Synthesis of multi-substituted dibenzo[b,d]furan

Article abstract of DOI:10.1002/jhet.5570450326

(Chemical Equation Presented) The synthesis of multi-substituted dibenzo[b,d]furan derivatives 7a-b and 11a-b from readily available starting materials is described. These compounds are important intermediates for synthesis of molecules having wide therap

Full text of DOI:10.1002/jhet.5570450326

May-Jun 2008
797
Synthesis of Multi-substituted Dibenzo[b,d]furan
Jitendra M. Gajera*, Balasubramanian Gopalan, Pravin S. Yadav,
Sandip D. Patil, Laxmikant A. Gharat
Glenmark Pharmaceuticals Limited, Glenmark Research Centre, Plot No. A/607, TTC Industrial Area, MIDC,
Mahape, Navi Mumbai 400 709, Maharashtra, India,
*corresponding author, E-mail: jitendrag@glenmarkpharma.com,
phone: +91 22 65132491. Fax: +91 22 27780367
Received August 28, 2007
R2
R1
R1
O
OH
R
R
7a-b
11a-b
The synthesis of multi-substituted dibenzo[b,d]furan derivatives 7a-b and 11a-b from readily available
starting materials is described. These compounds are important intermediates for synthesis of molecules
having wide therapeutic applications.
J. Heterocyclic Chem., 45, 797 (2008).
INTRODUCTION
scalable to multi-kilogram scale. Here, we wish to report
this method.
Polynuclear heterocyclic compounds such as
dibenzo[b,d]furan derivatives are important class of
heterocycles which have found wide applicability in
various therapeutic areas such as antidiabetics [1],
antiallergics and antiasthamatic [2], anticancers [3] and
PDE 4 inhibitors [4] etc.
Scheme 1
CHO
CHO
O2N
R2
O2N
F
R2
KF/DMSO
+
OH
O
In our attempts towards preparation of novel molecules
as non steroidal anti-inflammatory agents (NSAIDs), we
required to synthesize various appropriately multi-
substituted dibenzo[b,d]furans 7a-b and 11a-b as
intermediates.
OCH3
OCH3
2a: R2=H
3a: R2=H
3b: R2=CF3
1
2b: R2=CF3
COOH
O2N
COOH
H2N
A
literature survey revealed that most of the
R2
R2
NaO2Cl
Raney Ni
substituted dibenzo[b,d]furans have been synthesized by
electrophilic substitution of commercially available
dibenzo[b,d]furan. Such reactions provide, either mono
substituted [5] or multi-substituted dibenzo[b,d]furans
[6]. However the disadvantage of such reactions is that
we tend to get substitutions at undesired position on the
heterocycle. Therefore, constructing the dibenzo[b,d]-
furan moiety from appropriately substituted starting
materials would be a better strategy to get substitution
on desired positions. Very few methods in the literature
report such strategy for the synthesis of multi-
substituted dibenzo[b,d]furans [7].
NH2NH2/
methanol
NH2SO3H
O
O
OCH3
OCH3
4a: R2=H
4b: R2=CF3
5a: R2=H
5b: R2=CF3
R2
COOH
F4BN2
COOH
i) NaNO2/
HCl
R2
Cu(I)oxide
0.1N H2SO4
NH2SO3H
O
O
OCH3
OCH3
6a: R2=H
6b: R2=CF3
7a: R2=H
7b: R2=CF3
RESULTS AND DISCUSSION
In Scheme 1, diphenyl ethers 3a-b were prepared by
reacting isovanillin 1 with 2-fluoronitrobenzenes 2a-b in
the presence of anhydrous potassium fluoride using
DMSO as a solvent [8]. Oxidation of 3a-b by sodium
chlorite in presence of sulphamic acid gave corresponding
carboxylic acids 4a-b [9]. Reduction of 4a-b by hydrazine
In our attempts to synthesize multi-substituted
dibenzo[b,d]furan as intermediates towards our target
molecules, we have developed some synthetic methods
(Scheme 1 and Scheme 2) which not only gave the
corresponding dibenzo[b,d]furans but are also easily

798
J. M. Gajera, B. Gopalan, P. S. Yadav, S. D. Patil and L. A. Gharat
Vol 45
on Finnigan Navigator spectrometer at 20 eV or 50 eV.
