SNAr reaction of 2,5-dinitrofuran: A mild and efficient method for the preparation of 2-aryloxy-5-nitrofuran

Article abstract of DOI:10.1002/jhet.537

2,5-Dinitrofuran which can be easily prepared by nitration of 2-nitrofuran, on phase transfer catalysed S_NAr reaction with phenol gave good yield of 2-aryloxy-5-nitrofuran.

Full text of DOI:10.1002/jhet.537

458
SNAr Reaction of 2,5-Dinitrofuran: A Mild and Efficient Method
for the Preparation of 2-Aryloxy-5-nitrofuran
Vol 48
Sandip Gavade, Kamlesh Padiya, Swapnil Bajare, Ravi Balaskar,
and Dhananjay Mane*
Organic Research Laboratory, S.C.S. College, Omerga-413 606, Maharashtra, India
*E-mail: dr_dvmane@rediffmail.com
Received November 23, 2009
DOI 10.1002/jhet.537
Published online 10 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
2,5-Dinitrofuran which can be easily prepared by nitration of 2-nitrofuran, on phase transfer catalysed
SNAr reaction with phenol gave good yield of 2-aryloxy-5-nitrofuran.
J. Heterocyclic Chem., 48, 458 (2011).
INTRODUCTION
sulphonates, thiophenolates, and amines [23]. However,
there is no report of reaction of 2,5-dinitrofuran with
phenol.
Oxygen-containing heterocycle namely furans are im-
portant constituents of a variety of important classes of
pharmacologically active compounds. These compounds
are known to exhibit different activities, such as lipo-
genes inhibitors [1], antiarrhythmics [2], potassium
channel blockers [3], antimicrobials such as antimalar-
ials [4], EGFR (HER-1, erbB 1) inhibitors [5], cyclo-
genes-2 inhibitors [6], protein tyrosin kinase inhibitors
[7], anaesthetics [8], 5-HT1D receptor antagonists [9],
and nonsteroidal antiinflammatory drugs [10].
RESULTS AND DISCUSSION
2,5-Dinitrofuran can be readily prepared from 2-nitro-
furan by treatment of conc. HNO3 [23]. 2,5-Dinitrofuran
can under go SNAr substitution reaction to yield 2-sub-
stituted-5-nitrofuran. The SNAr substitution in case of 5-
nitro-2-furancarbaldehyde [11] and 5-nitro-2-furancar-
boxylate [16,17] is reported to give good yield with
NaH in DMSO. The same method when used for the
preparation of 2-substituted-5-nitrofuran from 2,5-dini-
trofuran, it gave a very poor yield of desired product.
We have carried out a series of reactions with different
base and solvent combinations to optimize the reaction
conditions (Scheme 1). The results are shown in Table 1.
It was found that high temperature or strong base
resulted in poor yield of desired product. Instability of
dinitrofuran could possibly be the reason for poor yield
as the unreacted nitro compound could not be isolated
from the reaction mixture. This reaction thus demands a
mild condition. It was observed that reaction goes
smoothly in biphasic system (entry 9; Table1), and the
rate of reaction accelerates by addition of Phase transfer
Catalyst 18Crown6 (entry 10; Table 1).
Initial attempt to react phenol with 2-chloro-5-nitro-
furan under different neutral, basic, and phase transfer
catalyst condition were unsuccessful. Starting material
could not be isolated, which indicates 2-chloro-5-nitro-
furan is unstable. In this communication, we report the
mild and efficient phase transfer catalyzed SNAr reaction
of 2,5-dinitrofuran with phenols. The nucleophilic sub-
stitution of nitro group in furan derivatives like 5-nitro-
2-furancarbaldehyde, with different nucleophiles like
phenoxide [11], alkoxide [12], hydrogen halide [13], az-
ide, arylmercaptides, benzenesulfinate [14], have been
reported. The similar reactions with other furan deriva-
tives like 5-nitro-2-furancarboxylate [15–17], 5-nitro fur-
furylnitrate [18], and 5-nitro-2-furfurylidenemalononi-
trile [19], since the 2-nitrofuran derivative is available
easily than corresponding 2-halofuran analogs, the for-
mer becomes the synthetic equivalent of choice 2-furyl
synthon. To overcome this problem we have used 2,5-
dinitrofuran as comparatively more stable alternative to
2-chloro-5-nitrofuran. Only a few examples have been
reported literature for nucleoplilic substitution of 2,5-
dinitrofuran [20–22], The nulceophiles used in majority
of these reports are soft carbon nucleophiles like anions
derived from ethyl acetate or diethyl malonate, benzene-
Effect of type of catalyst on condensation of 3-
hydroxyquinoline and 2,5-dinitrofuran was then studied
using different phase transfer catalysts and conditions.
