Synthesis of 1,3-diynes in the purine, pyrimidine, 1,3,5-triazine and acridine series

Article abstract of DOI:10.1016/S0040-4020(00)00016-8

A range of conjugated 1,3-diynes, R¹C≡CC≡CR², has been prepared that incorporate the following heteroaromatic units as head groups of the substituents R¹ and/or R²: pyrimidinyl, purinyl, 2,4-diamino-1,3,5- triaz

Full text of DOI:10.1016/S0040-4020(00)00016-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1233–1245
Synthesis of 1,3-Diynes in the Purine, Pyrimidine, 1,3,5-Triazine
and Acridine Series
*
*
W. Edward Lindsell, Christopher Murray, Peter N. Preston and Thomas A. J. Woodman
Department of Chemistry, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, Scotland, UK
Received 12 October 1999; revised 29 November 1999; accepted 16 December 1999
Abstract—A range of conjugated 1,3-diynes, R1CxCCxCR2, has been prepared that incorporate the following heteroaromatic units as head
groups of the substituents R1 and/or R2: pyrimidinyl, purinyl, 2,4-diamino-1,3,5-triazinyl and acridinyl. Compounds containing the first three
groups as terminal heterocyclic substituents in both R1 and R2 are bonded through methylene linkers {(CH2)n, nˆ1, 4 or 9} to the 1,3-diyne;
also reported are amphiphilic species with R2ˆn-C10H21 and a single heteroaromatic head group in chain R1. Compounds in the acridine
series are also amphiphiles and contain quaternised 10-(9-acridinylamino)- and 10-(6-chloro-2-methoxyacridinylamino)- terminal sub-
stituents linked by PEG and methylene units to the diyne function. The new diynes have been synthesised by oxidative coupling of the
corresponding v-heteroaromatic functionalised 1-alkyne or by transformation of terminal groups on preformed diynes. ᭧ 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
in the polymer (see Scheme 1). Also, discrete PDAs can
be envisaged which contain, separately, only R1 and R2
substituents such that self-assembly could be achieved
through intermolecular hydrogen bonding. In the present
work, the following base-pair combinations were selected
for use in 1,3-diyne synthesis: adenin-9-yl/thymin-1-yl,
guanin-9-yl/cytosin-1-yl, and 2,4-diamino-1,3,5-triazin-1-
yl/uracil-1-yl.9 Purine and pyrimidine derivatives are often
relatively insoluble in common organic solvents; therefore
the target 1,3-diynes also included aliphatic methylene
chains to aid solubility, and were of general structure:
[R(CH2)nCxC–]2 (Rˆadeninyl, thyminyl, guanyl, cyto-
sinyl); and R1CxC–CxC(CH2)nR2, R1ˆlong hydrocarbon
chain, R2ˆguanyl, cytosinyl, 2,4-diamino-s-triazinyl and
uracyl.
Polydiacetylenes (PDAs) [B, Scheme 1] can be generated
from conjugated 1,3-diynes (A) through a solid state (topo-
chemical) polymerisation by thermal treatment or by UV-
and g-irradiation.1 Highly conjugated polymers in this class
are often very insoluble, but many, including those with
urethane,2 sulfonate3 and ester4 side chains, are soluble in
common organic solvents. PDAs have generated interest in
the area of advanced materials because of their unusually
high third-order nonlinearity5 and through aspects of their
property of chromism.6 Recent investigations harnessing the
latter effect have been fruitful in the design and successful
demonstration of a biosensor for influenza viruses. Thus,
polymerised PDA liposomes incorporating a sialic acid
head group undergo a quantifiable colorimetric response
when exposed to influenza virus.7 It is apparent that
organised arrays of PDAs, as manifested in liposomes, can
exhibit unusual properties resulting from conformational
effects in side-chains.
The second type of 1,3-diyne, containing the DNA-inter-
calating acridinyl substituent,10 was designed with the inten-
tion of generating liposomes which might be expected to
exhibit chromic effects through binding to nucleic acids.
Therefore, in this work, the synthetic targets incorporated
the following: a long alkyl chain at one terminus and a
second chain at the other end comprising a polymethylene
segment, a polar linker [viz polyethyleneglycol (PEG)] and
an acridinyl head group.
In continuation of our studies of PDAs,8 we required two
classes of functionalised 1,3-diynes. The first type was
needed for the synthesis of monomers and polymers,
which might self-assemble through strong hydrogen bon-
ding. In principle, this effect could be achieved through
introduction of appropriate substituents (R1, R2) in the
monomer so as to achieve strong intermolecular bonding
Keywords: 1,3-diyne; purine; pyrimidine; 1,3,5-triazine; acridine.
* Corresponding authors. Tel.: ϩ44-131-449-5111; fax: ϩ44-131-451-
3180; e-mail: w.e.lindsell@hw.ac.uk; p.n.preston@hw.ac.uk
Scheme 1.
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00016-8

1234
W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
Scheme 2.
Results and Discussion
coupled12 to afford the 1,3-diyne (4b) in 75% yield. Unfor-
tunately, it proved impossible to obtain an analytically pure
sample, although the 1H NMR and mass spectral data were
in accord with the proposed structure; the molecular ion (EI)
or the Mϩ1 ion (FAB) were too weak to allow high reso-
lution mass measurements (Scheme 3).
Adenine derivatives
At the outset of the work a brief preliminary report appeared
on the synthesis of the hexa-2,4-diyne derivative (3a) and a
related uracil.11 In our work, the propargylic derivative (1a)
was oxidatively coupled by a modification12 of the Eglinton/
Galbraith procedure [Cu(OAc)2.H2O/pyridine]13 in which
the solvent is acetonitrile/pyridine; the poorly soluble
coupled product (3a) was formed in slightly improved
yield compared to the reported procedure.11 No success
was achieved in attempts to oxidatively couple longer
chain analogues of (1a) (e.g. 1b was not converted to 3b
through the Hay oxidative coupling but formed a black
intractable product). Therefore, the diyne (3b) was prepared
by treating the bis tosylate (2c) with adenine in the presence
of potassium carbonate in anhydrous DMF; in this reaction
the monoadenin-9-yl-substituted derivative (2d) was
isolated as a minor product but was not purified to analytical
standard. The preference for alkylation at the 9-position of
adenine under basic conditions is in accord with related
processes using dibromoalkanes14 (Scheme 2).
An attempt was then made to prepare analogues of (4a) (viz
4c, d) but no success was achieved in attempts to alkylate
the bis silyl derivative (5) by heating it in THF with a bis
tosylate (e.g. 2c) or dibromo analogue (e.g. 2c, Br for
OTos). Therefore, an alternative procedure was employed:17
3-methoxy-2-methacryloyl chloride (6a) was treated with
silver cyanate followed by 5-hexyn-1-ylamine18 to afford
the urea derivative (6b) [39%]. The latter did not cyclise
when heated with aqueous sodium hydroxide17 but afforded
only 5-hexyn-1-ylamine and 3-methoxy-2-methacrylic
acid.19 Successful conversion into the acetylene derivative
(4c) [25%] was achieved by pyrolysis of the potassium salt
of (6b) at 200ЊC in vacuo. Unfortunately, this compound
(4c) proved to be unreactive towards oxidative coupling
[e.g. CuCl/tetramethylethylenediamine (Hay) procedure20]
and no further work was carried out on thymine derivatives.
