A highly regio- And stereoselective synthesis of (Z)-3-arylidene-2,3-dihydro-5H-1,4-benzodioxepin-5-ones and (Z)-3-arylidene1,2,3,5-tetrahydro-4,1-benzoxazepin-5-ones through palladium-copper catalysis

Article abstract of DOI:10.1039/a908682j

Sodium 2-(prop-2′-ynyloxy)benzoate 1a reacted with the aryl iodides 2-10 in the presence of bis(triphenylphosphine)palladium(II) chloride, cuprous iodide and triethylamine in CH₃CN-DMF to yield the disubstituted alkynes 11-19 in good yields (48

Full text of DOI:10.1039/a908682j

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A highly regio- and stereoselective synthesis of (Z)-3-arylidene-
2,3-dihydro-5H-1,4-benzodioxepin-5-ones and (Z)-3-arylidene-
1,2,3,5-tetrahydro-4,1-benzoxazepin-5-ones through palladium–
copper catalysis
1
Gopeswar Chaudhuri and Nitya G. Kundu*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur,
Calcutta - 700 032, India
Received (in Cambridge, UK) 1st November 1999, Accepted 20th December 1999
Sodium 2-(prop-2Ј-ynyloxy)benzoate 1a reacted with the aryl iodides 2–10 in the presence of bis(triphenyl-
phosphine)palladium() chloride, cuprous iodide and triethylamine in CH3CN–DMF to yield the disubstituted
alkynes 11–19 in good yields (48–58%). Similarly, sodium 2-[N-benzyl-N-(prop-2Ј-ynyl)]aminobenzoate 1b on
reaction with aryl iodides under palladium–copper catalysis afforded the disubstituted alkynes 20–22. Compounds
11–19 on cyclisation with cuprous iodide in the presence of triethylamine in acetonitrile yielded the 3-arylidene-2,3-
dihydro-5H-1,4-benzodioxepin-5-ones 23–31 in 61–83% yields. Similarly, compounds 20–22 on cyclisation gave
3-arylidene-1,2,3,5-tetrahydro-4,1-benzoxazepin-5-ones 32–34.
Over the last few decades, palladium-catalysed reactions1 have
been of immense significance because of their role in carbo-
annulation2 and heteroannulation processes.3 In our laboratory,
we have developed methods based on palladium–copper
catalysed heteroannulation of terminal alkynes which have led
to various benzofused heterocycles, e.g., benzofurans,4 phthal-
ides,5 quinolines and quinolones,6 benzodioxans,7 isoindol-
inones,8 benzoxazines9 and isobenzofurans.10 In continuation
of those studies, we became interested in the development of
benzofused heterocycles containing seven-membered rings with
two heteroatoms, e.g. benzodioxepinone I and benzoxazepinone
II structures.
Scheme 1
cuprous iodide and triethylamine in CH3CN–DMF led to the
disubstituted alkynes 20–22 which on cyclisation with cuprous
iodide in triethylamine led to the 3-arylidene-1,2,3,5-tetra-
hydro-4,1-benzoxazepin-5-ones 32–34 (Scheme 1 and Table 1).
The starting materials (1a and 1b) were synthesised by
propargylation of methyl salicylate or methyl anthranilate with
propargyl bromide in the presence of potassium carbonate in
acetone and subsequent hydrolysis of the products with potas-
sium hydroxide.† The N-benzylation was carried out with benzyl
bromide in DMF in the presence of potassium carbonate.
The palladium-catalysed reactions of 1a or 1b with aryl
iodides were carried out with bis(triphenylphosphine)-
palladium() chloride in the presence of cuprous iodide as a
co-catalyst. The reactions were usually carried out at room tem-
perature when only the disubstituted alkynes were obtained. If
the reactions were carried out at a higher temperature (80 ЊC),
the yields of the disubstituted alkynes (11–22) were much lower,
although formation of some cyclic products (8–10%) could also
be seen. Usually the sodium salts 1a or 1b were used for the
palladium catalysed reactions. The corresponding free acids led
There have been many reports of compounds containing
these structures which occur naturally and are also of biological
importance.11 However, a search of the literature revealed only
a limited number of methods available for the synthesis of these
heterocyclic structures.12
In view of this, we wish to report in this paper our results
on the synthesis of benzodioxepinone and benzoxazepinone
structures.
Results and discussion
When sodium 2-(prop-2Ј-ynyloxy)benzoate 1a was treated with
aryl iodides 2–10 in the presence of bis(triphenylphosphine)-
palladium() chloride, cuprous iodide and triethylamine in
CH3CN–DMF, the disubstituted alkynes 11–19 were obtained
in good yields (48–58%). The cyclisation of 11–19 with cuprous
iodide in the presence of triethylamine in acetonitrile yielded
the 3-arylidene-2,3-dihydro-5H-1,4-benzodioxepin-5-ones 23–
31 in 61–83% yields (Scheme 1 and Table 1). Similarly, sodium
2-[N-benzyl-N-(prop-2Ј-ynyl)]aminobenzoate 1b on treatment
with aryl iodides 2, 8 or 9 in the presence of palladium catalyst,
† The IUPAC name for propargyl is prop-2-ynyl.