The results are shown in Table 2. It reveals that poly
ethylene glycol 600 (PEG 600), which is the most eco-
nomic, is also equally efficient to catalyze the reaction.
1
Kinetics of this reaction was studied by H NMR of the
reaction aliquots with 0, 0.1, 1, 2, and 5 mol % of PEG
C
V
2010 HeteroCorporation

March 2011
SNAr Reaction of 2,5-Dinitrofuran: A Mild and Efficient Method for the
Preparation of 2-Aryloxy-5-nitrofuran
459
Scheme 1
In Conclusion, A mild and efficient method for the
preparation of 2-aryloxy-5-nitrofuran is developed. It
provides the first example of phase transfer catalyzed
SNAr reaction of 2,5-dinitrofuran.
600. The results are shown in Figure 1. It appears from
the study that 1 mol % is the minimum requirement of
catalyst that gives 90% conversion in about 3 h.
The optimized condition of 1.0 mol % of PEG 600
was used for the reactions with different phenols.
(Scheme 2); the results are displayed in Table 3. Elec-
tron withdrawing substituents such as F, NO2, and Ph
groups facilitates the reaction allowing shorter reaction
times and yield was high (entry 3,4,5, and 11, Table 3).
Electron donating substituents OMe and Me groups
require comparatively longer time and low yield (entry
2,6, and 12, Table 3).
EXPERIMENTAL
2-Nitrofuran and 18crown6 were purchased from Aldrich.
Commercial solvents and reagents were used as received.
Flash column chromatography was performed over silica gel H
(100–200 or 200–300 mesh) using hexane/ethyl acetate. Melt-
ing points were recorded on a Buchi melting point apparatus
and are uncorrected. 1H and 13C NMR spectra were recorded
on either 300 MHz spectrometer. NMR chemical shifts were
reported in d (ppm) using the d 2.54 signal of DMSO (1H
NMR) and the d 39.94 signal of DMSO (13C NMR) as internal
standards. Mass spectra were recorded using either chemical
Table 1
Screening of reaction condition for the substitution of nitro from 2,5-dinitrofuran by ArAOH.
Sr. No.
1
ArAOH
Base
Solvent
DMF
Temp. ꢀC
RT
Catalyst
–
Yielda (%)
5
Cs2CO3
2
3
Cs2CO3
DMF
DMF
60
RT
RT
RT
60
–
6
3
K2CO3
–
4
TEA
CH3CN
DMAPb
0
5
–
DMF
KFc
0
6
–
–
DMF
–
0
7
CH2Cl2
RT
RT
RT
RT
–
0
8
–
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
–
0
9
K2CO3
K2CO3
–
33
89
10
18Crown6b
a The yields reported are after isolation and purification by the column chromatography.
b 0.1 mol %.
c 1.0 mmol.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

460
S. Gavade, K. Padiya, S. Bajare, R. Balaskar, and D. Mane
Vol 48
Table 2
Optimization of type and quantity of phase transfer catalyst for SNAr
reaction of 2,5-dinitrofuran with phenol in CH2Cl2:Water (1:1) at
room temperature.
Sr. No.
PTC
Mol % of PTC
Yielda (%)
1
2
3
4
5
6
18 Crown 6
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
1
90
98
99
98
89
83
5
2
1
0.1
0.01
a The yields reported are after isolation and purification by the column
chromatography.
ionization or electron impact ionization. Thin layer chromatog-
raphy was used to monitor reaction progress.
Figure 1. Effect of PTC concentration on kinetics of SNAr reaction of
2,5-dinitrofuran with phenol in CH2Cl2: water (1:1) at room
temperature.