Thymine derivatives
Cytosine derivatives
Thymine was selectively alkylated15 at N-1 with propargyl
bromide through use of the bis silylated derivative (5).
Analytical and NMR spectral data (1H, 13C) for the product
(4a) were in accord with expected values16 but the FAB
mass spectrum indicated a peak corresponding to a
N-1 Alkylation of cytosine is hampered by competing O-2
alkylation but this problem can be alleviated to some extent
by employing N-4 acetylcytosine as an intermediate.21
Thus, the product from base-promoted reaction of the latter
with propargyl bromide afforded a 96:4 regioisomeric
mixture of N-1 and O-2 alkylated products from which
the desired (7a) [52%] could be purified by recrystallisation
⅐ϩ
‘dimer’ (2Mϩ1) in addition to the molecular ion
⅐ϩ
(Mϩ1) . This acetylene derivative (4a) was oxidatively
Scheme 3.

W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
1235
Scheme 4.
from water. Since the oxidative coupling of acetylenes
containing amino groups can be problematical (see e.g.
earlier comment on (1b) and also Ref. 22), it was decided
to compare substrate (7a) and the parent cytosine derivative
(7b) in this type of process. Attempted hydrolysis of the
former (7a) with aqueous sodium hydroxide gave the allene
derivative (8) [75%] in good yield. The structure of (8) was
assigned on the basis of spectral data, with particular regard
DMF. The site of alkylation was assumed to be exclusively
at N-1 from the presence of a triplet resonance at d 3.77 (cf.
9c). The de-acetylated compound (9e) was prepared quan-
titatively from (9c) under the conditions described above for
the conversion (9a!9b) (NH3/MeOH). It was discovered
that, in general in this work, compounds bearing hetero-
aromatic groups at both termini were very insoluble in
common organic solvents. In contrast, the amphiphilic
1,3-diynes were more soluble in organic solvents. Prepa-
ration of the acetylamino derivative (7c) [30%] was accom-
plished by the method described above (cf. 2b!9c) but the
O-alkylated isomer was also formed as a minor product (3:1
ratio); the cytosine derivative (7d) was formed quan-
titatively from (7c) by treatment with 5% ammoniacal
methanol.
1
to the similarity of the H NMR spectrum to analogous
structures in the imidazole series, prepared in related
fashion.23 In contrast, hydrolysis of (7a) with 5% ammo-
niacal methanol afforded the required de-acetylated product
(7b) quantitatively. Oxidative coupling [Cu(OAc)2/MeCN/
pyridine12] of both acetylene derivatives (7a) and (7b)
proceeded satisfactorily to give 1,3-diynes (9a [58%] and
9b [80%], respectively) although only (9a) could be purified
to analytical standard; the latter (9b) was also obtained
quantitatively from hydrolysis of (9a) with 5% ammoniacal
methanol (Schemes 4 and 5).
1
An interesting feature in the H NMR spectra of two cyto-
sine derivatives prepared in this work (8, 9b) is the existence
of two separate, broad NH resonances for the amino groups.
Further investigations, for example, of solvent effects, are
required to identify the cause, but the existence of other
tautomers of (8) and (9b) is possible.
The higher homologue (9c) of (9a) was prepared in 47%
yield through alkylation of N-4 acetylcytosine with the bis
tosylate (2b) [K2CO3/18-crown-6], but two products of
O-alkylation (10, 11) were also formed in 33% combined
Guanine derivatives
1
yield. Using compounds (9c) and (11) as ‘models’, the H
NMR spectrum of (10) can be easily interpreted, with
triplets at d 3.78 and 4.23 assigned to CH2N and CH2O
moieties, respectively; also, doublets at d 7.12 and 8.06
are attributed to C5-H and C6-H of the N-alkylated ring,
whilst those at d 7.64 and 8.37 correspond to analogous
protons of the O-alkylated ring.
The regioselectivity of N-9 (versus N-7) alkylation of
guanine has been improved through use of intermediate
2-acetylamino-24 and 6-chloro-25 derivatives. In this work,
the latter approach was employed, with subsequent hydroly-
sis of chloroguanines under alkaline26 rather than acidic
conditions.25 6-Chloroguanine was alkylated in reasonable
yield (69%) with propargyl bromide (Na2CO3/DMF) to give
a regioisomeric mixture (82:18) of N-9 (12a) and N-7 (13a)
derivatives, respectively; structures were assigned from
spectroscopic data with particular reference to comparison
The analogue (9d) of (9c) was prepared in very low yield
[12%] from the reaction of N-4 acetylcytosine, the bis tosyl-
ate (2c), potassium carbonate and 18-crown-6 in anhydrous
Scheme 5.

1236
W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
Scheme 6.
of UV data with known25 N-9- and N-7-alkylguanines
(Scheme 6).
precursors to s-triazine derivatives (17b) and (18b). The
latter (18b) was formed in low yield (21%) and was accom-
panied by a product (17c) [29%] formed through incomplete
condensation with ensuing ester exchange. 13C NMR
resonances of s-triazine carbon atoms in compounds (17b)
and (18b) were in accord with anticipated values;32 (e.g. for
17b, C-6ˆ167.0 ppm: C-2 and C-4ˆ179.6 ppm) (Scheme
8).
Unfortunately, attempted oxidative coupling [Cu(OAc)2/
pyridine/MeCN]13 of the acetylene derivative (12a) afforded
a black tarry product that could not be purified. It was
assumed that the free amino group in (12a) was undesirable
and a protected compound (12b) was synthesised. However,
treatment of the chloroguanine (12a) with acetic anhydride
afforded a very low yield (15%) of the 2-acetylamino
derivative (12b) together with the diacetylated compound
(12c) [32%]. In view of the poor yields obtained in this step,
the oxidative coupling was not attempted. The alternative
approach of alkylation of 6-chloroguanine with the bis tosy-
late precursor [cf. synthesis of (3b)] afforded poorly soluble
guanine-containing compounds (14a,b; 15a,b)27 that were
characterised spectroscopically but were not isolated as
analytically pure species. In contrast, pure lipophilic
guanine derivatives, (12d) [72%] and (13b) [18%], were
obtained through alkylation of chloroguanine and the
former was successfully converted (NaOH, aqueous dioxan)
into the guanine derivative (16) [47%]. The 1H NMR purine
resonances of (16) were in accord with values recorded for
substituted guanines28 (Scheme 7).