Elemental analyses were carried out with a Perkin-Elmer Model
2400-Series II apparatus. The results of elemental Analyses (C,
H, N) were within ±0.4% of the calculated values.
monohydrate using raney nickel catalyst [10] in methanol
afforded the corresponding amines 5a-b. Copper (I) oxide
induced Pschorr ring closure [11] of 5a-b provided the
required title compounds 7a-b. In Scheme 2 appropriately
substituted bromohydroxy benzaldehydes 9a-b were
reacted with 4-fluoronitrobenzene in presence of
anhydrous potassium fluoride in DMSO to give the
diphenyl ethers. Palladium catalyzed cyclisation [12] of
10a-b in presence of anhydrous sodium carbonate
afforded the desired title compounds 11a-b in good yield.
The required bromohydroxy benzaldehydes were prepared
by bromination of corresponding hydroxybenzaldehydes 1
and 8.
4-Methoxy-3-(2-nitrophenoxy)benzaldehyde (3a). A
suspension of 3-hydroxy-4-methoxy benzaldehyde (5.0 g, 32
mmoles), 1-fluoro-2-nitro benzene (4.5 g, 32 mmoles) and
anhydrous potassium fluoride (2.2 g, 38 mmoles) in dry
dimethyl sulfoxide (50 mL) was stirred at 140-145°C for 2
hours. The mixture was cooled and 5% aqueous sodium
hydroxide solution was added and stirred for 30 minutes. The
crude product was collected by filtration, washed with water
(3x100 mL) and crystallized from ethanol to give 4.0 g (56%) of
3a as white solid, mp: 105-106°C; ir (potassium bromide): 2842,
1
1690, 1612, 1523, 1432, 1345, 1285, 1117, 1017 cm-1; H nmr
(dimethyl sulfoxide-d6): δ 3.87 (s, 3H, OCH3), 6.98 (d, 1H, J =
8.7 Hz, aromatic), 7.32 (t, 1H, J = 8.1 Hz, aromatic), 7.43 (d,
1H, J = 7.8 Hz, aromatic), 7.59 (s,1H, aromatic), 7.64 (t, 1H, J =
7.8 Hz, aromatic), 7.88 (d, 1H, J = 8.4 Hz, aromatic), 8.06 (d,
1H, J = 8.4 Hz, aromatic), 9.87 ppm (s, 1H, CHO); 13C nmr
(dimethyl sulfoxide-d6): δ 191.14, 156.00, 149.83, 143.65,
140.30, 135.14, 130.17, 129.59, 125.81, 123.77, 120.77, 118.80,
113.80, 56.63 ppm; ms: m/z (%) 274 (M+, 100), 123 (5), 137
(24), 95 (15). Anal. Calcd. for C14H11NO5: C, 61.54; H, 4.06, N,
5.13. Found: C, 61.55; H, 4.07, N, 5.15.
Scheme 2
CHO
CHO
cyclopentyl
bromide
K2CO3/DMF
OH
OH
O
OH
8
CHO
CHO
4-Methoxy-3-(2-nitrophenoxy) benzoic acid (4a). To a
solution of 3a (4.0 g, 14.6 mmoles), sulphamic acid (2.13 g,
21.9 mmoles) and water (12.5 mL) in acetone (50 mL), a
solution of sodium chlorite (1.35 g, 18.2 mmole) in water (12.5
mL) was slowly added at 5-10°C. The reaction mixture was
stirred at room temperature for 30 minutes and poured into water
(50 mL). The precipitated crude product was collected by
filtration, washed with water (3x25 mL) and crystallized from
ethanol to give 3.6 g (85%) of 4a as white solid, mp 231-233 °C;
ir (potassium bromide): 3425, 2573, 1687, 1614, 1523, 1442,
Br
Br2/AcOH
Fe powder
OH
OH
R
R
9a: R=OCH3
9b: R=O-cyclopentyl
1: R=OCH3
8: R=O-cyclopentyl
CHO
CHO
Br
Br
NO2
NO2
KF/DMSO
+
OH
1
1346, 1236, 1138, 1020, 735 cm-1; H nmr (dimethyl sulfoxide-
O
F
R
R
d6): δ 3.83 (s, 3H, OCH3), 6.94 (d, 1H, J = 8.1 Hz, aromatic),
7.34 (m,2H, aromatic), 7.61 (m, 2H, aromatic), 7.87 (dd, 1H, J =
8.4 and 2.4 Hz, aromatic), 8.04 (dd, 1H, J = 8.1 and 1.8 Hz,
aromatic), 13.92 ppm (br, s, 1H, COOH); 13C nmr (dimethyl
sulfoxide-d6): δ 166.59, 154.73, 150.16, 142.78, 140.26, 135.10,
128.46, 125.79, 123.97, 123.54, 121.98, 118.61, 113.38, 56.42
ppm; ms: m/z (%) 288 [(M-H)-, 100], 138 (95). Anal. Calcd. for
C14H11NO6: C, 58.13; H, 3.83, N, 4.84. Found: C, 58.32; H,
3.82; N, 4.85.
