Polyethylene glycol (PEG) mediated expeditious synthetic

route to 1,3-oxazine derivatives

Pravin V. Shinde, Amol H. Kategaonkar, Bapurao B. Shingate, Murlidhar S. Shingare
*
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, Maharashtra, India
Received 8 November 2010
Available online 18 May 2011
Abstract
Various 1,3-oxazine derivatives were synthesized in high yields, within shorter reaction times using PEG-400 as a safer medium/
mediator. This synthetic route is exceedingly easy and avoids the use of acid/base catalysts.
# 2011 Murlidhar S. Shingare. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Ecofriendly synthetic protocol; Green chemistry; 1,3-Oxazines; Polyethylene glycol (PEG)
In the recent years, there has been a growing demand for the development of more sustainable chemistry,
particularly in the synthesis of value added materials, in order to minimize the great amounts of waste and consecutive
treatment [1,2]. One of the key principles of green chemistry is the elimination of solvents in chemical processes or the
replacement of volatile/hazardous solvents with environmentally benign solvents [3]. In performing the majority of
organic transformations, solvents play a critical role in making the reaction homogeneous and allowing molecular
interactions to be more efcient [4].
In this connection, polyethylene glycol (PEG) is attracting much attention of organic chemists due to their
inexpensive and eco-friendly nature, high thermal stability, ease of workup, and the ability to act as phase transfer
catalysts. Furthermore, PEG and its monomethylethers have a low vapor pressure, are nonammable, non-
volatile, recyclable, and are available in high quantities at low prices. The application of PEG as a reaction
medium is highly benecial as the system remains neutral, which helps in maintaining a wide variety of functional
groups unchanged that are either acid or base susceptible [25]. For these reasons, PEG is considered to be an
environmentally benign surrogate to volatile organic solvents and a highly practical medium for the synthesis of
biodynamic heterocycles [69].
1,3-Oxazine ring system is a core structure present in a number of biodynamic heterocycles. They are pivotal
intermediate for the synthesis of medicinally active molecules [10]. Increasing interest towards the synthesis of 1,3-
oxazine derivatives is mainly due to their potential biological and pharmacological activities such as analgesic [11],
antitubercular [12], anticancer [13], anti-HIV [14], antihypertensive [15], antithromobotic [16], and antiulcer [17]. In
addition, naphthoxine derivatives possess therapeutic potential for the treatment of Parkinsons disease [18].
Moreover, certain kinds of 1,3-oxazines are of interest as photochromic compounds [19].
www.elsevier.com/locate/cclet
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Chinese Chemical Letters 22 (2011) 915918
* Corresponding author.
E-mail address: prof_msshingare@rediffmail.com (M.S. Shingare).
1001-8417/$ see front matter # 2011 Murlidhar S. Shingare. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.01.011
The Mannich reaction involving phenol, formaldehyde and primary amines is the best method available for the
synthesis of 1,3-oxazines. Several methods involving the use of different catalysts [20] have been developed with their
own merits and demerits. Considering the above discussed signicance of PEG and 1,3-oxazine compounds, and in
continuation of our endeavor towards the development of ecofriendly synthetic protocols [21], it was thought
worthwhile to develop a new, simple, greener, and expeditious synthetic route to 1,3-oxazine derivatives.
1. Experimental
Melting points were determined on a Veego apparatus and are uncorrected. Infrared spectra were recorded on a
Bruker spectrophotometer in a KBr disc, and the absorption bands are expressed in cm
1
.
1
H NMR and
13
C NMR
spectra were recorded on NMR spectrometer AC200 in DMSO-d
6
, chemical shifts (d) are in (parts per million) ppm
relative to TMS. Mass spectra were taken on a macro-mass spectrometer (waters) by electro-spray (ES) method.