Uracil derivatives
An attempt to prepare the bis uracil analogue of the thymine
derivative (9e) by analogy with the previously described
procedure (cf. 5!9e) was unsuccessful because the product
could not be purified chromatographically. In contrast, the
amphiphilic uracil derivative (18c) [30%] was prepared by
direct alkylation of uracil with the tosylate (2e) and anhy-
drous potassium carbonate in DMF. The site of alkylation
was determined to be N-1 by comparison of 13C NMR reso-
nances of the uracil ring with those of the reported 1,3-diyne
([UCH2CxC]2: Uˆuracil-1-yl).11
Acridine derivatives
Commercially available 10,12-pentacosadiynoic acid (18d)
was converted into N-succinimidyl-10,12-pentacosadiynate
(18e) [93%] by a reported method,33 but transformation of
the latter into the amine (18g) was initially unsuccessful.
Thus, dropwise addition of a solution of (18e) to a solution
of 1,8-diamino-3,6-dioxaoctane over 30 min afforded the
tetrayne (18f) in 85% yield, despite a successful reported
synthesis of an analogue of (18g) by this method.34 The
1,3,5-Triazine derivatives
Synthetic methods leading to 2,4-diamino-1,3,5-triazines
include the reaction of biguanide with esters29 or acid
chlorides,30 and of alkyl nitriles with dicyandiamide.31 In
the present work the first procedure29 was employed using
the mono- and di-esters (17a) and (18a), respectively, as
Scheme 7.

W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
1237
Scheme 8.
tetrayne (18f) is a colourless solid that rapidly turns blue in
ambient light, indicating a diacetylene derivative prone to
polymerisation. Synthesis of the desired amine (18g) was
achieved, albeit in poor yield (38%) by dropwise addition of
a solution of (18e) through a syringe pump to a solution of
the co-reactant diamine over 16 h. It was hoped that the
target acridine-containing 1,3-diyne (19a) could be
prepared in standard fashion35 from 9-chloroacridine and
(18g) in the presence of a catalytic amount of methane sul-
fonic acid; unfortunately, no reaction occurred even after
heating under reflux for 18 h. Therefore, the target acridines
(19a, 74%) and (19b, 69%) were prepared by an alternative
method36 involving heating 9-chloroacridine and, sepa-
rately, 6,9-dichloro-2-methoxyacridine37 with the amine
(18g) in a solution of phenol; both diacetylenes (19a,b)
turned from bright yellow to blue-green in the solid state
on exposure to ambient light, indicating partial topotactic
polymerisation (Scheme 9).
Conclusions
Two distinct series of heterocyclic-containing 1,3-diynes
have been synthesised: one contains heteroaromatic groups
Scheme 9.

1238
W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
which facilitate intermolecular hydrogen-bonding, and the
second contains a head group (acridinyl) known to bind to
nucleic acids. Preliminary investigations27,38 indicate that
the new 1,3-diynes reported herein will provide novel poly-
diacetylenes through topochemical polymerisation and in
the form of liposomes.
1H, H-2 or H-8), 8.37 (s, 1H, H-8 or H-2). dC (CDCl3): 18.2,
26.2, 28.3, 28.5, 28.8, 29.1, 30.0, 43.8, 68.0 (CxC), 84.6,
(CxC), 119.6, 140.3, 150.0, 152.8, 155.4. m/z (EI): 285.194
(1%). C16H23N5 requires 285.195. (Found: C, 67.4; H, 8.3;
N, 24.7%. C16H23N5 requires: C, 67.34; H, 8.12; N,
24.54%).
Undec-10-ynyl toluene-p-sulfonate (2a). To undec-10-yn-
1-ol (4.20 g, 25.0 mmol) and toluene-p-sulfonyl chloride
(6.79 g, 35.7 mmol) in chloroform at 0ЊC was added pyri-
dine (2.92 g, 37.0 mmol) dropwise over 5 min with the
temperature maintained at 0ЊC. After stirring for 3 h,
conc. HCl (10 cm3) in water (100 cm3) was added and the
lower chloroform layer was separated, washed with water
(100 cm3) and dried (CaCl2). The solvent was evaporated
under reduced pressure to afford the colourless title
compound (2a) (5.38 g; 70%), mp 39–40ЊC. nmax (KBr,
cmϪ1): 3293 (alkyne CH), 2918 (aliphatic CH). 2133
(CxC). dH (CDCl3): 1.18–1.72 (m, 14H), 1.85 (t, 1H,
Jˆ2.7 Hz, CxCH), 2.19 (td, 2H, Jˆ2.7, 6.9 Hz,
CH2CxC), 2.46 (s, 3H, ArCH3), 4.01 (t, 2H, Jˆ6.5 Hz,
CH2OTos), 7.35 and 7.80 (A2B2 system of Ar). dC
(CDCl)3: 18.2, 21.5, 25.2, 28.3, 28.5, 28.7, 28.8, 29.1,
68.0 (CxC), 70.5, (CxC), 84.6, 127.8, 129.7, 133.2,
144.5. (Found: C, 66.4; H, 8.0%. C18H26O3S requires: C,
67.04; H, 8.13%).
Experimental
Melting points were determined using an Electrothermal
instrument and are uncorrected. IR spectra were recorded
on Perkin–Elmer FTIR 1600 or 1430 instruments and cali-
1
brated against polystyrene. H and 13C{1H} NMR spectra
were recorded on Bruker AC 200 or DPX 400 spectro-
meters; chemical shifts are reported with respect to SiMe4
as reference (positive shifts to high frequency/low field) and
J values are given in Hz. UV–Vis spectra were recorded on
a Shimadzu UV-160 spectrophotometer. Mass spectra were
measured on an upgraded VG MS9 instrument; high reso-
lution mass spectra were also determined at the EPSRC
National Mass Spectrometry Service Centre, University of
Wales, Swansea. Elemental analyses were performed at
Heriot-Watt University or Napier University, Edinburgh.
Silica gel 60 (200–400 mesh) was used for column chroma-
tography unless otherwise stated, and analytical TLC was
carried out on aluminium plates precoated with silica gel 60
F254 (Merck). Drying agents for solvents were Na/benzo-
phenone [for petroleum ether, diethyl ether and tetrahydro-
furan (THF) and CaH2 for dichloromethane. HPLC grade
N,N-dimethylformamide (DMF) was used as supplied.
9,90-(Hexa-2,4-diyne-1,6-diyl)di-9H-purin-6-amine (3a).
9-(Prop-2-ynyl)-9H-purin-6-amine (1a) (0.50 g; 2.88 mmol)
and copper (II) acetate monohydrate (2.88 g; 14.4 mmol)
were stirred in acetonitrile/pyridine (10:1) (50 cm3) at
60ЊC for 2 h. Water (100 cm3) was then added and the
precipitate collected by filtration was washed with water
(25 cm3), followed by methanol (25 cm3), to give colourless
9,90-(hexa-2,4-diyne-1,6-diyl)di-9H-purin-6-amine (3a) (0.34
g; 69%), mp 195–197ЊC (lit.11 196–198ЊC). nmax (KBr,
cmϪ1): 3327, 3149 (N–H str.), 1657 (CyN str.), 1600
(N–H def.). dH (d6-DMSO): 5.20 (s, 4H, CH2CxC–), 7.30
(bs, 4H, NH2), 8.16 (s, 4H, H-2 and H-8).