9a: R=OCH3
9b: R=O-cyclopentyl
10a: R=OCH3
10b: R=O-cyclopentyl
NO2
CHO
[Pd(OAc)2]3
Na2CO3/DMF
O
R
11a: R=OCH3
3-(2-Aminophenoxy)-4-methoxybenzoic acid (5a). To a
suspension of compound 4a (3.6 g, 12.45 mmoles), raney nickel
catalyst (360 mg, 10% w/w) in methanol (40 mL), hydrazine
monohydrate (3.11 g, 62.25 mmoles) was added slowly at
reflux. Reflux was maintained for 3.0 hours. Reaction mixture
was cooled to room temperature. Catalyst was removed by
filtration. Filtrate was concentrated under reduced pressure and
acidified with 5% aqueous HCl solution (100 mL) and filtered to
give the crude product which was crystallized from ethyl acetate
to give 2.5 g (77%) of compound 5a as off-white solid, mp 206-
207 °C; ir (potassium bromide): 3450, 3369, 1601, 1501, 1439,
1307, 1277, 1217, 1153, 1098, 1017, 947 cm-1; 1H nmr (dimethyl
sulfoxide-d6): δ 3.89 (s, 3H, OCH3), 4.90 (br, s, 2H, NH2), 6.52
(t, 1H, J = 8.7, aromatic), 6.68 (d, 1H, J = 8.1 Hz, aromatic),
6.80 (d, 1H, J = 8.1, aromatic), 6.90 (t, 1H, aromatic), 7.20 (m,
2H, aromatic), 7.67 (dd, 1H, J = 8.4 and 1.8 Hz, aromatic),
13.72 ppm (br, s, 1H, COOH); 13C nmr (dimethyl sulfoxide-d6):
11b: R=O-cyclopentyl
Thus, we have successfully demonstrated the synthesis of
appropriately substituted dibenzo[b,d]furans in multigram
quantities from commercially available starting materials
using the methods described above.
EXPERIMENTAL
General. Melting points were measured using LABINDIA
(MR-VRS) visual melting range apparatus and are uncorrected.
1H and 13C nmr spectra were recorded on Varian Mercury VX
300 spectrometer, using tetramethylsilane as an internal
standard. The infrared spectra were acquired on Perkin-Elmer
Spectrum One FT-IR spectrometer. The mass spectra were run

May-Jun 2008
Synthesis of Multi-substituted Dibenzo[b,d]furan
799
δ 167.03, 153.97, 146.00, 142.19, 140.31, 125.61, 125.11,
123.31, 119.52, 117.93, 116.76, 116.04, 112.45, 56.16 ppm; ms:
m/z (%) 258 [(M-H)-, 100], 226 (13), 214 (9), 199 (16), 182
(12).Anal. Calcd. for C14H13NO4: C, 64.86; H, 5.02, N, 5.41.
Found: C, 64.76; H, 5.03; N, 5.43.
Anal. Calcd. for C15H10F3NO5: C, 52.79; H, 2.93, N, 4.11.
Found: C, 52.67; H, 2.92; N, 4.12.
