O
Me
4j (73%)
11
12
2b
3k (99%)
Br
O
O
O
NH2
Br
Boc
N
S
Boc
N
HN
c
Boc NH
N
H
1a
3l (65%)
4k (35%)c
2e
a
Isolated yield.
b,c
Compounds 4a8 and 4k9 are known.
by the reaction of the sulfamidate 1a and 2-hydroxy-3-bromo-5-
methyl pyridine (2c) produced the dihydrobenzo[1,4]oxazine
derivative 4c.
The adducts (3) underwent smooth cyclization to dihydro-
benzo[1,4]oxazines (4) by the present developed conditions
(Scheme 1). Earlier this cyclization was carried out6 using Pd(OAc)2
at 100 °C but here the easily available and inexpensive CuI has
been added. Replacing an expensive metal catalyst with more
abundant and relatively less expensive one to execute a similar
conversion is of great importance in current organic syntheses.12
All the dihydrobenzo[1,4]oxazine derivatives prepared13 by the
present method were characterized from their spectral (1H, 13C
NMR, and MS) and analytical data.14
The present method was also extended for the synthesis of
quinoxaline derivative 4k by the copper catalyzed cyclization of
the adduct 3l prepared from the cyclic sulfamidate 1a and 2-bromo
aniline (2e) (Table 3, entry 12). However, the yield of 4k (35%) was
not impressive.

3456
P. Jangili et al. / Tetrahedron Letters 54 (2013) 3453–3456
13. General experimental procedure for preparation of dihydrobenzo[1,4]oxazines 4: In
a 10 mL round bottom flask CuI (5 mol %), DMEDA (5 mol %), CS2CO3 (2 equiv),
and compound 3 in THF (5.0 mL) were taken under nitrogen. The mixture was
stirred at 80 °C, and the progress of the reaction was monitored by TLC. After
18 h the reaction mixture was allowed to cool, and subsequently extracted
with EtOAc (2 ꢀ 10 mL). The combined organic extract was dried over
anhydrous Na2SO4. Concentration in vacuo followed by column
chromatography (EtOAc/hexane: 5:95 to 10:90) gave pure compound 4.
14. The spectral (IR, 1H, 13C NMR and MS) and analytical data of some compounds
are given below.
H
N
Me
Me
N
N
H
N
N, N'-Dimethylethylenediamine
1, 10-Phenantroline
(Phen)
(DMEDA)
Tert-butyl 7-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4] oxazine-1-carboxylate
(4c): IR (KBr): 1707, 1481, 1346, 1238 cmꢁ1 1H NMR (200 MHz, CDCl3): d
;
8.12 (1H, br s), 7.75 (1H, br s), 4.34 (2H, t, J = 7.0 Hz), 3.84 (2H, t, J = 7.0 Hz),
2.25 (3H, s), 1.53 (9H, s); 13C NMR (50 MHz, CDCl3): d 152.2, 150.5, 142.0,
131.9, 126.7, 121.9, 82.0, 65.1, 42.1, 28.2, 17.9; ESIMS: m/z 251 [M+H]+; Anal.
Calcd for C13H18N2O3: C, 62.38; H, 7.25%. Found: C, 62.30; H, 7.33%.
N
N
2, 2'-Bipyridine
(Bipy)
(S)-Tert-butyl 3-methyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (4d): ½ ꢂ
a 2D0
Figure 1. Ligands used in copper-catalyzed cyclization of adducts.
ꢁ26.6 (c 0.1, CHCl3); IR (KBr): 1706, 1495, 1369, 1263 cmꢁ1
;
1H NMR
(200 MHz, CDCl3): d 7.86 (1H, d, J = 8.0 Hz), 6.98 (1H, t, J = 8.0 Hz), 6.90–6.85
(2H, m), 4.70–4.62 (2H, m), 4.21 (1H, m), 1.52 (9H, s), 1.20 (3H, d, J = 7.0 Hz);
13C NMR (50 MHz, CDCl3): d 152.2, 145.1, 124.2, 124.0, 123.9, 120.3, 116.9,
81.8, 69.0, 46.1, 28.2, 15.2; ESIMS: m/z 272 [M+Na]+; Anal. Calcd for
The developed method was also applied for preparation of the
seven membered heterocycle 7 by cyclization of the adducts 6 pre-
pared from the sulfamidates
(Scheme 1). However, the reaction was unsuccessful and the ad-
ducts 6 were recovered intact.