9-(Prop-1-ynyl)-9H-purin-6-amine (1a). Adenine (1.00 g;
7.40 mmol), potassium carbonate (1.53 g; 11.07 mmol) and
propargyl bromide (1.32 g; 11.10 mmol) were stirred in
anhydrous dimethylformamide (20 cm3) at 20ЊC for 24 h.
The solvent was evaporated under reduced pressure and
the resulting solid was recrystallised from methanol to
give colourless 9-(prop-1-ynyl)-9H-purin-6-amine (1a)
(0.85 g; 66%), mp 213–214ЊC (lit.11 214ЊC). nmax (KBr,
cmϪ1): 3369, 3272, 3249 (N–H str.), 3146 (alkyne C–H
str.), 2928, 2878 (aliphatic C–H str.), 2111 (CxC str.),
1693 (CyN str.), 1610 (N–H def.). dH (d6-DMSO): 3.46
(t, 1H, Jˆ2.5 Hz, CxC–H), 5.02 (d, 2H, Jˆ2.5 Hz,
CH2CxC), 7.29 (br s, 2H, NH2) 8.16 (s, 1H, H-2 or H-8),
8.19 (s, 1H, H-8 or H-2). dC (d6-DMSO): 32.7, 76.3, (CxC)
78.8 (CxC) 118.9, 140.5, 149.5, 153.2, 156.4. m/z (EI)
Docosa-10,12-diyne-1,22-diyl bis(toluene-p-sulfonate) (2c).
This compound was prepared as previously described.5a
Tricosa-10,12-diynyl toluene-p-sulfonate (2e). Tricosa-
10,12-diyn-1-ol (2.44 g, 7.33 mmol) and toluene-p-sulfonyl
chloride (1.54 g; 8.07 mmol) were dissolved in dry chloro-
form (50 cm3). Pyridine (1.27 g; 16.14 mmol) was slowly
added and the mixture was stirred at room temperature over-
night. The solution was washed with a mixture of water
(90 cm3) and hydrochloric acid (10 cm3). The organic
layer was separated, washed with water (50 cm3) and
dried (CaCl2). The chloroform was evaporated under
reduced pressure and diethylether was added. The volume
of diethylether was reduced by half by evaporation with
cooling to cause precipitation of the title compound: this
process was repeated to give a second crop, giving
tricosa-10,12-diynyl toluene-p-sulfonate (2e) (1.50 g;
42%) as a colourless crystalline solid which rapidly turned
blue on exposure to daylight, mp 47–48ЊC. nmax (KBr,
cmϪ1): 2920, 2847 (aliphatic C–H str.), 1470 (C–H def.),
1356, 1174 (SyO str.). dH (CDCl3): 0.87 (t, 3H, Jˆ6.4 Hz,
CH3), 1.10–1.72 (m, 30H), 2.24 (t, 4H, Jˆ6.6 Hz,
CH2CxC), 2.46 (s, 3H, CH3), 4.01 (t, 2H, Jˆ6.5 Hz,
⅐ϩ
173.0745; C8H7N5 requires 173.0701(M )
9-(Undec-10-ynyl)-9H-purin-6-amine (1b). Undec-10-
ynyl toluene-p-sulfonate (5.2 g, 16.1 mmol), potassium car-
bonate (3.2 g, 23.2 mmol) and adenine (2.10 g, 15.5 mmol)
were stirred for 18 h at 20ЊC in N,N-dimethylformamide
(DMF, 50 cm3). The solvent was evaporated under reduced
pressure to leave a solid that was pre-adsorbed on to silica
from methanol. Purification by column chromatography
[CH2Cl2/CH3OH (95:5) eluant] afforded the colourless
title compound (1b) (2.8 g, 63%), mp 145–146ЊC. nmax
(KBr, cmϪ1): 3170 (N–H str.), 2930, 2920, 2850 (aliphatic
C–H str.), (CyN str.), 1612 (N–H def.). dH (CDCl3) 1.20–
1.58 (m, 12H), 1.81–1.99 (m, 2H, CH2–CH2N), 1.92 (t, 1H,
Jˆ2.6 Hz, CxCH), 2.17 (td, 2H, Jˆ2.6, 6.9 Hz, CH2CxC),
4.29 (t, 2H, Jˆ7.2 Hz, CH2N), 5.79 (s, 2H, NH2), 7.80 (s,

W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
1239
CH2OTs), 7.35 (d, 2H, Jˆ8.2 Hz, Ar–H), 7.80 (d, 2H,
Jˆ8.2 Hz, Ar–H). dC (CDCl3): 14.1, 19.1, 21.6, 22.6,
25.2, 28.2, 28.7, 28.8, 29.0, 29.1, 29.2, 29.4, 29.5, 31.8,
65.2, 70.6, 77.3, 127.8, 129.7, 133.1, 144.6. m/z (FAB,
NOBA matrix): 488 (3%, [Mϩ1]ϩ). (Found: C, 74.1; H,
9.4%. C30H46O3S requires: C, 74.03; H 9.53%.)
(d6-DMSO): 12.3, 36.7, 76.1, 79.1, 109.6, 140.6, 150.8,
164.6. m/z (FAB, NOBA matrix) 165 (100%, [Mϩ1]ϩ),
329 (6%, [2Mϩ1]ϩ). (Found: C, 58.6; H, 4.7; N, 17.3%.
C8H8N2O2 requires: C, 58.5; H, 4.9; N, 17.0%.)
5,50-Dimethyl-1,10-(hexa-2,4-diyne-1,6-diyl)dipyrimidine-
2,4(1H,3H)-dione (4b). 1-(Prop-2-ynyl)-5-methylpyrimi-
dine-2,4(1H,3H)-dione (4a) (1.45 g; 8.85 mmol) and copper
(II) acetate monohydrate (7.06 g; 35.34 mmol) were
dissolved in acetonitrile/pyridine (60 cm3, 85:15) under a
nitrogen atmosphere and stirred at 60ЊC for 2 h. The result-
ing suspension was filtered and the solid portion was sepa-
rated and washed with water (100 cm3) then filtered to give
yellow 5,50-dimethyl-1,10-(hexa-2,4-diyne-1,6-diyl)dipyri-
midine-2,4(1H,3H)-dione (4b) (1.08 g, 75%), mp 204ЊC
dec. (from methanol). nmax (KBr, cmϪ1): 3195, 3070
(N–H str.), 2980, 2940, 2820 (aliphatic C–H str.), 1707,
1680 (amide I, II). dH (d6-DMSO): 1.73 (s, 6H, CH3), 4.59
(s, 4H, CH2CxC), 7.55 (s, 2H, HCy), 11.41 (s, 2H, NH). dC
(d6-DMSO): 12.0, 37.1, 67.5, 74.9, 109.7, 140.2, 150.4,
164.2. m/z (FAB, NOBA matrix): 327 (4%, [Mϩ1]ϩ).