DOI: 10.1039/a908682j
J. Chem. Soc., Perkin Trans. 1, 2000, 775–779
This journal is © The Royal Society of Chemistry 2000
775

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Table 1 Synthesis of 1,4-benzodioxepinones (23–31) and 4,1-benzoxazepinones (32–34)
Disubstituted
alkynes 11–22
(Yield %)a
Dioxepinones or
oxazepinones
(Yield %)b
Monosubstituted
alkynes, 1 X
Entry
Aryl iodides, ArI Ar
1
2
3
4
5
6
7
8
9
O, 1a
Ph, 2
o-MeOC6H4, 3
m-ClC6H4, 4
o-MeO2CC6H4, 5
2-Thienyl, 6
11 (56)
12 (57)
13 (55)
14 (54)
15 (58)
16 (48)
17 (58)
18 (58)
19 (50)
20 (68)
21 (65)
22 (64)
23 (83)
24 (80)
25 (80)
26 (75)
27 (76)
28 (83)
29 (79)
30 (75)
31 (61)
32 (84)
33 (81)
34 (73)
O, 1a
O, 1a
O, 1a
O, 1a
O, 1a
o-CH3CO-OC6H4, 7
p-MeOC6H4, 8
2,4-Dimethoxypyrimidin-5-yl, 9
o-IC6H4, 10
O, 1a
O, 1a
O, 1a
10
11
12
N-Bn, 1b
N-Bn, 1b
N-Bn, 1b
Ph, 2
p-MeOC6H4, 8
2,4-Dimethoxypyrimidin-5-yl, 9
a Yields are based on 1 and refer to chromatographically pure isolated materials. b Based on the disubstituted alkynes 11–22 and refer to the
chromatographically pure isolated materials.
to lower yields. The reactions were carried out in a mixture of
acetonitrile and dimethyl formamide. Use of DMF alone led to
lower yields due to the formation of strongly coloured materials.
The use of other catalysts like tetrakis(triphenylphosphine)pal-
ladium(0) in the presence of potassium carbonate in dimethyl
formamide at 60 ЊC or palladium() acetate in the presence
of potassium tert-butoxide, tetrabutylammonium chloride,
triphenylphosphine in acetonitrile at room temperature for 8 h
did not yield the disubstituted alkynes. Various substituted aryl
iodides could be used in the palladium-catalysed reactions
leading to the disubstituted alkynes. However, when 1,2-diiodo-
benzene was used, only one of the iodo-groups participated
in the palladium-catalysed reactions, the other iodo-group
remained unaffected.
Varian EM-360, and a Bruker DPX-300 spectrometer for sam-
ples in solvents as indicated with tetramethylsilane as internal
reference; J values given in Hz. TLC was performed on 60F-254
precoated silica gel sheets (E. Merck) and column chrom-
atography was done on silica gel (60–120 mesh) or neutral
alumina. Light petroleum refers to the fraction with distil-
lation range 60–80 ЊC. Elemental analyses were performed on a
Perkin-Elmer 240C analyser.
The aryl iodides 2–10 were synthesised according to the
known procedures.7
Synthesis of the sodium salt of 2-(prop-2Ј-ynyloxy)benzoic acid
1a
A mixture of methyl salicylate (5 g, 32.89 mmol) and anhydrous
potassium carbonate (4.54 g, 32.89 mmol) in dry acetone (20
cm3) was stirred for 2 h at room temperature. Propargyl brom-
ide (4.69 g, 39.46 mmol) in dry acetone (10 cm3) was then added
very carefully over 30 min. The whole mixture was then heated
under reflux for 16 h with constant stirring under a N2 atmos-
phere. After removal of acetone, the residue was poured into
water (50 cm3) and extracted with chloroform (3 times 50 cm3).
The combined organic layer was washed with water (3 times 50
cm3) and dried over anhydrous sodium sulfate. After removal of
solvent, the residue was purified by column chromatography
over silica gel, using 1:1 chloroform–light petroleum as eluting
solvent, to yield methyl 2-(prop-2Ј-ynyloxy)benzoate as a
colourless oil, yield 5.80 g (93%) (Found: C, 69.28; H, 5.03.
C11H10O3 requires C, 69.46; H, 5.29%); νmax (neat)/cmϪ1 3280
The cyclisation of the disubstituted alkynes was carried out
by heating with cuprous iodide (5 mol%) in the presence of
triethylamine in acetonitrile. The cyclised products were
obtained in 61–83% yields. The cyclisation of the disubstituted
alkynes could also be carried out by refluxing them in aceto-
nitrile in the presence of PdCl2 (5 mol%) as catalyst. However,
the yields were much lower (40%). For the formation of the 4,1-
benzoxazepinones, the presence of a benzyl (Bn) or an alkyl
group on the nitrogen atom was found to be essential for
cyclisation. The cyclisation step leading to the dioxepinone or
the oxazepinone structure was found to be highly regio- and
stereoselective. Only seven-membered ring heterocycles were
formed. The establishment of the Z-configuration of the
3
3-arylidene group follows from the JCH values13 of the vinylic
proton and the methylenic carbon of the heterocyclic rings and
from the NOE data.14 The compounds of Z-configuration were
found to be quite stable. Attempted isomerisation of compound
23 by (i) stirring in concentrated sulfuric acid at room temper-
ature for 2–5 h or (ii) by heating in nitrobenzene in the presence
of iodine at 100–110 ЊC for 16 h did not afford the correspond-
ing E-isomer.
Thus, we have reported a highly efficient regio- and stereo-
selective method for the synthesis of (Z)-3-arylidene-2,3-
dihydro-5H-1,4-benzodioxepin-5-ones and (Z)-3-arylidene-
1,2,3,5-tetrahydro-4,1-benzoxazepin-5-ones starting from
readily available materials under extremely mild conditions. We
believe this is the first report of a general procedure for the
synthesis of benzodioxepinones and benzoxazepinones using
palladium–copper catalysis.
᎐
and 1715; δH (60 MHz; CCl ) 2.43 (1H, t, J 2.0, C᎐CH), 3.79
᎐
4
(3H, s, -CO2Me), 4.70 (2H, d, J 2.0, -OCH2), 6.825–7.13 (2H,
m, ArH), 7.26–7.82 (2H, m, ArH).
Potassium hydroxide (2.94 g, 52.57 mmol) dissolved in water
(10 cm3) was added dropwise to a methanolic solution (20 cm3)
of methyl 2-(prop-2Ј-ynyloxy)benzoate (5 g, 26.28 mmol) with
constant stirring. This was stirred at room temperature for
about 24 h. The residue obtained after the removal of methanol
was neutralised with dilute HCl (6 M). It was extracted with
chloroform (3 times 50 cm3). The combined chloroform extract
was washed with water (3 times 50 cm3) and dried over
anhydrous sodium sulfate. After removal of solvent, the solid
residue was crystallised from ether–light petroleum. 2-(Prop-2Ј-
ynyloxy)benzoic acid was obtained as a white crystalline solid,
yield 4.21 g (91%); mp 82–83 ЊC (Found: C, 68.22; H, 4.64.