Typical procedure for the synthesis of 2,5-
dinitrofuran. A mixture of 5.8 g (50 mmol) of 2-nitrofuran and
100 mL of conc. HNO3(70%) was heated to 60ꢀC for 4 h. Mix-
ture was then cool to room temperature diluted with 100 mL of
cold water and neutralized with Na2CO3 solution. Extracted with
CH2Cl2. Combined organic layer washed with brine and dried
over anhydrous Na2SO4. Recrystallisation from ethanol gave 4.0
g of 2,5-dinitrofuran as a yellow solid, mp 100ꢀC.
Typical procedure for the synthesis of compounds 1–14
using PEG 600. Mixture of 2,5-dinitrofuran (1.0 mmol), phe-
nol (1.0 mmol), and K2CO3 (1.0 mmol) was taken in 3.0 mL
mix of 1:1 dichloromethane (CH2Cl2) and water. PEG 600
(0.01 mmol) was then added and mixture was stirred at room
temperature till the good conversion was observed on TLC.
Organic layer separated. Aqueous layer washed with CH2Cl2.
Combined organic layer washed with water and then with
brine. Organic layer dried over anhydrous Na2SO4, evaporated
and purified by column chromatography.
3-[(5-Nitro-2-furyl)oxy]quinoline: (Table 1, entry 10). Yellow
solid, yield 89%; mp 167–170ꢀC. 1H NMR (DMSO-d6, 300
MHz) d: 6.30(1H, d, J ¼ 3.8 Hz, F H-4), 7.69(1H, m,),
7.81(1H, td, J ¼ 7.7, 1.5 Hz,), 7.85(1H, d, J ¼ 4.2 Hz, F H-
3), 8.02(1H, d, J ¼ 6.8 Hz,), 8.10(1H, d, J ¼ 8.7 Hz,),
8.41(1H, d, J ¼ 2.6 Hz,), 9.01(1H, d, J ¼ 2.6 Hz,); 13C NMR
(DMSO, 75 MHz) : d ¼ 157.8, 147.8, 145.9, 144, 129.9,
129.3, 128.5, 128.3, 123.2, 117.7, 93.6. HRMS (EI, m/e) calcd
for C13H8N2O4 (Mþ) 256.22, found 256.02.
2-Nitro-5-phenoxyfuran: (Table 2, entry 1). Brown solid,
yield 79%; mp 53–55ꢀC. 1H NMR (DMSO-d6, 300 MHz) d:
6.04(1H, d, J ¼ 3.8 Hz, F H-4), 7.35(3H, m, P H), 7.50(2H,
m, P H), 7.79(1H, d, J ¼ 3.8 Hz, F H-3). HRMS (EI, m/e)
calcd for C10H7NO4 (Mþ) 205.17, found 204.96.
13C NMR (DMSO, 75 MHz) : d ¼ 159.8, 177.7, 147.1, 120.8,
118,115.7, 91.3. HRMS (EI, m/e) calcd for C11H9NO5 (Mþ)
235.19, found 235.02.
2-(4-Fluorophenoxy)-5-nitrofuran: (Table 2, entry 3). Yellow
1
solid, yield 96%; mp 73–75ꢀC. H NMR (DMSO-d6, 300MHz)
d: 6.00(1H, d, J ¼ 3.8 Hz, F H-4), 7.35(2H, m, P H), 7.44(2H,
m, P H), 7.78(1H, d, J ¼ 3.8 Hz, F H-3); 13C NMR (DMSO,
75 MHz): d ¼ 161.3, 158.4, 158.1, 149.6, 149.5, 144.0, 121.1,
120.9, 117.5, 117.2, 116.9, 91.8. HRMS (EI, m/e) calcd for
C10H6FNO4 (Mþ) 223.16, found 223.02.
2-Nitro-5-(4-nitrophenoxy)furan: (Table 2, entry 4). Yellow
solid, yield 98%; mp 87–90ꢀC. 1H NMR (DMSO-d6, 300
MHz) d: 6.40(1H, d, J ¼ 4.2 Hz, F H-4), 7.59(2H, m, P H),
7.85(1H, d, J ¼ 4.2 Hz, F H-3), 8.35(2H, m, P H); 13C NMR
(DMSO, 75 MHz): d ¼ 163.9, 158.6, 155.3, 144.8, 144.7,
126.3, 126.1, 118.8, 116.7, 115.7, 95.2. HRMS (EI, m/e) calcd
for C10H6N2O6 (Mþ) 250.16, found 249.95.
