Double intramolecular hetero Diels-Alder reactions of α,β-unsaturated hydrazones as 1-azadienes: A new route to 2,2′-bipyridines

Article abstract of DOI:10.1039/b105409k

Salicylaldehyde was converted into the O-propynyl- and O-butynyl α,β-unsaturated aldehydes 4 and ketones 6, subsequent reaction of which with N,N-dimethylhydrazine and alkyne homocoupling gave the 1,3-diyne bis-(hydrazones) 8, substrates for a double intramolecular hetero Diels-Alder reaction. Similar substrates 11, 15a/15c and 15b/15d were prepared from 2-(N-benzoylamino)cinnamaldehyde, hex-5-ynol and hept-6-ynol respectively. Heating the 1,3-diynyl bis(α,β-unsaturated hydrazones) 8a, 8c, 11 and 15a resulted in double intramolecular Diels-Alder reaction to give, after aromatisation by loss of dimethylamine, 2,2′-bipyridines 21-24.

Full text of DOI:10.1039/b105409k

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Double intramolecular hetero Diels–Alder reactions of
ꢀ,ꢁ-unsaturated hydrazones as 1-azadienes:
a new route to 2,2Ј-bipyridines
1
Nicholas Bushby,a Christopher J. Moody,*a,b David A. Riddickb and Ian R. Waldronc
a School of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
b Department of Chemistry, Loughborough University, Loughborough, UK LE11 3TU
c Astra Zeneca, Hurdsfield Industrial Estate, Macclesfield, UK SK10 2NA
Received (in Cambridge, UK) 20th June 2001, Accepted 17th July 2001
First published as an Advance Article on the web 20th August 2001
Salicylaldehyde was converted into the O-propynyl- and O-butynyl α,β-unsaturated aldehydes 4 and ketones 6,
subsequent reaction of which with N,N-dimethylhydrazine and alkyne homocoupling gave the 1,3-diyne bis-
(hydrazones) 8, substrates for a double intramolecular hetero Diels–Alder reaction. Similar substrates 11, 15a/15c
and 15b/15d were prepared from 2-(N-benzoylamino)cinnamaldehyde, hex-5-ynol and hept-6-ynol respectively.
Heating the 1,3-diynyl bis(α,β-unsaturated hydrazones) 8a, 8c, 11 and 15a resulted in double intramolecular
Diels–Alder reaction to give, after aromatisation by loss of dimethylamine, 2,2Ј-bipyridines 21–24.
aza-dienes as components in such reactions is well known.11
Introduction
One useful route to pyridine derivatives employs α,β-un-
saturated hydrazones as 1-azadienes, and since the pioneering
work of Ghosez,12 these dienes have found use in inter-
molecular Diels–Alder reactions to give pyridine derivatives,
the reaction with quinones as dienophiles being particularly
well investigated.13 Intramolecular Diels–Alder (IMDA)
reactions of α,β-unsaturated hydrazones with alkynes have also
been reported,14 and this is an attractive route to annelated
pyridines since the initial Diels–Alder adduct readily aromatises
by loss of dimethylamine.15 Therefore, we decided to adapt this
procedure to the direct synthesis of annelated 2,2Ј-bipyridines
by the incorporation of an oxidative homocoupling step giving
a 1,3-diyne as a bis(dienophile) capable of undergoing the
desired double IMDA reaction (Scheme 1).
2,2Ј-Bipyridine was first synthesised by Fritz Blau in 1888 by
distilling a salt of picolinic acid (pyridine-2-carboxylic acid).1
Its ability to form complexes with metal salts was recognised
immediately, and in the intervening 110 years it has been exten-
sively used as a chelating ligand in organometallic chemistry.2
In fact, 2,2Ј-bipyridine is one of the best known and most
effective bidentate ligands for a range of metals, and with the
recent emphasis on the use of metal catalysts in asymmetric
synthesis, it is not surprising that chiral 2,2Ј-bipyridine ligands
have found wide application. Thus, for example, chiral 2,2Ј-
bipyridines have found use in the asymmetric addition of
diethylzinc to aldehydes,3 asymmetric cyclopropanation
reactions,4 and asymmetric allylic alkylation.5 However, the
methods used to prepare functionalised bipyridines often
rely on the modification of existing pyridine rings followed by
transition-metal catalysed heteroaryl coupling reactions. In
view of our work on the preparation of substituted pyridines
using ring synthesis reactions,6 we became interested in develop-
ing a route to 2,2Ј-bipyridines in which both pyridine rings
are constructed from an acyclic precursor in a single step. There
is a previous example of this approach involving cobalt()
catalysed [2 ϩ 2 ϩ 2]-cycloadditions between hex-5-ynenitrile
and 1,3-diynes,7 and we now report full details of a different
approach based on the double intramolecular hetero Diels–
Alder reaction of 1,3-diynyl bis(α,β-unsaturated hydrazones)
(Scheme 1).8,9
Results and discussion
The substrates for the double IMDA reactions were prepared
by a number of routes (Schemes 2–6). The first series of com-
pounds was based on salicylaldehyde 1; thus, reaction of the
aldehyde 1 with (formylmethylene)triphenylphosphorane gave
o-hydroxycinnamaldehyde 2 in 83% yield on a small scale.
Although this aldehyde 2 could be readily converted into the
required propargyl (prop-2-ynyl) derivative 4a, its preparation
proved irreproducible and low yielding on a larger scale. There-
fore, the α,β-unsaturated aldehyde 4a was prepared by carrying
out the O-propargylation first, and reacting the aldehyde 3a
with α,α-bis(trimethylsilyl)-N-tert-butylacetaldehyde imine in
the presence of zinc bromide.16 This reagent proved superior to
the Wittig reagent (formylmethylene)triphenylphosphorane. A
similar sequence of reactions was used to prepare the O-butynyl
derivative 4b (Scheme 2). The corresponding α,β-unsaturated
methyl ketones 6 were also prepared as shown in Scheme 3.
The α,β-unsaturated aldehydes 4 and methyl ketones 6 were
readily converted into the corresponding N,N-dimethyl-
hydrazones 7 and hence to the ‘dimeric’ 1,3-diynes 8 by Glaser–
Eglinton coupling with copper() acetate17 as shown on
Scheme 4.
Scheme 1 Alkynes and dienes are drawn aligned in the correct
orientation for Diels–Alder cycloaddition.
The preparation of 6-membered ring heterocyclic com-
pounds by the hetero Diels–Alder reaction is an established
tactic in organic synthesis,10 and the use of both 1-aza- and 2-
The IMDA substrate 11 was prepared from the known
hydrazone 9,18 obtained from quinoline and benzoyl chloride
DOI: 10.1039/b105409k
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This journal is © The Royal Society of Chemistry 2001
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Scheme 2
Scheme 4
Scheme 3
in an abnormal Reissert reaction to give o-(N-benzoylamino)-
cinnamaldehyde followed by hydrazone formation. The sub-
sequent N-propargylation and oxidative homocoupling of the
alkyne both proceeded in good yield as shown in Scheme 5.
The final set of substrates were obtained from hex-5-ynol
12a or hept-6-ynol 12b. Although the former alkynol is com-
mercially available, the latter was obtained by base catalysed
isomerisation of hept-3-ynol.19 Homocoupling reaction of
the alkynols 12 gave the corresponding 1,3-diynes 13, readily
oxidised to the dialdehydes 14 using 1-hydroxy-3-oxo-1,3-
dihydro-1,2-benziodoxole 1-oxide (2-iodylbenzoic acid, IBX) in
DMSO.20 The dialdehydes 14 were converted directly into the
hydrazones 15a and 15b of the homologous α,β-unsaturated
aldehydes by reaction with the N,N-dimethylhydrazone of
diethyl formylmethylphosphonate in a Wadsworth–Emmons
reaction.15 Alternatively the α,β-unsaturated ketones 16 were
prepared by Wittig reaction with aldehydes 14, followed by
reaction with N,N-dimethylhydrazine to give the hydrazones
15c and 15d as shown in Scheme 6.
Scheme 5
yield as reported by Dolle and co-workers in their original
paper,15 although a minor byproduct was also isolated. This was
identified as the benzopyran 18, and presumably results from
a [3,3]-sigmatropic rearrangement followed by [1,5]-hydrogen
shift and cyclisation, a known reaction of aryl propargyl
ethers.21 Attempts to catalyse the IMDA reaction using
LiNTf2, a system employed successfully by Ghosez and co-
workers with α,β-unsaturated hydrazone based azadienes,12c
proved unsuccessful.
The α,β-unsaturated ketone hydrazone 7c also underwent
IMDA reaction to give the pyridine 19 in modest yield. α,β-
Unsaturated hydrazones with a substituent at C-2 are known
to be poorer 1-azadienes, since the substituent (methyl in
this case) forces the dimethylamino group out of the diene
plane thereby preventing the delocalisation of the nitrogen lone
pair which enhances the diene reactivity.12c The two butynyl
derivatives 7b and 7d, however, failed to give any of the
benzoxepinopyridines 20 on heating in xylene (Scheme 7). The
formation of 7-membered rings in IMDA reactions is generally
less favourable than the corresponding reactions which form
6- (or 5-) membered rings.22
Although the main aim was to investigate the double IMDA
reaction of the 1,3-diynes (see below), the IMDA reactions of
the mono-alkynes 7 were also briefly investigated. The IMDA
reaction of the hydrazone 7a occurred upon heating in xylene in
a sealed tube and gave the chromeno[3,4-c]pyridine 17 in 59%
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The key double IMDA reactions were next investigated.
Heating the 1,3-diyne bis(hydrazone) 8a in xylene gave the
desired annelated 2,2Ј-bipyridine 21 as the only isolable
product. (ca. 80% yield), although considerable losses occurred
during purification. The ketone derived substrate 8c was less
satisfactory in the double IMDA reaction, and gave a poor
yield of the unsymmetrical 2,2Ј-bipyridine 22 in which one of
the benzopyran rings has undergone oxidation at the activated
CH2 position to give the observed lactone (Scheme 8). As with
Scheme 6
Scheme 8
the mono-alkynes 7b and 7d, the diynes 8b and 8d failed to
undergo IMDA reaction. The N-benzoyl compound 11, a
nitrogen containing analogue of 8a, underwent smooth double
IMDA reaction on heating in xylene to give, after loss of
dimethylamine, the N-benzoylated dihydro 4,4Ј-bi(benzo[c]-
[2,7]naphthyridine) 23 in 68% yield. Compound 23 could be
deprotected by reaction with DIBAL-H, and the resulting
dihydro compound dehydrogenated with palladium-on-carbon
to give the aromatic bi(benzonaphthyridine) 25 (Scheme 9).