C10H8O3 requires C, 68.17; H, 4.57%); νmax (KBr)/cmϪ1 3280
Experimental
᎐
and 1703; δH (60 MHz; CCl ) 2.50 (1H, t, J 2.0, C᎐CH), 4.84
᎐
4
Mps were determined in an open sulfuric acid bath or on a
Reichert (285980) (Austria) bath and are uncorrected. IR spec-
tra were taken on a Perkin-Elmer 298 instrument for samples as
KBr plates or liquid films. 1H NMR spectra were recorded on a
(2H, d, J 2.0, -OCH2), 6.89–7.23 (2H, m, ArH), 7.39–7.72 (1H,
m, ArH), 8.00–8.16 (1H, m, ArH) and 11.09 (1H, s, -CO2H).
To a solution of sodium (45 mg, 1.98 mmol) in methanol
(10 cm3), 2-(prop-2Ј-ynyloxy)benzoic acid (350 mg, 1.98 mmol)
776
J. Chem. Soc., Perkin Trans. 1, 2000, 775–779

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was added and stirred for 5 min and the sodium salt 1a was
obtained after the removal of methanol under reduced pressure
in quantitative yield.
(5 mol%) and triethylamine (2.5 equiv.) was stirred in dry
acetonitrile (9 cm3) for about 25 min under an argon atmos-
phere. The sodium salt of the acetylenic compound 1a or 1b
(1 mmol) in dry DMF (7 cm3) was added very slowly and the
reaction mixture was stirred at room temperature for 24 h.
After removal of solvent, the residue was neutralised with
dilute HCl (6 M) and this was extracted with chloroform
(3 times 25 cm3) and water (50 cm3). The combined chloroform
layer was washed with water (3 times 25 cm3) and dried over
anhydrous sodium sulfate. The material obtained after the
removal of solvent was purified by chromatography on silica gel
(60–120 mesh) using chloroform as eluent, the disubstituted
alkynes (11–22) were obtained as gum.
Synthesis of the sodium salt of 2-(N-benzyl-N-prop-2Ј-ynyl)-
aminobenzoic acid 1b
A mixture of methyl anthranilate (5 g, 33.07 mmol) and
anhydrous potassium carbonate (4.56 g, 33.07 mmol) in dry
DMF (20 cm3) was stirred for 8 h at room temperature under a
N2 atmosphere. Propargyl bromide (4.72 g, 39.68 mmol) in dry
DMF (10 cm3) was then added slowly over 30 min. The whole
mixture was heated at 80 ЊC for 48 h with constant stirring
under a N2 atmosphere. DMF was removed from the reaction
mixture under reduced pressure and the residue was extracted
with chloroform (3 times 50 cm3) and distilled water (50 cm3). The
chloroform extract was washed with water (2 times 50 cm3) and
dried over anhydrous sodium sulfate. After removal of solvent,
the residue was purified by column chromatography over silica
gel, using 1:1 chloroform–light petroleum as eluting solvent to
yield methyl 2-(N-prop-2Ј-ynyl)aminobenzoate, yield 4.43 g
(71%); mp 63 ЊC (Found: C, 69.69; H, 5.68; N, 7.29. C11H11NO2
2-[(3Ј-Phenyl)prop-2Ј-ynyloxy]benzoic acid 11. Gum (Found:
C, 75.78; H, 5.15. C16H12O3 requires C, 76.17; H, 4.79%);
νmax (neat)/cmϪ1 1702; δH (60 MHz; CCl4) 5.13 (2H, s, -CH2),
7.0–7.72 (6H, m, ArH) and 8.0–8.33 (3H, m, ArH).
2-[3Ј-(o-Methoxyphenyl)prop-2Ј-ynyloxy]benzoic acid 12.
Gum (Found: C, 72.21; H, 5.13. C17H14O4 requires C, 72.32; H,
4.99%); νmax (neat)/cmϪ1 1701; δH (60 MHz; CCl4) 3.76 (3H, s,
-OCH3), 5.09 (2H, s, -CH2), 6.72–7.52 (7H, m, ArH), 8.0–8.2
(1H, m, ArH) and 10.4 (1H, s, -CO2H, broad).
requires C, 69.82; H, 5.86; N, 7.40%); νmax (KBr)/cmϪ1 3369,
᎐
3284 and 1686; δH (60 MHz; CCl ) 2.03 (1H, t, J 2.0, C᎐CH),
᎐
4
3.66 (3H, s, -CO2Me), 3.79–3.95 (2H, dd, J 4.0), 6.36–6.69 (2H,
m, ArH), 7.09–7.42 (1H, m, ArH) and 7.66–7.89 (1H, m, ArH).
A mixture of methyl 2-(N-prop-2Ј-ynyl)aminobenzoate (3 g,
15.85 mmol) and anhydrous potassium carbonate (2.19 g, 15.85
mmol) in dry DMF (15 cm3) was stirred for 8 h at room tem-
perature under a N2 atmosphere. Benzyl bromide (4.06 g, 23.77
mmol) in dry DMF (10 cm3) was then added slowly over 20
min. The whole mixture was heated at 80 ЊC for 48 h with con-
stant stirring under a N2 atmosphere. The residue obtained
after removal of DMF under reduced pressure was extracted
with chloroform (3 times 50 cm3) and water (50 cm3). The
combined chloroform layer was washed with water (2 times
50 cm3) and dried over anhydrous sodium sulfate. After
removal of solvent, the residue was purified by column chrom-
atography over silica gel using 3:1 chloroform–light petroleum
as eluent. Methyl 2-(N-benzyl-N-prop-2Ј-ynyl)aminobenzoate
was obtained as a colourless oil, yield 2.50 g (56.56%) (Found:
C, 77.36; H, 6.12; N, 4.92. C18H17NO2 requires C, 77.39; H,
6.13; N, 5.01%); νmax (neat)/cmϪ1 3285 and 1715; δH (60 MHz;
2-[3Ј-(m-Chlorophenyl)prop-2Ј-ynyloxy]benzoic acid 13. Gum
(Found: C, 67.01; H, 4.15. C16H11O3Cl requires C, 67.02; H,
3.86%); νmax (neat)/cmϪ1 1702; δH (60 MHz; CCl4) 5.03 (2H, s,
-CH2), 6.82–7.66 (7H, m, ArH), 7.8–8.13 (1H, m, ArH) and
10.5 (1H, s, -CO2H, broad).
