One-pot synthesis of fluorine containing 3-cyano/ethoxycarbonyl-2-methyl- benzo[b]furans

Article abstract of DOI:10.1016/j.tet.2004.10.019

Fluoro-substituted 3-cyano-2-methyl-benzo[b]furans and ethyl 2-methyl-benzo[b]furan-3-carboxylates are conveniently prepared in a single step in good yield by the microwave induced tandem intramolecular Wittig and Claisen rearrangement reactions of the corresponding [(aryloxyacetyl) (cyano) methylene] triphenylphosphorane and [(aryloxyacetyl) (ethoxycarbonyl) methylene] triphenylphosphoranes, respectively. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.10.019

Tetrahedron 60 (2004) 12231–12237
One-pot synthesis of fluorine containing
3-cyano/ethoxycarbonyl-2-methyl-benzo[b]furans*
V. V. V. N. S. RamaRao, G. Venkat Reddy, D. Maitraie, S. Ravikanth, R. Yadla,
*
B. Narsaiah and P. Shanthan Rao
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 13 April 2004; revised 13 September 2004; accepted 7 October 2004
Available online 20 October 2004
Abstract—Fluoro-substituted 3-cyano-2-methyl-benzo[b]furans and ethyl 2-methyl-benzo[b]furan-3-carboxylates are conveniently
prepared in a single step in good yield by the microwave induced tandem intramolecular Wittig and Claisen rearrangement reactions of
the corresponding [(aryloxyacetyl) (cyano) methylene] triphenylphosphorane and [(aryloxyacetyl) (ethoxycarbonyl) methylene]
triphenylphosphoranes, respectively.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
cyano/ethoxycarbonyl-benzofurans have not been reported.
In the present investigation, we report for the first time the
microwave assisted, facile synthesis of 3-cyano-2-methyl-
benzo[b]furan and ethyl 2-methyl-benzo[b]furan-3-car-
boxylate derivatives from the corresponding [(fluoro-
aryloxyacetyl) alkylidene] triphenylphosphoranes.
Benzo[b]furan derivatives are an important class of organic
compounds, which are known to be present in many natural
products and possess physiological activity. Their appli-
cation in agrochemicals,1,2 pharmaceuticals,1,3 cosmetics,4,5
polymers and dyes1 prompted development of various
synthetic methods.6 Claisen rearrangement of aryl pro-
pargylic ethers offers7 the most elegant route for the
synthesis of 2-alkyl-3-substituted benzo[b]furans. Previous
research in our laboratory8 established the formation of
2-alkyl-3-cyano-benzo[b]furans and 4-cyanobenzopyrans
during thermolysis of [(aryl-oxyacetyl) (cyano) methylene]
triphenylphosphoranes. In this method, decomposition of
phosphoranes is conducted at elevated temperatures (250–
300 8C) and the product is continuously distilled out of the
reaction vessel under high vacuum. The aryl propargylic
ether, allenyl phenol and the dienone intermediates are
thermally unstable and decompose due to prolonged heating
and result in the formation of phenols and polymeric mass,
thereby reducing the isolated yield of the benzopyrans/
benzofurans. We have overcome this problem by subjecting
the solid phosphoranes to microwave irradiation for shorter
duration. To our knowledge, fluorine-containing 2-alkyl-3-
2. Results and discussion
[(Aryloxyacetyl) (cyano/ethoxycarbonyl) methylene] tri-
phenylphosphoranes 8/9 were prepared in good yield by
the transylidation reaction9 of [(cyano/ethoxycarbonyl)
methylene] triphenylphosphoranes 6/7 with corresponding
aryloxyacetyl chloride 5. The aryloxyacetyl chlorides 5 are
prepared starting from the corresponding phenol 1 via ethyl
aryloxyacetate 3 and aryloxyacetic acid 4. The sequence of
reactions is depicted in Scheme 1. Ethyl 3-chloro-4-fluoro-
phenoxyacetate 3d, 3-chloro-4-fluoro-phenoxy-acetic acid
4d, 2-chloro-4-fluoro-phenoxyacetyl chloride 5b, 3-chloro-
4-fluoro-phenoxyacetyl chloride 5d and all the ylides 8/9
reported in this study are new compounds and were fully
characterized.
The [(aryloxyacetyl) alkylidene] triphenylphosphoranes 8/9
on microwave irradiation for 6–8 min resulted in the
exclusive formation of 2-methyl-benzo[b]furan derivatives
13/14 (32–82%) along with triphenylphosphine oxide 12
(Table 1). The formation of 2-methyl-benzo[b]furan
derivatives 13/14 is seen as a result of tandem intra-
molecular Wittig, Claisen rearrangement reactions8
* IICT Communication No. 040405.
Keywords: Transylidation; Aryloxyacetyl alkylidenetriphenylphosphorane;
Intramolecular Wittig reaction; Claisen rearrangement; 3-Cyano-2-methyl-
benzofurans.
* Corresponding author. Tel.: C91 040 27193185; fax: C91 040
27160757; e-mail: shanthanpp@yahoo.co.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.019

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V. V. V. N. S. RamaRao et al. / Tetrahedron 60 (2004) 12231–12237
Scheme 1. K2CO3/acetone/NaI, 6/3 h; (ii) 10% aq KOH, 6/2 h; (iii) SOCl2, hexane, 6/1 h; (iv) DCM, rt/3 h; (v) MW/6–8 min. (a) R1ZR2ZH, R3ZF;
(b) R1ZCl, R2ZH, R3ZF; (c) R1ZR3ZF, R2ZH; (d) R1ZH, R2ZCl, R3ZF; (e) R1ZR3ZH, R2ZCF3; (f) R1ZR3ZH, R2ZCH3.
followed by ring closure of the allenyl phenol intermediate
18. The reaction pathway is shown in Scheme 1.
form of triphenylphosphine oxide, 12 and the microwave
energy seem to favor dissociation of phenol 18 in to the
phenolate anion 19.