Scheme 9
Finally, in the series of substrates 15, in which the azadiene
fragment is connected to the alkyne dienophile by a simple alkyl
chain, compound 15a readily underwent the desired double
IMDA reaction in boiling xylene to give the 1,1Ј-bi(cyclo-
penta[c]pyridine) 24 in good yield. Unfortunately no bipyridine
products were isolated from the hydrazones 15b, 15c, or 15d.
Scheme 7
J. Chem. Soc., Perkin Trans. 1, 2001, 2183–2193
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Although the IMDA reactions of 1,3-diyne bis(hydrazones)
successfully demonstrated our aim of achieving 2,2Ј-
in vacuo. The residue was purified by distillation under reduced
a
pressure and the title compound was obtained as a yellow oil
(5.0 g, 41%); bp 104–107 ЊC at 20 mmHg (lit.,16 93–94 ЊC at 12
mmHg); νmax (film)/cmϪ1 2964, 2900, 2868, 1637, 1252, 840;
bipyridine synthesis in which both heterocyclic rings are formed
in a single step from an acyclic precursor, the results are
somewhat mixed. For a successful double IMDA reaction to
occur the substrates need to be carefully designed, and this is
clearly a major consideration if chiral 2,2Ј-bipyridines are to be
made by this route.
δ (300 MHz; CDCl ) 7.49 (1 H, d, J 10.1, CH᎐N), 1.58 (1 H, d,
᎐
H
3
J 10.1, (TMS)2CH), 1.14 (9 H, s, CMe3), 0.04 (18 H, s, SiMe3);
δC (75 MHz; CDCl3) 157.9 (CH), 56.4 (C), 31.6 (CH), 30.0
(Me), Ϫ0.2 (Me).
Diethyl formylmethylphosphonate N,N-dimethylhydrazone
Experimental
Diethyl formylmethylphosphonate24 (2.1 g, 12 mmol) was
stirred in dichloromethane (26 ml) at 0 ЊC, and N,N-dimethyl-
hydrazine (3.54 ml, 46.6 mmol) was added dropwise. After 3 h,
the mixture was filtered and the solvent removed in vacuo to
give the title compound as a light yellow oil (2.4 g, 92%) (lit.,15
bp 122–124 ЊC at 10 mmHg) (Found: Mϩ, 222.1136. C8H19-
N2O3P requires 222.1133); νmax (film)/cmϪ1 2938, 2907, 2805,
2827, 1256, 1026; δH (300 MHz; CDCl3) 6.44 (1 H, dt, J 10.3,
General
Commercially available reagents and solvents were used
throughout without further purification unless otherwise
stated. Light petroleum refers to the fraction that boils between
40 and 60 ЊC and was distilled from calcium chloride through a
36 cm Vigreux column before use. Ether, which refers to diethyl
ether, and THF were distilled from sodium–benzophenone
ketyl under nitrogen prior to use. Dichloromethane was puri-
fied and dried by distillation from phosphorus pentaoxide
under nitrogen.
Analytical thin layer chromatography was carried out using
aluminium or glass backed plates coated with Merck Kieselgel
60 GF254. Developed plates were visualised under ultraviolet
light (254 nm) and/or potassium permanganate or ninhydrin
dip. Flash chromatography was carried out using Merck
Kieselgel 60 H silica. Fully characterised compounds were
chromatographically homogeneous.
IR Spectra were recorded on Nicolet FT-205, Nicolet Magna
550 or Perkin Elmer Paragon 1000 FT-IR spectrometers with
internal calibration. Spectra were recorded as thin films on
sodium chloride plates, in solution or potassium bromide discs.
NMR spectra were recorded on Bruker AC-250, AM-300 or
Advance DRX-400 spectrometers at the frequencies stated.
Chemical shifts are recorded in ppm and J values in Hz.
Multiplets less than 0.2 ppm in width were recorded from the
centre, those greater were reported as a range. Chemical shift
values are referenced against residual chloroform at 7.27 ppm
for CDCl3, and are accurate to 0.01 ppm (δH) and 0.10 ppm
(δC). High resolution mass spectra (CI and EI) were obtained
either on Kratos MS80 or Profile HV3 spectrometers or at the
EPSRC National Mass Spectrometry Service at the University
of Wales, Swansea.
5.8, CH᎐N), 4.07 (4 H, m, OCH ), 2.78 (2 H, dd, J 21.4,
᎐
2
5.8, PCH2), 2.74 (6 H, s, NMe2), 1.28 (6 H, td, J 7.0, 0.3, Me);
δC (75 MHz; CDCl3) 126.2 (CH), 62.0 (CH2), 43.0 (Me), 31.4
(CH2), 16.4 (Me); δP (121 MHz; CDCl3) 26.6; m/z (EI) 222 (Mϩ,
12%), 180 (4), 152 (51), 125 (68), 108 (22), 97 (37), 85 (100).
(E )-3-(2-Prop-2-ynyloxyphenyl)propenal 4a
Method 1. To a stirred suspension of (formylmethylene)-
triphenylphosphorane (486 mg, 1.6 mmol) in dry tetrahydro-
furan was added a solution of salicylaldehyde (100 mg,
0.8 mmol) in tetrahydrofuran (1 ml). The reaction mixture was
stirred at room temperature for 3 h. The solvent was evaporated
and the crude residue was filtered through a pad of silica
gel (light petroleum–ethyl acetate 2 : 1) to remove base line
impurities. Concentration of the filtrate yielded (E)-3-(2-
hydroxyphenyl)propenal 2 as a yellow solid (100 mg, 83%),
mp 131–132 ЊC (lit.,16 mp 122 ЊC); δH (250 MHz; CDCl3) 9.60
(1 H, d, J 8.0, CHO), 7.91 (1 H, d, J 16.0, PhCH᎐), 7.57 (1 H,
᎐
td, J 16.0, 8.0, ᎐CHCHO), 6.93–6.86 (4 H, m, ArH); δ (62.5
᎐
C
MHz; CDCl3) 199.5 (CHO), 161.2 (C), 154.7 (CH), 136.4 (CH),
133.0 (CH), 131.8 (CH), 124.9 (C), 123.3 (CH), 119.6 (CH).
On a larger scale, this reaction was irreproducible, and gave
yields of ca. 30%.
A mixture of the above hydroxyaldehyde 2 (100 mg,
0.6 mmol), propargyl chloride (50 µl, 1.0 mmol) and potassium
carbonate (80 mg) in anhydrous ethanol (10 ml) was heated to
reflux for 18 h under an inert atmosphere. The mixture was
filtered, evaporated in vacuo, diluted with dichloromethane,
washed with sodium hydroxide solution (3 × 50 ml, 10% solu-
tion), and washed with water (3 × 50 ml). The organic extracts
were dried (MgSO4) and concentrated in vacuo to leave a yellow
oil which was chromatographed on silica gel (light petroleum–
ethyl acetate 2 : 1) to give the title compound as a yellow
semi-solid (113 mg, 90%), data given below.
Reagents and starting materials
N-tert-Butylacetaldehyde imine was prepared by the conden-
sation of acetaldehyde with tert-butylamine in 54% yield.23
Diethyl formylmethylphosphonate was prepared by hydrolysis
of the commercially available diethyl acetal (diethyl 2,2-
diethoxyethylphosphonate) in 62% yield.24 Hept-6-ynol 12b
was prepared by the base catalyzed isomerization of hept-3-
ynol (52% yield).19 IBX (1-hydroxy-3-oxo-1,3-dihydro-1,2-
benziodoxole 1-oxide) (CAUTION! IBX has been reported to
explode when heated above 200 ЊC and when subjected to
shock) was prepared from 2-iodobenzoic acid, according to the
method of Dess and Martin25 in 71% yield.
Method 2. Propargyl chloride (3.6 ml, 50 mmol) was added
dropwise to a stirred solution of salicylaldehyde (1.1 ml,
10 mmol) and potassium carbonate (2.1 g, 15 mmol) in ethanol
(50 ml). The solution was heated at reflux for 20 h and then
allowed to cool to room temperature and the solvent removed
in vacuo. The residue was partitioned between sodium
hydroxide solution (2 M; 70 ml) and ether (70 ml), the organic
phase was washed with further sodium hydroxide solution
(2 M; 2 × 70 ml) and water (2 × 70 ml) and dried (MgSO4). The
mixture was filtered and concentrated in vacuo and purified by
flash chromatography (elution with 2 : 1 light petroleum–ether)
to give 2-prop-2-ynyloxybenzaldehyde 3a as a colourless solid
(1.2 g, 76%); mp 69 ЊC (from light petroleum) (lit.,26 68 ЊC);
δH (300 MHz; CDCl3) 10.5 (1 H, s, CHO), 7.86 (1 H, dd, J 7.7,
ꢀ,ꢀ-Bis(trimethylsilyl)-tert-butylacetaldehyde imine
Diisopropylamine (14 ml, 100 mmol) was stirred in THF
(50 ml) at Ϫ20 ЊC, n-butyllithium (1.6 M in hexane; 63 ml,
100 mmol) was added slowly and the temperature reduced to
Ϫ60 ЊC. tert-Butylacetaldehyde imine23 (5.0 g, 50 mmol) was
added dropwise, the solution was stored at Ϫ78 to Ϫ60 ЊC for
18 h and then chlorotrimethylsilane (6.5 ml, 50 mmol) was
added dropwise. After 5 h another portion of chlorotrimethyl-
silane (6.5 ml, 50 mmol) was added, the solution was stirred for
45 min and then allowed to warm to room temperature. The
suspension was filtered through Celite and the solvent removed
1.7, ArH), 7.57 (1 H, ddd, J 8.6, 7.3, 1.7, ArH), 7.13–7.06 (2 H,
᎐
m, ArH), 4.83 (2 H, d, J 2.4, OCH ), 2.57 (1 H, t, J 2.4, ᎐CH).