2-[3Ј-(o-Methoxycarbonylphenyl)prop-2Ј-ynyloxy]benzoic
acid 14. Gum (Found: C, 69.41; H, 4.72. C18H14O5 requires C,
69.67; H, 4.54%); νmax (neat)/cmϪ1 1715 and 1702; δH (60 MHz;
CCl4) 3.89 (3H, s, -CO2Me), 5.10 (2H, s, -CH2), 6.81–7.72 (7H,
m, ArH) and 8.01–8.26 (1H, m, ArH).
2-[3Ј-(2-Thienyl)prop-2Ј-ynyloxy]benzoic acid 15. Gum
(Found: C, 64.79; H, 4.04. C14H10O3S requires C, 65.09; H,
3.90%); νmax (neat)/cmϪ1 1703; δH (60 MHz; CCl4) 5.06 (2H, s,
-CH2), 6.76–7.69 (5H, m, ArH), 7.90–8.16 (2H, m, ArH) and
10.92 (1H, s, -CO2H, broad).
᎐
᎐
CCl ) 2.03 (1H, t, J 2.0, C᎐CH), 3.69 (2H, d, J 2.0, CH C᎐C),
᎐
᎐
4
2
2-[3Ј-(o-Acetoxyphenyl)prop-2Ј-ynyloxy]benzoic acid 16.
Gum (Found: C, 69.40; H, 4.79. C18H14O5 requires C, 69.60;
H, 4.54%); νmax (neat)/cmϪ1 1715 and 1701; δH (60 MHz; CCl4),
2.03 (3H, s, -OCOCH3), 5.0 (2H, s, -CH2), 6.79–7.62 (6H, m,
ArH), 7.76–8.06 (2H, m, ArH) and 10.03 (1H, s, -CO2H,
broad).
3.75 (3H, s, -CO2Me), 4.33 (2H, s, -NCH2Ph), 6.79–7.58 (8H,
m, ArH) and 7.58–7.75 (1H, m, ArH).
Potassium hydroxide (1.0 g, 17.82 mmol) dissolved in water
(10 cm3) was added dropwise to a methanolic solution (20 cm3)
of methyl 2-(N-benzyl-N-prop-2Ј-ynyl)aminobenzoate (2.5 g,
8.94 mmol) with constant stirring. This was stirred at room
temperature for 24 h. The residue obtained after the removal of
methanol was neutralised with dilute HCl (6 M) and worked up
with chloroform (3 times 50 cm3) and water (50 cm3). The solid
residue obtained after the removal of chloroform was crystal-
lised from ether–light petroleum. 2-(N-Benzyl-N-prop-2Ј-ynyl)-
aminobenzoic acid was obtained as a white crystalline solid,
yield 1.97 g (83.12%); mp 117–118 ЊC (Found: C, 76.95; H, 5.69;
N, 5.28. C17H15NO2 requires C, 76.93; H, 5.58; N, 5.21%);
νmax (KBr)/cmϪ1 3293 and 1691; δH (60 MHz; CCl4) 2.36 (1H, t,
J 2.0), 3.66 (2H, d, J 2.0), 4.23 (2H, s, -NCH2Ph), 7.09–7.75
(8H, m, ArH) and 8.06–8.29 (1H, m, ArH).
2-[3Ј-(p-Methoxyphenyl)prop-2Ј-ynyloxy]benzoic acid 17.
Gum (Found: C, 72.09; H, 5.18. C17H14O4 requires C, 72.32; H,
4.99%); νmax (neat)/cmϪ1 1702; δH (60 MHz; CCl4) 3.79 (3H, s,
-OCH3), 5.09 (2H, s, -CH2), 6.72–7.56 (6H, m, ArH), 8.03–8.40
(2H, m, ArH) and 10.13 (1H, s, -CO2H, broad).
2-[3Ј-(2,4-Dimethoxypyrimidin-5-yl)prop-2Ј-ynyloxy]benzoic
acid 18. Gum (Found: C, 60.94; H, 4.74; N, 8.78. C16H14N2O5
requires C, 61.14; H, 4.48; N, 8.91%); νmax (neat)/cmϪ1 1702;
δH (300 MHz; CDCl3) 4.00 (3H, s, -OCH3), 4.03 (3H, s, -OCH3),
5.18 (2H, s, -CH2), 7.15–7.27 (2H, m, ArH), 7.55–7.61 (1H, m,
ArH), 8.16–8.19 (1H, q, ArH) and 8.31 (1H, s, ArH).
To a solution of sodium (30 mg, 1.3 mmol) in methanol (10
cm3), 2-(N-benzyl-N-prop-2Ј-ynyl)aminobenzoic acid (350 mg,
1.3 mmol) was added and stirred for 5 min and the sodium salt
1b was obtained after the removal of methanol under reduced
pressure in quantitative yield.
2-[3Ј-(o-Iodophenyl)prop-2Ј-ynyloxy]benzoic acid 19. Gum
(Found: C, 50.56; H, 3.25. C16H11IO3 requires C, 50.81; H,
2.93%); νmax (neat)/cmϪ1 1701; δH (60 MHz; CCl4) 5.05 (2H, s,
-CH2), 6.74–7.68 (7H, m, ArH) and 7.91–8.15 (1H, m, ArH).
