Poly(ethylene glycol) (PEG) as an efficient and recyclable reaction medium for the synthesis of dibenz[b,f]-1,4-oxazepine

Article abstract of DOI:10.1016/j.tetlet.2007.12.115

Poly(ethylene glycol) (PEG) has been used as a sustainable, non-volatile, and environmentally friendly reaction solvent for the synthesis of dibenz[b,f]-1,4-oxazepine (2a). PEG-400 as a promoter provided 89% of 2a within 8 h. We compared the reactivity of PEG-400 with 18-crown-6, tetra-n-butylammonium bromide and ionic liquids as phase transfer catalysts. Further, we investigated our protocol with various PEGs, with molecular weight 200, 300, 1000, 2000, 8000, 10,000, and 20,000. The reaction provided excellent yields with low as well as high molecular weight PEGs. We also studied the effect of various organic cosolvents (polar protic/aprotic/non-polar) on the reactivity of PEG-400 for the synthesis of 2a.

Full text of DOI:10.1016/j.tetlet.2007.12.115

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1495–1497
Poly(ethylene glycol) (PEG) as an efficient and recyclable
reaction medium for the synthesis of dibenz[b,f]-1,4-oxazepine
a,
b
c
d
*
Yogesh R. Jorapur , Gurusamy Rajagopal , Prakash J. Saikia , Ravindra R. Pal
a
Department of Chemical Engineering, Nara National College of Technology, 22 Yata Yamatokoriyama Nara, 639-1080, Japan
b
Department of Chemistry, Govt. Arts College (Autonomous), Nandanam, Chennai 600 035, India
Department of Chemical Engineering, Inha University, 253 Yonghyundong Namgu, Inchon 402-751, Republic of Korea
c
d
National Institute for Materials Science, Organic Nanomaterial Center, 1-1 Namiki, Tsukuba 305-0044, Japan
Received 29 October 2007; revised 19 December 2007; accepted 21 December 2007
Available online 25 December 2007
Abstract
Poly(ethylene glycol) (PEG) has been used as a sustainable, non-volatile, and environmentally friendly reaction solvent for the syn-
thesis of dibenz[b,f]-1,4-oxazepine (2a). PEG-400 as a promoter provided 89% of 2a within 8 h. We compared the reactivity of PEG-400
with 18-crown-6, tetra-n-butylammonium bromide and ionic liquids as phase transfer catalysts. Further, we investigated our protocol
with various PEGs, with molecular weight 200, 300, 1000, 2000, 8000, 10,000, and 20,000. The reaction provided excellent yields with
low as well as high molecular weight PEGs. We also studied the effect of various organic cosolvents (polar protic/aprotic/non-polar)
on the reactivity of PEG-400 for the synthesis of 2a.
Ó 2008 Elsevier Ltd. All rights reserved.
Reducing or eliminating the use of volatile organic sol-
vents can minimize the generation of waste, which is a
requirement of one of the principles of green chemistry.
environmentally benign protocol proved to have many
applications particularly, in substitution, oxidation, and
reduction reactions.
1
The demand for environmentally friendly reaction solvents
to lower volatile organic compounds (VOCs) or toxic air
emissions has grown, partly spurred by various govern-
Dibenz[b,f]-1,4-oxazepine (2a) has been synthesized by
intramolecular nucleophilic displacement of nitro or fluoro
or chloro groups in high boiling polar aprotic solvents like
dimethyl sulphoxide (DMSO) or dimethyl formamide
2
ment regulations. The use of water as solvent is probably
8
the most desirable approach but this is often not possible
due to the hydrophobic nature of the reactants and the sen-
(DMF) over 100 °C. Further, there are few reports on
the synthesis of polyfluorodibenz[b,f]-[1,4]-oxazepines by
cyclization of polyfluorinated o-hydroxybenzylideneani-
3
sitivity of many catalysts to aqueous conditions. Alterna-
9
tive solvents have been the subject of much research in
lines. In this Letter, we describe the use of a simple and
4
recent years including studies of supercritical CO , near
widely available polymer, PEG and optionally its deriva-
tives as non-toxic, inexpensive, and non-ionic liquid sol-
vents of low volatility for the synthesis of oxazepine (2a)
via intramolecular cyclization.
2
4
5
6
critical water, ionic liquids, and fluorous based systems.