9,90-(Docosa-10,12-diyne-1,22-diyl)di-9H-purin-6-amine
(3b) and 9-[22-(4-methylphenylsulfonyloxy)docosa-10,
12-diynyl)-9H-purin-6-amine (2d). Adenine (0.63 g,
4.66 mmol), anhydrous potassium carbonate (0.65 g;
4.70 mmol) and 10,12-docosadiyn-1,22-bis(4-methylben-
zenesulfonate) (0.99 g; 1.55 mmol) (2c) were stirred in
DMF (25 cm3) at 20ЊC for 72 h. The solvent was evaporated
under reduced pressure and the residual solid was dissolved
in methanol, pre-adsorbed on to silica and chromatographed
with CH2Cl2/MeOH (95:5) as eluant. The following were
isolated:
9,90-(docosa-10,12-diyne-1,22-diyl)di-9H-purin-6-amine (3b):
(0.20 g; 22%) as a colourless amorphous solid, mp 178–
179ЊC. nmax (KBr, cmϪ1): 3300, 3100 (N–H str.), 2940,
2860 (aliphatic C–H str.), 1650 (CyN str.), 1600 (N–H
def.). dH (d6-DMSO): 1.18–1.49 (m, 24H), 1.78–1.87 (m,
4H), 2.23 (t, 4H, Jˆ6.6 Hz, CH2CxC), 4.11 (t, 4H,
Jˆ7.0 Hz, CH2N), 7.18 (s, 4H, NH2), 8.12 (s, 4H, H-2 and
H-8). m/z (FAB, NOBA matrix): 569 (9%, [Mϩ1]ϩ).
(Found: C, 65.6; H, 7.6; N, 24.6%. C32H44N10·H2O requires:
C, 65.5; H, 7.9; N, 23.9%.)
1-(Hex-5-ynyl)-5-methylpyrimidine-2,4(1H,3H)-dione (4c).
N-(3-Methoxy-2-methacryloyl)-N0-(hex-5-ynyl)urea (6b)
(100 mg; 0.41 mmol), potassium hydroxide (450 mg;
0.81 mmol) and 18-crown-6 (11 mg; 0.04 mmol) were
stirred in toluene (25 cm3) for 16 h at 20ЊC. The solvent
was evaporated under reduced pressure and the residue
was fused by heating at 200ЊC for 10 min. The product was
cooled, water (2 cm3) was added and the solution was
neutralised with conc. hydrochloric acid. This product
was extracted with dichloromethane (3×10 cm3) and the
organic extract was dried (MgSO4) and evaporated under
reduced pressure. The residue was chromatographed
[40:60 petroleum ether/diether ether (1:1) eluant] to afford
colourless 1-(hex-5-ynyl)-5-methylpyrimidine-2,4(1H,3H)-
dione (4c) (20 mg; 25%), mp 103–104ЊC. nmax (KBr,
cmϪ1): 3158, 3065 (N–H str.), 3029 (alkene C–H str.),
2831 (aliphatic C–H str.), 1691, 1657 (amide I, II), 1475,
1423 (aliphatic C–H def.). dH (CDCl3): 1.80 (t, 1H,
Jˆ2.5 Hz, CxCH), 1.87 (t, 4H, Jˆ2.5 Hz, CH2CH2), 1.93
(d, 3H, Jˆ1.2 Hz, CH3Cy), 2.20 (td, 2H, Jˆ2.5, 6.6 Hz,
CH2CxC), 3.83 (t, 2H, Jˆ6.9 Hz, NCH2), 7.05 (q, 1H,
Jˆ1.2 Hz, HCy), 8.38 (s, 1H, NH). dC (CDCl3): 3.8, 12.9,
28.8, 40.0, 77.3, 78.6, 110.6, 140.7, 152.1, 165.4. m/z (EI)
9-(22-(4-methylphenylsulfonyloxy)docosa-10,12-diynyl)-9H-
purin-6-amine (2d): (0.01 g; 10%) as a colourless solid, mp
68–70ЊC. nmax (KBr, cmϪ1): 3304, 3146 (N–H str.), 2925,
2854 (aliphatic C–H str.), 1675 (CyN str.), 1602 (N–H def.)
dH (d6-DMSO): 1.14–1.78 (m, 28H), 2.26 (t, 4H, Jˆ6.4 Hz,
CH2CxC), 2.41 (s, 3H, CH3), 3.98 (t, 2H, Jˆ6.2 Hz,
CH2OTs), 4.10 (t, 2H, Jˆ6.9 Hz, CH2N), 7.20 (s, 2H,
NH2), 7.45 (d, 2H, Jˆ8.1 Hz, Ar–H), 7.77 (d, 2H,
Jˆ8.1 Hz, Ar–H), 8.11 (s, 2H, H-2 and H-8). dC
(d6-DMSO): 18.7, 21.5, 25.1, 26.4, 28.1, 28.6, 28.7, 29.1,
29.8, 43.3, 65.8, 71.3, 78.4, 119.2, 128.0, 130.6, 133.0,
141.2, 145.2, 150.0, 152.7, 156.4. m/z (FAB, NOBA
matrix): 606 (94%, [Mϩ1]ϩ).
1-(Prop-2-ynyl)-5-methylpyrimidine-2,4(1H,3H)-dione
(4a). Chlorotrimethylsilane (0.77 cm3; 7.12 mmol) and
thymine (3.84 g; 30.46 mmol) were heated under reflux in
excess hexamethyldisilazane (5.89 g; 36.55 mmol) for 21 h.
Excess hexamethyldisilazane was evaporated under reduced
pressure to give crude 5-methyl-bis-2,4-trimethylsilyloxy-
pyrimidine (5).15 This was not purified further but was then
stirred at room temperature with propargyl bromide (3.35 g;
28.4 mmol) for 9 days. Water (50 cm3) was then added and
the mixture was extracted with chloroform (5×50 cm3). The
chloroform solution was dried (MgSO4) and evaporated
to afford colourless 1-(prop-2-ynyl)-5-methylpyrimidine-
2,4(1H,3H)-dione (4a) (3.28 g; 70%), mp 157–158ЊC.
nmax (KBr, cmϪ1): 3265 (alkyne C–H str.), 3170, 3120
(N–H str.), 3040 (alkene C–H str.), 2945, 2905, 2845
(aliphatic C–H str), 2135 (CxC str.), 1710, 1665 (amide
I, II). dH (CDCl3): 1.96 (d, 3H, Jˆ1.2 Hz, CH3), 2.47 (t,
1H, Jˆ2.6 Hz, CxCH), 4.55 (d, 2H, Jˆ2.6 Hz, CH2CxC),
7.26 (q, 1H, Jˆ1.2 Hz, CHyC), 9.12 (s, 1H, NH). dC
⅐ϩ
⅐ϩ
206.10354 (M ), C11H14N2O2 requires 206.10553 (M ).
(Found: C, 64.4; H, 7.0; N, 13.7%. C11H14N2O2 requires:
C, 64.1; H, 6.8; N, 13.6%.)
N-(3-Methoxy-2-methacryloyl)-N0-(hex-5-ynyl)urea (6b).