᎐
2
2186
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Prop-2-ynyloxybenzaldehyde 3a (640 mg, 4.0 mmol) and
zinc bromide (900 mg, 4.0 mmol) were stirred in THF (4 ml)
at room temperature. α,α-Bis(trimethylsilyl)-tert-butylacet-
aldehyde imine (1.1 g, 4.4 mmol) in THF (2 ml) was added
dropwise. After 3 h the reaction was quenched by addition of
aqueous zinc chloride (800 mg in 8 ml of water) and ether
(10 ml) with stirring for 1 h. After filtration through Celite the
solution was extracted with ether (2 × 40 ml) and the combined
organic extracts were washed with water (3 × 40 ml) and dried
(MgSO4). The solution was concentrated in vacuo and the
residue purified by flash chromatography (elution with 3 : 2
light petroleum–ether and then 1 : 1 light petroleum–ether)
to give the title compound as a yellow solid (530 mg, 71%);
mp 77–79 ЊC (from ether–light petroleum) (Found: Mϩ,
186.0681. C12H10O2 requires 186.0681); νmax (KBr)/cmϪ1 3209,
2833, 2121, 1675, 1622, 1616, 1600; δH (300 MHz; CDCl3) 9.70
dd, J 16.1, 7.8, ᎐CHCHO), 4.19 (2 H, t, J 6.8, OCH ), 2.76
᎐
2
᎐
᎐
(2 H, td, J 6.8, 2.7, CH C᎐), 2.08 (1 H, t, J 2.7, ᎐CH); δ (75
᎐
᎐
2
C
MHz; CDCl3) 194.6 (CHO), 157.1 (C), 148.0 (CH), 132.6 (CH),
129.2 (CH), 129.0 (CH), 123.3 (C), 121.4 (CH), 112.4 (CH),
80.1 (C), 70.3 (CH), 66.5 (CH2), 19.6 (CH2); m/z (EI) 200
(Mϩ, 28%), 171 (14), 147 (38), 131 (100), 118 (25), 103 (18),
91 (53).
(E )-4-(2-Hydroxyphenyl)but-3-en-2-one 5
Salicylaldehyde (2.0 g, 16 mmol) in THF (2 ml) was added to a
stirred suspension of (acetylmethylene)triphenylphosphorane
(7.8 g, 25 mmol) in THF (50 ml) at room temperature. After
16 h, the mixture was filtered and solvent removed in vacuo, the
title compound was isolated by flash chromatography (elution
with 2 : 1 ether–light petroleum) and obtained as a colourless
solid (2.40 g, 91%); mp 139–140 ЊC (from light petroleum–
ether) (lit.,28 mp 140.5–141.5 ЊC) (Found: C, 73.9; H, 6.2.
C10H10O2 requires C, 74.1; H, 6.2%); δH (300 MHz; d6-acetone)
(1 H, d, J 7.8, CHO), 7.86 (1 H, d, J 16.1, PhCH᎐), 7.58 (1 H,
᎐
dd, J 7.6, 1.6, ArH), 7.42 (1 H, ddd, J 8.6, 7.4, 1.6, ArH), 7.06–
7.03 (2 H, m, ArH), 6.77 (1 H, dd, J 16.1, 7.8, ᎐CHCHO), 4.81
᎐
7.93 (1 H, d, J 16.5, ArCH᎐CH), 7.63 (1 H, dd, J 7.8, 1.7,
᎐
᎐
(2 H, d, J 2.4, OCH ), 2.56 (1 H, t, J 2.4, ᎐CH); δ (75 MHz;
᎐
2
C
ArH), 7.27 (1 H, ddd, J 8.2, 7.3, 1.7, ArH), 7.00 (1 H, dd, J 8.2,
CDCl3) 194.5 (CHO), 156.1 (C), 147.7 (CH), 132.5 (CH), 129.3
(CH), 128.8 (CH), 123.6 (C), 121.8 (CH), 112.8 (CH), 77.9 (C),
76.3 (CH), 56.2 (CH2); m/z (EI) 186 (Mϩ, 25%), 157 (23), 147
(47), 131 (93), 118 (28), 91 (100).
1.1, ArH), 6.92 (1 H, m, ArH), 6.88 (1 H, d, J 16.5, ArCH᎐
᎐
CH), 2.34 (3 H, s, Me); δ (75 MHz; d -acetone) 198.4 (C᎐O),
᎐
C
6
157.5 (C), 139.1 (CH), 132.4 (CH), 129.4 (CH), 127.9 (CH),
126.0 (C), 120.9 (CH), 117.1 (CH), 27.4 (Me).
2-But-3-ynyloxybenzaldehyde 3b
(E )-4-(2-Prop-2-ynyloxyphenyl)but-3-en-2-one 6a
Salicylaldehyde (2.3 g, 19 mmol) was stirred in toluene (100 ml),
sodium ethoxide (21% w/w in ethanol, 1.1 g, 15 mmol) in
ethanol was added dropwise and the suspension stirred for
1.5 h. But-3-yn-1-yl methanesulfonate27 (4.6 g, 31 mmol) was
added slowly and the mixture heated to reflux for 7 days. The
solution was cooled and partitioned between ether (300 ml) and
sodium hydroxide solution (2 M; 300 ml). The organic layer
was washed with more sodium hydroxide solution (2 M; 2 ×
300 ml), water (3 × 300 ml) and dried (MgSO4). The mixture
was filtered and evaporated in vacuo and the residue purified by
flash chromatography (elution with 2 : 1 light petroleum–ether)
to give the title compound as a red oil (580 mg, 21%) (Found:
Mϩ, 174.0685. C11H10O2 requires 174.0681); νmax (CHCl3)/cmϪ1
3309, 2956, 2889, 2764, 2125, 2125, 1732, 1689, 1601; δH (300
MHz; CDCl3) 10.5 (1 H, s, CHO), 7.82 (1 H, dd, J 7.7, 1.9,
ArH), 7.53 (1 H, ddd, J 8.5, 7.4, 1.9, ArH), 6.95–7.05 (2 H,
m, ArH), 4.20 (2 H, t, J 6.8, OCH2), 2.73 (2 H, td, J 6.8,
A suspension of 4-(2-hydroxyphenyl)but-3-en-2-one 5 (800 mg,
4.9 mmol) and potassium carbonate (2.0 g) in ethanol (30 ml)
was stirred at 45 ЊC. Propargyl chloride (1.8 ml, 25 mmol) was
added. After 3 days, the mixture was filtered and solvent was
removed, the residue was dissolved in dichloromethane (100 ml)
and washed with aqueous sodium hydroxide (2 M; 3 × 50 ml)
and water (3 × 50 ml), the organic layer was dried (MgSO4).
The mixture was filtered and the solvent removed in vacuo,
the residue was purified by flash chromatography (elution with
3 : 1 light petroleum–ethyl acetate) to give the title compound as
a yellow oil (750 mg, 76%) (Found: Mϩ, 200.0841. C13H12O2
requires 200.0837); νmax (CHCl3)/cmϪ1 3307, 2125, 1667, 1600,
1485; δH (300 MHz; CDCl ) 7.87 (1 H, d, J 16.5, ArCH᎐), 7.55
᎐
3
(1 H, dd, J 7.7, 1.7, ArH), 7.35 (1 H, ddd, J 8.5, 7.7, 1.7, ArH),
7.05 (1 H, dd, J 8.5, 0.8, ArH), 7.01 (1 H, br t, J 7.7, ArH), 6.72
᎐
(1 H, d, J 16.5, PhCH᎐CH), 4.78 (2 H, d, J 2.4, CH C᎐), 2.54
᎐
᎐
2
᎐
(1 H, t, J 2.4, ᎐CH), 2.37 (3 H, s, Me); δ (75 MHz; CDCl3)
᎐
C
᎐
᎐
2.7, CH C᎐), 2.05 (1 H, t, J 2.7, ᎐CH); δ (75 MHz; CDCl3)
᎐
᎐
2
C
198.9 (C᎐O), 156.2 (C), 138.3 (CH), 131.5 (CH), 128.3 (CH),
᎐
189.6 (CHO), 160.8 (C), 135.8 (CH), 128.3 (CH), 125.2 (C),
121.2 (CH), 112.3 (CH), 79.9 (C), 70.3 (CH), 66.6 (CH2), 19.5
(CH2); m/z (EI) 174 (Mϩ, 12%), 144 (44), 135 (42), 121 (100),
110 (16).
128.1 (CH), 124.1 (C), 121.8 (CH), 112.9 (CH), 78.1 (C), 76.1
(CH), 56.2 (CH2), 27.1 (Me); m/z (EI) 200 (Mϩ, 12%), 185 (16),
157 (16), 145 (100), 128 (17), 118 (26), 89 (15).
(E )-4-(2-But-3-ynyloxyphenyl)but-3-en-2-one 6b
(E )-3-(2-But-3-ynyloxyphenyl)propenal 4b
To a stirred suspension of (acetylmethylene)triphenylphos-
phorane (1.2 g, 3.6 mmol) in THF (10 ml) was added 2-but-3-
ynyloxybenzaldehyde 3b (420 mg, 2.4 mmol). After 16 h, the
mixture was filtered and concentrated in vacuo and the residue
purified by flash chromatography (elution with 3 : 1 light
petroleum–ether) to give the title compound as a colourless solid
(260 mg, 51%); mp 61–62 ЊC (from ether) (Found: C, 78.3; H,
6.6. C14H14O2 requires C, 78.5; H, 6.5%) (Found: Mϩ, 214.0990.
C14H14O2 requires 214.0994); νmax (KBr)/cmϪ1 3268, 3061, 2964,
2916, 1668, 1646, 1618, 1599; δH (400 MHz; CDCl3) 7.91 (1 H,
2-But-3-ynyloxybenzaldehyde 3b (100 mg, 0.57 mmol) and
zinc bromide (130 mg, 0.57 mmol) were stirred in THF (1 ml),
α,α-bis(trimethylsilyl)-tert-butylacetaldehyde imine (150 mg,
0.63 mmol) in THF (0.5 ml) was added dropwise and the solu-
tion stirred at room temperature for 3 h. The reaction was
quenched by addition of aqueous zinc chloride solution (0.73
M; 3 ml) and ether (4 ml), after stirring for 15 min the aqueous
phase was extracted with more ether (2 × 20 ml) and the
combined organic extracts were washed with water (3 × 20 ml)
and dried (MgSO4). The mixture was filtered and the solvent
removed in vacuo, the residue was purified by flash chroma-
tography (elution with 1 : 1 light petroleum–ether) to give the
title compound as a light yellow oil (82 mg, 72%) (Found: Mϩ,
200.0831. C13H12O2 requires 200.0837); νmax (film)/cmϪ1 3293,
2949, 2817, 2741, 2122, 1675, 1621, 1599; δH (300 MHz; CDCl3)
d, J 16.7, PhCH᎐), 7.55 (1 H, dd, J 7.8, 1.6, ArH), 7.53 (1 H,
᎐
ddd, J 8.3, 7.3, 1.6, ArH), 6.99 (1 H, m, ArH), 6.92 (1 H, dd,
J 8.3, 0.9, ArH), 6.79 (1 H, d, J 16.5, ᎐CHC(Me)O), 4.18 (2 H,
᎐
᎐
t, J 6.7, OCH ), 2.75 (2 H, td, J 6.7, 2.6, CH C᎐), 2.38 (3 H,
s, Me), 2.07 (1 H, t, J 2.6, ᎐CH); δ (100 MHz; CDCl3) 199.0
᎐
2
2
᎐
᎐
C
(C᎐O), 157.1 (C), 138.5 (CH), 131.7 (CH), 128.6 (CH), 128.0
᎐
9.70 (1 H, d, J 7.8, CHO), 7.86 (1 H, d, J 16.1, PhCH᎐), 7.56
(1 H, dd, J 7.8, 1.7, ArH), 7.40 (1 H, ddd, J 8.4, 7.4, 1.7, ArH),
7.02 (1 H, m, ArH), 6.94 (1 H, d, J 8.4, ArH), 6.81 (1 H,
(CH), 123.9 (C), 121.4 (CH), 112.5 (CH), 80.2 (C), 70.1 (CH),
66.5 (CH2), 27.2 (Me), 19.6 (CH2); m/z (EI) 215 (48), 214 (Mϩ,
20%), 172 (17), 146 (100), 119 (49), 104 (41).