In conclusion, we have developed a high yielding efficient
method for the synthesis of several new dihydrobenzo[1,4]oxazine
derivatives by employing copper catalyzed cyclization of the ad-
ducts prepared by the reaction of 1,2-cyclic sulfamidates and 2-
halophenols. The application of an easily available and less expen-
sive catalyst is a great advantage in this method.
C
14H19NO3: C, 67.45; H, 7.68%. Found: C, 67.49; H, 7.64%.
(S)-Tert-butyl 3,6-dimethyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (4e): IR
(KBr): 1701, 1508, 1373, 1264 cmꢁ1 1H NMR (200 MHz, CDCl3): d 7.72 (1H, br
1 and 2-iodobenzoic acid (5)
;
s), 6.79 (2H, br s), 4.69–4.60 (2H, m), 4.30 (1H, m), 2.28 (3H, s), 1.53 (9H, s),
1.21 (3H, d, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 152.2, 143.0, 129.9, 124.6,
124.0, 123.9, 116.2, 81.1, 69.0, 46.2, 28.4, 21.0, 15.8; ESIMS: m/z 286 [M+Na]+;
Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04%. Found: C, 68.44; H, 8.02%.
(R)-Tert-butyl 3-phenyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (4f): ½ ꢂ
a 2D0
ꢁ61.1 (c 0.4, CHCl3); IR (KBr): 1711, 1495, 1335, 1257 cmꢁ1
;
1H NMR
(200 MHz, CDCl3): d 8.08 (1H, d, J = 8.0 Hz), 7.30–7.18 (5H, m), 6.98–6.32
(3H, m), 5.59 (1H, dd, J = 6.0, 2.0 Hz), 4.52 (1H, dd, J = 12.0, 2.0 Hz), 4.34 (1H, dd,
J = 12.0, 6.0 Hz), 1.45 (9H, s); 13C NMR (50 MHz, CDCl3): d 152.8, 146.1, 138.9,
128.8, 127.8, 126.7, 126.5, 124.0, 123.0, 121.1, 117.1, 82.0, 68.3, 55.0, 28.1;
ESIMS: m/z 334 [M+Na]+; Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80%. Found:
C, 73.23; H, 6.86%.
Acknowledgments
(R)-Tert-butyl 6-methyl-3-phenyl-2H-benzo[b][1,4]oxazi- ne-4(3H)-carboxylate
(4g): ½a 2D0
ꢂ
ꢁ57.6 (c 0.4, CHCl3); IR (KBr): 1706, 1508, 1333, 1262 cmꢁ1
;
1H
The authors thank the UGC and CSIR, New Delhi for financial
assistance.
NMR (200 MHz, CDCl3): d 7.92 (1H, br s), 7.31–7.18 (5H, m), 6.72 (2H, br s),
5.53 (1H, dd, J = 6.0, 4.0 Hz), 4.48 (1H, dd, J = 12.0, 4.0 Hz), 4.30 (1H, dd, J = 12.0,
6.0 Hz), 2.29 (3H, s), 1.41 (9H, s); 13C NMR (50 MHz, CDCl3): d 153.0, 144.2,
139.4, 130.9, 128.8, 127.6, 126.2, 126.0, 124.4, 123.2, 116.8, 81.8, 68.5, 55.2,
28.2, 21.1; ESIMS: m/z 348 [M+Na]+; Anal. Calcd for C20H23NO3: C, 73.82; H,
7.12%. Found: C, 73.87; H, 7.07%.
References and notes
1. Ilas, J.; Anderluh, P. S.; Dolenc, M. S.; Kikelj, D. Tetrahedron 2005, 61, 7325.
2. (a) Lestage, P.; Lockhart, B.; Fleury, M. B.; Largeron, M. WO Patent Appl.
9,962,889, 1999.; (b) Burton, G. A.; Rehwinkel, H.; Jaroch, S.; Hoelscher, P.;
Suelzle, D.; Hillmann, M.; McDonald, F. M. WO Patent Appl. 0,017,173, 2000.
3. (a) Zhen, Y. S.; Ming, X. Y.; Yu, B.; Otani, T.; Saito, H.; Yamada, Y. J. Antibiol.
1989, 42, 1294; (b) Sugimoto, Y.; Otani, T.; Oie, S.; Wierzba, K.; Yamada, Y. J.
Antibiol. 1990, 43, 417.