2-(Biphenyl-4-yloxy)-5-nitrofuran: (Table 2, entry 5). Yellow
solid, yield 97%; mp 153–156ꢀC. 1H NMR (DMSO-d6, 300
MHz) d: 6.13(1H, d, J ¼ 4.2 Hz, F H-4), 7.45(5H, m, P H),
7.71(2H, m, P H), 7.78(3H, m, P H); 13C NMR (DMSO, 75
MHz) : d ¼ 158.3, 153.6, 139.3, 138.6, 129.4, 129.1, 128.1,
127.1, 119.5, 117.9, 93.1. HRMS (EI, m/e) calcd for
C16H11NO4 (Mþ) 281.27, found 281.05.
2-Methyl-5-[(5-nitrofuran-2-yl)oxy]pyridine: (Table 2, entry
1
6). Yellow solid, yield 83%; mp 122–124ꢀC. H NMR (DMSO-
d6, 300 MHz) d: 2.50(3H, s, CH3), 6.09(1H, d, J ¼ 4.2 Hz, F H-
4), 7.40(1H, d, J ¼ 8.7 Hz, P H), 7.76(1H, dd, J ¼ 8.7, 3.0 Hz, P
H), 7.79(1H, d, J ¼ 4.2 Hz, F H-3), 8.53(1H, d, J ¼ 3.0 Hz, P H);
13C NMR (DMSO, 75 MHz): d ¼ 157.9, 156.1, 148.5, 144.1,
139.9, 127.1, 124.3, 117.4, 92.0. HRMS (EI, m/e) calcd for
C10H8N2O4 (Mþ) 220.18, found 220.02.
2-(4-Methoxyphenoxy)-5-nitrofuran: (Table 2, entry 2). Brown
1
solid, yield 82%; mp 69–71ꢀC. H NMR (DMSO-d6, 300MHz)
d: 3.77(3H, s, CH3), 5.86(1H, d, J ¼ 3.8 Hz, F H-4), 7.05(2H,
m, P H), 7.30(2H, m, P H), 7.76(1H, d, J ¼ 3.8 Hz, F H-3);
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
SNAr Reaction of 2,5-Dinitrofuran: A Mild and Efficient Method for the
Preparation of 2-Aryloxy-5-nitrofuran
461
Table 3
2-Nitro-5-[3-(trifluoromethoxy)phenoxy]furan: (Table 2,
entry 7). Yellow liquid, yield 77%. 1H NMR (DMSO-d6,
300MHz) d: 6.21(1H, d, J ¼ 5.3 Hz, F H-4), 7.40(2H, m, P H),
7.49(1H, s, P H), 7.64(1H, m, P H), 7.81(1H, d, J ¼ 5.3 Hz, P H);
HRMS (EI, m/e) calcd for C11H6F3NO5 (Mþ) 289.16, found 289.01.
3-[(5-Nitrofuran-2-yl)oxy]benzonitrile: (Table 2, entry
PTC catalyzed SNAr reaction of 2,5-dinitrofuran with different phenols
(Scheme 2).
S. No.
1
Ar
Time (h) Isolated yielda (%)
1
4
79
8). White solid, yield 85%; mp 112–116ꢀC. H NMR (DMSO-
d6, 300MHz) d: 6.25(1H, d, J ¼ 4.2 Hz, F H-4), 7.70(2H, m,
P H), 7.81(2H, m, P H), 7.95(1H, m, P H); 13C NMR (DMSO,
75 MHz): d ¼ 156.5, 153.9, 131.8, 130.0, 123.7, 122.0, 117.6,
117.0, 113.1, 93.8. HRMS (EI, m/e) calcd for C11H6N2O4
(Mþ) 230.18, found 230.02.