The formation of benzo[b]furan derivatives 13/14 is
believed to have been facilitated by the formation of
phenolate anion 19 which cyclizes7 in preference to the
1,5-H shift.
1
The H NMR spectra of all the benzofurans showed the
presence of methyl proton signals as a singlet in the range d
2.7–2.8 ppm. The IR spectra of the new 3-cyano-2-methyl-
benzofuran analogues 13 prepared in this study showed the
presence of CN absorption in the region 2230–2233 cmK1
.
The presence of polar substituents, polar medium in the
Table 1. Synthesis of 2-methyl-benzo[b]furans 13 and 14
S. No.
Ylide
R1
R2
R3
Time (min)
Thermal
Product
Yield (%)
Thermal
MW
MW
1
2
3
4
5
6
7
8
9
10
8a
8b
8c
8d
8e
8f
9a
9b
9c
9d
H
Cl
F
H
H
H
H
Cl
F
H
H
H
Cl
CF3
CH3
H
H
H
Cl
F
F
F
F
H
H
F
F
F
F
8
8
8
7
6
7
7
7
6
7
35
—
—
—
28
—
30
—
—
—
13a
13b
13c
13d
13e
13g
14a
14b
14c
14d
73
82
76
76
32b
70
71
79
75
78
5a
—
—
—
0c
—
56
—
—
—
H
a In addition to compound 13a, phenoxy acetylene 15a was isolated in 51% yield.
b In addition to compound 13e, phenoxy acetylene 15e was isolated in 9% yield.
c Phenol 1e was isolated in 73% yield.

V. V. V. N. S. RamaRao et al. / Tetrahedron 60 (2004) 12231–12237
12233
The ester group present in the newly prepared ethyl
2-methyl-benzo[b]furan-3-carboxylates 14 showed C]O
absorptions in the region 1705–1708 cmK1 in IR spectra.
microwave assisted tandem intramolecular-Wittig, Claisen
rearrangement and cyclization reactions is demonstrated by
the presence of substituents at various positions in the aryl
moiety. However, the presence of electron withdrawing
substituents in the aryl moiety had a detrimental effect on
the yield of 2-methyl-benzofuran 13/14. The presence of a
meta CF3 group in the aryl moiety resulted in the formation
of 4-[(31-trifluoromethyl) phenoxy] but-2-ynenitrile, 15e
along with 13e. All the benzofuran derivatives 13/14
prepared in this study are new compounds and were
characterized by NMR and IR spectroscopy and mass
spectrometry.
The decomposition of ylides 8a–c and 9a–c (R2ZH) is
expected to yield only one regioisomer of the corresponding
2-methyl-benzofurans 13a–c and 14a–c (Scheme 1). The
ylides 8d–f and 9d (R1ZH; R2ZCl, CF3 or CH3) could
result in the formation of two regio-isomers of the
respective 2-methyl-benzofurans due to the possibility of
Claisen rearrangement of the initially formed aryl pro-
pargylic ethers 15d–f and 16d occurring in either direction
(Schemes 1 and 2). In this study we have obtained a single
2-methyl-benzofuran regioisomer for each of these ylides.
Thermolysis of [(4-fluorophenoxyacetyl) (cyano) methyl-
ene] triphenylphosphorane 8a at 250–270 8C gave 4-(41-
fluorophenoxy)-but-ynenitrile 15a as the major compound
with traces of 3-cyano-5-fluoro-2-methyl-benzofuran 13a
along with triphenylphosphine oxide 12. Under similar
conditions, [(4-fluorophenoxyacetyl) (cyano) methylene]
triphenylphosphorane 9a resulted in the formation of
3-ethoxycarbonyl-5-fluoro-2-methyl-benzofuran 14a in
56% yield. However, in the thermolysis of [(3-trifluoro-
methylphenoxyacetyl) (cyano) methylene] triphenyl-
phosphorane 8e at 240–270 8C, 3-trifluoromethylphenol 1e
and triphenylphosphine oxide 12 are the only isolable
products.
The exclusive formation of 6-chloro-3-cyano-5-fluoro-2-
methyl-benzofuran 13d and 6-chloro-3-ethoxycarbonyl-5-
fluoro-2-methyl-benzofuran 14d is explained by the
presence of a bulky Cl group at meta position in the aryl
propargylic ether intermediates 15d and 16d which hinders
its ortho position and favors Claisen rearrangement to take
place away from it. Support for the structure of 13d came
from 1H NMR which showed two doublets for 1H each at d
7.40 (JZ8.1 Hz) and 7.56 ppm (JZ6.0 Hz) with different
3
4
coupling constants attributable to JH–F and JH–F for the
C4–H and C7–H, respectively. H NMR signals for C4–H
1
and C7–H in 14d appeared at d 7.67 (d, 1H, JZ8.2 Hz) and
7.46 ppm (d, 1H, JZ6.0 Hz). The absence of any H–H
couplings and the observed H–F couplings (three bond and
four bond) further support the structure 14d for this
regioisomer. Similarly, the presence of a powerful electron
withdrawing CF3 group at meta position in 15e does not
favor Claisen rearrangement towards its ortho position.