4-Methoxy-3-(2-nitro-4-trifluoromethylphenoxy) benzoic
acid (4b). This compound was obtained from 3b, similarly to
4a, yield 83%, mp 221-222°C; ir (potassium bromide): 3079,
2944, 2567, 1693, 1609, 1542, 1442, 1327, 1284, 1132, 1016,
906 cm-1; 1H nmr (dimethyl sulfoxide-d6): δ 3.83 (s, 3H, OCH3),
7.04 (d, 1H, J = 9.3 Hz, aromatic), 7.36 (d, 1H, J = 9.0 Hz,
aromatic), 7.75 (s, 1H, aromatic), 7.94 (d, 2H, J = 8.7 Hz,
aromatic), 8.45 (s, 1H, aromatic), 12.52 ppm (br, s, 1H, COOH);
13C nmr (dimethyl sulfoxide-d6): δ 166.46, 154.81, 153.28,
141.24, 139.26, 131.65, 129.51, 124.32, 123.51, 123.42, 123.32,
123.02, 118.41, 113.69, 56.56 ppm; ms: m/z (%) 356 [(M-H)-,
100], 206 (60). Anal. Calcd. for C15H10F3NO6: C, 50.42; H, 2.80,
N, 3.92. Found: C, 50.26; H, 2.81; N, 3.91.
4-Methoxy-3-(2-diazoniumfluoroborylphenoxy) benzoic
acid (6a). To a suspension of compound 5a (2.5 g, 9.65
mmoles), concentrated HCl (12.5 mL) and water (12.5 mL), a
solution of sodium nitrite (0.8 g, 11.5 mmoles) in water (4.0mL)
was added slowly at 0-5°C. The reaction mixture was stirred at
0-5 °C for 30 minutes. A solution of sodium fluoroborate (1.57
g, 14.4 mmoles) in water (7.5 mL) was added to the reaction
mixture at 0-5°C and stirred for 30 minutes. The precipitated
product was collected by filtration and washed with 5% aqueous
sodium fluoroborate solution and dried to give 2.5 g (74%) of
compound 6a as yellow solid, mp 189-190°C (decom.); ir
(potassium bromide): 3317, 2924, 2259, 1726, 1710, 1616,
1574, 1481, 1382, 1219, 1127, 1069, 1021 cm-1; 1H nmr
(dimethyl sulfoxide-d6): δ 3.91 (s, 3H, OCH3), 7.14 (d, 1H, J =
9.0 Hz, aromatic), 7.45 (d, 1H, J = 8.7 Hz, aromatic), 8.01 (m,
2H, aromatic), 8.12 (t, 1H, J = 8.4 Hz, aromatic), 8.66 (d, 1H, J
= 8.4 Hz, aromatic), 13.09 ppm (br, s, 1H, COOH); 13C nmr
(dimethyl sulfoxide-d6): δ 166.34, 159.85, 154.86, 143.94,
140.46, 132.94, 130.48, 124.85, 124.29, 123.90, 116.99, 113.97,
104.20, 56.71 ppm; ms: m/z (%) 358 (6.2), 271 (88), 243 (34),
228 (91), 198 (100), 183 (94), 171 (50). Anal. Calcd. for
C14H11BF4N2O4: C, 46.96; H, 3.10, N, 7.82. Found: C, 46.79; H,
3.09, N, 7.84.
3-(2-Amino-4-trifluoromethylphenoxy)-4-methoxy benzoic
acid (5b). This compound was obtained as off white solid from
4b, similarly to 5a, yield 78%, mp178-179 °C; ir (potassium
bromide): 3458, 3369, 1689, 1611, 1514, 1442, 1336, 1278,
1
1209, 1167, 1099, 947 cm-1; H-nmr (dimethyl sulfoxide-d6): δ
3.85 (s, 3H, OCH3), 5.45 (br, s, 2H, NH2), 6.60 (d, 1H, J = 7.8,
aromatic), 6.76 (d, 1H, J = 7.8 Hz, aromatic), 7.06 (s,1H,
aromatic), 7.23 (d, 1H, J = 9.0 Hz, aromatic), 7.38 (s, 1H,
aromatic), 7.77 (d, 1H, J = 8.4 Hz, aromatic), 12.75 ppm (br, s,
1H, COOH); 13C nmr (dimethyl sulfoxide-d6): δ 164.25, 154.13,
146,24, 143,68, 139.80, 127.04, 126.47, 124.83, 124.41, 123.99,
122.87, 120.75, 116.40, 112.71, 111.24, 56.16 ppm; ms: m/z (%)
326 [(M-H)-, 76], 306 (48), 294 (28), 262 (12), 176 (100), 156
(5). Anal. Calcd. for C15H12F3NO4: C, 55.04; H, 3.66, N, 4.28.