᎐
J. Chem. Soc., Perkin Trans. 1, 2001, 2183–2193
2187

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(E )-3-(2-Prop-2-ynyloxyphenyl)propenal N,N-dimethyl-
hydrazone 7a
m/z (EI) 242 (Mϩ, 71%), 187 (75), 158 (57), 145 (100), 118 (54),
91 (50), 85 (69).
(E)-3-(2-Prop-2-ynyloxyphenyl)propenal 4a (88 mg, 0.47
mmol) and magnesium sulfate (200 mg) were stirred in dichloro-
methane (10 ml) at 0 ЊC. N,N-Dimethylhydrazine (110 µl,
1.4 mmol) was added dropwise and then the mixture allowed
to warm to room temperature. The solution was filtered and the
solvent was removed in vacuo. The crude residue was purified by
flash chromatography (elution with 1 : 1 light petroleum–ether)
to give the title compound as a yellow oil (93 mg, 87%) (lit.,15
no data given) (Found: Mϩ, 228.1264. C14H16N2O requires
228.1263); νmax (film)/cmϪ1 3290, 2955, 2859, 2787, 2121, 1522,
1485, 1457, 750; δH (400 MHz; CDCl3) 7.53 (1 H, dd, J 7.8, 1.4,
(E )-4-(2-But-3-ynyloxyphenyl)but-3-en-2-one N,N-dimethyl-
hydrazone 7d
4-(2-But-3-ynyloxyphenyl)but-3-en-2-one 6b (210 mg, 1.0
mmol) was stirred in THF (15 ml) with magnesium sulfate (700
mg), and N,N-dimethylhydrazine (0.76 ml, 10 mmol) was added
dropwise. After 7 days, the mixture was filtered, the solution
was concentrated in vacuo and the residue was purified by flash
chromatography (elution with 1 : 1 ether–light petroleum
containing 3% triethylamine) to give the title compound as an
orange oil (130 mg, 50%) (inseparable mixture of 2 isomers)
(Found: Mϩ, 256.1575. C16H20N2O requires 256.1576); νmax
(CHCl3)/cmϪ1 3309, 2960, 2929, 2858, 1599, 1489, 1454, 1261;
ArH), 7.21 (1 H, m, ArH), 7.20 (1 H, d, J 7.0, CH᎐N), 7.00–
᎐
6.95 (4 H, m, CH᎐CH-, 2 × ArH), 4.74 (2 H, d, J 2.4, OCH ),
᎐
2
᎐
2.92 (6 H, s, NMe ), 2.52 (1 H, t, J 2.4, ᎐CH); δ (100 MHz;
δH (300 MHz; CDCl ) 7.64–6.77 (6 H, m, 4 × ArH, PhCH᎐
᎐
᎐
2
C
3
᎐
CDCl3) 154.5 (C), 136.3 (CH), 128.24 (CH), 128.21 (CH), 127.1
(C), 126.23 (CH), 126.18 (CH), 121.8 (CH), 78.7 (C), 75.5 (CH),
56.3 (CH2), 42.8 (Me); m/z (EI) 228 (Mϩ, 100%), 184 (43), 169
(23), 156 (15), 146 (52), 131 (76), 118 (34), 91 (29).
CH), 4.13 (2 H, m, OCH ), 2.73 (2 H, m, CH C᎐), 2.56 (4.2 H,
᎐
2
2
s, NMe2), 2.54 (1.8 H, s, NMe2), 2.20 (3 H, s, Me), 2.05 (1 H, t,
᎐
J 2.7, ᎐CH); δ (75 MHz; CDCl3) major isomer: 163.2 (C),
᎐
C
155.7 (C), 130.0 (CH), 129.5 (CH), 128.3 (CH), 126.3 (CH),
126.0 (C), 121.5 (CH), 112.6 (CH), 80.4 (C), 69.9 (CH), 66.6
(CH2), 47.4 (Me), 19.6 (CH2), 13.5 (Me); minor isomer: 161.9
(C), 156.3 (C), 130.7 (CH), 130.1 (CH), 127.2 (CH), 125.9 (C),
121.3 (CH), 120.6 (CH), 112.5 (CH), 80.3 (C), 70.0 (CH), 66.5
(CH2), 48.1 (Me), 20.5 (Me), 19.6 (CH2); m/z (EI) 256 (Mϩ,
25%), 240 (41), 201 (24), 188 (71), 171 (25), 160 (24), 145 (100),
131 (33).
(E )-3-(2-But-3-ynyloxyphenyl)propenal N,N-dimethylhydrazone
7b
(E)-3-(2-But-3-ynyloxyphenyl)propenal 4b (67 mg, 0.34 mmol)
and magnesium sulfate (200 mg) were stirred in dichlorometh-
ane (10 ml) at 0 ЊC. N,N-Dimethylhydrazine (76 µl, 1.0 mmol)
was added dropwise, and after 15 min the reaction mixture was
allowed to warm to room temperature and stirred for a further
3 h. The mixture was then filtered and the solvent removed
in vacuo. The crude residue was filtered through a short plug of
silica (elution with 1 : 1 light petroleum–ether) to give the title
compound as a viscous yellow oil (69 mg, 84%) (Found:
Mϩ, 242.1414. C15H18N2O requires 242.1419); νmax (film)/cmϪ1
3295, 2953, 2882, 2858, 2827, 2786, 2122, 1616, 1597, 750;
δH (400 MHz; CDCl3) 7.53 (1 H, dd, J 7.7, 1.6, ArH), 7.20–7.16
1,6-Bis[2-(2-formylethenyl)phenoxy]hexa-2,4-diyne bis(N,N-
dimethylhydrazone) 8a
A solution of 3-(2-prop-2-ynyloxyphenyl)propenal N,N-di-
methylhydrazone 7a (200 mg, 0.88 mmol) in ether (5 ml) was
added to a stirred solution of ether (80 ml), methanol (20 ml)
and pyridine (20 ml) containing copper() acetate monohydrate
(530 mg, 2.6 mmol) for 16 h at 55 ЊC. The cooled solution was
then filtered and the solvents removed in vacuo, the residue was
partitioned between HCl (2 M; 100 ml) and dichloromethane
(100 ml), the organic phase was washed with water (2 × 100 ml)
and brine (100 ml) and dried (Na2SO4). After filtration and
evaporation of the solvent in vacuo, the crude residue was
purified by flash chromatography (elution with 3 : 1 ether–light
petroleum) to give the title compound as a light yellow solid
(97 mg, 48%); mp 130–132 ЊC (from ether) (Found: Mϩ,
454.2375. C28H30N4O2 requires 454.2369); νmax (KBr)/cmϪ1
2997, 2958, 2784, 2146, 1670, 1616, 1597, 1578, 1485, 746;
δH (300 MHz; CDCl3) 7.52 (2 H, dd, J 7.7, 1.6, ArH), 7.22–7.17
(1 H, m, ArH), 7.19 (1 H, d, J 8.1, CH᎐N), 7.01 (1 H, d, J 16.1,
᎐
PhCH᎐), 6.95 (1 H, dd, J 16.1, 8.1, ᎐CHCHN), 6.94 (1 H,
᎐
᎐
m, ArH), 6.86 (1 H, dd, J 8.3, 1.0, ArH), 4.14 (2 H, t, J 7.0,
᎐
᎐
2
OCH ), 2.92 (6 H, s, NMe ), 2.73 (2 H, td, J 7.0, 2.6, CH C᎐),
2
2
᎐
2.05 (1 H, t, J 2.6, ᎐CH); δ (100 MHz; CDCl ) 155.3 (C), 136.4
᎐
C
3
(CH), 128.4 (CH), 127.9 (CH), 126.8 (C), 126.2 (CH), 126.0
(CH), 121.4 (CH), 112.5 (CH), 80.5 (C), 70.0 (CH), 66.6
(CH2), 42.8 (Me), 19.6 (CH2); m/z (EI) 242 (Mϩ, 100%), 173
(55), 158 (7), 146 (16), 131 (74), 118 (23), 103 (9), 91 (18), 71
(16).
(4 H, m, 2 × CH᎐N, 2 × ArH), 7.01–6.91 (8 H, m, 2 × PhCH᎐
᎐
᎐
(E )-4-(2-Prop-2-ynyloxyphenyl)but-3-en-2-one N,N-dimethyl-
CH, 4 × ArH), 4.79 (4 H, s, OCH2), 2.92 (12 H, s, NMe2); δC (75
MHz; CDCl3) 154.3 (C), 136.2 (CH), 128.34 (CH), 128.30
(CH), 127.0 (C), 126.2 (CH), 125.9 (CH), 122.0 (CH), 112.6
(CH), 74.7 (C), 71.1 (C), 56.7 (CH2), 42.8 (Me); m/z (EI) 454
(Mϩ, 0.06%), 409 (1), 365 (4), 277 (39), 144 (45), 106 (80), 88
(66), 57 (100).