(R)-Tert-butyl 7-methyl-2-phenyl-2,3-dihydro-1H-pyrido [2,3-b][1,4]oxazine-1-
carboxylate (4h):
½ ꢂ ꢁ85.0 (c 0.4, CHCl3); IR (KBr): 1708, 1481, 1329,
a 2D0
1242 cmꢁ1 1H NMR (200 MHz, CDCl3): d 8.35 (1H, br s), 7.72 (1H, br s), 7.30–
;
7.21 (5H, m), 5.52 (1H, dd, J = 4.0, 2.0 Hz), 4.64 (1H, dd, J = 12.0, 2.0 Hz), 4.43
(1H, dd, J = 12.0, 4.0 Hz), 2.28 (3H, s), 1.42 (9H, s); 13C NMR (50 MHz, CDCl3): d
152.3, 150.0, 141.2, 138.5, 131.4, 128.5, 127.5, 127.4, 126.2, 121.4, 82.1, 68.0,
54.9, 28.0, 17.4; ESIMS: m/z 327 [M+H]+; Anal. Calcd for C19H22N2O3: C, 69.92;
H, 6.79%. Found: C, 69.90; H, 6.81%.
4. Ebner, C.; Pfaltz, A. Tetrahedron 2011, 67, 10287.
(S)-Tert-butyl 3-benzyl-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (4i):
½ ꢂ
a 2D0
5. (a) Das, B.; Salvanna, N.; Reddy, G. C.; Balasubramanyam, P. Tetrahedron Lett.
2011, 52, 6497; (b) Reddy, G. C.; Balasubramanyam, P.; Salvanna, N.; Das, B. Eur.
J. Org. Chem. 2012, 471; (c) Das, B.; Reddy, G. C.; Salvanna, N.;
Balasubramanyam, P. Tetrahedron 2012, 68, 300.
6. Bower, J. F.; Szeto, P.; Gallagher, T. Org. Lett. 2007, 9, 3283.
7. Minatti, A.; Buchwald, L. Org. Lett. 2008, 10, 2721.
8. Buon, C.; Chacun-Lefévre, L.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron
2000, 56, 605.
9. Suzuki, R.; Mikami, A.; Tanaka, H.; Fukushima, H. WO Patent Appl. 2,172,453,
2010.
10. (a) Melendez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581; (b) Bower, J. F.;
Rujirawanich, J.; Galagher, T. T. Org. Biomol. Chem. 2010, 8, 1505.
11. Das, B.; Reddy, Ch. R.; Nagendra, S.; Lingaiah, M. Tetrahedron Lett. 2011, 52,
3496.
12. (a) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185; (b)
Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You, J. Angew. Chem., Int.
Ed. 2009, 48, 3296.
ꢁ42.8 (c 0.5, CHCl3); IR (KBr): 1707, 1496, 1328, 1258 cmꢁ1
;
1H NMR
(200 MHz, CDCl3): d 7.96 (1H, br s, J = 8.0 Hz), 7.32–7.17 (5H, m), 7.01–6.90
(3H, m), 4.68 (1H, m), 4.18 (1H, dd, J = 12.0, 2.0 Hz), 4.05 (1H, dd, J = 12.0,
4.0 Hz), 2.84 (1H, dd, J = 12.0, 6.0 Hz), 2.74 (1H, dd, J = 12.0, 8.0 Hz), 1.41 (9H,
s); 13C NMR (50 MHz, CDCl3): d 152.0, 145.2, 137.9, 129.7, 128.8, 126.5, 124.4,
124.1, 123.7, 120.9, 116.8, 81.3, 66.2, 51.9, 36.0, 28.1; ESIMS: m/z 348 [M+Na]+;
Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12%. Found: C, 73.85; H, 7.09%.
(S)-Tert-butyl 3-benzyl-6-methyl-2H-benzo[b][1,4]oxazi- ne-4(3H)-carboxylate
(4j): ½a 2D0
ꢂ
ꢁ25.5 (c 0.2, CHCl3); IR (KBr): 1708, 1507, 1325, 1262 cmꢁ1
;
1H
NMR (200 MHz, CDCl3): d 7.83 (1H, br s,), 7.34–7.13 (5H, m), 6.81 (2H, br s),
4.65 (1H, m), 4.18 (1H, dd, J = 12.0, 2.0 Hz), 4.02 (1H, dd, J = 12.0, 4.0 Hz), 2.90–
2.72 (2H, m), 2.23 (3H, s), 1.42 (9H, s); 13C NMR (50 MHz, CDCl3): d 152.0,
143.1, 138.2, 130.0, 129.4, 128.9, 126.8, 124.9, 123.8, 123.2, 116.4, 81.1, 76.2,
52.8, 36.0, 28.2, 21.0; ESIMS: m/z 340 [M+H]+; Anal. Calcd for C21H25NO3: C,
74.31; H, 7.42%. Found: C, 74.32; H, 7.41%.