Found: C, 54.89; H, 3.67; N, 4.27.
3-(2-Diazoniumfluoroboryl-4-(trifluoromethylphenoxy)-4-
methoxybenzoic acid (6b). This compound was obtained as
yellow solid form 5b, similarly to 6a, yield 70%, mp 204-205
°C; ir (potassium bromide): 3107, 2277, 1688, 1609, 1576, 1510,
1433, 1332, 1290, 1184, 1010, 948 cm-1; 1H nmr (dimethyl
sulfoxide-d6): δ 3.91 (s, 3H, OCH3), 7.35 (d, 1H, J = 9.0 Hz,
aromatic), 7.48 (d, 1H, J = 9.0 Hz, aromatic), 8.04 (m, 2H,
aromatic), 8.45 (d, 1H, J = 9.0 Hz, aromatic), 9.24 (s, 1H,
aromatic), 13.15 ppm (br, s, 1H, COOH); 13C nmr (dimethyl
sulfoxide-d6): δ 166.27, 161.75, 154.58, 140.21, 140.05, 131.35,
130.91, 124.58, 124.39, 124.12, 123.82, 118.40, 114.16, 106.03,
56.82 ppm; ms: m/z (%) 426.9 [(M+H)+, 100], 302 (28), 285
(15), 274 (8). Anal. Calcd. for C15H10BF7N2O4: C, 42.27; H,
2.35, N, 6.57. Found: C, 42.42; H, 2.35, N, 6.55.
4-Methoxydibenzo[b,d]furan-1-carboxylicacid (7a). To a
suspension of Cu (I) oxide (1.5 g, 10.5 mmoles) in 0.1 N H2SO4
(750 mL), finely powdered compound 6a (2.5 g, 7.0 mmoles)
was added at 40-45°C and stirred for 30 minutes. The mixture
was cooled to room temperature; ethyl acetate (250 mL) was
added and stirred rapidly for 10 minutes. The inorganic material
was removed by filtration. The organic layer was separated and
dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure to give crude product. The
crude product was purified on silica gel column using
chloroform:ethyl acetate (98:2) as eluent to give 250 mg (15%)
of compound 7a as white solid, mp 278-280 °C; ir (potassium
bromide): 3320, 2977, 1682, 1570, 1416, 1286, 1235, 1149,
1
1096, 744 cm-1; H nmr (dimethyl sulfoxide-d6): δ 4.06 (s, 3H,
OCH3), 7.27 (d, 1H, J = 8.7 Hz, aromatic), 7.42 (t, 1H, J = 8.1,
Hz, aromatic), 7.76 (d, 1H, J = 8.4 Hz, aromatic), 8.02 (d, 1H, J
= 8.7 Hz, aromatic), 8.88 (d, 1H, J = 7.8 Hz, aromatic), 13.11
ppm (br, s, 1H, COOH); 13C nmr (dimethyl sulfoxide-d6): δ
167.38, 157.83, 149.01, 145.68, 128.84, 125.38, 124.24, 124.04,
123.78, 123.31, 122.85, 118.06, 112.94, 110.04, 56.57 ppm; ms:
m/z (%) 241 [(M-H)-, 100], 182 (42), 197 (27), 167 (5). Anal.
Calcd. for C14H10O4: C, 69.42; H, 4.16. Found: C, 69.36; H,
4.15.
4-Methoxy-3-(2-nitro-4-trifluoromethylphenoxy)benzalde-
hyde (3b). This compound was obtained from 2b, similarly to
3a, yield 71%, mp 95-97°C; ir (potassium bromide): 2847, 1697,
1630, 1607, 1540, 1335, 1284, 1117, 1015 cm-1; 1H nmr
(dimethyl sulfoxide-d6): δ 3.87 (s, 3H, OCH3), 7.06 (d, 1H, J =
8.4 Hz, aromatic), 7.48 (d, 1H, J = 8.4 Hz, aromatic), 7.80 (d,
1H, J = 1.8 Hz, aromatic), 8.47 (d, 1H, J = 2.4 Hz, aromatic),
9.90 ppm (s, 1H, CHO); 13C nmr (dimethyl sulfoxide-d6): δ
191.14, 156.00, 149.83, 143.65, 140.30, 135.14, 130.17, 129.59,
125.81, 123.77, 120.77, 118.80, 113.80, 56.63 ppm; ms: m/z (%)
340 (M-, 16), 326 (26), 308 (23), 206 (59), 151 (82), 87 (100).