Silver cyanate (1.79 g; 12.00 mmol) and absolute chloro-
form (25 cm3) were cooled to 0ЊC and 3-methoxy-2-metha-
cryloyl chloride17 (6a) (1.68 g; 12.5 mmol) was added. The
mixture was allowed to warm to room temperature and
stirred at 20ЊC for 12 h. The product was filtered through
celite, 5-hexyn-1-ylamine18 (1.15 g; 11.8 mmol) was added
and the solution was stirred at 20ЊC for 3 h. The solvent was
evaporated under reduced pressure to leave colourless N-(3-
methoxy-2-methacryloyl)-N0-(hex-5-ynyl)urea (6b) (1.14 g;
39%), mp 75ЊC (from n-hexane). nmax (KBr, cmϪ1): 3248
(alkyne C–H str.), 2944, 2857 (aliphatic C–H str.), 1685,
1656 (amide I, II). dH (CDCl3): 1.47–1.80 (m, 4H), 1.78 (d,
3H, Jˆ1.1 Hz, CH3Cy), 1.98 (t, 1H, Jˆ2.7 Hz, CxCH),

1240
W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
2.25 (td, 2H, Jˆ2.7, 6.7 Hz, CH2CxC), 3.35 (q, 2H,
Jˆ6.4 Hz, NCH2), 3.88 (s, 3H, CH3O), 7.36 (s, 1H, HCy),
7.99 (br s, 1H, NH), 9.70 (br s, 1H, NHCH2). dC (CDCl3): 6.7,
18.0, 25.6, 28.6, 39.1, 61.4, 68.6, 83.8, 107.0, 154.2, 158.4,
169.3. m/z (EI): 238 (1%, M ). (Found: C, 60.0; H, 7.4; N,
11.9%. C12H18N2O3 requires: C, 60.5; H, 7.6; N, 11.8%.)
2922, 2848 (aliphatic C–H str.), 1690, 1664 (CyO str.).
dH (CDCl3): 0.88 (t, 3H, Jˆ6.4 Hz, CH3), 1.16–1.85 (m,
30H), 2.25 (t, 4H, Jˆ6.8 Hz, CH2CxC), 2.30 (s, 3H,
CH3), 3.87 (t, 2H, Jˆ7.3 Hz, CH2N), 7.41 (d, 1H,
Jˆ7.3 Hz, H-5), 7.58 (d, 1H, Jˆ7.3 Hz, H-6), 10.18 (br s,
1H, NH). dC (CDCl3): 14.1, 19.1, 22.6, 24.8, 26.4, 28.2,
28.2, 28.6, 28.8, 29.0, 29.2, 29.4, 29.5, 31.8, 51.0, 65.1,
77.4, 96.7, 148.6, 155.7, 162.8, 171.2. m/z (FAB, NOBA
matrix): 468 (17%, [Mϩ1]ϩ). (Found: C, 74.1; H, 9.7; N,
8.9%. C29H45N3O2 requires: C, 74.47; H, 9.70; N, 8.98%.)
⅐ϩ
1-(Prop-2-ynyl)-4-acetylaminopyrimidin-2(1H)-one (7a).
A suspension of 4N-acetylcytosine (1.00 g; 6.53 mmol),
anhydrous potassium carbonate (1.04 g; 7.50 mmol) and
propargyl bromide (0.67 g; 5.64 mmol) DMF (50 cm3)
was stirred for 18 h at room temperature. The mixture was
filtered and the solvent was evaporated under reduced
pressure to leave a brown solid. This solid was then
dissolved in hot water (20 cm3) and the solution treated
with decolourising charcoal (0.2 g). The mixture was
filtered and the filtrate cooled to precipitate a colourless
solid. This solid was separated and dried to afford colourless
1-(prop-2-ynyl)-4-acetylaminopyrimidin-2(1H)-one (7a)
(0.56 g; 52%), mp 199ЊC. nmax (KBr, cmϪ1): 3450, 3195
(N–H str.), 2980 (aliphatic C–H str.), 2114 (CxC str.),
1695 (CyO str.), 1657, 1619 (amide I, II). dH (d6-DMSO):
2.12 (s, 3H, CH3), 3.50 (t, 1H, Jˆ2.5 Hz, CxCH), 4.67 (d,
2H, Jˆ2.5 Hz, NCH2), 7.20 (d, 1H, Jˆ7.3 Hz, H-5 or H-6),
8.20 (d, 1H, Jˆ7.3 Hz, H-6 or H-5), 10.89 (br s, 1H, NH).
dC (d6-DMSO): 24.8, 38.8, 76.8, 78.7, 96.1, 149.7, 155.0,
2-(Tricosa-10,12-diynyloxy)-4-acetylaminopyrimidine: mp
63–64ЊC. nmax (KBr, cmϪ1): 3204 (N–H str.), 2923, 2850
(aliphatic C–H str.), 1713 (CyO str.). dH (CDCl3) 0.88 (t,
3H, Jˆ6.4 Hz, CH3), 1.13–1.88 (m, 30H), 2.22 (t, 4H,
Jˆ6.7 Hz, CH2CxC), 4.28 (t, 2H, Jˆ6.6 Hz, CH2O), 7.76
(d, 1H, Jˆ7.3 Hz, H-5), 8.09 (br s, 2H, NH), 8.40 (d, 1H,
Jˆ7.3 Hz, H-6). dC (CDCl3): 14.0, 19.1, 22.6, 24.7, 25.8,
28.2, 28.7, 28.9, 29.0, 29.2, 29.4, 29.5, 31.8, 65.2, 67.6,
77.4, 103.7, 158.8, 160.4, 164.6, 169.3. m/z (FAB, NOBA
matrix) 468 (100%, [Mϩ1]ϩ). (Found: C, 74.0; H, 9.8; N
8.6%. C29H45N3O2 requires: C, 74.47; H, 9.70; N, 8.98%.)
1-(Tricosa-10,12-diynyl)-4-aminopyrimidin-2(1H)-one (7d).
1-(Tricosa-10,12-diynyl)-4-acetylaminopyrimidin-2(1H)-one
(7c) (213 mg; 0.45 mmol) was stirred with 5% ammoniacal
methanol (25 cm3) for 18 h. The solvent was evaporated
under reduced pressure to leave a pink solid which was
dried in vacuo to afford 1-(tricosa-10,12-diynyl)-4-amino-
pyrimidin-2(1H)-one (7d) (192 mg; 100%), mp 188–190ЊC.
nmax (KBr, cmϪ1): 3347, 3127 (N–H str.), 2915, 2850
(aliphatic C–H str.), 1663, 1618 (CyO str., N–H def.). dH
(CDCl3): 0.87 (t, 3H, Jˆ6.4 Hz, CH3), 1.13–1.79 (m, 30H),
2.25 (t, 4H, Jˆ6.7 Hz, CH2CxC), 3.73 (t, 2H, Jˆ7.3 Hz,
CH2N), 5.73 (d, 1H, Jˆ6.8 Hz, H-5), 6.38 (br s, 2H, NH2),
7.22 (d, 1H, Jˆ6.8 Hz, H-6). dC (CDCl3): 14.0, 19.1, 22.6,
26.5, 28.2, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.4, 29.5,
31.8, 50.1, 65.2, 77.4, 93.8, 145.4, 156.5, 165.8. m/z
(FAB, NOBA matrix): 426 (100%, [Mϩ1]ϩ), 852 (3%,
[2Mϩ1]ϩ). (Found: C, 76.0; H, 10.3; N, 9.7%. C27H43N3O
requires: C, 76.17; H, 10.19; N, 9.88%.)