3-[(5-Nitrofuran-2-yl)oxy]pyridine: (Table 2, entry 9). White
solid, yield 98%; mp 88–91ꢀC. 1H NMR (DMSO-d6, 300
MHz) d: 6.18(1H, d, J ¼ 3.8 Hz, F H-4), 7.56(1H, dd, J ¼
7.7, 4.7 Hz, P H), 7.81(1H, d, J ¼ 3.8 Hz, F H-3), 7.87(1H,
ddd, J ¼ 8.5, 2.8, 1.1 Hz, P H), 8.56(1H, dd, J ¼ 4.5, 1.1 Hz,
P H), 8.68(1H, d, J ¼ 3.0 Hz, P H); HRMS (EI, m/e) calcd for
C9H6N2O4 (Mþ) 206.16, found 206.09.
2-(3-Chlorophenoxy)-5-nitrofuran: (Table 2, entry 10). Yellow
1
liquid, yield 79%. H NMR (DMSO-d6, 300 MHz) d: 6.18(1H,
d, J ¼ 4.2 Hz, F H-4), 7.34(1H, m, P H), 7.41(1H, m, P H),
7.53(2H, m, P H), 7.80(1H, d, P H); HRMS (EI, m/e) calcd for
C10H6ClNO4 (Mþ) 239.61, found 239.02.
2
3
4
5
6
4
3
2
2
3
82
96
98
97
83
2-Nitro-5-(2-nitrophenoxy)furan: (Table 2, entry 11). Yellow
solid, yield 97%; mp 97–99ꢀC. 1H NMR (DMSO-d6, 300
MHz) d: 6.20(1H, d, J ¼ 4.2 Hz, F H-4), 7.59(2H, m, P H),
7.85(1H, d, J ¼ 4.2 Hz, F H-3), 8.35(2H, m, P H); 13C NMR
(DMSO, 75 MHz): d ¼ 157.0, 145.8, 144.8, 140.7, 136.4,
127.9, 126.7, 122.4, 117.6, 93.3. HRMS (EI, m/e) calcd for
C10H6N2O6 (Mþ) 250.16, found 249.95.
7
4
4
3
1
2
77
85
98
79
97
5-[(5-Nitrofuran-2-yl)oxy]-1,3-benzodioxole: (Table 2, entry
1
8
12). Yellow solid, yield 84%; mp 96–98ꢀC. H NMR (DMSO-
d6, 300 MHz) d: 5.92(1H, d, J ¼ 4.2 Hz, F H-4), 6.10(2H, s,
CH2), 6.83(1H, m, P H), 6.99(1H, d, J ¼ 8.7 Hz, P H),
7.09(1H, d, J ¼ 2.6 Hz, P H), 7.76(1H, d, J ¼ 3.8 Hz, F H-3);
13C NMR (DMSO, 75 MHz): d ¼ 159.5, 148.2, 147.6, 145.5,
143.8, 117.7, 11.9, 108.5, 102.1, 101.6, 91.2. HRMS (EI, m/e)
calcd for C11H7NO6 (Mþ) 249.18, found 249.15.
9
2-(Naphthalen-2-yloxy)-5-nitrofuran: (Table 2, entry
1
13). Brown solid, yield 87%; mp 73–76ꢀC. H NMR (DMSO-
10
11
d6, 300 MHz) d: 6.15(1H, d, J ¼ 4.2 Hz, F H-4), 7.55(3H, m,
P H), 7.82(1H, d, J ¼ 3.8 Hz, F H-3), 7.87(1H, d, J ¼ 2.6 Hz,
P H), 7.97(2H, dt, J ¼ 9.3, 7.3 Hz, P H), 8.08(1H, d, J ¼ 9.1
Hz, P H); 13C NMR (DMSO, 75 MHz): d ¼ 158.5, 151.5,
144.7, 133.9, 131.4, 131.1, 128.2, 128.0, 127.6, 126.5, 118.8,
117.9, 115.5, 93.2 ppm. HRMS (EI, m/e) calcd for C14H9NO4
(Mþ) 255.23, found 255.08.