4-Methoxy-8-trifluoromethyldibenzo[b,d]furan-1-carbox-
ylic acid (7b).This compound was obtained as white solid form
6b, similarly to 7a, yield 15%, mp 255-257 °C; ir (potassium
bromide): 2975, 1693, 1575, 1421, 1327, 1273, 1154, 1105,
1
1058, 913 cm-1; H nmr (dimethyl sulfoxide-d6): δ 4.09 (s, 3H,
OCH3), 7.38 (d, 1H, J = 9.0 Hz, aromatic), 8.0 (m, 2H,
aromatic), 8.10 (d, 1H, J = 9.0 Hz, aromatic), 9.32 (s, 1H,
aromatic), 13.25 ppm (br, s, 1H, COOH); 13C nmr (dimethyl
sulfoxide-d6): δ 167.62, 156.28, 148.91, 144.91, 128.58, 128.20,
126.48, 124.75, 123.22, 122.97, 118.10, 111.79, 109.07, 56.44
ppm; ms: m/z (%) 309 [(M-H)-, 100], 285 (42), 235 (35). Anal.
Calcd. for C15H9F3O4: C, 58.06; H, 2.90. Found: C, 57.88; H,
2.89.
2-Bromo-3-hydroxy-4-methoxy benzaldehyde (9a). To a
well stirred solution of compound 1 (5.0 g, 32 mmoles),
anhydrous sodium acetate (5.4 g, 65 mmoles) and iron powder
(0.146 g, 2.6 mmoles) in glacial acetic acid (30 mL), bromine
(5.75 g, 36 mmoles) was added under nitrogen atmosphere at

800
J. M. Gajera, B. Gopalan, P. S. Yadav, S. D. Patil and L. A. Gharat
Vol 45
10-15 °C and stirred at room temperature for 1 hour. The
mixture was poured into ice water (150 mL). The crude product
was collected by filtration and crystallized from ethanol to give
4.5 g (60 %) of compound 9a as white solid, mp 205-206 °C
(dec.); ir (potassium bromide): 3233, 1669, 1593, 1564, 1494,
using petroleum ether: ethyl acetate (9:1) as an eluent. The
desired compound was crystallized from petroleum ether:ethyl
acetate (8:2) to give 5 g (67%) of 8b as white solid, mp 88-
89°C; ir (potassium bromide): 3271, 2948, 1671, 1605, 1580,
1
1463, 1358, 1270, 1153, 976 cm-1; H nmr (dimethyl sulfoxide-
1
1286, 1205, 1019, 805 cm-1; H nmr (dimethyl sulfoxide-d6): δ
d6): δ 1.69 (m, 2H, CH2), 1.88 (m, 4H, 2xCH2), 1.99 (m, 2H,
CH2), 4.91 (m, 1H, CH), 7.39 (dd, 1H, J = 8.1 Hz and 2.1 Hz,
aromatic), 7.08 (d, 1H, J = 8.7 Hz, aromatic), 7.25 (s,1H,
aromatic), 9.76 (s, 1H, CHO), 9.35 ppm (s, 1H, OH),; 13C nmr
(dimethyl sulfoxide-d6): δ 191.54, 151.99, 147.81, 129.76,
124.54, 113.92, 80.01, 32.51, 23.98 ppm; ms: m/z (%) 205[(M-
H)-, 100], 137 (4). Anal. Calcd. for C12H14O3: C, 69.90; H, 6.79.
Found: C, 69.87; H, 6.80.
4.05 (s, 3H, OCH3), 6.10 (br, s, 1H, OH), 6.89 (d, 1H, J = 8.4
Hz), 7.56 (d, 1H, J = 8.4 Hz), 10.22 ppm (s, 1H, CHO); 13C nmr
(dimethyl sulfoxide-d6): δ 191.03, 153.52, 144.21, 126.84,
122.18, 113.64, 110.58, 56.66 ppm; ms: m/z (%) 229 [(M-H)-,
100], 215 (10). Anal. Calcd. for C8H7BrO3: C, 41.57; H, 3.03.