hydrazone 7c
N,N-Dimethylhydrazine (0.21 ml, 2.7 mmol) was added to a
mixture of 4-(2-prop-2-ynyloxyphenyl)but-3-en-2-one 6a (705
mg, 0.27 mmol) and magnesium sulfate (240 mg) in THF (4 ml)
at room temperature. After 3 days, the mixture was filtered
and the solvent removed in vacuo, the residue was purified by
flash chromatography (elution with: 2 : 1 light petroleum–ethyl
acetate) to give the title compound as a yellow oil (590 mg, 69%)
(inseparable mixture of 2 isomers: TLC, 2 : 1 light petroleum–
ethyl acetate, isomer 1: Rf = 0.29, isomer 2: Rf = 0.25) (Found:
Mϩ, 242.1413. C15H18N2O requires 242.1419); νmax (CHCl3)/
cmϪ1 3307, 2959, 2864, 2823, 2779, 2475 (br), 2125, 1734, 1599;
δH (400 MHz; CDCl ) 7.65–6.83 (6 H, m, 4 × ArH, PhCH᎐
CH), 4.74 (2 H, d, J 2.4, OCH2), 2.56 (1.8 H, s, NMe2), 2.53
(4.2 H, s, NMe ), 2.51 (1 H, t, J 2.3, ᎐CH), 2.20 ϩ 2.14 (3 H, s,
Me); δC (75 MHz; CDCl3) isomer 1: 163.1 (C), 155.0 (C), 130.4
(CH), 129.9 (CH), 129.3 (CH), 126.7 (CH), 126.2 (C), 121.8
(CH), 112.8 (CH), 78.5 (C), 75.7 (CH), 56.3 (CH2), 47.3 (Me),
13.5 (Me); isomer 2: 161.7 (C), 155.4 (C), 130.4 (CH), 129.9
(CH), 129.3 (CH), 127.1 (CH), 126.2 (C), 121.8 (CH), 112.8
(CH), 78.5 (C), 75.8 (CH), 56.3 (CH2), 48.1 (Me), 21.0 (Me);
1,8-Bis[2-(2-formylethenyl)phenoxy]octa-3,5-diyne bis(N,N-
dimethylhydrazone) 8b
A
solution of 3-(2-but-3-ynyloxyphenyl)propenal N,N-di-
methylhydrazone 7b (100 mg, 0.42 mmol) was stirred in ether
(40 ml), methanol (10 ml) and pyridine (10 ml) with copper()
acetate monohydrate (250 mg, 1.3 mmol) at reflux. After 16 h,
the reaction mixture was filtered and the solvent removed
in vacuo, the residue was partitioned between HCl (2 M; 80 ml)
and dichloromethane (80 ml), and the organic extracts were
washed with water (2 × 80 ml) and brine (80 ml) and dried
(MgSO4). After filtration the solvent was removed in vacuo and
the crude residue purified by flash chromatography (elution
with 2 : 1 ether–light petroleum containing 3% triethylamine)
to give the title compound as a viscous orange oil (31 mg,
᎐
3
᎐
᎐
2
2188
J. Chem. Soc., Perkin Trans. 1, 2001, 2183–2193

View Article Online
31%) (Found: Mϩ, 482.2683. C30H34N4O2 requires 482.2682);
νmax (film)/cmϪ1 3034, 2953, 2787, 1676, 1597, 1487, 750; δH (300
MHz; CDCl3) 7.53 (2 H, dd, J 7.9, 1.8, ArH), 7.20 (2 H, d, J 8.1,
(E )-3-[2-(N-Benzoyl-N-prop-2-ynylamino)phenyl]propenal N,N-
dimethylhydrazone 10
A solution of 3-[2-(N-benzoylamino)phenyl]propenal N,N-
dimethylhydrazone 918 (1.0 g, 3.4 mmol) in DMF (5 ml) was
added dropwise to a stirred suspension of potassium hydride
(0.15 g, 3.8 mmol) in DMF (5 ml) and stirred at 25 ЊC for 1 h.
Propargyl chloride (0.25 g, 3.5 mmol) was added and the reac-
tion mixture was heated at 60 ЊC for 18 h. Upon cooling the
mixture was diluted with dichloromethane (50 ml) and washed
with brine (4 × 50 ml) and water (3 × 50 ml). The organic
extracts were pooled, dried (Na2SO4), and concentrated in
vacuo. The crude residue was chromatographed on silica gel
(ether) to yield the desired product as a pale yellow solid (0.94 g,
83%), mp 137–138 ЊC (Found: C, 75.9; H, 6.3; N, 12.4.
C21H21N3O requires C, 76.1; H, 6.4; N, 12.7%) (Found: Mϩ,
331.1684. C21H21N3O requires 331.1685); νmax (KBr)/cmϪ1 3442,
3308, 1641, 1618, 1482; δH (400 MHz; CDCl3) 7.51 (1 H, d, J
CH᎐N), 7.18 (2 H, ddd, J 9.0, 7.5, 1.8, ArH), 7.01 (2 H, d,
᎐
J 16.0, PhCH᎐), 6.96 (2 H, dd, J 16.0, 8.1, PhCH᎐CH), 6.94
᎐
᎐
(2 H, m, ArH), 6.83 (2 H, dd, J 7.5, 0.9, ArH), 4.12 (4 H, t,
᎐
᎐
2
J 7.0, OCH ), 2.92 (12 H, s, NMe ), 2.79 (4 H, t, J 7.0, CH C᎐);
2
2
δC (75 MHz; CDCl3) 155.1 (C), 136.4 (CH), 128.4 (CH), 127.9
(CH), 126.8 (C), 126.1 (CH), 125.9 (CH), 121.5 (CH), 112.5
(CH), 73.9 (C), 66.7 (C), 66.3 (CH2), 42.9 (Me), 20.4 (CH2);
m/z (EI) 482 (Mϩ, 4%), 438 (4), 395 (13), 248 (10), 218 (10), 173
(13), 146 (19), 131 (100), 91 (19), 77 (42).
1,6-Bis[2-(3-oxobut-1-enyl)phenoxy]hexa-2,4-diyne bis(N,N-
dimethylhydrazone) 8c
(E)-4-(2-Prop-2-ynyloxyphenyl)but-3-en-2-one N,N-dimethyl-
hydrazone 7c (300 mg, 1.2 mmol) was added to a stirred mixture
of copper() acetate monohydrate (740 mg, 3.7 mmol) in ether
(100 ml), methanol (30 ml) and pyridine (30 ml). The reaction
mixture was heated to 55 ЊC for 16 h, the cooled solution was
filtered and the solvents were removed in vacuo. The residue
was then partitioned between HCl (2 M; 150 ml) and dichloro-
methane (150 ml). The organic phase was washed with brine
(2 × 150 ml) and water (150 ml) and dried (Na2SO4). After
filtration the solvent was evaporated in vacuo and the crude
residue purified by flash chromatography (elution with ether
containing 3% triethylamine) to give the title compound as a
viscous yellow oil (148 mg, 50%) (unseparated mixture of
8.0, CH᎐N), 7.25 (1 H, dd, J 16.0, 8.0, ᎐CHCHN), 7.20–6.94 (8
᎐
᎐
H, m, ArH), 6.86 (1 H, d, J 8.0, ArH), 6.73 (1 H, d, J 16.0,
PhCH᎐), 4.91 (1 H, dd, J 17.0, 2.0, NCHH), 4.21 (1 H, dd, J
᎐
17.0, 2.0, NCHH), 2.90 (6 H, s, NMe2), 2.22 (1 H, t, J 1.0,
᎐
᎐CH); δ (100 MHz; CDCl ) 171.3 (C), 140.0 (CH), 135.4 (CH),
᎐
C
3
135.2 (CH), 134.4 (CH), 131.0 (C), 130.6 (C), 128.8 (CH), 128.6
(CH), 128.2 (CH), 128.1 (CH), 126.1 (CH), 125.3 (CH), 78.9
(C), 72.8 (CH), 43.1 (2 × Me), 39.8 (CH2); m/z (EI) 331 (Mϩ,
25%), 134 (80), 44 (100).
isomers) (Found: Mϩ, 482.2694. C30H34N4O2 requires
1,6-Bis[2-(2-formylethenyl)phenylamino]hexa-2,4-diyne
bis(N,N-dimethylhydrazone) 11
2
482.2682); νmax (CHCl3)/cmϪ1 2961, 2862, 2779, 1668, 1599,
1485, 1456; δH (300 MHz; CDCl3) 7.88–7.22 (6 H, m, 2 ×
The acetylene 10 (134 mg, 0.4 mmol) and copper() acetate
monohydrate (200 mg, 1.0 mmol) were heated in a mixture of
pyridine (10 ml), methanol (10 ml) and ether (40 ml) for 18 h.
The cooled mixture was filtered and concentrated in vacuo. The
residue was washed with dilute hydrochloric acid (50 ml),
extracted with dichloromethane (50 ml) and washed with brine
(2 × 50 ml) and water (2 × 50 ml). The combined organic
extracts were dried (Na2SO4), and concentrated in vacuo. The
residue was chromatographed on silica gel (ether) to yield the
desired product as a pale brown solid (110 mg, 83%), mp 179–
180 ЊC (Found: MHϩ, 661.3290. C42H40N6O2 ϩ H requires
661.3291); νmax (KBr)/cmϪ1 3430, 2212, 1644, 1619, 1482; δH
PhCH᎐, 4 × ArH), 7.06–6.70 (6 H, m, 2 × PhCH᎐CH,
᎐
᎐
4 × ArH), 4.81 (4 H, s, OCH2), 2.58 (9 H, m, NMe2), 2.54 (3 H,
m, NMe2), 2.20 (6 H, m, Me); δC (100 MHz; CDCl3) major
isomer: 163.0 (C), 154.8 (C), 130.6 (CH), 129.4 (CH), 128.0
(CH), 126.8 (CH), 126.3 (C), 122.1 (CH), 112.7 (CH), 74.7 (C),
71.2 (C), 56.7 (CH2), 47.3 (Me), 13.6 (Me); minor isomer: 161.6
(C), 155.2 (C), 131.6 (CH), 130.2 (CH), 130.0 (CH), 127.3 (CH),
126.3 (C), 122.1 (CH), 112.7 (CH), 74.5 (C), 71.3 (C), 56.2
(CH2), 48.1 (Me), 20.5 (Me); m/z (EI) 482 (Mϩ, 0.8%), 468 (1),
437 (9), 393 (44), 379 (40), 352 (19), 234 (76), 145 (100), 91 (26).
1,8-Bis[2-(3-oxobut-1-enyl)phenoxy]octa-3,5-diyne bis(N,N-
dimethylhydrazone) 8d
(400 MHz; CDCl ) 7.45 (2 H, d, J 8, CH᎐N), 7.21–6.90 (18 H,
᎐
3
m, ArH), 6.80 (2 H, dd, J 16.0, 8.0, ᎐CHCHN), 6.63 (2 H, d, J
᎐
16.0, PhCH᎐), 4.92 (2 H, d, J 17.0, NCHH), 4.13 (2 H, d, J
᎐
A solution of 4-(2-but-3-ynyloxyphenyl)but-3-en-2-one N,N-
dimethylhydrazone 7d (130 mg, 0.49 mmol) was stirred in ether
(40 ml), methanol (10 ml) and pyridine (10 ml) with copper()
acetate monohydrate (290 mg, 1.5 mmol) at reflux. After 16 h,
the reaction mixture was filtered and the solvent removed in
vacuo. The residue was partitioned between HCl (2 M; 50 ml)
and dichloromethane (50 ml), the organic extracts were washed
with water (2 × 50 ml) and brine (50 ml) and dried (Na2SO4).