Typical experimental procedure for synthesis of compound (4a): a-Naphthol 1 (1 mmol), formaldehyde 2
(2.2 mmol) and aniline 3a (1 mmol) were mixed in a dry round-bottomed ask (25 mL), to which PEG-400 (0.3 mL)
was added and reaction mixture was allowed to stir vigorously. Progress of the reaction was monitored by TLC. After
completion of the reaction, water (5 mL) was added to the reaction mass and obtained solid was ltered out and
washed with water. Thus obtained crude product was recrystallized from aqueous ethanol to afford the pure product
(4a).
3,4-Dihydro-3-phenyl-2H-naphtho[2,1-e][1,3]oxazine (4a): IR (KBr, cm
1
): v 1027, 1219;
1
H NMR (DMSO-d
6
,
200 MHz): d 4.73 (s, 2H, ArCH
2
N), 5.50 (s, 2H, OCH
2
N), 6.897.58 (m, 11H, ArH);
13
CNMR(DMSO-d
6
,
50 MHz): d 48.9, 79.6, 112.2, 115.7, 117.0, 120.1, 120.7, 124.5, 125.9, 126.2, 126.8, 127.6, 129.5, 133.4, 147.7, 149.0;
ES-MS: 262.18 (M
+
).
3,4-Dihydro-3-o-tolyl-2H-naphtho[2,1-e][1,3]oxazine (4b): IR (KBr, cm
1
): v 1033, 1237;
1
H NMR (DMSO-d
6
,
200 MHz): d 2.24 (q, 3H, CH
3
), 4.86 (s, 2H, ArCH
2
N), 5.77 (s, 2H, OCH
2
N), 6.847.61 (m, 10H, ArH);
13
C
NMR (DMSO-d
6
, 50 MHz): d 19.9, 50.6, 78.6, 113.7, 116.4, 117.1, 119.5, 120.8, 125.1, 125.8, 126.1, 126.8, 127.9,
129.7, 130.4, 147.0, 147.4, 149.5, 150.8; ES-MS: 276.31 (M
+
).
3,4-Dihydro-3-p-tolyl-2H-naphtho[2,1-e][1,3]oxazine (4c): IR (KBr, cm
1
): v 1025, 1238;
1
H NMR (DMSO-d
6
,
200 MHz): d 2.37 (s, 3H, CH
3
), 4.94 (s, 2H, ArCH
2
N), 5.67 (s, 2H, OCH
2
N), 6.907.82 (m, 10H, ArH);
13
C
NMR (DMSO-d
6
, 50 MHz): d 21.5, 49.1, 79.3, 110.7, 115.4, 117.8, 119.1, 120.1, 124.9, 125.5, 126.0, 126.6, 127.4,
129.2, 132.0, 148.3, 148.2; ES-MS: 276.24 (M
+
).
2. Results and discussion
For our initial study, one-pot three-component reaction of a-naphthol, formaldehyde and aniline was considered as
a standard model reaction (Scheme 1). To effect the model reaction, various attempts were made using polyethylene
glycol (PEG) 400 in different amounts (Table 1, entry 2) and best result was achieved when 0.3 mL of PEG 400 was
employed for 1 mmol of aniline (Table 1, entry 2). Using more than 0.3 mL of PEG 400 did not improve the yield of
the product, and at the same time, no reaction took place in the absence of PEG 400 (Table 1, entry 1). Thus, the use of
PEG found to be absolutely essential for the reaction.
In subsequent optimization studies, PEG was used in combination with various solvent systems (Table 1, entries 3
7). However, use of solvents for the reaction failed to improve the product yield and rate of the reaction. Rather,
solvent-free conditions worked well for the reaction. Since, only 0.3 mL of PEG 400 is used it cannot act as a solvent,
but it plays the role of promoter for the reaction without need of any additional catalyst.
P.V. Shinde et al. / Chinese Chemical Letters 22 (2011) 915918 916

OH
HCHO
N O
Ph
NH Ph
2
PEG-400
2 1 3a
4a
OH
NH Ph
2
O
N
Ph
HCHO
PEG-400
2 5 3a 6a
Scheme 1.