Found: C, 41.55; H, 3.02.
2-Bromo-4-methoxy-3-(4-nitrophenoxy)benzaldehyde (10a).
To a solution of compound 9a (4.5 g, 19 mmoles) and 4-fluoro-
1-nitro benzene (4.5 g, 23 mmoles) in dry dimethyl sulfoxide
(45 mL), potassium fluoride (1.24 g, 21 mmoles) was added and
stirred at 120-125 °C for 3 hours. The mixture was cooled and
water (250 mL) was added. The crude product was purified on
silica gel column using petroleum ether: ethyl acetate (8:2) as
eluent. The desired compound was crystallized from
chloroform:methanol (9:1) to give 3.5 g (51%) of 10a as white
solid, mp 136-137 °C; ir (potassium bromide): 3435, 1689,
1584, 1486, 1348, 1285, 1253, 1025, 848 cm-1; 1H-nmr
(dimethyl sulfoxide-d6): δ 3.86 (s, 3H, OCH3), 6.91 (d, 2H, J =
7.2 Hz), 7.08 (d, 1H, J = 8.4 Hz), 7.91 (d, 1H, J = 8.4 Hz), 8.19
(d, 2H, J = 7.2 Hz), 10.24 ppm (s, 1H, CHO); 13C nmr (dimethyl
sulfoxide-d6): δ 190.18, 161.68, 157.73, 142.62, 139.24, 129.59,
127.29, 126.39, 121.91, 115.59, 113.06, 57.15 ppm; ms: m/z (%)
353 (M+, 8], 274 (8), 199 (44), 184 (100), 171 (81), 155 (22),
137 (42). Anal. Calcd. for C14H10BrNO5: C, 47.74; H, 2.84, N,
3.97. Found: C, 47.65; H, 2.85; N, 3.96.
2-Bromo-4-cyclopentyloxy-3-hydroxybenzaldehyde (9b).
This compound was obtained as white solid from 8, similarly to
9a, yield 72%, mp107-109 °C; ir (potassium bromide): 3327,
2956, 1674, 1587, 1487, 1281,987 cm-1; 1H nmr (dimethyl
sulfoxide-d6): δ 1.69 (m, 2H, CH2), 1.88 (m, 4H, 2xCH2), 1.99
(m, 2H, CH2), 4.95 (m, 1H, CH), 6.15(s, 1H, OH), 6.89 (d, 1H, J
= 8.7 Hz, aromatic), 7.55 (d, 1H, J = 8.7 Hz, aromatic), 10.25 (s,
1H, CHO); 13C nmr (dimethyl sulfoxide-d6): δ 190.82, 151.94,
144.55, 126.34, 122.08, 113.59, 111.85, 80.88, 32.40, 23.98
ppm; ms: m/z (%) 326[(M-H)-, 76], 214 (100). Anal. Calcd. for
C12H13BrO3: C, 50.54; H, 4.60. Found: C, 50.64; H, 4.61.
2-Bromo-4-cyclopentyloxy-3-(4-nitrophenoxy)benzalde-
hyde (10b). This compound was obtained as white solid from
9b, similarly to 10a, yield 62%, mp 115-116 °C; ir (potassium
bromide): 2976, 1683, 1593, 1515, 1344, 1280, 1246, 984 cm-1;
1H nmr (dimethyl sulfoxide-d6): δ 1.21 ppm (m, 2H, CH2), 1.45
(m, 4H, 2xCH2), 1.77 (m, 2H, CH2), 5.01 (m, 1H, CH), 7.09 (d,
2H, J = 9.3 Hz, aromatic), 7.43 (d, 1H, J = 8.7 Hz, aromatic),
7.88 (d,1H, J = 8.7 Hz, aromatic), 8.23 (d, 1H, J = 9.3 Hz,
aromatic), 10.13 ppm (s, 1H, CHO); 13C nmr (dimethyl
sulfoxide-d6): δ 190.12, 162.07, 155.78, 142.55, 140.16, 129.21,
126.82, 126.21, 121.86, 115.79, 114.37, 81.29, 32.22, 23.31
ppm; ms: m/z (%) 407[(M+, 22], 336 (26), 155 (33), 137 (61),
106 (100). Anal. Calcd. for C18H16BrNO5: C, 53.22; H, 3.93; N,
3.44. Found: C, 53.11; H, 3.92; N, 3.43.
4-Methoxy-8-nitrobenzo[b,d]furan-1-carbaldehyde (11a).