General procedure for the synthesis of 11–22
A
mixture of iodoarene 2–10 (1 mmol), bis(triphenyl-
2-[N-Benzyl-N-(3Ј-phenylprop-2Ј-ynyl)amino]benzoic acid 20.
phosphine)palladium() chloride (2.5 mol%), cuprous iodide
Gum (Found: C, 80.59; H, 5.79; N, 3.83. C23H19NO2 requires C,
J. Chem. Soc., Perkin Trans. 1, 2000, 775–779
777

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80.91; H, 5.60; N, 4.10%); νmax (neat)/cmϪ1 1702; δH (60 MHz;
4.73. C18H14O5 requires C, 69.67; H, 4.54%); νmax (neat)/cmϪ1
1720, 1710 and 1660; δH (300 MHz; CDCl3) 3.74 (3H, s,
-CO Me), 4.81 (2H, s, -CH ), 6.82 (1H, s, ᎐CH), 6.97–7.04 (2H,
᎐
CCl ) 3.86 (2H, s, -CH -C᎐), 4.33 (2H, s, -NCH Ph), 7.16–7.8
᎐
4
2
2
(13H, m, ArH) and 8.16–8.42 (1H, m, ArH).
᎐
2
2
m, ArH), 7.22–7.28 (1H, m, ArH), 7.39–7.45 (2H, m, ArH),
7.65–7.68 (1H, m, ArH) and 7.83–7.87 (2H, m, ArH); δC (75
MHz; CDCl3) 52.49, 73.09, 117.89, 118.54, 120.97, 122.88,
128.36, 129.31, 130.99, 131.26, 132.59, 133.77, 134.44, 135.42,
144.07, 157.38, 165.64 and 167.70; δC (75 MHz; CDCl3; DEPT
135) 52.21, 72.80 (inverted), 117.61, 120.68, 122.59, 128.08,
130.70, 130.98, 132.30, 134.15 and 135.13.
2-{N-Benzyl-N-[3Ј-(p-methoxyphenyl)prop-2Ј-ynyl]amino}-
benzoic acid 21. Gum (Found: C, 77.32; H, 5.95; N, 3.46.
C24H21NO3 requires C, 77.60; H, 5.69; N, 3.77%); νmax (neat)/
cmϪ1 1701; δH (60 MHz; CCl4) 3.75 (3H, s, -OCH3), 3.82 (2H,
᎐
s, -CH C᎐), 4.30 (2H, s, -NCH Ph), 6.70–6.82 (2H, m, ArH),
᎐
2
2
7.13–7.92 (10H, m, ArH) and 8.13–8.33 (1H, m, ArH).
2-{N-Benzyl-N-[3Ј-(2,4-dimethoxypyrimidin-5-yl)prop-2Ј-
ynyl]amino}benzoic acid 22. Gum (Found: C, 68.21; H, 5.49; N,
10.65. C23H21N3O4 requires C, 68.47; H, 5.24; N, 10.41%); νmax
(Z)-2,3-Dihydro-3-[(2-thienyl)methylidene]-5H-1,4-benzo-
dioxepin-5-one 27. Mp 95–96 ЊC (Found: C, 65.38; H, 4.27.
C14H10O3S requires C, 65.09; H, 3.90%); νmax (KBr)/cmϪ1 1720
and 1660; δH (300 MHz; CDCl3) 4.86 (2H, s, -CH2), 6.34 (1H, s,
(neat)/cmϪ1 1702; δH (60 MHz; CCl4) 4.03 (3H, s, -OCH3), 4.06
᎐
(3H, s, -OCH ), 3.83 (2H, s, -CH C᎐), 4.31 (2H, s, -NCH Ph),
᎐
3
2
2
᎐CH), 6.98–7.16 (4H, m, ArH), 7.35–7.50 (2H, m, ArH) and
᎐
7.13–7.71 (8H, m, ArH) and 8.17–8.32 (2H, m, ArH).
7.92 (1H, dd, J 9.0 and 1.8, ArH); δC (75 MHz; CDCl3) 72.68,
114.14, 118.94, 121.10, 123.10, 127.28, 128.83, 129.51, 134.36,
135.24, 135.40, 141.23, 157.03 and 165.52; δC (75 MHz; CDCl3;
DEPT 135) 72.39 (inverted), 113.85, 120.81, 122.83, 127.00,
128.54, 129.22, 134.08 and 135.12.
General procedure for the synthesis of 23–34
To a solution of the disubstituted alkynes 11–22 (1 mmol) in
dry acetonitrile, cuprous iodide (5 mol%) and triethylamine
(4 equiv.) was added and the whole mixture was refluxed at
80 ЊC for 16 h under an argon atmosphere. After the removal
of solvent under reduced pressure, the residue was purified by
column chromatography on silica gel (60–120 mesh) using 1:1
chloroform–light petroleum (60–80 ЊC) as eluent to yield the
cyclic products 23–34 in good yields (61–83%). The products
were finally crystallised from ether–light petroleum.
(Z)-2,3-Dihydro-3-[(o-acetoxyphenyl)methylidene]-5H-1,4-
benzodioxepin-5-one 28. Mp 113–114 ЊC (Found: C, 69.50; H,
4.69. C18H14O5 requires C, 69.60; H, 4.54%); νmax (KBr)/cmϪ1
1760, 1735 and 1670; δH (300 MHz; CDCl3) 2.26 (3H, s, -CH3),
4.87 (2H, s, -CH ), 6.10 (1H, s, ᎐CH), 7.05–7.14 (3H, m, ArH),
᎐
2
7.24–7.34 (2H, m, ArH), 7.48–7.54 (1H, m, ArH) and 7.97–8.01
(2H, m, ArH); δC (75 MHz; CDCl3) 21.26, 72.98, 118.89,
118.12, 120.77, 122.79, 122.922, 125.44, 126.69, 129.79, 130.69,
134.75, 135.51, 145.08, 148.61, 157.34, 165.19 and 169.42;
δC (75 MHz; CDCl3; DEPT 135) 20.98, 72.69 (inverted), 111.60,
120.48, 122.50, 122.63, 126.40, 129.50, 130.40, 134.46 and
135.22.
(Z)-2,3-Dihydro-3-(phenylmethylidene)-5H-1,4-benzo-
dioxepin-5-one 23. This was synthesised according to the gen-
eral procedure; crude product was crystallised from diethyl
ether–light petroleum, mp 89–91 ЊC (Found: C, 76.32; H, 5.04.