Recently PEG is found to be an interesting solvent sys-
7
tem. The important difference between using PEG and
other neoteric solvents is that all of the toxicological prop-
erties, the short and long-term hazards, and the biodegrad-
ability, etc., are established and known. PEG as
In the initial studies, the reaction was performed in tra-
ditional organic solvent (CH CN, Table 1, entry 1). The
3
reaction mixture was stirred for 12 h at 100 °C to obtain
5% of oxazepine (2a) with 24% of imine (2b). The reac-
4
tions in DMF (entries 3 and 4) at 50 °C and 100 °C pro-
vided 21% and 74% of 2a, respectively, after 12 h
whereas, the same reaction in the presence of PEG-400 as
*
Corresponding author. Tel.: +81 743 52 5623; fax: +81 743 55 6154.
E-mail address: yogesh.jorapur@gmail.com (Y. R. Jorapur).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.115

1496
Y. R. Jorapur et al. / Tetrahedron Letters 49 (2008) 1495–1497
Table 1
with very low yield (<5%) of cyclized compound 2a
whereas, with bromo substrate, reaction did not proceed.
The search for alternative reaction media to replace vol-
atile and often toxic solvents commonly used in organic
synthetic procedures is an important objective of signifi-
cant environmental consequence. So to check the eco-
Synthesis of dibenz[b,f]-1,4-oxazepine in poly(ethylene glycol)-400 under
various reaction conditions
a
N
CHO H N
2
PEG, K CO3
2
1
00 o
C
O
F
HO
friendliness of PEG, we recycled PEG-400 for several times
1
a
2a, 89%
Time (h)
10
(Table 2). The reaction proceeded cleanly with consistent
b
Entry
1
Promoter (g)
CH
3
CN (mL)
Yield (%)
results, although a weight loss of ꢀ5% of PEG-400 was
observed from cycle to cycle due to mechanical loss.
There are many potential advantages of replacing VOCs
with PEGs. The most obvious are low cost, reduced flam-
mability, toxicity, and environmental risk as a result of dis-
charges of the supporting phase. We next performed the
synthesis of 2a in various PEGs with molecular weight
2
a
2b
—
—
—
—
2.0
2.0
—
12
12
12
12
14
10
8
45
42
21
74
86
88
89
24
28
57
2
c
2
d
3
e
4
—
5
6
7
PEG-400 (0.5)
PEG-400 (1.0)
PEG-400 (2.0)
PEG-400 (2.0)
PEG-400 (1.0)
PEG-400 (1.0)
PEG-400 (0.05)
18-Crown-6 (0.05)
TBABr (0.05)
1.5
1.0
—
—
—
—
90
89
90
24
23
20
25
25
200, 300, 1000, 2000, 8000, 10,000, and 20,000 (Table 3,
f
entries 1–7). Entries 1–3 completed within 12 h with excel-
lent yields of 2a. However, as the molecular weight of
PEGs increases, viscosity increase is observed which led
to highly viscous reaction mixture even after using certain
amount of acetonitrile as cosolvent. Entries 4–7 provided
comparatively low yield of 2a.
In most of the methodologies, cosolvents place a dra-
matic effect on the reactivity, selectivity, and yield of the
reaction. To check the effect of cosolvents along with
PEG on the intramolecular aromatic nucleophilic displace-
ment reaction towards the synthesis of 2a, we performed a
series of reactions in different cosolvents (polar protic/
aprotic/non-polar). However, we did not observe any
noticeable effect of cosolvents in the case of our methodol-
ogy (Table 4).
8
9
—
1
—
g
1.0
1.0
2.0
2.0
2.0
2.0
2.0
24
24
24
24
24
24
24
Trace
Trace
60
60
64
h
10
11
12
13
14
15
a
[bmim][BF
[bmim][PF
4
] (0.05)
] (0.05)
58
57
6
All reactions were carried out on a 1.0 mmol reaction scale of 2-fluoro
benzaldehyde (1a) and 1.1 mmol of 2-amino phenol in the presence of
.0 mmol of K CO at 100 °C.
Isolated yield.
1
2
3
b
c
d
e
2 3
Reaction was carried out in the absence of K CO .
Reaction was carried out in DMF (2.0 mL) at 50 °C.
Reaction was carried out in DMF (2.0 mL) at 100 °C.
Reaction was performed in sonicator at rt.
Reaction was carried out at rt.
f
g
h
Reaction was carried out at 50 °C.
Table 2
Synthesis of dibenz[b,f]-1,4-oxazepine in recycled poly(ethylene glycol)-
environmentally friendly medium provided 89% of 2a
a
4
00
1
0
(
entry 7). PEG-400 as a reaction solvent markedly pro-
Run
1
2
3
4
5
moted the cyclization. Presumably, PEG-400 stabilizes
b
Yield (%)
89
90
90
89
88
the transition state for the reaction more than did CH CN
3
1
1
a
All reactions were carried out on a 1.0 mmol reaction scale of 2-fluoro
and DMF resulting in an increase in the reaction rate.
benzaldehyde (1a), 2-amino phenol (1.1 mmol), K
recycled PEG-400 at 100 °C.