Consequently, the decomposition of 8d resulted in the
formation of 4-[31-(trifluoromethyl) phenoxy]-but-2-yneni-
trile 15e along with 3-cyano-2-methyl-6-trifluoromethyl-
benzofuran 13e in reduced yield due to the rearrangement
occurring at para position to CF3 group. The product 13e
3. Conclusions
In this investigation, we have developed a solvent free
microwave assisted one-pot synthesis of several new fluoro-
substituted benzo[b]furans from the corresponding
[(aryloxyacetyl) alkylidene] triphenylphosphoranes. The
reaction combines intramolecular Wittig reaction of phos-
phoranes and Claisen rearrangement of the resulting aryl
propargylic ethers followed by ring closure resulting in the
exclusive formation of the corresponding benzo[b]furan
derivatives and triphenylphosphine oxide in good yield.
This method involves simple and general sequence,
and offers a convenient one-pot synthesis of any
3-cyano/ethoxycarbonyl-2-methyl-benzo[b]furans in the
laboratory.
1
showed in its H NMR spectrum a singlet for 1H at d 7.64
for C7–H and two doublets for 1H each at 7.47 and
3
7.68 ppm with a JH–H of 7.5 Hz assignable to C4–H and
C5–H, respectively. The presence of a singlet and the
absence of a triplet eliminates the presence of other possible
regioisomer. The methyl substituent present in 15f favors
the rearrangement to its ortho position resulting in the
formation of 3-cyano-2,4-dimethyl-benzofuran 13g
4. Experimental
4.1. General
1
(Scheme 2). The H NMR of the product 13g showed a
triplet for H and d 7.16 and two doublets at 7.03 and
1
7.28 ppm with 3JH–H of 7.5 Hz supporting the 3-cyano-2,4-
dimethyl-benzofuran 13g structure for this regioisomer.
Melting points were determined in open glass capillaries on
a Fisher Johnes melting point apparatus and are uncorrected
IR spectra were recorded on FT-IR Schimadzu Perkin–
Elmer 1310 infrared spectrophotometer. 1H NMR
(200 MHz) and 13C NMR (50 MHz) spectra were recorded
The versatility of the exclusive formation of 2-methyl-
benzo[b]furans 13/14 in excellent yield from [(aryloxy-
acetyl) alkylidene] triphenylphosphoranes 8/9 by
Scheme 2.

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V. V. V. N. S. RamaRao et al. / Tetrahedron 60 (2004) 12231–12237
on Varian Gemini spectrometer in CDCl3 solvent using
TMS as internal standard. Mass spectra were recorded on a
VG-micro mass 7070H instrument at 70 eV. Elemental
analyses were carried out on EI Elemental Vario EL
(Germany) apparatus. Microwave irradiations were carried
out using sealed tube (Aldrich, Ace pressure tube, 10.2 cm,
15 mL) in a domestic microwave oven (BPL BMO 700T).
4.4.2. 3-Chloro-4-fluoro-phenoxyacetyl chloride (5d).
1.84 g, 83% as a colourless liquid; bp 110–112 8C/13 mm;
[found: C, 43.06; H, 2.26. C8H5Cl2FO2 requires C, 43.08; H,
2.26%]; nmax (CHCl3) 3036, 2920, 1793, 1088 cmK1; dH
3
4
4.89 (2H, s, CH2), 6.74 (1H, ddd, JH–HZ8.1 Hz, JH–F
Z
4
4
3.1 Hz, JH–HZ2.6 Hz), 6.87 (1H, dd, JH–FZ3.2 Hz,
4JH–HZ2.6 Hz), 7.04–7.14 (1H, m); m/z (EI-MS) 222 (MC,
22), 161 (100), 129 (64%).
4.2. General method for the preparation of ethyl
aryloxyacetylacetate, 3a–f
4.5. General method for the synthesis of [(aryloxyacetyl)
alkylidene] triphenylphosphoranes (8a–f and 9a–d)
Equimolar quantities of the respective fluoro-phenol 1
(10 mmol), ethyl bromoacetate 2 (1.67 g, 10 mmol) and
catalytic amount of sodium iodide (10 mg) were refluxed in
dry acetone (10 mL) in the presence of excess anhydrous
potassium carbonate (2.76 g, 10 mmol) for 3 h. Acetone was
removed from the reaction mixture and the residue was
washed with water (25 mL). The resulting sufficiently pure
solid ethyl aryloxyacetylacetate 3a–f was filtered and dried.
Phosphorane 6/7 (10 mmol), dry dichloromethane (10 mL)
were taken in a two necked round bottom flask, cooled to
10–15 8C, added dropwise a solution of aryloxyacetyl
chloride 5 (5 mmol) in dichloromethane (5 mL) in about
15 min and the reaction mixture was stirred at room
temperature for 12 h. The reaction mixture was diluted
with DCM (10 mL) and washed with water (3!20 mL), the
organic layer separated and dried over anhydrous sodium
sulphate. The solvent was removed on rotavapor and the
crude product was purified by recrystallization (1:4 mixture
of chloroform/hexane).
4.2.1. Ethyl 3-chloro-4-fluoro-phenoxyacetate (3d).
1.46 g, 92% as a white solid; mp 48 8C; [found: C, 51.63;
H, 4.31. C10H10ClFO3 requires C, 51.62; H, 4.33%]; nmax
(KBr) 2926, 1738, 1155 cmK1; dH (200 MHz, CDCl3) 1.41
(3H, t, JZ7.1 Hz, CH3), 4.26 (2H, q, JZ7.1 Hz, CH2), 4.53
(2H, s, OCH2), 6.71–6.78 (1H, m), 6.90–6.95 (1H, m) and
6.98–7.04 (1H, m); m/z (EI-MS) 232 (MC, 78), 234 (MC2,
26), 161 (33), 159 (100), 141 (16), 129 (71%).
4.5.1. [(4-Fluorophenoxyacetyl) (cyano) methylene] tri-
phenylphosphorane (8a). 2.08 g, 92.3% as a pale yellow
solid; mp 155 8C; [found: C, 74.31; H, 4.85; N, 3.15.
C28H21FNO2P: C, 74.16; H, 4.66; N, 3.08%]; nmax (KBr)
3060, 2895, 2172, 1622, 1190, 1105 cmK1; dH (200 MHz,
CDCl3) 4.92 (2H, s, –COCH2–), 6.82–6.93 (4H, m), 7.40–
7.75 (15H, unresolved); dC (50 MHz, CDCl3) 47.0 (d,
4.3. General method for the preparation of aryloxyacetic
acid (4a–f)
3
1JC–PZ126.2 Hz, ylide carbon), 70.9 (d, JC–PZ9.8 Hz,
The ester 3 (10 mmol) was hydrolyzed in refluxing 10% aq
potassium hydroxide (0.56 g, 10 mmol) solution for 1 h.
The reaction mixture was cooled and neutralized with dilute
HCl (2.5 mL). The title compound fluorophenoxyacetic acid
4a–f obtained as solid, was filtered, washed with water
(25 mL) and dried.
2
CH2), 115.5 (d, JC–FZ23.1 Hz, sp2-carbon ortho to –F),
3
115.9 (d, JC–FZ7.9 Hz, sp2-carbon meta to –F), 120.8 (d,
1
2JC–PZ14.6 Hz, CN), 122.5 (d, JC–PZ93.7 Hz, phenyl
3
carbon attached to –P), 129.2 (d, JC–PZ13.0 Hz, phenyl
carbon meta to –P), 133.3 (d, 4JC–PZ2.3 Hz, phenyl carbon
para to –P), 133.6 (d, 2JC–PZ10.4 Hz, phenyl carbon ortho
to –P), 154.4 (s, sp2-carbon attached to –O and para to –F),
4.3.1. 3-Chloro-4-fluoro-phenoxyacetic acid (4d). 1.62 g,
80% as a white solid; mp 104–105 8C; [found: C, 47.01; H,
2.96. C8H6ClFO3 requires C, 46.96; H, 2.96%]; nmax (KBr)
3320, 2925, 1715, 1199 cmK1; dH (200 MHz, CDCl3) 4.88
(2H, s, OCH2), 6.73–6.77 (1H, m), 6.85–6.88 (1H, m), 7.18–
7.21 (1H, m); m/z (EI-MS) 204 (MC, 100), 187 (75%).
1
157.4 (d, JC–FZ238.3 Hz, sp2-carbon attached to –F) and
2
190.2 ppm (d, JC–PZ3.8 Hz, C]O); m/z: 453 (MHC, 2),
327 (42), 328 (100), 314 (18), 278 (9), 277 (33), 183 (25), 91
(63%).
4.5.2. [(2-Chloro-4-fluorophenoxyacetyl) (cyano)
methylene] triphenylphosphorane (8b). 2.04 g, 84% as a
yellow solid; mp 143 8C; [found: C, 69.13; H, 4.25; N, 2.91.
C28H20ClFNO2P requires C, 68.92; H, 4.13; N, 2.17%]; nmax
(KBr) 3049, 2985, 2175, 1618, 1094 cmK1; dH (200 MHz,
CDCl3) 5.03 (2H, s, –COCH2–), 6.83–6.92 (2H, m), 7.11–
7.18 (1H, m) 7.42–7.68 (15H, unresolved); m/z (LSIMS)
488 (MHC, 100), 489 (MC2, 33), 328 (96), 314 (28), 279
(76%).
4.4. General method for the preparation of aryloxyacetyl
chloride (5a–f)
The fluorophenoxyacetic acid 4 (10 mmol) was refluxed
with freshly distilled thionyl chloride (2.36 g, 20 mmol) in
hexane (10 mL) for 1–2 h. The hexane and excess thionyl
chloride was removed by distillation at atmospheric
pressure. Pure aryloxyacetyl chloride 5a–f was obtained
by distillation under reduced pressure.
4.5.3. [(2,4-Difluorophenoxyacetyl) (cyano) methylene]
triphenylphosphorane (8c). 2.15 g, 91.6% as a pale yellow
solid; mp 105 8C; [found: C, 71.39; H, 4.26; N, 3.01.
C28H20F2NO2P requires C, 71.33; H, 4.27; N, 2.97%]; nmax
(KBr) 3056, 2989, 2184, 1615, 1094 cmK1; dH (200 MHz,
CDCl3) 4.98 (2H, s, –COCH2–), 6.62–6.96 (3H, m) 7.35–
7.72 (15H, unresolved); m/z (LSIMS) 472 (MHC, 98), 328
(100), 314 (22), 279 (44%).
4.4.1. 2-Chloro-4-fluoro-phenoxyacetyl chloride (5b).
1.78 g, 81% as a colourless liquid; bp 90–91 8C/12 mm;
[found: C, 43.12; H, 2.27. C8H5Cl2FO2 requires C, 43.08; H,
2.26%]; nmax (CHCl3) 3040, 2925, 1795, 1210, 1088 cmK1
;
dH (200 MHz, CDCl3) 4.89 (2H, s, –OCH2), 6.83–6.88 (2H,
m), 7.07–7.11 (1H, m); m/z (EI-MS) 222 (MC, 18), 159
(100), 85 (54%).

V. V. V. N. S. RamaRao et al. / Tetrahedron 60 (2004) 12231–12237
12235
4.5.4. [(3-Chloro-4-fluorophenoxyacetyl) (cyano)
methylene] triphenylphosphorane (8d). 2.11 g, 87% as a
pale yellow solid; mp 138 8C; [found: C, 68.91; H, 4.23; N,
2.88. C28H20ClFNO2P requires C, 68.92; H, 4.13; N,
2.17%]; nmax (KBr) 3050, 2989, 2172, 1606, 1492, 1263,
1188, 1090 cmK1; dH (200 MHz, CDCl3) 4.93 (2H, s,
–COCH2–), 6.78–6.87 (1H, m), 6.86–7.02 (2H, m) 7.40–
7.80 (15H, unresolved); m/z (LSIMS) 488 (MHC, 77), 328
(100), 279 (31%).
bonyl) methylene] triphenylphosphorane (9d). 2.33 g,
87.4% as a pale yellow solid; mp 116–118 8C; [found: C,
66.89; H, 4.65. C30H25ClFO4P requires C, 67.35; H,
4.71%]; nmax (KBr) 3053, 2981, 1654, 1585, 1490, 1295,
1200, 1099 cmK1; dH (200 MHz, CDCl3) 0.69 (3H, t, JZ
7.1 Hz, –COO–CH2CH3), 3.73 (2H, q, JZ7.1 Hz, –COO–
CH2CH3), 5.14 (2H, s, –COCH2–), 6.64–6.71 (1H, m),
6.74–6.91 (2H, m) 7.37–7.72 (15H, unresolved); m/z
(LSIMS) 535 (MHC, 48), 375 (100), 279 (34%).
4.5.5. [(3-Trifluoromethylphenoxyacetyl) (cyano)
methylene] triphenylphosphorane (8e). 2.12 g, 84.3% as
a yellow solid; mp 149 8C; [found: C, 69.30; H, 4.28; N,
2.65. C29H21F3NO2P requires C, 69.24; H, 4.20; N, 2.78%];
nmax (KBr) 3062, 2986, 2174, 1606, 1120 cmK1; dH
(200 MHz, CDCl3) 5.08 (2H, s, –COCH2–), 7.08–7.14
(2H, m), 7.14–7.19 (1H, m), 7.29–7.36 (1H, m) 7.46–7.71
(15H, unresolved); m/z (LSIMS) 504 (MHC, 92), 328 (100),
314 (22), 279 (18%).
4.6. General method for the synthesis of 2-methyl-
benzofuran derivatives (13a–e, 13g and 14a–d)
The procedure for the synthesis of substituted 2-methyl-
benzofurans is explained by taking the example of 13a.
[(4-Fluorophenoxyacetyl) (cyano) methylene] triphenyl-
phosphorane, 8a 2.0 g (4.41 mmol) was taken in a sealed
tube and subjected to controlled10 microwave irradiation for
8 min. The dark brown reaction mixture was cooled to room
temperature, dissolved in DCM (10 mL) and purified by
column chromatography on silica gel (100–200 mesh) using
hexane as eluent. Concentration of the initial fractions
afforded 0.56 g (73%) of 3-cyano-5-fluoro-2-methyl-benzo-
furan, 13a. The later fractions eluted with a 1:1 mixture of
hexane and ethyl acetate contained triphenylphosphine
oxide, 12.
4.5.6. [(3-Methylphenoxyacetyl) (cyano) methylene] tri-
phenylphosphorane (8f). 2.06 g, 92% as a pale yellow
solid; mp 138–140 8C; [found: C, 77.81; H, 5.45; N, 3.12.
C29H24NO2P requires C, 77.49; H, 5.38; N, 3.11%]; nmax
(KBr) 3055, 2980, 2169, 1612, 1162, 1099 cmK1; dH
(200 MHz, CDCl3) 2.31 (3H, s, CH3), 4.92 (2H, s, –
COCH2–), 6.62–6.75 (3H, m), 7.03–7.14 (1H, m) 7.4–7.73
(15H, unresolved); m/z (LSIMS) 450 (MHC, 100), 328 (93),
314 (43), 279 (81%).
4.6.1. 3-Cyano-5-fluoro-2-methyl-benzofuran (13a).
0.56 g, 73% as a white solid; mp 102 8C; [found: C,
68.59; H, 3.48; N, 7.98. C10H6FNO requires C, 68.57; H,
3.45; N, 7.99%]; nmax (KBr) 3058, 2231 cmK1; dH
(200 MHz, CDCl3) 2.71 (3H, s, CH3), 7.08 (1H, ddd,
3JH–HZ9.0 Hz, 3JH–FZ8.7 Hz, 4JH–HZ2.7 Hz, C6–H), 7.28
(1H, dd, 3JH–FZ8.0 Hz, 4JH–HZ2.7 Hz, C4–H) 7.4 (1H, dd,
4.5.7. [(4-Fluorophenoxyacetyl) (ethoxycarbonyl)
methylene] triphenylphosphorane (9a). 2.29 g, 91.6% as
a white solid; mp 96 8C; [found: C, 72.12; H, 5.24.
C30H26FO4P requires C, 71.99; H, 5.23%]; nmax (KBr)
3051, 2984, 1660, 1185 cmK1; dH (200 MHz, CDCl3) 0.69
(3H, t, JZ7.1 Hz, –COO–CH2CH3), 3.75 (2H, q, JZ
7.1 Hz, –COO–CH2CH3), 5.16 (2H, s, –COCH2–), 6.72–
6.88 (4H, m), 7.34–7.69 (15H, unresolved); m/z (LSIMS)
501 (MHC, 41), 455 (23), 375 (100%).
4
3JH–HZ8.9 Hz, JH–FZ3.7 Hz, C7–H); dC (50 MHz,
2
CDCl3) 14.0 (s, CH3), 91.7 (s, C3), 105.6 (d, JC–F
Z
3
26.4 Hz, C4), 112.4 (d, JC–FZ9.5 Hz, C7), 112.7 (s, CN),
113.4 (d, 2JC–FZ26.4 Hz, C6), 127.1 (d, 3JC–FZ7.6 Hz, C9),
149.9 (s, C8), 160.0 (d, 1JC–FZ242.3 Hz, C5), 166.5 (s, C2);
m/z (EI-MS) 175 (mC, 100), 174 (100), 147 (4), 141 (6), 120
(9), 75 (6), 43 (8%).
4.5.8. [(2-Chloro-4-fluorophenoxyacetyl) (ethoxy-carbo-
nyl) methylene] triphenylphosphorane (9b). 2.42 g,
90.6% as a white solid; mp 117 8C; [found: C, 67.41; H,
4.68. C30H25ClFO4P requires C, 67.35; H, 4.71%]; nmax
(KBr) 3056, 2978, 1654, 1190, 1102 cmK1; dH (200 MHz,
CDCl3) 0.69 (3H, t, JZ7.1 Hz, –COO–CH2CH3), 3.72 (2H,
q, JZ7.1 Hz, –COOCH2CH3), 5.21 (2H, s, –COCH2–),
6.52–6.58 (1H, m), 6.60–6.67 (1H, m), 6.93–7.0 (1H, m),
7.27–7.63 (15H, unresolved); m/z (LSIMS) 535 (MHC, 37),
489 (18), 375 (100), 279 (21%).
4.6.2. 7-Chloro-3-cyano-5-fluoro-2-methyl-benzofuran
(13b). 0.75 g, 82% as a white solid; mp 124 8C); [found:
C, 57.43; H, 2.45; N, 6.67. C10H5ClFNO requires C, 57.30;
H, 2.40; N, 6.68%]; nmax (KBr) 3050, 2925, 2233, 1478,
1175, 1100 cmK1; dH (200 MHz, CDCl3) 2.71 (3H, s, CH3),
3
4
7.14 (1H, dd, JH–FZ8.5 Hz, JH–HZ2.6 Hz, C6–H) 7.23
3
4
(1H, dd, JH–FZ8.6 Hz, JH–HZ2.6 Hz, C4–H); dC
(50 MHz, CDCl3) 13.9 (s, CH3), 92.6 (s, C3), 104.3 (d,
2
2JC–FZ26.2 Hz, C4), 112.0 (s, CN), 114.1 (d, JC–F
Z
4.5.9. [(2,4-Difluorophenoxyacetyl) (ethoxycarbonyl)
methylene] triphenylphosphorane (9c). 2.40 g, 92.8% as
a white solid; mp 122 8C; [found: C, 69.50; H, 4.88.
C30H25F2O4P requires C, 69.48; H, 4.88%]; nmax (KBr)
3054, 2986, 1653, 1583, 1508, 1437, 1301, 1188,
1113 cmK1; dH (200 MHz, CDCl3) 0.69 (3H, t, JZ7.1 Hz,
–COO–CH2CH3), 3.72 (2H, q, JZ7.1 Hz, –COO–
CH2CH3), 5.23 (2H, s, –COCH2–), 6.45–6.79 (3H, m)
7.65–7.70 (15H, unresolved); m/z (LSIMS) 519 (MHC, 47),
375 (100), 279 (29%).
3
28.9 Hz, C6), 117.6 (d, JC–FZ12.0 Hz, C7), 127.7 (d,
1
3JC–FZ11.7 Hz, C9), 146.2 (s, C8), 159.4 (d, JC–F
Z
245.9 Hz, C5) and 167.0 (s, C2); m/z (EI-MS) 209 (MC,
100), 211 (MC2, 33), 208 (99), 175 (21), 147 (17%).
4.6.3. 3-Cyano-5,7-difluoro-2-methyl-benzofuran (13c).
0.64 g, 76% as a white solid; mp 83 8C; [found: C, 61.20; H,
2.65; N, 7.27. C10H5F2NO requires C, 62.18; H, 2.61; N,
7.25%]; nmax (KBr) 3065, 2233, 1112, 1108 cmK1; dH
(200 MHz, CDCl3) 2.71 (3H, s, CH3), 6.88 (1H, ddd,
3
4
4.5.10. [(3-Chloro-4-fluorophenoxyacetyl) (ethoxycar-
3JH–FZ9.7 Hz, JH–FZ9.7 Hz, JH–HZ2.3 Hz, C6–H) 7.14

12236
V. V. V. N. S. RamaRao et al. / Tetrahedron 60 (2004) 12231–12237
3
4
(1H, dd, JH–FZ8.2 Hz, JH–HZ2.3 Hz, C4–H); m/z
(200 MHz, CDCl3) 1.41 (3H, t, JZ7.1 Hz, –OCH2CH3),
2.82 (3H, s, CH3 on C2), 4.41 (2H, q, JZ7.1 Hz,
–OCH2CH3), 7.06 (1H, dd, JH–FZ8.6 Hz, JH–HZ2.6 Hz,
C6–H), 7.52 (1H, dd, 3JH–FZ8.6 Hz, 4JH–HZ2.6 Hz, C4–H);
m/z (EI-MS) 256 (MC, 78), 227 (63), 211 (100), 183 (16%).
(EI-MS) 193 (MC, 100), 192 (93%).
3
4
4.6.4. 6-Chloro-3-cyano-5-fluoro-2-methyl-benzofuran
(13d). 0.69 g, 76% as a pale yellow solid; mp 99 8C;
[found: C, 57.31; H, 2.32; N, 6.90. C10H5ClFNO requires C,
57.30; H, 2.40; N, 6.68%]; nmax (KBr) 3061, 2922, 2231,
1480, 1171, 1105 cmK1; dH (200 MHz, CDCl3) 2.70 (3H,
4.6.10. 3-Ethoxycarbonyl-5,7-difluoro-2-methyl-benzo-
furan (14c). 0.79 g, 75% as a white solid; mp 72 8C;
[found: C, 60.03; H, 4.21. C12H10F2O3 requires C, 60.0; H,
4.19%]; nmax (KBr) 3060, 1706, 1075 cmK1; dH (200 MHz,
CDCl3) 1.45 (3H, t, –OCH2CH3, JZ7.1 Hz), 2.81 (3H, s,
CH3 on C2), 4.41 (2H, q, JZ7.1 Hz, –OCH2CH3), 6.8 (1H,
3
s, CH3), 7.40 (1H, d, JH–FZ8.1 Hz, C4–H) 7.56 (1H, d,
4JH–FZ6.0 Hz, C7–H); m/z (EI-MS) 209 (MC, 98), 211
(MC2, 28), 208 (55), 174 (100%).
3
3
4
ddd, JH–FZ9.7 Hz, JH–FZ9.7 Hz, JH–HZ2.3 Hz, C6–H)
7.4 (1H, dd, 3JH–FZ8.2 Hz, 4JH–HZ2.3 Hz, C4–H); m/z (EI-
MS) 240 (MC, 78), 211 (53), 195 (100), 120 (41%).
4.6.5. 3-Cyano-2-methyl-6-trifluoromethyl-benzofuran
(13e). 0.31 g, 32% as a colourless liquid; [found: C,
58.70; H, 2.69; N, 6.36. C11H6F3NO requires C, 58.67; H,
2.68; N, 6.22%]; nmax (CHCl3) 3059, 2953, 2230,
1089 cmK1; dH (200 MHz, CDCl3) 2.88 (3H, s, CH3),
7.47 (1H, d, JZ7.5 Hz, C4–H), 7.64 (1H, s, C7–H) 7.68 (1H,
d, JZ7.5 Hz, C5–H); m/z (EI-MS) 225 (MC, 100), 224
(96%).
4.6.11. 6-Chloro-3-ethoxycarbonyl-5-fluoro-2-methyl-
benzofuran (14d). 0.88 g, 78% as a white solid; mp
70 8C; [found: C, 56.19; H, 4.05. C12H10ClFO3 requires C,
56.16; H, 3.93%]; nmax (KBr) 3062, 1705, 1093 cmK1; dH
(200 MHz, CDCl3) 1.46 (3H, t, –OCH2CH3, JZ7.1 Hz),
2.79 (3H, s, CH3 on C2), 4.40 (2H, q, JZ7.1 Hz,
4.6.6. 4-[31-(Trifluoromethyl) phenoxy]-but-2-ynenitrile
(15e). 0.09 g, 9% as a colourless liquid; [found: C, 58.75; H,
2.61; N, 6.33. C11H6F3NO requires C, 58.67; H, 2.68; N,
6.22%]; nmax (CHCl3) 3054, 2950, 2245, 2310 cmK1; dH
(200 MHz, CDCl3) 4.83 (2H, s, –OCH2), 7.11 (1H, d,
7.5 Hz, C6–H); 7.31 (1H, d, JZ7.5 Hz, C4–H), 7.44 (1H, t,
JZ7.5 Hz, C5–H) 7.62 (1H, s, C2–H); m/z (EI-MS) 225
(MC, 100%).
4
–OCH2CH3), 7.46 (1H, d, JH–FZ6.0 Hz, C7–H) 7.67 (1H,
3
d, JH–FZ8.2 Hz, C4–H); m/z (EI-MS) 256 (MC, 88), 227
(100), 211 (69%).
4.7. General method for the thermolysis of [(aryloxy-
acetyl) alkylidene] triphenylphosphoranes (8a, 8e
and 9a)
The [(aryloxyacetyl) alkylidene] triphenylphosphorane
(4.41 mmol) was taken in a short path vacuum distillation
apparatus with wide ground glass joints and was heated for
20–30 min at 2–5 Torr, by immersing in a Wood’s metal
bath, to an external bath temperature ranging from 240 to
275 8C. The distillate collected in the receiver, cooled in dry
ice acetone, was dissolved in dichloromethane (10 mL) and
subjected to column chromatography as per the procedure
in Section 4.6. Thermolysis results of the individual
phosphoranes 8a, 8e and 9a are given in Table 1.
4.6.7. 3-Cyano-2,4-dimethyl-benzofuran (13g). 0.52 g,
70% as a pale yellow solid; mp 52 8C; [found: C, 77.32;
H, 5.21; N, 8.26. C11H9NO requires C, 77.17; H, 5.30; N,
8.18%]; nmax (KBr) 3058, 2221, 1486, 1101 cmK1; dH
(200 MHz, CDCl3) 2.63 (3H, s, CH3), 2.67 (3H, s, CH3),
7.03 (1H, d, JZ7.5 Hz, C7–H), 7.16 (1H, t, JZ7.5 Hz, C6–
H), 7.28 (1H, d, JZ7.5 Hz, C5–H); dC (50 MHz, CDCl3)
13.7 (s, CH3 on C2), 17.7 (s, CH3 on C4), 90.6 (s, C3), 109.0
(s, C7), 111.6 (s, CN), 125.3 (s, C5), 125.4 (s, C6), 125.7 (s,
C9), 131.1 (s, C4), 153.7 (s, C8), 164.9 (s, C3); m/z (EI-MS)
171 (MC, 98), 170 (100), 113 (46%).