3-Bromo-5-[(5-nitrofuran-2-yl)oxy]pyridine: (Table 2, entry
14). White solid, yield 85%; mp 106–109ꢀC. 1H NMR
(DMSO-d6, 300MHz) d: 6.30(1H, d, J ¼ 4.2 Hz, F H-4),
7.81(1H, d, P H), 8.28(1H, m, P H), 8.70(2H, t, J ¼ 1.9 Hz, P
H); 13C NMR (DMSO, 75 MHz) : d ¼ 156.4, 150.7, 147.9,
144.5, 139.4, 129.2, 120.2, 117.0, 93.7. HRMS (EI, m/e) calcd
for C9H5BrN2O4 (Mþ) 285.05, found 284.01.
12
13
1
1
84
87
14
4
85
REFERENCES AND NOTES
a The yields reported are after isolation and purification by the column
chromatography.
[1] Summers, J. B.; Gunn, B. P.; Broos, D. W.; Holms, J. H.
PCT Int Appl, WO 8904299 A1 890518, 1989, pp 71.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

462
S. Gavade, K. Padiya, S. Bajare, R. Balaskar, and D. Mane
Vol 48
[2] Pelosi, S. S., Jr.; Yu, C. N. PCT Int Appl, WO 9304060 A1
930304, 1993, pp 57.
[3] Pelosi, S. S., Jr.; Yu, C. N.; Calcagno, M. A. US Patent
5,462,940, 1995.
[4] Hall, J. E.; Tidwell, R. R.; Boykin, D. W. US Patent
5,843,980, 1998.
[5] Clive, C. M.; Stuart, C. G.; Barry, G. S.; Elizabeth, L. K.;
[12] Murakami, N.; Aihara, S.; Iwata, K.; Saito, T.; Naruse, T.
Jpn J Pharmacol 1999, 79, 439.
[13] Tanaka, A.; Usiu, T.; Shimadzu, M. Chem Pharm Bull
1980, 28, 2846.
[14] Olivered, J.; Heotis, J. P. J Org Chem 1968, 33, 2552.
[15] Snyder, H. R., Jr.; Seehausen, P. H. J Heterocycl Chem
1973, 10, 385.
Jane, S. K. US Patent 6,727,256, 2004.
[16] Lieb, F.; Eiter, K. Ann Chem 1972, 761, 130.
[17] Tanaka, A.; Usiu, T.; Shimadzu, M. J Heterocycl Chem
1981, 18, 1241.
[6] Burdan, F.; Dudka, J.; Szumilo, J.; Korobowicz, A.; Kle-
pacz, L. Reprod Toxicol 2003, 17, 413.
[7] (a) Carter, M. C.; Cockerill, G. S.; Guntrip, S. B.; Lackey,
K. E.; Smith, K. J. US Patent 6,727,256, 1999; (b) Cockerill, G. S.;
Lackey, K. E. US Patent 66,933,299. 2000.
[18] Kuo, C. H.; Wu, J. S.; Huang, L. J.; Wu, C. H.; Chou, T.
C. J Heterocycl Chem 1989, 26, 605.
[19] Yamamoto, K.; Koyanagi, J.; Horie, I.; Ogawa, M.;
Sakuma, K.; Tanaka, A. Chem Pharm Bull 1995, 43, 2064.
[20] Povazanec, F.; Kovak, J.; Hesek, D. Collect Czech Chem
Commun 1979, 44, 3301.
[8] Krause, T.; Gerbershagen, M. U.; Fiege, M.; Wisshorn, R.;
Wappler, F. Anaesthesia 2004, 59, 364.
[9] Scopes, D. I. C.; Clitherow, J. W.; Mitchell, W. L.; Carter,
M. UK Pat Appl, GB 2276164 A1 940921, 1994, pp 44.
[10] Peterson, J. W.; Gessell-Lee, D. L.; Saini, S. S. EP
1353664, 2003.
[21] Knoppova, V.; Kada, R.; Kovak, J. Collect Czech Chem
Commun 1979, 44, 2417.
[22] Shimadzu, M.; Ishikawa, N.; Yamamoto, K.; Tanaka, A.
J Heterocyclic Chem 1986, 23, 1179.
[11] Horisawa, E.; Danjo, K.; Haruna, M. Drug Dev Ind Pharm
2000, 26, 1271.
[23] Stegel, F.; Doddi, G.; Porreti, A. J Heterocycl Chem 1974, 11, 97.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet