Effect of aqueous polyethylene glycol on 1,3-dipolar cycloaddition of benzoylnitromethane/ethyl 2-nitroacetate with dipolarophiles: Green synthesis of isoxazoles and isoxazolines

Article abstract of DOI:10.1002/adsc.201300712

A 1:1 mixture of water-polyethylene glycol (PEG) facilitated the 1,3-dipolar cycloaddition of benzoylnitromethane/ethyl 2-nitroacetate with terminal alkynes or alkenes leading to isoxazoles or isoxazolines under green conditions. The methodology is free f

Full text of DOI:10.1002/adsc.201300712

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DOI: 10.1002/adsc.201300712
Effect of Aqueous Polyethylene Glycol on 1,3-Dipolar
Cycloaddition of Benzoylnitromethane/Ethyl 2-Nitroacetate with
Dipolarophiles: Green Synthesis of Isoxazoles and Isoxazolines
R. Gangadhara Chary,a,b G. Rajeshwar Reddy,a Y. S. S. Ganesh,a K. Vara Prasad,a
Akula Raghunadh,a T. Krishna,a Soumita Mukherjee,c and Manojit Palc,*
a
Custom Pharmaceutical Services, Dr. Reddyꢀs Laboratories Limited, Bollaram Road Miyapur, Hyderabad 500049, India
JNT University, Kukatpally, Hyderabad 500085, Andhra Pradesh, India
Dr. Reddyꢀs Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India
b
c
E-mail: manojitpal@rediffmail.com
Received: August 8, 2013; Revised: October 3, 2013; Published online: January 13, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300712.
Abstract: A 1:1 mixture of water-polyethylene
glycol (PEG) facilitated the 1,3-dipolar cycloaddi-
tion of benzoylnitromethane/ethyl 2-nitroacetate
with terminal alkynes or alkenes leading to isoxa-
zoles or isoxazolines under green conditions. The
methodology is free from the use of any base, cata-
lyst, dehydrating agent or hazardous solvent.
chloride (DMTMM).[14] The tertiary diamine (e.g.,
DABCO or TMEDA)-promoted, thermodynamically
favoured dehydration of primary nitro compounds
has also been reported by De Sarloa and Machetti
et al.[15,16] The problem of the facile decomposition of
the activated nitro compounds in the presence of
water (generated in situ) and base was overcome by
using a catalytic base.[17] In 2008, the same group re-
ported the Cu/NMP-catalysed synthesis of 4,5-dihy-
droisoxazoles that avoided the use of anhydrous and
inert atmospheres.[18] Later, Itoh et al. reported silica
gel-supported polyphosphoric acid (PPA/SiO2) as a re-
usable acid catalyst for the synthesis of 3-benzoylisox-
azoles via the reaction of benzoylnitromethane with
Keywords: cycloaddition; isoxazoles; isoxazolines;
PEG; polyethylene glycol; water
The development of economic and eco-friendly meth- alkynes (dipolarophiles).[19] Despite being effective
odologies that are free from the use of any catalyst, and efficient, many of these methods are either not
reagent, promoter or surfactant and are performed in economic or not eco-friendly. This and our continuing
aqueous media are the central focus of green and sus- interest in greener approaches[20] towards various het-
tainable chemistry. Accordingly, we have devoted our erocyclic structures[21] prompted us to develop an al-
efforts towards the construction of isoxazole and iso- ternative and catalyst-, reagent-, promoter- or surfac-
xazoline rings under clean reaction conditions.
tant-free synthesis of isoxazoles and isoxazolines. We
Isoxazoles are of considerable interest because of now report the 1,3-dipolar cycloaddition of benzoylni-
their versatile pharmacological properties.[1] They are tromethane/ethyl 2-nitroacetate (1) with dipolaro-
also key building blocks for various complex mole- philes (2/3) in 1:1 H2O:PEG 400 affording isoxazoles
cules both in organic syntheses[2] and materials sci- (4) and isoxazolines (5) (Scheme 1).
ence.[3] Various methods have been reported for the
Initially, the reaction of benzoylnitromethane (1a)
synthesis of isoxazoles[4–8] including 1,3-dipolar cyclo- and phenylacetylene (2a) was examined in acetoni-
additions where the primary nitro compounds (used trile under reflux when no product was formed even
as precursors of 1,3-dipoles) on cycloaddition with after 20 h (entry 1, Table 1). Similar results were ob-
various dipolarophiles afforded isoxazoles and isoxa- tained in 1,4-dioxane (entry 2, Table 1), DMF
zolines. Indeed, the activated nitro compounds after (entry 3, Table 1) or DMSO (entry 4, Table 1). We
dehydration under acidic[9] or acylating conditions[10] then used PEG 400 (entry 5, Table 1) whereupon the
or on severe heating[11] formed cycloadducts with di- desired isoxazole 4a was isolated in 30% yield after
polarophiles. These reactions can also be performed 12 h. Notably, the reaction did not proceed in water
under milder conditions in the presence of ceric am- (entry 6, Table 1) perhaps due to the poor solubility
monium nitrate (CAN),[12] Boc2O[13] or 4-(4,6- of the reactants in water. We then used a range of
dimethoxy
G
aqueous media, for example, water/1,4-dioxane
160
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Effect of Aqueous Polyethylene Glycol on 1,3-Dipolar Cycloaddition
of Table 1 (i.e., heating at 908C in 1:1 water/PEG)
were found to be optimum and used for further study.
To examine the generality and scope of this meth-
odology various alkynes (2) as well as alkenes (3)
were employed as dipolarophiles (Table 2). The reac-
tion proceeded well with both aromatic (entries 1, 2,
3, 6, 7 and 9, Table 2) and aliphatic (entries 4, 5, 8, 10,
11, 12 and 13, Table 2) alkynes affording isoxazoles
(4) in good yields. Isoxazoline derivatives (5) were ob-
tained in moderate to good yields when alkenes (en-
tries 14, 15, 16 and 17, Table 2) were used. We then
examined the use of ethyl 2-nitroacetate (1b), 1-(4-
Scheme 1. Synthesis of isoxazole and isoxazoline derivatives.
Table 1. Optimization of the reaction conditions.[a]
chlorophenyl)-2-nitroethanone
(1c)
and
1-(4-
Table 2. Synthesis of isoxazoles (4a–m) and isoxazolines
(5a–d).[a]
Entry
Solvent
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
MeCN
1,4-dioxane
DMF
DMSO
PEG 400
H2O
H2O/1,4-dioxane (1:1)
H2O/MeCN (1:1)
H2O/DMF (1:1)
H2O/DMSO (1:1)
H2O/PEG-400 (1:1)
H2O/PEG-400 (1:1)
H2O/PEG-400 (1:1)
H2O/EG[c] (1:1)
EG[c]
20
24
20
20
12
48
12
12
12
12
4
0
0
0
0
30
0
0
0
0
Entry Terminal alkyne/alkene Products Time Yield[b]
(2/3, R=)
[h]
[%]
1
2
Ph
2a 4a
2b 4b
6
6
88
83
9
3
2c 4c
5
80
10
11
12
13
14
15
0
4
5
-(CH2)4CH3
-(CH2)5CH3
2d 4d
2e 4e
5
5
82
83
80
88
82
70
35
6
12
6
6
7
2f 4f
6
5
77
73
6
2g 4g
[a]
Reactions were carried out using 1a (1.0 mmol), phenyl-
acetylene (2a) (1.0 mmol) and solvent (5 mL) at 908C.
Isolated yield.
8
9
2h 4h
2i 4i
5
6
85
93
ACHTUNGTRENNUNG
[b]
[c]
EG=ethylene glycol.
10
11
12
-(CH2)4OH
-(CH2)3Cl
-CH2OH
2j 4j
2k 4k
2l 4l
5
5
5
82
79
80
(entry 7,
Table 1),
water/acetonitrile
(entry 8,
Table 1), water/DMF (entry 9, Table 1), water/DMSO
(entry 10, Table 1) and water/PEG (entry 11, Table 1).
However, the desired product 4a was only obtained
when a 1:1 mixture of water-PEG 400 was used. An
increase in reaction time from 4 h to 6 h (entry 12,
Table 1) or 12 h (entry 13, Table 1) did not improve
the product yield significantly. Moreover, an attempt
to perform the reaction at room temperature was not
successful. To understand the role of the diol moiety
of PEG 400, the same reaction was performed in
water/ethylene glycol (1:1) whereby 4a was obtained
in 70% yield after 6 h (entry 14, Table 1). On the
other hand, 4a was isolated in only 35% yield when
the reaction was performed in pure ethylene glycol
(entry 15, Table 1). Overall, the conditions of entry 11
13
14
15
2m 4m
3a 5a
3b 5b
6
6
5
71
46
93
Ph
16
3c 5c
3d 5d
5
5
82
80
17
[a]
Reactions were carried out using 1a (1.0 mmol) and 2 or
3 (1.0 mmol) in 1:1 H2O-PEG-400 (5 mL) at 908C.