2
CO
3
(1.0 mmol) in
The series of reactions was performed to investigate the
effect of concentration of solvent on the reactivity. The
reaction with 0.5 g of PEG-400 provided 86% of 2a after
b
Isolated yield.
1
4 h whereas 1.0 g of PEG-400 gave 88% of 2a after 10 h
(
entries 5 and 6). We also carried out the same reaction
Table 3
a
Synthesis of dibenz[b,f]-1,4-oxazepine in various poly(ethylene glycols)
in sonicator at room temperature but the reaction
remained incomplete with 90% of imine 2b (entry 8).
Entries 9 and 10 clearly indicate the temperature effect on
the synthesis of 2a. The use of PEG-400 as a catalyst
showed slow reactivity with 60% of 2a and 24% of unre-
acted imine 2b after 24 h (entry 11) whereas the very com-
mon but expensive phase transfer catalysts like 18-crown-6
and tetra-n-butylammonium bromide (TBABr) showed
similar reactivity (entries 12 and 13). We also performed
the reactions with ionic liquid as a catalyst (entries 14
and 15). Further, we conducted the reactions with 2-
chloro- and 2-bromo benzaldehyde as two other substrates.
In the case of chloro substrate, we observed slow reactivity
b
Entry
Promoter (g)
CH
3
CN (mL)
Yield (%)
2a
2b
1
2
3
4
5
6
7
a
PEG-200 (2.0)
PEG-300 (2.0)
PEG-1000 (2.0)
PEG-2000 (1.0)
PEG-8000 (0.5)
PEG-10000 (0.5)
PEG-20000 (0.5)
—
—
—
1.0
1.5
1.5
1.5
88
87
88
67
65
68
65
—
—
—
18
20
20
22
All reactions were carried out on a 1.0 mmol reaction scale of 2-fluoro
benzaldehyde (1a) and 1.1 mmol of 2-amino phenol in the presence of
1.0 mmol of K CO at 100 °C for over 12 h.
2
3
b
Isolated yield.

Y. R. Jorapur et al. / Tetrahedron Letters 49 (2008) 1495–1497
1497
Table 4
Synthesis in Water; Blackie Academic & Professional: London, 1998;
(c) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; Wiley:
New York, NY, 1997; p 199; (d) Leadbeater, N. E.; Marco, M. Org.
Lett. 2002, 417, 2973–2976.
Synthesis of dibenz[b,f]-1,4-oxazepine in polyethylene glycol-400 and
various cosolvents
a
b
Entry
Cosolvent (mL)
Yield (%)
4
5
. (a) Kamalakar, G.; Komura, K.; Sugi, Y. Ind. Eng. Chem. Res. 2006,
2
a
4
5, 6118–6126; (b) Weingaertner, H.; Franck, E. U. Angew. Chem.,
1
2
3
4
5
6
a
EtOH (1.0)
DMF (1.0)
C H (1.0)
6 6
THF (1.0)
Ethylene glycol (1.0)
Ethylene glycol dimethylether (1.0)
89
88
89
89
89
88
Int. Ed. 2005, 44, 2672–2692.
. For recent reviews on ionic liquids, see: (a) Sheldon, R. Chem.
Commun. 2001, 2399–2407; (b) Zhao, H.; Malhotra, S. V. Aldrichim.
Acta 2002, 35, 75–83; (c) Wasserscheid, P.; Keim, W. Angew. Chem.,
Int. Ed. 2000, 39, 3772–3789; (d) Welton, T. Chem. Rev 1999, 99,
2
2
071–2083; (e) Jorapur, Y. R.; Chi, D. Y. Bull. Korean Chem. Soc.
006, 27, 345–354.
All reactions were carried out on a 1.0 mmol reaction scale of 2-fluoro
6
7
. (a) Kitazume, T. ACS Symposium Series 819; American Chemical
Society: Washington, DC, 2002; pp 50–63; (b) Yoshida, A.; Hao, X.;
Nishikido, J. Green Chem. 2003, 5, 554–557.
benzaldehyde (1a), 1.1 mmol of 2-amino phenol and 1.0 mmol of K
in PEG-400 (1.0 g) and cosolvent (1.0 mL) at 100 °C over 10 h.
2 3
CO
b
Isolated yield.
. Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D. Green Chem.
2
005, 7, 64–82.