After filtration the solvent was removed in vacuo and the crude
residue purified by flash chromatography (elution with ether
containing 3% triethylamine) to give the title compound as a
viscous yellow oil (63 mg, 50%) (inseparable mixture of 2 iso-
mers) (Found: Mϩ, 510.3007. C32H38N4O2 requires 510.2995);
νmax (film)/cmϪ1 3059, 2953, 2856, 2819, 2775, 1599, 1489, 1454,
17.0, NCHH), 2.89 (12 H, s, NMe2); δC (100 MHz; CDCl3)
171.5 (C), 140.3 (C), 135.6 (C), 135.5 (CH), 134.7 (CH), 131.6
(CH), 131.6 (CH), 131.0 (CH), 130.9 (CH), 129.2 (CH), 129.1
(CH), 128.7 (CH), 128.5 (CH), 126.5 (CH), 125.4 (CH), 74.3
(C), 69.6 (C), 43.3 (2 × Me), 40.8 (CH2); m/z (CI) 661 (MHϩ,
75%), 44 (100).
Dodeca-5,7-diyne-1,12-diol 13a
A solution of copper() acetate monohydrate (8.0 g, 40 mmol)
in ether (400 ml), methanol (100 ml) and pyridine (120 ml) was
stirred at reflux. Hex-5-ynol 12a (1.0 g, 10 mmol) was added
and the solution stirred for 16 h. The mixture was concentrated
in vacuo and the product was partitioned between HCl (2 M;
500 ml) and dichloromethane (500 ml). The organic layer was
washed with water (2 × 500 ml) and brine (2 × 500 ml) and
dried (Na2SO4). The mixture was filtered and the solvent
removed in vacuo. The residue was purified by flash chroma-
tography (elution with ether) to give the title compound as a
colourless solid (600 mg, 61%); mp 51–52 ЊC (from light
petroleum–ethyl acetate) (lit.,29 mp 49–50 ЊC) (Found: C, 74.1;
H, 9.45. C12H18O2 requires C, 74.2; H, 9.3%); νmax (KBr)/cmϪ1
752; δH (400 MHz; CDCl3) 7.59–6.81 (12 H, m, 8 × ArH,
᎐
2 × PhCH᎐CH), 4.14 (4 H, m, OCH ), 2.80 (4 H, m, CH C᎐),
᎐
᎐
2
2
2.56 (8.5 H, s, NMe2), 2.54 (3.5 H, s, NMe2), 2.22 (6 H, s, Me);
δC (100 MHz; CDCl3) major isomer: 163.1 (C), 155.6 (C), 130.1
(CH), 129.4 (CH), 128.1 (CH), 126.4 (CH), 126.2 (C), 121.6
(CH), 112.6 (CH), 73.9 (C), 66.7 (C), 66.2 (CH2), 47.3 (Me),
20.4 (CH2), 13.5 (Me); minor isomer: 161.9 (C), 156.1 (C), 130.6
(CH), 130.1 (CH), 127.2 (CH), 126.1 (C), 121.5 (CH), 120.7
(CH), 112.6 (CH), 73.8 (C), 66.7 (C), 66.2 (CH2), 48.1 (Me),
20.42 (Me), 20.39 (CH2); m/z (EI) 510 (Mϩ, 2%), 495 (3), 466
(37), 452 (35), 409 (61), 187 (35), 145 (100), 91 (37).
3430, 3623, 2175; δH (300 MHz; CDCl3) 3.63 (4 H, t, J 6.1,
᎐
CH O), 2.28 (4 H, t, J 6.7, ᎐CCH ), 2.11 (2 H, s, OH), 1.62 (8
᎐
2
2
J. Chem. Soc., Perkin Trans. 1, 2001, 2183–2193
2189

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H, m, CH2CH2); δC (75 MHz; CDCl3) 76.6 (C), 65.6 (C), 62.1
was allowed to warm to room temperature. The reaction was
(CH2), 31.7 (CH2), 24.6 (CH2), 19.0 (CH2).
then quenched by addition of ammonium chloride solution
(saturated aqueous, 50 ml), the solution was extracted with
ether (3 × 50 ml) and the combined organic extracts were
washed with water (3 × 50 ml) and brine (50 ml) and then dried
(Na2SO4). The mixture was filtered and the solvent removed in
vacuo; the crude residue was purified by flash chromatography
(elution with 9 : 1 ether–light petroleum) to give the title com-
pound as a viscous yellow oil (54 mg, 35%) (Found: Mϩ,
326.2468. C20H30N4 requires 326.2470); νmax (film)/cmϪ1 2939,
2858, 2785, 2160, 1560, 1468, 1030; δH (300 MHz; CDCl3) 6.97
Tetradeca-6,8-diyne-1,14-diol 13b
To a stirred solution of copper() acetate monohydrate in
methanol (100 ml), ether (400 ml) and pyridine (200 ml) was
added hept-6-ynol 12b (2.6 g, 23 mmol) in ether (5 ml). The
temperature was raised to 55 ЊC. After 4 days, the mixture was
filtered and resulting solution partitioned between HCl (2 M;
350 ml) and dichloromethane (350 ml). The aqueous phase was
extracted with more dichloromethane (100 ml). The combined
organic phases were washed with water (2 × 350 ml) and brine
(350 ml) and were dried (Na2SO4). The solution was filtered and
the solvent was removed in vacuo; the residue was purified by
flash chromatography (elution with 1 : 1 ether–ethyl acetate)
to give the title compound as a pink solid (2.2 g, 85%); mp 62–
64 ЊC (from ether) (Found: Mϩ, 222.1619. C14H22O2 requires
222.1620); νmax (KBr)/cmϪ1 3405 (br), 3444 (br), 2939, 2893,
(2 H, d, J 8.9, CH᎐N), 6.18 (2 H, ddt, J 15.6, 8.9, 1.3, CHCH᎐
᎐
᎐
N), 5.73 (2 H, dt, J 15.6, 7.0, CH CH᎐), 2.80 (12 H, s, NMe ),
᎐
2
2
2.26–2.18 (8 H, m, CH2), 1.61 (4 H, m, CH2); δC (75 MHz;
CDCl3) 136.4 (CH), 133.8 (CH), 129.9 (CH), 77.0 (C), 65.7 (C),
42.9 (Me), 31.6 (CH2), 27.7 (CH2), 18.6 (CH2); m/z (EI) 326
(Mϩ, 1%), 282 (34), 237 (100), 210 (58), 182 (52), 170 (61), 157
(56), 144 (42), 130 (92).
2860, 1464, 1057; δH (300 MHz; CDCl3) 3.62 (4 H, t, J 6.4,
(2E,16E )-Octadeca-2,16-diene-8,10-diyne-1,18-dial bis(N,N-
dimethylhydrazone) 15b
᎐
CH O), 2.25 (4 H, t, J 6.6, CH C᎐), 1.74 (2 H, br, OH), 1.41–
᎐
2
2
1.60 (12 H, m, CH2CH2CH2); δC (75 MHz; CDCl3) 77.3 (C),
65.5 (C), 62.6 (CH2), 32.2 (CH2), 28.1 (CH2), 25.0 (CH2), 19.2
(CH2); m/z (EI) 223 (11%), 222 (Mϩ, 3), 179 (8), 149 (51), 131
(28), 117 (53), 105 (54), 91 (100).
Diethyl formylmethylphosphonate N,N-dimethylhydrazone
(420 mg, 1.9 mmol) was stirred in THF (2.5 ml) at Ϫ78 ЊC. n-
Butyllithium (1.6 M in hexane; 1.2 ml, 1.9 mmol) was added
dropwise and the solution stirred for 15 min. A solution of
tetradeca-6,8-diyne-1,14-dial 14b (89 mg, 0.40 mmol) in THF
(1.5 ml) was added slowly and after 45 min the reaction was
allowed to warm to room temperature. After 2 h, the reaction
was quenched by addition of aqueous ammonium chloride
solution (saturated, 50 ml), the solution was extracted with
ether (3 × 50 ml) and the combined organic extracts were
washed with water (3 × 50 ml) and brine (50 ml) and were dried
(Na2SO4). The mixture was filtered and the solvent removed in
vacuo to give a crude residue that was purified by flash chroma-
tography (elution with 7 : 3 ether–light petroleum containing
3% triethylamine) to give the title compound as a viscous yellow
oil (33 mg, 23%) (Found: Mϩ, 354.2787. C22H34N4 requires
354.2783); νmax (film)/cmϪ1 2937, 2858, 2784, 1566, 1468, 1032,
Dodeca-5,7-diyne-1,12-dial 14a
A suspension of IBX (6.52 g, 23.3 mmol) in DMSO (25 ml)
was stirred vigorously at room temperature for 1.5 h. Dodeca-
5,7-diyne-1,12-diol 13a (910 mg, 4.7 mmol) in DMSO (7 ml)
was added and the mixture stirred overnight. After 16 h, the
reaction mixture was diluted with water (100 ml) and the white
precipitate was filtered off. The solution was extracted with
ether (3 × 80 ml) and the combined organic extracts were
washed with water (3 × 150 ml) and dried (Na2SO4). The
mixture was filtered and the solvent removed to give the title
compound as a viscous yellow oil (850 mg, 96%) used without
further purification; νmax (CHCl3)/cmϪ1 2944, 2904, 2833, 2729,
2214, 1724, 1391, 1410, 1429; δH (300 MHz; CDCl3) 9.77 (2 H,
733; δH (300 MHz; CDCl ) 6.99 (2 H, d, J 8.9, CH᎐N), 6.17
᎐
3
t, J 1.2, CHO), 2.56 (4 H, td, J 7.0, 1.2, CH2CHO), 2.32 (4 H, t,
(2 H, ddt, J 15.5, 8.9, 1.4, CHCH᎐N), 5.77 (2 H, dt, J 15.5, 7.0,
᎐
᎐
J 7.0, ᎐CCH ), 1.83 (4 H, quin, J 7.0, CH CH CH ); δ (75
᎐
2
2
2
2
C
CH CH᎐), 2.80 (12 H, s, NMe ), 2.26–2.21 (4 H, m, CH ),
᎐
2
2
2
MHz; CDCl3) 201.5 (CHO), 76.4 (C), 66.2 (C), 42.5 (CH2), 20.7
(CH2), 18.5 (CH2).
2.17–2.10 (4 H, m, CH2), 1.54–1.49 (8 H, m, CH2CH2); δC (75
MHz; CDCl3) 136.7 (CH), 134.9 (CH), 129.3 (CH), 77.3 (C),
65.4 (C), 42.9 (Me), 32.0 (CH2), 28.2 (CH2), 27.7 (CH2), 19.0
(CH2); m/z (EI) 354 (Mϩ, 1%), 310 (27), 283 (21), 265 (30), 250
(23), 223 (19), 59 (100).