In further set of experiments, optimized reaction condition was applied for the synthesis of another 1,3-oxazine
derivative replacing a-naphthol with b-naphthol (Scheme 1). In this experiment, reaction of b-naphthol, aniline and
formaldehyde was subjected to optimized reaction conditions and reaction was observed to proceed smoothly in
agreement with the reaction of a-naphthol.
This success of PEG 400 could be attributed to the following facts: (i) PEG possess two active sites viz. free
hydroxyl groups and ethereal oxygen linkages. (ii) These hydroxyl groups, via hydrogen bonding with carbonyl
oxygen of formaldehyde increases its electrophilic character, whereas, ethereal oxygen linkages assists in enhancing
the nucleophilicity of amines and naphthols. (iii) Consequently, the chemical reactivity of the reactants considerably
increases, which results in signicant rate acceleration of chemical reaction leading to the formation of desired product
within short reaction times, avoiding undesirable side products.
P.V. Shinde et al. / Chinese Chemical Letters 22 (2011) 915918 917
Table 1
Screening of reaction medium.
a
Entry PEG 400 (mL) Solvent (mL) Time (min) Yield
b
(%)
1 30 Trace
2
c
0.1, 0.2, 0.3, 0.5, 1.0 20, 10, 5, 5,5 77, 78, 91, 87, 88
3 0.3 Water (5) 30 59
4 0.3 Ethanol (5) 30 67
5 0.3 DMF (5) 30 38
6 0.3 THF (5) 30 45
7 0.3 CH
3
CN (5) 30 62
a
Reaction conditions: 1 (1 mmol), 2 (2.2 mmol), 3a (1 mmol).
b
Isolated yields.
c
Consider respective time and yield.
Table 2
Synthesis of 1,3-oxazine derivatives.
a

OH
OH
NH
2
O
N
R
N O
2 CH
2
O
PEG-400
1
5
PEG-400
2 3
4a-h
6a-j
R
R
.
Product code R Compound 4ah Compound 6aj
Time (min) Yield
b
(%) M.P.
c
(8C) Time (min) Yield
b
(%) M.P.
c
(8C)
a H 5 91 6365 5 89 5052
b 2-Me 5 89 8788 10 90 5557
c 4-Me 10 86 193195 10 85 9091
d 3-OMe 15 91 278 (d) 15 88 6566
e 4-OMe 10 88 301 (d) 10 85 7980
f 2-OEt 10 85 202 (d) 15 87 102104
g 4-OEt 10 87 7880 10 84 6869
h 4-F 5 92 117118 10 91 134135
i 2-NO
2
# # # 15 85 113115
j 4-NO
2
# # # 15 86 166168
# reaction was not performed.
a
Reaction conditions: 1 or 5 (1 mmol), 2 (2.2 mmol), 3 (1 mmol) and PEG-400 (0.3 mL).
b
Isolated yields.
c
Melting points match with literature [20].
To further establish the scope of optimized reaction conditions and in order to generalize the synthetic procedure,
variety of electronically divergent aromatic amines were treated with a-naphthol as well as b-naphthol and
formaldehyde solution, and all these substrates were found to be equally amenable to these conditions affording good
to excellent yields (see the supporting information). Notably, liquid amines underwent the reaction rapidly in
comparison with solid amines. Representative results are summarized in Table 2. Structures of the products were
conrmed on the basis of IR,
1
H NMR,
13
C NMR and mass spectroscopic data.
3. Conclusions
In summary, we have developed an exceedingly simple, mild, clean and expeditious synthetic protocol for 1,3-
oxazine derivatives. Remarkable advantages of this synthetic strategy over the others are (i) high yields, (ii) no need of
acid/base catalyst and solvent, (iii) decreased reaction times, (iv) simplied work-up procedure, and (v) ambient
reaction temperature.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/
j.cclet.2011.01.011.
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