Isolated yield.
[b]
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R. Gangadhara Chary et al.
Table 3. Synthesis of isoxazoles (4n–s) and isoxazolines (5e–g).[a]
Entry
Z= (1)
Terminal alkyne/alkene (2/3, R=)
Products
Time [h]
Yield[b] [%]
1
2
EtO (1b)
(1b)
Ph
2a
2b
4n
4o
6
6
80
86
3
4
(1b)
(1b)
2c
2g
4p
4q
5
5
84
91
5
6
7
p-ClC6H4 (1c)
p-MeOC6H4 (1d)
(1b)
2a
2a
3a
4r
4s
5e
6
6
6
77
74
51
Ph
8
(1b)
(1b)
3b
3d
5f
5g
5
5
81
77
9
[a]
Reactions were carried out using 1b–d (1.0 mmol) and 2 or 3 (1.0 mmol) in 1:1 H2O-PEG-400 (5 mL) at 908C.
Isolated yield.
[b]
methoxyACHTUNGTRENNUNGphenyl)-2-nitroethanone (1d) separately in
place of 1a (Table 3). Once again the reaction pro-
ceeded smoothly affording the corresponding prod-
ucts (e.g., 4n–s and 5e–g) in good yields. The recycla-
bility of water-PEG mixture was examined by recov-
ering (during work-up, see the Experimental Section)
and reusing the solvent mixture twice in the reaction
of 1a with 2a when 4a was obtained in 83% and 80%
yields after first and second cycle, respectively. All
the compounds 4 and 5 synthesized were well charac-
terized by NMR, IR, MS and HR-MS spectral data.
À
The =CH moiety of the isoxazole ring appeared at
d=6.5–7.0 (singlet) and d=99–100 ppm in the H and
1
Scheme 2. Structural elaboration of 4i via Suzuki coupling.
13C NMR spectra, respectively. The benzoyl/ester car-
bonyl appeared at d=185.8/171.5 ppm in the
13C NMR and at 1662/1725 cmÀ1 in the IR spectra. tween 1 and PEG-H2O was tautomerized to E-II that
À
À
Similarly, the CH2 moiety of the isoxazoline ring underwent 1,3-dipolar cycloaddition with 2 or 3 (path
appeared as a double doublet near d=3.63 and 3.55 a, Scheme 3) to form E-III, which on elimination of
1
13
À
( H NMR) and d=37–38 ppm ( C NMR) while the
water and PEG afforded the product 4 or 5. While
À
CH moiety appeared at d=5.10 (double doublet, the formation of 4/5 via generation of nitrile oxide 8
1H NMR) and 79-84 ppm (13C NMR). To expand the (path b, Scheme 3) followed by its cycloaddition with
scope of the present methodology, further the struc- 2/3 cannot be ruled out, the dimerization of 8 to
tural elaboration of a representative isoxazole 4i was furoxan 9 (in absence or presence of dipolarophiles)
performed via Suzuki coupling with the boronic acid was often found to be a side reaction in such
6 (Scheme 2).
a case.[15,20] Since the formation of 9 was not detect-
Based on the fact that PEG/H2O played a key role ed[24] in the present case the reaction perhaps did
in the present reaction (Table 1) a plausible mecha- follow the path a.
nism[7,22] involving the activation of the nitro group
In conclusion, the present research demonstrates
aided by PEG/H2O is shown in Scheme 3. Thus a che- the first use of aqueous PEG-400 in facilitating the
late type of complex E-I, formed via H-bonding[23] be- 1,3-dipolar cycloaddition of benzoylnitromethane/
162
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Effect of Aqueous Polyethylene Glycol on 1,3-Dipolar Cycloaddition
Scheme 3. Proposed reaction mechanism.
ethyl 2-nitroacetate with terminal alkynes or alkenes
leading to isoxazoles or isoxazolines under green con-
ditions. The methodology is free from the use of any
base, catalyst, dehydrating agent or hazardous solvent
and is amenable for the synthesis of complex mole-
cules.
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