A suspension of compound 10a (3.5 g, 9.9 mmoles), anhydrous
sodium carbonate (1.28 g, 12.1 mmoles) and hexakis-
(acetato)tripalladium (II) (0.22 g, 0.99 mmoles) in dry dimethyl
formamide (35 mL) was stirred at 120-125°C for 10 hours. The
hot mixture was filtered through celite bed. The filtrate was
cooled and water (250 mL) was added. The crude product was
collected by filtration and purified on silica gel column using
chloroform:ethyl acetate (9:1) as eluent. The desired compound
was crystallized from chloroform: ethanol (7:3) to give1.5 g
(55%) of 11a as white solid, mp 256-257 °C; ir (potassium
bromide): 3434, 3115 1682, 1522, 1343, 1295, 1076, 846 cm-1;
1H nmr (dimethyl sulfoxide-d6): δ 4.15 (s, 3H, OCH3), 7.57
(d,1H, J = 8.4 Hz, aromatic), 8.07 (d, 1H, J = 9.0 Hz, aromatic),
8.22 (d, 1H, J = 8.4 Hz, aromatic), 8.53 (dd, 1H, J = 9.0 and J =
2.4 Hz, aromatic), 9.85 (d, 1H, J = 2.4 Hz aromatic), 10.18 ppm
(s, 1H, CHO); 13C nmr (dimethyl sulfoxide-d6): δ 192.20,
158.80, 153.02, 144.11, 140.61, 136.29, 128.80, 127.39, 127.23,
124.50, 118.40, 115.70, 109.80, 56.95 ppm;; ms: m/z (%)
271[(M+H)+, 100], 228 (65), 199 (90), 184 (85). Anal. Calcd. for
C14H9NO5: C, 61.99; H, 3.32, N, 5.17. Found: C, 61.99; H, 3.33;
N, 5.15.
4-Cyclopentyloxy-8-nitrodibenzo[b,d]furan-1-carbalde-
hyde (11b). This compound was obtained as light yellow solid
from 10b, similarly to 11a, yield 73%, mp: 207-208 °C; ir
1
(potassium bromide): 1527, 1341, 1291, 1074 cm-1; H nmr
(dimethyl sulfoxide-d6): δ 1.69 (m, 2H, CH2), 1.86 (m, 4H,
2xCH2), 2.09 (m, 2H, CH2), 5.25 (m, 1H, CH), 7.52 (d, 1H, J =
8.7 Hz), 8.05 (d, 2H, J = 9.3 Hz, aromatic), 8.14 (d, 1H, J = 8.1
Hz, aromatic), 8.44 (dd, J = 9.0 Hz and 2.4 Hz, aromatic), 9.80
(s, 1H, aromatic), 10.14 ppm (s, 1H, CHO); 13C nmr (dimethyl
sulfoxide-d6): δ 192.43, 159.24, 148.96, 146.84, 143.52, 135.05,
124.71, 124.50, 123.59, 122.33, 122.25, 113.15, 112.45, 81.52,
32.53, 23.94 ppm; ms: m/z (%) 326 [(M+H)+, (28)], 277 20),
256 (100). Anal. Calcd. for C18H15NO5: C, 66.46; H, 4.61; N,
4.30. Found: C, 66.32; H, 4.62; N, 4.29.
4-Cyclopentyloxy-3-hydroxybenzaldehyde (8). A suspen-
sion of 3,4-dihydroxy benzaldehyde (5.0 g, 36.2 mmoles),
cyclopentyl bromide (6.5 g, 43.4 mmoles) and anhydrous
potassium carbonate (6.0 g, 43.4 mmoles) in dry N,N-
dimethylformamide (35 mL) was stirred at 70-75 °C for 24
hours. The mixture was cooled, filtered and water (250 mL) was
added to the filtrate. The filtrate was extracted with ethyl acetate
(3x50 mL), dried over anhydrous sodium sulfate and the solvent
was evaporated. The residue was purified on silica gel column
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