⅐ϩ
163.1, 171.4. m/z (EI) 191.06984 (M ), C9H9N3O2 requires
⅐ϩ
191.06948 (M ). (Found: C, 56.2; H, 4.5; N, 21.9%.
C9H9N3O2 requires: C, 56.5; H, 4.7; N, 22.0%.)
1-(Prop-2-ynyl)-4-aminopyrimidin-2(1H)-one (7b). 1-(Prop-
2-ynyl)-4-acetylaminopyrimidin-2(1H)-one (7a) (0.10 g;
0.54 mmol) was stirred with 5% (v/v) methanolic ammonia
(10 cm3) at 20ЊC for 5 h. The solvent was evaporated under
reduced pressure giving 1-(prop-2-ynyl)-4-aminopyrimidin-
2(1H)-one (7b) (0.08 g; 100%) as colourless needles, mp
226–227ЊC dec. nmax (KBr, cmϪ1): 3380 (N–H str.), 2230
(alkyne C–H str.), 3100 (alkene C–H str.), 2120 (CxC str.),
1730 (CyO str), 1625 (N–H def.). lmax H2O (nm): 232 (e
6152), 271 (7954). dH (d6-DMSO): 3.35 (t, 1H, Jˆ2.5 Hz,
CxCH), 4.47 (d, 2H, Jˆ2.5 Hz, CHCxC), 5.73 (d, 1H,
Jˆ7.2 Hz, H-5), 7.29 (br s, 2H, NH2), 7.65 (d, 1H,
Jˆ7.2 Hz, H-6). dC (d6-DMSO): 37.8, 75.7, 79.9, 94.6,
1-(Propa-1,2-dienyl)-4-aminopyrimidin-2(1H)-one (8). 1-
(Prop-2-ynyl)-4-acetylamino-pyrimidin-2(1H)-one (7a) (0.36
g; 1.87 mmol) and sodium hydroxide (0.14 g; 3.50 mmol)
were heated in water (10 cm3) at 80ЊC for 30 min. The
mixture was cooled and filtered to afford cream 1-(propa-
1,2-dienyl)-4-aminopyrimidin-2(1H)-one (8) (0.21 g; 75%),
mp 207ЊC dec. nmax (KBr, cmϪ1): 3361 (N–H str.), 3086,
2923 (alkene C–H str.), 1669, (CyO str.), 1626 (N–H def.),
1488 (alkene C–H def.). lmax H2O (nm): 240 (e 8250), 289
(10609). dH (d6-DMSO): 5.70 (d, 2H, Jˆ6.6 Hz, yCH2),
5.84 (d, 1H, Jˆ7.4 Hz, H-5), 7.33 (t, 1H, Jˆ6.6 Hz,
yCHN), 7.43 and 7.47 (br, 2H, NH2), 7.50 (d, 1H,
Jˆ7.4 Hz, H-6). dC (d6-DMSO): 89.9, 96.2, 98.3, 141.2,
⅐ϩ
145.3, 155.6, 166.5. m/z (EI): 149.05726 (M ), C7H7N3O
requires 149.05891. (Found: C, 56.6; H, 4.7; N, 28.1%.
C7H7N3O requires: C, 56.37; H, 4.73; N, 28.17%.)
1-(Tricosa-10,12-diynyl)-4-acetylaminopyrimidin-2(1H)-
one (7c). Tricosa-10,12-diynyl toluene-p-sulfonate) (2e)
(0.75 g; 1.54 mmol), 4N-acetylcytosine (0.24 g; 1.61 mmol),
potassium carbonate (0.22 g; 1.61 mmol) and DMF
(50 cm3) were stirred under an atmosphere of nitrogen for
24 h. The solvent was evaporated under reduced pressure
and the crude product was purified by column chroma-
tography [CH2Cl2/MeOH (98:2), eluant] to give 1-(tricosa-
10,12-diynyl)-4-acetylaminopyrimidin-2(1H)-one (7c) (213
mg; 30%) and 2-(tricosa-10,12-diynyloxy)-4-acetyl-
aminopyrimidine (72 mg; 10%). Both of these compounds
were isolated as colourless amorphous solids and both
turned pink on exposure to daylight.
⅐ϩ
154.0, 165.9, 201.2. m/z (EI) 149.05957 (M ), C7H7N3O
requires: 149.05891.
4,40-Bis(acetylamino)-1,10-(hexa-2,4-diyne-1,6-diyl)dipy-
rimidin-2(1H)-one (9a). 1-(Prop-2-ynyl)-4-acetylamino-
pyrimidin-2(1H)-one (7a) (1.22 g; 6.37 mmol), copper(II)
acetate monohydrate (5.09 g; 25.48 mmol), acetonitrile
(40 cm3) and pyridine (10 cm3) were stirred at 60ЊC for
1-(Tricosa-10,12-diynyl)-4-acetylaminopyrimidin-2(1H)-one
(7c): mp 96–97ЊC. nmax (KBr, cmϪ1): 3326 (N–H str.),

W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
1241
2 h under an atmosphere of nitrogen. The solid product was
separated and washed with water (100 cm3). The resultant
pale green solid was stirred with water (100 cm3) and tetra-
sodium ethylenediaminetetraacetic acid (1.00 g; 2.63
mmol) for 24 h at room temperature. Filtration and further
washing with water afforded 4,40-bis(acetylamino)-1,10-
(hexa-2,4-diyne-1,6-diyl)dipyrimidin-2(1H)-one (9a) (0.71
g; 58%) as a lilac powder, mp Ͼ360ЊC. nmax (KBr, cmϪ1):
3420, 3290, 3130 (N–H str.), 2925, 2855 (C–H str.), 1695,
1670 (Amide I,II), 1625 (N–H def.). dH (d6-DMSO): 2.10
(s, 6H, CH3), 4.80 (s, 4H, NCH2), 7.20 (d, 2H, Jˆ7.3 Hz,
H-5), 8.13 (d, 2H, Jˆ7.3 Hz, H-6), 10.92 (s, 2H, NH). dC
(d6-DMSO): 24.8, 74.9, 96.2, 163.2, 171.4 (Signals for four
other carbons were not observed due to the high insolubility
of this compound.) m/z (FAB, NOBA matrix) 381 (23%,
[Mϩ1]ϩ). (Found: C, 55.1; H, 4.1; N, 21.6%.
C18H16N6O4·0.5H2O requires: C, 55.5; H, 4.4; N, 21.6%.)