Tetradeca-6,8-diyne-1,14-dial 14b
IBX (340 mg, 1.2 mmol) was stirred in DMSO (0.5 ml) until
complete dissolution was achieved (ca. 10 min). Tetradeca-6,8-
diyne-1,14-diol 13b (44 mg, 0.2 mmol) was added and the
solution stirred for 16 h. Water (10 ml) was added and the
precipitate filtered off. The solution obtained was extracted
with ether (10 ml) and the organic extracts were washed with
water (3 × 10 ml) and dried (Na2SO4). The drying agent was
removed by filtration and the solvent removed in vacuo to give
the title compound as a viscous yellow oil (40 mg, 92%) used
without further purification; νmax (CHCl3)/cmϪ1 2937, 2867,
2832, 1723, 757; δH (300 MHz; CDCl3) 9.75 (2 H, t, J 1.6,
(3E,15E )-Octadeca-3,15-diene-8,10-diyne-2,17-dione 16a
To a suspension of (acetylmethylene)triphenylphosphorane
(3.0 g, 9.3 mmol) in THF (20 ml) was added dodeca-5,7-diyne-
1,12-dial 14a (800 mg, 1.2 mmol) in THF (6 ml). After heating
at reflux for 16 h, the solvent was removed and the residue
was purified by flash chromatography (elution with 2 : 1 ether–
light petroleum) to give the title compound as a light yellow
oil (340 mg, 34%) (Found: Mϩ, 270.1618. C18H22O2 requires
270.1620); νmax (CHCl3)/cmϪ1 2936, 2866, 2162, 1617, 1637,
1627; δ (300 MHz; CDCl ) 6.74 (2 H, dt, J 16.0, 6.9, CH CH᎐),
CHO), 2.45 (4 H, td, J 7.2, 1.6, CH2CHO), 2.27 (4 H, t, J 6.9,
᎐
᎐
᎐CCH ), 1.78–1.68 (4 H, m, CH CH CHO), 1.59–1.51 (4 H, m,
H
3
2
᎐
2
2
2
6.07 (2 H, dt, J 16.0, 1.5, ᎐CHC(Me)O), 2.36–2.25 (8 H, m,
᎐
᎐
᎐CCH CH ); δ (75 MHz; CDCl ) 202.3 (CHO), 76.8 (C), 65.7
᎐
2
2
C
3
᎐
᎐CCH , CH CH᎐), 2.21 (6 H, s, Me), 1.68 (4 H, quin, J 7.1,
᎐
᎐
(C), 43.2 (CH2), 27.6 (CH2), 21.2 (CH2), 19.0 (CH2).
2
2
CH CH CH ); δ (75 MHz; CDCl ) 198.3 (C᎐O), 146.4 (CH),
᎐
2
2
2
C
3
131.0 (CH), 76.6 (C), 66.0 (C), 31.3 (CH2), 26.9 (Me), 26.6
(CH2), 18.7 (CH2); m/z (EI) 270 (Mϩ, 0.9%), 227 (100), 213 (21),
199 (44), 174 (26), 149 (42), 128 (38), 115 (37).
(2E,14E )-Hexadeca-2,14-diene-7,9-diyne-1,16-dial bis(N,N-
dimethylhydrazone) 15a
Diethyl formylmethylphosphonate N,N-dimethylhydrazone
(330 mg, 1.5 mmol) was stirred in THF (2 ml) at Ϫ78 ЊC. n-
Butyllithium (1.6 M in hexane; 0.94 ml, 1.5 mmol) was added
dropwise and the solution stirred for 10 min. A solution of
dodeca-5,7-diyne-1,12-dial 14a (89 mg, 0.46 mmol) in THF
(1.5 ml) was added slowly and after 30 min the reaction mixture
(3E,17E )-Icosa-3,17-diene-9,11-diyne-2,19-dione 16b
A solution of tetradeca-6,8-diyne-1,14-dial 14b (190 mg,
0.86 mmol) was stirred in toluene (10 ml), (acetylmethylene)-
triphenylphosphorane (600 mg, 1.9 mmol) was added and the
2190
J. Chem. Soc., Perkin Trans. 1, 2001, 2183–2193

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suspension heated at reflux for 45 min. The mixture was allowed
to cool to room temperature and stirred for a further 16 h and
then concentrated in vacuo. The crude residue was purified by
flash chromatography (elution with 2 : 1 ether–light petroleum)
to give the title compound as a viscous pale yellow oil (100 mg,
41%) (Found: Mϩ, 298.1931. C20H26O2 requires 298.1933); νmax
(film)/cmϪ1 3004, 2939, 2862, 1696, 1673; δH (300 MHz; CDCl3)
1608, 1600, 1476, 1416, 1247; δH (400 MHz; CDCl3) 8.58 (1 H,
d, J 5.2, ArH), 8.41 (1 H, s, ArH), 7.73 (1 H, dd, J 7.8, 1.6,
ArH), 7.51 (1 H, d, J 5.2, ArH), 7.33 (1 H, m, ArH), 7.08 (1 H,
m, ArH), 7.01 (1 H, m, ArH), 5.15 (2 H, s, OCH2); δC (100
MHz; CDCl3) 155.7 (C), 150.1 (CH), 145.8 (CH), 137.6 (C),
131.8 (CH), 125.9 (C), 124.0 (CH), 122.4 (CH), 120.4 (C), 117.8
(CH), 115.9 (CH), 65.8 (CH2); m/z (EI) 183 (Mϩ, 99%), 182
(100), 154 (9), 127 (10), 99 (1); and (ii) 3-(2H-chromen-8-yl)-
propenal N,N-dimethylhydrazone 18 as a brown oil (4.0 mg,
6%) (Found: Mϩ, 228.1259. C14H16N2O requires 228.1263);
νmax (film)/cmϪ1 3045, 2954, 2853, 2827, 1551, 1462, 1443, 1037;
6.77 (2 H, dt, J 16.0, 6.9, CH CH᎐), 6.07 (2 H, dt, J 16.0, 1.5,
᎐
2
᎐CHC(Me)O), 2.30–2.19 (14 H, m, 4 × CH , 2 × Me), 1.61–
᎐
2
1.53 (8 H, m, 4 × CH ); δ (75 MHz; CDCl ) 198.6 (C᎐O), 147.7
᎐
2
C
3
(CH), 131.6 (CH), 77.0 (C), 65.6 (C), 31.9 (CH2), 27.7 (CH2),
27.1 (CH2), 26.9 (Me), 19.0 (CH2); m/z (EI) 298 (Mϩ, 2%), 297
(5), 281 (10), 255 (27), 187 (36), 173 (55), 129 (62).
δ (400 MHz; C D ) 7.48 (1 H, dd, J 16.7, 8.8, ᎐CHCHN), 7.38
᎐
H
6
6
(1 H, dd, J 7.6, 1.8, ArH), 7.23 (1 H, d, J 16.4, PhCHCHCHN),
7.12 (1 H, d, J 8.8, CH᎐N), 6.74–6.70 (2 H, m, ArH), 6.19 (1 H,
᎐
(3E,15E )-Octadeca-3,15-diene-8,10-diyne-2,17-dione bis(N,N-
dt, J 9.8, 1.9, PhCH᎐CHCH ), 5.29 (1 H, dt, J 9.8, 3.5,
᎐
2
dimethylhydrazone) 15c
᎐CHCH ), 4.48 (2 H, dd, J 3.5, 1.9, CH O), 2.64 (6 H, s,
᎐
2 2
NMe2); δC (100 MHz; CDCl3) 151.1 (C), 136.5 (CH), 128.1
(CH), 126.1 (CH), 126.0 (CH), 125.7 (CH), 125.0 (C), 124.8
(CH), 122.6 (C), 121.8 (CH), 121.1 (CH), 65.6 (CH2), 42.8
(Me); m/z (EI) 228 (Mϩ, 72%), 182 (57), 169 (100), 154 (35), 141
(32), 128 (75), 115 (57), 102 (32).
Magnesium sulfate (1.0 g) and octadeca-3,15-diene-8,10-diyne-
2,17-dione 16a (340 mg, 1.3 mmol) were stirred in THF (20 ml);
N,N-dimethylhydrazine (950 µl, 13 mmol) was added at 0 ЊC.
After 3 days, the mixture was filtered and the title compound
isolated by flash chromatography (elution with ether containing
3% triethylamine, TLC showed isomer 1 at Rf = 0.22 and isomer
2 at Rf = 0.19) as a yellow oil (160 mg, 35%) (Found: MHϩ,
355.2862. C22H34N4 ϩ H requires 355.2862); νmax (CHCl3)/cmϪ1
2959, 2864, 1645, 1584, 1468; δH (300 MHz; CDCl3) 6.82–6.02
2-Methyl-5H-chromeno[3,4-c]pyridine 19
A solution of 4-(2-prop-2-ynyloxyphenyl)but-3-en-2-one N,N-
dimethylhydrazone 7b (35 mg, 0.14 mmol) in mesitylene (5 ml)
was heated at reflux under an atmosphere of nitrogen for 3 days.
The mixture was then transferred to high pressure sealed tube
apparatus, the solvent was degassed, the space was filled with
nitrogen and the tube sealed. The mixture was then heated to
210 ЊC for 4 days. The mixture was concentrated in vacuo
and the title compound was isolated by flash chromatography
(elution with ether) as a brown oil (11 mg, 41%) (Found: Mϩ,
197.0845. C13H11NO requires 197.0841); νmax (CHCl3)/cmϪ1
2962, 2929, 2855, 1609, 1458; δH (400 MHz; CDCl3) 8.31 (1 H,
s, ArH), 7.74 (1 H, dd, J 7.8, 1.6, ArH), 7.41 (1 H, s, ArH), 7.33
(1 H, ddd, J 8.2, 7.5, 1.6, ArH), 7.08 (1 H, ddd, J 7.8, 7.5, 1.2,
ArH), 7.01 (1 H, dd, J 8.2, 1.2, ArH), 5.15 (2 H, s, OCH2), 2.61
(3 H, s, Me); δC (100 MHz; CDCl3) 158.7 (C), 155.8 (C), 145.0
(CH), 137.9 (C), 131.6 (CH), 123.9 (CH), 123.2 (C), 122.3 (CH),
120.6 (C), 117.8 (CH), 115.3 (CH), 65.8 (CH2), 24.5 (Me);
m/z (EI) 197 (Mϩ, 66%), 196 (73), 168 (7), 141 (5), 118 (36),
83 (100).