C16H12O3 requires C, 76.17; H, 4.79%); νmax (KBr)/cmϪ1 1725
and 1660; δH (300 MHz; CDCl3) 4.86 (2H, s, -CH2), 6.03 (1H, s,
᎐CH), 7.03–7.11 (2H, m, ArH), 7.25–7.37 (3H, m, ArH), 7.45–
᎐
(Z)-2,3-Dihydro-3-[(p-methoxyphenyl)methylidene]-5H-1,4-
benzodioxepin-5-one 29. Mp 99–100 ЊC (Found: C, 72.51; H,
5.12. C17H14O4 requires C, 72.32; H, 4.99%); νmax (KBr)/cmϪ1
1720 and 1660; δH (300 MHz; CDCl3) 3.77 (3H, s, -OCH3), 4.83
7.51 (1H, m, ArH), 7.59–7.63 (2H, m, ArH) and 7.95 (1H, dd,
J 7.8 and 1.8, ArH); δC (75 MHz; CDCl3) 73.01, 118.30, 119.30,
120.57, 122.57, 128.57, 128.61, 129.54, 132.50, 134.12, 135.06,
143.20, 156.84 and 165.32; δC (75 MHz; CDCl3; DEPT 135)
73.09 (inverted), 119.38, 120.65, 122.65, 128.66, 128.76, 129.63,
134.21 and 135.15.
(2H, s, -CH ), 5.96 (1H, s, ᎐CH), 6.83–6.88 (2H, m, ArH), 7.01–
᎐
2
7.09 (2H, m, ArH), 7.43–7.58 (3H, m, ArH) and 7.92 (1H, dd,
J 8.1 and 1.8, ArH); δC (75 MHz; CDCl3) 55.25, 73.14, 114.06,
118.47, 119.18, 120.58, 122.45, 125.14, 130.99, 133.97, 134.92,
141.37, 156.71, 159.71 and 165.68; δC (75 MHz; CDCl3; DEPT
135) 55.38, 73.27 (inverted), 114.18, 119.31, 120.70, 122.58,
131.12, 134.10 and 135.04.
(Z)-2,3-Dihydro-3-[(o-methoxyphenyl)methylidene]-5H-1,4-
benzodioxepin-5-one 24. Mp 116–117 ЊC (Found: C, 71.99; H,
4.94. C17H14O4 requires C, 72.32; H, 4.99%); νmax (KBr)/cmϪ1
1720 and 1660; δH (300 MHz; CDCl3) 3.81 (3H, s, -OCH3), 4.89
(2H, s, -CH ), 6.53 (1H, s, ᎐CH), 6.84–6.87 (1H, d, J 8.3, ArH),
᎐
2
(Z)-2,3-Dihydro-3-[(2,4-dimethoxypyrimidin-5-yl)methyl-
idene]-5H-1,4-benzodioxepin-5-one 30. Mp 146–147 ЊC (Found:
C, 60.90; H, 4.34; N, 8.72. C16H14N2O5 requires C, 61.14; H,
4.48; N, 8.91%); νmax (KBr)/cmϪ1 1725 and 1660; δH (300 MHz;
CDCl3) 3.90 (3H, s, -OCH3), 3.92 (3H, s, -OCH3), 4.78 (2H, s,
6.96–7.12 (3H, m, ArH), 7.24–7.30 (1H, m, ArH), 7.46–7.52
(1H, m, ArH) and 7.94–7.98 (2H, m, ArH); δC (75 MHz;
CDCl3) 55.53, 73.20 (3JCH = 4.2 Hz), 110.51, 112.97, 118.36,
120.59, 120.86, 121.29, 122.39, 129.78, 130.22, 134.08, 134.93,
143.00, 156.78, 156.87 and 165.64; δC (75 MHz; CDCl3; DEPT
135) 55.61, 73.20 (inverted), 110.59, 113.05, 120.66, 120.93,
122.47, 129.86, 130.30, 134.16 and 135.00.
-CH ), 6.08 (1H, s, ᎐CH), 6.95–7.05 (2H, m, ArH), 7.39–7.45
᎐
2
(1H, m, ArH), 7.87–7.91 (1H, m, ArH) and 8.78 (1H, s, ArH);
δC (75 MHz; CDCl3) 54.26, 55.01, 72.27, 108.31, 108.38, 117.68,
120.46, 122.49, 134.31, 135.14, 143.88, 156.98, 158.57, 164.36,
164.69 and 167.86; δC (75 MHz; CDCl3; DEPT 135) 54.34,
55.09, 72.35 (inverted), 108.46, 120.54, 122.57, 134.39, 135.22
and 158.65.
(Z)-2,3-Dihydro-3-[(m-chlorophenyl)methylidene]-5H-1,4-
benzodioxepin-5-one 25. Mp 101–102 ЊC (Found: C, 67.07; H,
4.04. C16H11O3Cl requires C, 67.02; H, 3.86%); νmax (KBr)/cmϪ1
1700 and 1660; δH (300 MHz; CDCl3) 4.86 (2H, s, -CH2), 5.96
(1H, s, ᎐CH), 7.05–7.14 (2H, m, ArH), 7.24–7.32 (2H, m, ArH),
᎐
(Z)-2,3-Dihydro-3-[(o-iodophenyl)methylidene]-5H-1,4-benzo-
dioxepin-5-one 31. Liquid (Found: C, 50.87; H, 3.10. C16H11IO3
requires C, 50.81; H, 2.93%); νmax (neat)/cmϪ1 1720 and 1660;
7.48–7.57 (3H, m, ArH) and 7.98 (1H, dd, J 8.1 and 1.8, ArH);
δC (75 MHz; CDCl3) 72.61, 117.31, 117.80, 120.46, 122.61,
127.51, 128.49, 129.35, 129.89, 134.27, 134.31, 134.47, 135.22,
144.43, 156.98 and 164.72; δC (75 MHz; CDCl3; DEPT 135)
72.60 (inverted), 117.39, 120.54, 122.69, 127.59, 128.57, 129.44,
129.97, 134.39 and 135.30.