In entry 2, polar aprotic solvent like DMF was used as a
cosolvent which provided 88% of 2a. When benzene and
THF were used as a cosolvent we observed the same kind
of behavior with 89% of 2a (entries 3 and 4). The monomer
of PEG as a cosolvent also provided high yield of 2a (entry
8. (a) Samet, A. V.; Marshalkin, V. N.; Kislyi, K. A.; Chernysheva, N.
B.; Strelenko, Y. A.; Semenov, V. V. J. Org. Chem. 2005, 70, 9371–
9
376; (b) McKenzie, T. C. J. Heterocycl. Chem. 1980, 17, 657–659; (c)
Wardrop, A. W. H.; Sainsbury, G. L.; Harrison, J. M.; Inch, T. D. J.
Chem. Soc., Perkin Trans. 1 1976, 12, 1279–1285; (d) Higginbottom,
R.; Suschitzky, H. J. Chem. Soc. 1962, 2367–2370.
5
). Ethylene glycol dimethylether was also found to be a
9. (a) Allaway, C. L.; Daly, M.; Nieuwenhuyzen, M.; Saunders, G. C. J.
Fluorine Chem. 2002, 115, 91–99; (b) Petrenko, N. I.; Kozlova, M. M.;
Gerasimova, T. N. J. Fluorine Chem. 1987, 36, 93–98.
good cosolvent which provided 88% of 2a (entry 6). In
the case of entry 1 where PEG and ethanol was used as a
mixture solvent system, 89% of 2a was obtained.
1
0. Typical experimental procedure: To the argon purged glass vial 2-
amino phenol (112.3 mg, 1.1 mmol) in polyethylene glycol (400 MW,
In conclusion, a simple, efficient, and environmentally
benign methodology towards the synthesis of oxazepine
has been reported. Here PEG not only acts as a phase
transfer catalyst but also as a clean solvent by significantly
enhancing the intramolecular cyclization. Our protocol is a
practical approach which uses PEG as a readily commer-
cially available non-ionic liquid solvent with low cost and
recyclable property. Moreover, the workup procedure is
simple and convenient without any major equipment. Fur-
ther studies to develop new clean methodology towards the
synthesis of biologically active compounds are in progress.
2
.0 mL) were added potassium carbonate (138.2 mg, 1.0 mmol) and 2-
fluoro benzaldehyde (124.1 mg, 1.0 mmol) and stirred at 100 °C for
the appropriate time (see Table 1) during which the reaction was
monitored by means of Thin Layer Chromatography. The reaction
mixture was extracted with ether (3 Â 6 mL). The combined ether
layers were washed with water, brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. Subsequent column
chromatography over silica gel gave product 2a. Dibenz[b,f]-1,4-
1
oxazepine: Yellow crystalline solid; mp 72.0–72.5 °C; H NMR
(
1
1
200 MHz, CDCl
3
) d 7.13–7.28 (m, 6H), 7.36–7.49 (m, 2H), 8.56 (s,
H); C NMR (100 MHz, CDCl ) d 121.0, 121.7, 125.4, 126.0, 127.5,
29.2, 129.5, 130.5, 133.8, 140.6, 153.0, 160.8, 160.9; MS (EI) 195
1
3
3
+
(
M , 100). Anal. Calcd: C, 79.98; H, 4.65; N, 7.17. Found: C, 79.75;
H, 4.58; N, 7.23; Registry No. 257-07-8. Poly(ethylene glycol)
recycling procedure: To the recovered crude PEG (ꢁ2.0 mL) was
added distilled ethanol (10 mL) and passed through a very short pad
of silica gel and activated charcoal. The colorless organic layer was
evaporated under reduced pressure. PEG was further dried under
high vacuum over night and used for the next run.
References and notes
1. (a) Lankey, R. L.; Anastas, P. T. Ind. Eng. Chem. Res. 2002, 41, 4498–
4502; (b) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press, 1998; (c) Tucker, J. L. Org. Process
Res. Dev. 2006, 10, 315–319.
1
1. (a) Wang, M. L.; Chang, K. R. Can. J. Chem. Eng. 1991, 69, 340–346;
(
b) Wei, T. B.; Chen, J. C.; Wang, X. C.; Zhang, Y. M.; Wang, L. L.
2
3
. US EPA Green Chemistry web site. http://www.epa.gov/opptintr/
greenchemistry/ (accessed July 2001).
. (a) Anastas, P. T. ACS Symposium Series 819; American Chemical
Society: Washington, DC, 2002; p 1; (b) Greico, P. A. Organic
Synth. Commun. 1996, 26, 1447–1454; (c) Davidson, R. S.; Patel, A.
M.; Safdar, A.; Thornthwaite, D. Tetrahedron Lett. 1983, 24, 5907–
5
910.