4.7.1. 4-(41-Fluorophenoxy)-but-2-ynenitrile (15a).
0.39 g, 51% as a colourless liquid; [found: C, 68.56; H,
3.47; N, 8.01. C10H6FNO requires C, 68.57; H, 3.45; N,
7.99%]; nmax (KBr) 2243, 2309, 3054 cmK1; dH (200 MHz,
4.6.8. 3-Ethoxycarbonyl-5-fluoro-2-methyl-benzofuran
(14a). 0.69 g, 71% as a colourless liquid; [found: C,
64.93; H, 4.96. C12H11FO3 requires C, 64.86; H, 4.98%];
nmax (KBr) 3060, 1708, 1490, 1300, 1144, 1075 cmK1; dH
(200 MHz, CDCl3) 1.43 (3H, t, JZ7.1 Hz, –OCH2CH3),
2.76 (3H, s, CH3 on C2), 4.38 (2H, q, JZ7.1 Hz,
3
CDCl3) 4.75 (2H, s, CH2), 6.86 (2H, ddd, JH–HZ7.5 Hz,
4
3JH–FZ6.8 Hz, JH–HZ2.3 Hz, C3–H), 7.01 (2H, ddd,
4
4
3JH–HZ7.5 Hz, JH–FZ5.6 Hz, JH–HZ2.3 Hz, C2–H); dC
(50 MHz, CDCl3), 56.4 (s, OCH2), 61.3 (s, sp-carbon
attached to –CN), 79.4 (s, sp-carbon attached to –CH2),
104.2 (s, CN), 116.3 (d, 2JC–FZ23.3 Hz, sp2-carbon ortho to
–F), 116.5 (d, 3JC–FZ7.9 Hz, sp2-carbon meta to –F), 153.0
(s, sp2-carbon attached to –O and para to –F), 158.4 (d,
1JC–FZ238 Hz, sp2-carbon attached to –F); m/z (EI-MS)
175 (MC, 100%).
3
3
–OCH2CH3), 6.95 (1H, ddd, JH–HZ9.0 Hz, JH–F
Z
Z
4
3
8.7 Hz, JH–HZ2.7 Hz, C6–H), 7.3 (1H, dd, JH–H
4
3
8.9 Hz, JH–FZ3.7 Hz, C7–H) 7.5 (1H, dd, JH–FZ8.0 Hz,
4JH–HZ2.7 Hz, C4–H); dC (50 MHz, CDCl3) 12.4 (s,
OCH2CH3), 13.9 (s, CH3 on C2), 58.3 (s, OCH2), 105.8
2
3
(d, JC–FZ26.4 Hz, C4), 106.5 (s, C3), 109.5 (d, JC–F
Z
2
9.6 Hz, C7), 109.9 (d, JC–FZ26.6 Hz, C6), 125.4 (d,
3JC–FZ11.2 Hz, C9), 147.8 (s, C8), 157.9 (d, JC–F
238.8 Hz, C5), 161.9 (s, –COO–), 168.0 (s, C2); m/z (EI-
Z
1
MS) 222 (MC, 65), 193 (66), 177 (100%).
Acknowledgements
4.6.9. 7-Chloro-3-ethoxycarbonyl-5-fluoro-2-methyl-
benzofuran (14b). 0.89 g, 79% as a pale yellow solid; mp
83 8C; [found: C, 56.16; H, 3.95. C12H10ClFO3 requires C,
56.16; H, 3.93%]; nmax (KBr) 3068, 1705, 1093 cmK1; dH
The authors are thankful to Dr. J. S. Yadav, Director, IICT,
Hyderabad for his constant encouragement. V. V. V. N. S.
R. R., G. V. R., D. M. and S. R. K. are thankful to CSIR,
New Delhi for the award of senior research fellowship.

V. V. V. N. S. RamaRao et al. / Tetrahedron 60 (2004) 12231–12237
12237
6. Friedrichsen, W. In Comprehensive Heterocyclic Chemistry II-
A Review of the Literature 1982–1995; Pergamon: New York,
1996; Vol. 2, pp 368–378.
References and notes
1. Keay, B. A.; Dibble, P. W. In Comprehensive Heterocyclic
Chemistry II-A Review of the Literature 1982–1995;
Pergamon: New York, 1996; Vol. 2, pp 413–436.
2. Bos, M.; Stadler, H.; Wichmann, J. U.S. Patent US 5, 955, 495;
Chem. Abstr. 1999, 131, 214186n.
7. Rao, U.; Balasubramanian, K. K. Tetrahedron Lett. 1983, 24,
5023–5024.
8. (a) Yadla, R.; Rao, J. M. Heterocycles 1987, 26, 329–331.
(b) Rehman, H.; Rao, J. M. Synth. Commun. 1987, 17,
1119–1128. (c) Rehman, H.; Rao, J. M. Tetrahedron 1987, 43,
5335–5340.
3. (a) Powers, L. J. J. Med. Chem. 1976, 19, 57–62. (b) Lambert,
C. M. P.; Ple, P. PCT Int. Appl. WO 0230,924; Chem. Abstr.
2002, 136, 325553d.
9. Bestmann, H. J. Chem. Ber. 1962, 95, 58.
10. 600 W microwave power was used for decomposition of
13a–f. For the remaining ylides 14a–d 450 W microwave
power was used.
4. Chatterjee, R.; Kapoor, R. US Patent US 5118707; Chem.
Abstr. 1992, 117, 97119r.
5. Leung, A. Y.; Foster, S. Encyclopedia of Common Natural
Ingredients Used in Food, Drugs and Cosmetics; Wiley: New
York, 1996.