(4 H, m, CH CH᎐, CH CH᎐CH), 2.49 ϩ 2.46 (12 H, s, NMe ),
᎐
᎐
2
2
2
᎐
2.29–2.24 (8 H, m, CH CH᎐, ᎐CCH ), 2.04 ϩ 2.03 (6 H, s,
᎐ ᎐
2
2
Me), 1.66 (4 H, quin, J 7.2, CH2CH2CH2); δC (100 MHz;
CDCl3) major isomer: 162.8 (C), 135.6 (CH), 132.6 (CH), 76.8
(C), 65.8 (C), 47.2 (Me), 31.7 (CH2), 27.5 (CH2), 18.7 (CH2),
13.3 (Me); minor isomer: 138.5 (C), 135.6 (CH), 123.9 (CH),
76.8 (C), 65.8 (C), 47.8 (Me), 32.1 (CH2), 27.4 (CH2), 20.3 (Me),
18.8 (CH2); m/z (CI) 355 (MHϩ, 20%), 63 (100).
(3E,17E )-Icosa-3,17-diene-9,11-diyne-2,19-dione bis(N,N-
dimethylhydrazone) 15d
N,N-Dimethylhydrazine (220 µl, 2.9 mmol) was added to
magnesium sulfate (150 mg) and icosa-3,17-diene-9,11-diyne-
2,19-dione 16b (87 mg, 0.29 mmol) in THF (5 ml), at 0 ЊC. After
3 days, the mixture was filtered and the solvent removed in
vacuo to give a residue that was purified by flash chroma-
tography (elution with ether containing 3% triethylamine) to
give the title compound as a yellow oil (18 mg, 16%) (Found:
Mϩ, 382.3096. C24H38N4 requires 382.3096); νmax (CHCl3)/cmϪ1
2939, 2858, 2773, 1645, 1583; δH (300 MHz; CDCl3) 6.79–6.03
4,4Ј-Bi(5H-chromeno[3,4-c]pyridine) 21
A solution of the bis(N,N-dimethylhydrazone) 8a (97 mg, 0.21
mmol) in xylene (6 ml) was degassed by freeze–pump–thaw
techniques in a sealable tube. The headspace of the tube was
flushed with nitrogen and the solution was heated to 150 ЊC for
3.5 h. The solvent was removed in vacuo and the crude residue
purified by flash chromatography (elution with 4 : 1 THF–
dichloromethane) to give a brown solid (61 mg, 81%) that
was further purified by flash chromatography (elution with
chloroform) to give the title compound as a light brown solid
(14 mg, 18%); mp 208–209 ЊC (from chloroform) (Found: Mϩ,
364.1210. C24H16N2O2 requires 364.1212); νmax (CHCl3)/cmϪ1
2964, 2856, 1608, 1589, 1581, 1554, 1468; δH (400 MHz; CDCl3)
8.63 (2 H, d, J 5.2, ArH), 7.80 (2 H, dd, J 7.9, 1.5, ArH), 7.62 (2
H, d, J 5.2, ArH), 7.37 (2 H, m, ArH), 7.12 (2 H, m, ArH), 7.03
(2 H, dd, J 8.2, 1.2, ArH), 5.33 (4 H, s, OCH2); δC (100 MHz;
CDCl3) 156.0 (C), 153.1 (C), 147.8 (CH), 139.3 (C), 131.7 (CH),
126.5 (C), 124.1 (CH), 122.3 (CH), 120.8 (C), 117.7 (CH), 116.0
(CH), 65.7 (CH2); m/z (EI) 364 (Mϩ, 100%), 363 (25), 345 (10),
335 (16), 308 (11), 279 (10), 149 (27).
(4 H, m, CH CH᎐CH), 2.50 ϩ 2.47 (12 H, s, NMe ), 2.27–2.14
᎐
2
2
᎐
(8 H, m, CH CH᎐, CH C᎐), 2.04 ϩ 2.03 (6 H, s, Me), 1.56–
᎐
᎐
2
2
1.53 (8 H, m, CH2CH2CH2CH2); δC (75 MHz; CDCl3) major
isomer: 163.0 (C), 136.6 (CH), 132.0 (CH), 77.1 (C), 65.8 (C),
47.3 (Me), 32.2 (CH2), 27.7 (CH2), 27.9 (CH2), 19.0 (CH2), 13.3
(Me); minor isomer: 139.6 (C), 136.6 (CH), 123.4 (CH), 77.1
(C), 65.5 (C), 47.8 (Me), 32.5 (CH2), 27.9 (CH2), 27.7 (CH2),
20.4 (Me), 19.0 (CH2); m/z (EI) 382 (Mϩ, 2%), 367 (6), 338 (43),
324 (100), 304 (24), 281 (96).
Diels–Alder reactions
5H-Chromeno[3,4-c]pyridine 17
A solution of (E)-3-(2-prop-2-ynyloxyphenyl)propenal N,N-
dimethylhydrazone 7a (69 mg, 0.30 mmol) in xylene (5 ml) was
degassed by freeze–pump–thaw techniques in a sealable tube,
the headspace in the tube was flushed with nitrogen and the
tube sealed. The solution was heated to 165 ЊC for 1 day and
then to 200 ЊC for 6 days. The solvent was removed in vacuo
and the residue purified by flash chromatography (elution with
ether containing 3% triethylamine followed by 1 : 1 ether–ethyl
acetate) to give (i) the title compound as a brown oil (33 mg,
59%) (lit.,15 no data given) (Found: Mϩ, 183.0685. C12H9NO
requires 183.0684); νmax (film)/cmϪ1 3034, 2974, 2918, 2853,
2,2Ј-Dimethyl-4,4Ј-bi(5H-chromeno[3,4-c]pyridin)-5-one 22
A solution of the bis(N,N-dimethylhydrazone) 8c (120 mg,
0.25 mmol) in mesitylene (10 ml) was heated at reflux for 48 h.
The solvent was removed in vacuo and the crude residue
J. Chem. Soc., Perkin Trans. 1, 2001, 2183–2193
2191

View Article Online
purified by flash chromatography (elution with 2 : 1 ether–ethyl
acetate containing 3% triethylamine) to give the title compound
as a brown oil (17 mg, 17%) (Found: Mϩ, 406.1310. C26H18N2O3
requires 406.1317); νmax (CHCl3)/cmϪ1 2962, 2927, 2856, 1741,
1598, 1262; δH (400 MHz; CDCl3) 8.11 (1 H, dd, J 8.0, 1.3,
ArH), 7.89 (1 H, s, ArH), 7.80 (1 H, dd, J 7.8, 1.5, ArH), 7.58
(1 H, ddd, J 8.0, 7.5, 1.5, ArH), 7.51 (1 H, s, ArH), 7.40–7.36
(1 H, m, ArH), 7.34 (1 H, dd, J 8.3, 1.2, ArH), 7.30 (1 H, ddd,
J 6.4, 5.7, 1.6, ArH), 7.08 (1 H, m, ArH), 6.95 (1 H, dd, J 8.2,
1.6, ArH), 4.90 (2 H, br, OCH2), 2.79 (3 H, s, Me), 2.64 (3 H, s,
Me); δC (100 MHz; CDCl3) 163.2 (CO), 160.7 (C), 158.1 (C),
157.6 (C), 155.6 (C), 153.8 (C), 152.9 (C), 143.5 (C), 138.4 (C),
132.8 (CH), 131.3 (CH), 124.7 (CH), 124.1 (CH), 123.6 (CH),
122.1 (CH), 120.9 (C), 120.8 (C), 117.9 (CH), 117.6 (CH), 116.0
(C), 115.3 (CH), 114.5 (CH), 113.2 (C), 64.9 (CH2), 25.3 (Me),
24.6 (Me); m/z (EI) 406 (Mϩ, 100%), 391 (11), 378 (38), 363 (6),
350 (21), 335 (7), 196 (21).
A solution of the above compound (29 mg, 0.07 mmol)
in ethyl acetate (2 ml) was treated with excess palladium on
charcoal, with stirring for 48 h at 25 ЊC. The reaction mixture
was filtered through a pad of Celite, and concentrated in vacuo
to yield the title compound as a brown semi-solid (27 mg, 97%)
(Found: MHϩ, 359.1296. C24H14N4 ϩ H requires 359.1298);
νmax (CCl4)/cmϪ1 1642, 762; δH (400 MHz; CDCl3) 9.45 (2 H, s,
ArH), 9.26 (2 H, d, J 8.0, ArH), 8.64 (2 H, dd, J 8.0, 1.0, ArH),
8.54 (2 H, dd, J 8.0, 1.0, ArH), 8.16 (2 H, dd, J 8.0, 1.0, ArH),
7.87–7.71 (4 H, m, ArH); δC (100 MHz; CDCl3) 157.4 (C), 150.0
(CH), 148.1 (C), 135.7 (C), 132.8 (CH), 129.2 (CH), 128.2 (CH),
128.0 (C), 127.8 (CH), 126.3 (CH), 123.5 (CH), 120.8 (C);
m/z (CI) 359 (MHϩ, 100%).
Acknowledgements
We thank the EPSRC for support of this work, the EPSRC and
Zeneca Pharmaceuticals (now AstraZeneca) for a CASE Award
(to D.A.R.), and the EPSRC Mass Spectrometry Service at
Swansea for mass spectra.
6,6Ј-Dibenzoyl-5,5Ј,6,6Ј-tetrahydro-4,4Ј-bi(benzo[c][2,7]-
naphthyridine) 23
A solution of the bis(N,N-dimethylhydrazone) 11 (100 mg,
0.1 mmol) in xylene (2 ml) was heated at reflux for 2 h. After
cooling, the solvent was removed in vacuo and the crude residue
was chromatographed on silica gel (ether) to yield the desired
Diels–Alder adduct as a pale brown solid (58 mg, 68%), mp
163–165 ЊC (Found: MHϩ, 571.2133. C38H26N4O2 ϩ H requires
571.2134); νmax (KBr)/cmϪ1 3432, 1653; δH (400 MHz; CDCl3)
8.66 (1 H, d, J 5.0, ArH), 7.85 (1 H, dd, J 8.0, 1.0, ArH), 7.76
(1 H, d, J 5.0, ArH), 7.40–7.09 (7 H, m, ArH), 6.83 (1 H, d,
J 5.0, ArH), 5.16 (2 H, s, NCH2); δC (100 MHz; CDCl3) 169.8
(C), 154.2 (C), 148.3 (CH), 139.8 (C), 138.2 (C), 135.3 (CH),
131.0 (CH), 130.3 (CH), 129.8 (CH), 129.5 (CH), 128.6 (CH),
128.5 (CH), 128.4 (CH), 126.6 (CH), 126.4 (CH), 125.9 (CH),
125.3 (C), 117.6 (CH), 44.9 (CH2); m/z (CI) 571 (MHϩ, 100%).
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6,6Ј,7,7Ј-Tetrahydro-1,1Ј-bi(5H-cyclopenta[c]pyridine) 24
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2192
J. Chem. Soc., Perkin Trans. 1, 2001, 2183–2193

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