δH (300 MHz; CDCl ) 4.88 (2H, s, -CH ), 6.24 (1H, s, ᎐CH),
᎐
3
2
6.94–7.13 (3H, m, ArH), 7.34–7.36 (1H, m, ArH), 7.47–7.50
(1H, m, ArH), 7.78–7.84 (2H, m, ArH) and 7.95 (1H, dd, J 7.8
and 1.6, ArH); δC (75 MHz; CDCl3) 72.87, 100.71, 118.24,
120.89, 122.44, 122.99, 128.80, 130.15, 130.81, 134.61, 135.56,
135.84, 139.79, 144.86, 157.43 and 165.24; δC (75 MHz; CDCl3;
(Z)-2,3-Dihydro-3-[(o-methoxycarbonylphenyl)methylidene]-
5H-1,4-benzodioxepin-5-one 26. Liquid (Found: C, 69.30; H,
778
J. Chem. Soc., Perkin Trans. 1, 2000, 775–779

View Article Online
S. Sukirthalingam and V. Sridharan, Tetrahedron Lett., 1991, 32,
DEPT 135) 72.58 (inverted), 120.60, 122.15, 122.770, 128.51,
129.86, 130.52, 134.32, 135.27 and 139.50.
2545; F. E. Meyer, J. Brandenburg, P. J. Parson and A. De Meijere,
J. Chem. Soc., Chem. Commun., 1992, 390; L. E. Overman, M. M.
Abelman, D. J. Kucera, V. D. Trans and D. J. Ricca, Pure Appl.
Chem., 1992, 64, 1813; B. M. Trost and Y. Shi, J. Am. Chem. Soc.,
1993, 115, 12491; S. Brown, S. Clarkson, R. Grigg and V. Sridharan,
Tetrahedron Lett., 1993, 34, 157; N. C. Ihle and C. H. Heathcock,
J. Org. Chem., 1993, 58, 560; R. C. Larock, M. J. Doty and
S. Cacchi, J. Org. Chem., 1993, 58, 4579; B. M. Trost, G. J. Tanoury,
M. Lautens, C. Chan and D. T. MacPherson, J. Am. Chem. Soc.,
1994, 116, 4255; S. Ma and E.-I. Negishi, J. Am. Chem. Soc., 1995,
117, 6345.
(Z)-1,2,3,5-Tetrahydro-1-benzyl-3-(phenylmethylidene)-4,1-
benzoxazepin-5-one 32. Mp 159–161 ЊC (Found: C, 80.80; H,
5.82; N, 3.88. C23H19NO2 requires C, 80.91; H, 5.60; N, 4.10%);
νmax (KBr)/cmϪ1 1720 and 1670; δH (300 MHz; CDCl3) 3.97
(2H, s, -CH -C᎐C), 4.55 (2H, s, -NCH Ph), 5.68 (1H, s, ᎐CH),
᎐
᎐
2
2
6.90–6.92 (2H, m, ArH), 7.23–7.36 (9H, m, ArH), 7.55–7.58
(2H, m, ArH) and 7.85–7.89 (1H, m, ArH); δC (75 MHz;
CDCl3) 56.19, 57.96 (3JCH = 3.2 Hz), 114.57, 117.40, 119.94,
120.24, 127.36, 127.70, 127.73, 128.56, 128.92, 129.06, 133.21,
133.80, 134.02, 136.94, 145.46, 149.15 and 167.45; δC (75 MHz;
CDCl3; DEPT 135) 56.29 (inverted), 58.06 (inverted), 114.67,
117.50, 120.34, 127.46, 127.83, 129.02, 129.17, 133.90 and
134.12.
3 L. S. Hegedus, Angew. Chem., Int. Ed. Engl., 1988, 27, 1113; R. C.
Larock, N. G. Berrios-Pena, C. A. Fried, E. K. Yum, C. Tu and
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McIntosh, J. Am. Chem. Soc., 1995, 117, 7255; R. C. Larock and
E. K. Yum, Tetrahedron, 1996, 52, 2743; R. Grigg, V. Loganathan
and V. Sridharan, Tetrahedron Lett., 1996, 37, 3399; E.-I. Negishi,
C. Coperet, S. Ma, S.-Y. Liou and F. Liu, Chem. Rev., 1996, 96, 365;
D. Bouyssi, M. Cavicchioli and G. Bahme, Synlett, 1997, 944; R. C.
Larock, E. K. Yum and M. D. Refvik, J. Org. Chem., 1998, 63, 7652;
A. Yasuhara, Y. Kanamori, M. Maneko, A. Numata, Y. Kando and
T. Sakamoto, J. Chem. Soc., Perkin Trans. 1, 1999, 529.
4 N. G. Kundu, M. Pal, J. S. Mahanty and S. K. Dasgupta, J. Chem.
Soc., Chem. Commun., 1992, 41; N. G. Kundu, M. Pal, J. S. Mahanty
and M. De, J. Chem. Soc., Perkin Trans. 1, 1997, 2815.
5 N. G. Kundu and M. Pal, J. Chem. Soc., Chem. Commun., 1993, 86;
N. G. Kundu, M. Pal and B. Nandi, J. Chem. Soc., Perkin Trans. 1,
1998, 561.
(Z)-1,2,3,5-Tetrahydro-1-benzyl-3-[(p-methoxyphenyl)meth-
ylidene]-4,1-benzoxazepin-5-one 33. Mp 113–115 ЊC (Found: C,
77.49; H, 5.92; N, 3.43. C24H21NO3 requires C, 77.60; H, 5.69;
N, 3.77%); νmax (KBr)/cmϪ1 1720 and 1670; δH (300 MHz;
CDCl ) 3.80 (3H, s, -OCH ), 3.96 (2H, s, -CH -C᎐C), 4.54 (2H,
᎐
3
3
2
s, -NCH Ph), 5.67 (1H, s, ᎐CH), 6.85–6.93 (4H, m, ArH), 7.33–
᎐
2
7.38 (6H, m, ArH), 7.51–7.54 (2H, m, ArH) and 7.83–7.86 (1H,
m, ArH); δC (75 MHz; CDCl3) 55.66, 56.54, 58.68, 114.37,
115.36, 117.91, 120.71, 120.97, 126.25, 127.80, 128.03, 129.26,
130.86, 133.92, 134.229, 137.74, 143.98, 139.44, 159.50 and
168.31; δC (75 MHz; CDCl3; DEPT 135) 55.37, 56.25 (inverted),
58.39 (inverted), 114.08, 115.07, 117.61, 120.42, 127.51, 127.74,
128.97, 130.57, 133.63 and 134.00.
6 N. G. Kundu, J. S. Mahanty, P. Das and B. Das, Tetrahedron Lett.,
1993, 34, 1625; J. S. Mahanty, M. De, P. Das and N. G. Kundu,
Tetrahedron, 1997, 53, 13397.
7 C. Chowdhury and N. G. Kundu, Chem. Commun., 1996, 1067;
C. Chowdhury, G. Chaudhuri, S. Guha, A. K. Mukherjee and
N. G. Kundu, J. Org. Chem., 1998, 63, 1863.
8 (a) M. W. Khan and N. G. Kundu, Synlett, 1997, 1435; (b) N. G.
Kundu and M. W. Khan, Tetrahedron Lett., 1997, 38, 6937.
9 G. Chaudhuri, C. Chowdhury and N. G. Kundu, Synlett, 1998,
1273.
(Z)-1,2,3,5-Tetrahydro-1-benzyl-3-[(2,4-dimethoxypyrimidin-
5-yl)methylidene]-4,1-benzoxazepin-5-one 34. Mp 114–115 ЊC
(Found: C, 68.70; H, 5.18; N, 10.80. C23H21N3O4 requires
C, 68.47; H, 5.24; N, 10.41%); νmax (KBr)/cmϪ1 1720 and 1660;
10 M. W. Khan and N. G. Kundu, Synlett, 1999, 456.
11 J. T. Sharp, ‘Seven-membered Rings with Two or more
Heteroatoms’, in Comprehensive Heterocyclic Chemistry, ed. A. R.
Katritzky and C. W. Rees, Pergamon Press Ltd, Oxford, 1998, vol. 7,
pp. 620–622; (b) Y. Masuoka, T. Asaki, G. Goto, S. Gonuchi, Chem.
Pharm. Bull., 1986, 34, 140; (c) J.-F. F. Liegeois, F. A. Rogister,
J. Bruhwyler, J. Damas, T. P. Nguyen, M.-O. Inarejos, E. M. G.
Chleide, M. G. A. Mercier and J. E. Delarge, J. Med. Chem., 1994,
37, 519.
12 (a) C. Weizmann, E. D. Bergmann and M. Sulzbacher, J. Org.
Chem., 1948, 13, 796; (b) J. W. Bird and J. K. N. Jones, Can. J.
Chem., 1963, 41, 1877; (c) D. Roussele, G. Jacques and P. Rumpf,
Bull. Soc. Chim. Fr., 1975, 283; (d) M. S. Ashwood, J. A. Gourlay,
P. G. Houghton, M. A. Nagel and S. H. B. Wright, J. Chem. Soc.,
Perkin Trans. 1, 1989, 1889; (e) F. Lucchesini, V. Bertini, M. Pocci,
G. Munno De and A. Crispini, Tetrahedron, 1995, 51, 9757.
13 The 3JCH values of more than 8 or less than 5 Hz were attributed to
(E) or (Z) isomers respectively. In the case of compounds 24 and 32,
3JCH = 4.2 and 3.2 Hz respectively. See also: (a) P. Moreau, M. Al.
Neirabeyeh, G. Guillaumet and G. Coudert, Tetrahedron Lett.,
1991, 32, 5525; (b) U. Vogeli, W. Von Philipsborn, Org. Magn.
Reson., 1975, 7, 617.
δH (300 MHz; CDCl ) 3.95 (2H, s, -CH -C᎐C), 3.98 (3H, s,
᎐
3
2
-OCH3), 3.99 (3H, s, -OCH3), 4.58 (2H, s, -NCH2Ph), 5.77 (1H,
s, ᎐CH), 6.88–6.93 (2H, m, ArH), 7.26–7.39 (6H, m, ArH),
᎐
7.90–7.93 (1H, m, ArH) and 8.84 (1H, s, ArH); δC (75 MHz;
CDCl3) 54.53, 55.29, 56.57, 57.63, 103.31, 109.31, 117.63,
119.36, 120.43, 127.60, 128.10, 129.31, 134.49, 134.54, 137.23,
146.81, 149.65, 158.35, 164.24, 167.17 and 167.96; δC (75 MHz;
CDCl3; DEPT 135) 54.25, 55.01, 56.29 (inverted), 57.34
(inverted), 103.02, 117.34, 120.15, 127.322, 127.81, 129.03,
134.25 and 158.06.
References
1 (a) R. F. Heck, Org. React., 1982, 27, 345; (b) R. F. Heck, Palladium
Reagents in Organic Synthesis, Academic Press, London, 1985; (c)
R. F. Heck, Comprehensive Organic Synthesis, Pergamon Press,
Oxford, 1991; (d) A. J. de Meijere and F. F. Meyer, Angew. Chem.,
Int. Ed. Engl., 1994, 33, 2379; (e) L. S. Hegedus, Transition Metals in
the Synthesis of Complex Organic Molecules, University Science
Book, California, 1994; ( f ) W. Cabri and J. Candiani, Acc. Chem.
Res., 1995, 28, 2; (g) J. Tsuji, Palladium Reagents and Catalysts,
Wiley, Chichester, 1995.
14 An NOE experiment on 23 showed ca. 3.87% enhancement of the
intensity of the –CH2– peak on irradiation of the vinylic proton at
δ 6.03.
2 Y. Zhang and E.-I. Negishi, J. Am. Chem. Soc., 1989, 111,
3454; B. M. Trost, Acc. Chem. Res., 1990, 23, 34; R. Grigg,
Paper a908682j
J. Chem. Soc., Perkin Trans. 1, 2000, 775–779
779