26%), softens and polymerises at ca.Ͼ100ЊC. nmax (KBr,
cmϪ1): 3418, 3245 (N–H str.), 2933, 2863 (aliphatic C–H
str.), 1706 (CyO str.), 1662, 1583, 1492, 1435 (amide I,II,
alkene and aliphatic C–H def ). dH (d6-DMSO): 1.33–1.85
(m, 8H), 2.08 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.21 (t, 2H,
Jˆ6.4 Hz, CH2CxC), 2.26 (t, 2H, Jˆ6.5 Hz, CH2CxC),
3.78 (t, 2H, Jˆ6.9 Hz, CH2N), 4.23 (t, 2H, Jˆ6.2 Hz,
CH2), 7.12 (d, 1H, Jˆ7.2 Hz, H-5), 7.64 (d, 1H,
Jˆ5.6 Hz, H-5 or H-6), 8.06 (d, 1H, Jˆ7.2 Hz, H-6), 8.37
(d, 1H, Jˆ5.6 Hz, H-5 or H-6), 10.80 (br s, 2H, NH). dC (d6-
DMSO): 18.4, 18.5, 24.6, 24.7, 24.8, 25.2, 28.0, 28.0, 49.4,
65.9, 66.4, 78.1, 78.3, 95.4, 103.8, 150.6, 155.7, 160.0,
160.6, 162.7, 164.7, 170.9, 171.3. m/z (FAB, NOBA matrix)
465 (100%, [Mϩ1]ϩ). (Found: C, 61.8; H, 6.1; N, 17.8%.
C24H28N6O4 requires: C, 62.1; H, 6.1; N, 18.1%.)
2,20-(Dodeca-5,7-diyne-1,12-diyldioxy)bis-(4-acetylamino-
pyrimidine) (11): (0.09 g; 9%), mp 142–143ЊC. nmax (KBr,
cmϪ1): 3418, 3241 (N–H str.), 2963, 2926 (aliphatic C–H
str.), 1709 (CyO str.), 1604, 1587 (amide I,II). dH
(d6-DMSO): 1.41–1.84 (m, 8H), 2.09 (s, 6H, CH3), 2.37
(t, 4H, Jˆ6.9 Hz, CH2CxC), 4.25 (t, 4H, Jˆ6.3 Hz,
CH2O), 7.66 (d, 2H, Jˆ5.7 Hz, H-5), 8.39 (d, 2H,
Jˆ5.7 Hz, H-6), 10.82 (s, 2H, NH). dC (d6-DMSO): 18.4,
24.6, 24.8, 28.0, 65.9, 66.4, 78.3, 103.9, 160.1, 160.7, 164.8,
170.9. m/z (FAB, NOBA matrix) 465 (15%, [Mϩ1]ϩ).
(Found: C, 62.4; H, 5.8; N, 17.8%. C24H28N6O4 requires:
C, 62.1; H, 6.1; N, 18.1%.)
4,40-Diamino-1,10-(hexa-2,4-diyne-1,6-diyl)dipyrimidin-2-
(1H)-one (9b). 1-(Prop-2-ynyl)-4-aminopyrimidin-2(1H)-
one (7b) (0.30 g; 2.01 mmol), copper(II) acetate mono-
hydrate (0.80 g; 4.04 mmol), acetonitrile (40 cm3) and
pyridine (10 cm3) were stirred at 60ЊC for 2 h under an
atmosphere of nitrogen. Work-up as described above gave
4,40-diamino-1,10-(hexa-2,4-diyne-1,6-diyl)dipyrimidin-2-
(1H)-one (9b) (0.24 g; 80%) as a brown powder, mp
Ͼ360ЊC. nmax (KBr, cmϪ1): 3417, 3127 (N–H str.), 1677
(CyO str.), 1639, 1619 (N–H def.). dH (d6-DMSO): 4.61 (s,
4H, NCH2), 5.70 (d, 2H, Jˆ7.3 Hz, H-5), 7.15 and 7.22 (br,
4H, NH2), 7.62 (d, 2H, Jˆ7.3 Hz, H-6). dC (d6-DMSO):
38.0, 67.1, 75.2, 94.2, 144.7, 154.9, 166.0. m/z (FAB,
NOBA matrix): 149 (100%, [Mϩ1]ϩϪC7H6N3O).
4,40-Bis(acetylamino)-1,10-(docosa-10,12-diyne-1,22-diyl)-
4
dipyrimidin-2(1H)-one) (9d).- N-Acetylcytosine (0.84 g;
5.48 mmol), potassium carbonate (0.78 g; 5.64 mmol) and
18-crown-6 (0.03 g; 0.01 mmol) and DMF (50 cm3) were
stirred at room temperature for 2 h. Docosa-10,12-diyne-
1,22-diyl bis(toluene-p-sulfonate) (1.50 g; 2.33 mmol) was
added and the mixture was stirred for a further 5 days at
room temperature. The solvent was evaporated under
reduced pressure and the resulting yellow solid was pre-
adsorbed on to silica gel and purified by column chroma-
tography [CH2Cl2/MeOH (95:5) eluant] to afford 4,40-bis-
(acetylamino)-1,10-(docosa-10,12-diyne-1,22-diyl)dipyrim-
idin-2(1H)-one) (9d) (0.17 g; 12%), mp 139ЊC. nmax (KBr,
cmϪ1): 3235 (N–H str.), 2925, 2850 (aliphatic C–H str.),
1662, 1636 (amide I, II), 1497 (aliphatic C–H str.). dH
(d6-DMSO) 1.15–1.69 (m, 28H), 2.08 (s, 6H, CH3), 2.26
(t, 4H, Jˆ6.2 Hz, CH2CxC), 3.77 (t, 4H, Jˆ7.2 Hz,
CH2N), 7.11 (d, 2H, Jˆ7.1 Hz, H-5), 8.05 (d, 2H,
Jˆ7.1 Hz, H-6), 10.78 (s, 2H, NH). m/z (FAB, NOBA
matrix) 605 (25%, [Mϩ1]ϩ). (Found: C, 67.5; H, 8.3; N,
13.9%. C34H48N6O4 requires: C, 67.5; H, 8.0; N, 13.9%.)
4,40-Bis(acetylamino)-1,10-(dodeca-5,7-diyne-1,12-diyl)-
dipyrimidin-2(1H)-one (9c), dodeca-5,7-diyne-1-yl-(1-(4-
acetylaminopyrimidin-2(1H)-one))-12-yloxy-(2-(4-acetyl-
aminopyrimidine)) (10) and 2,20-(dodeca-5,7-diyne-1,12-
diyldioxy)bis-(4-acetylamino-pyrimidine) (11). 4N-Acetyl-
cytosine (0.73 g; 4.74 mmol), anhydrous potassium carbo-
nate (0.66 g; 4.74 mmol) and 18-crown-6 (0.04 g; 0.15
mmol) were suspended in dry DMF (50 cm3) and stirred
at 20ЊC for 1 h. Dodeca-5,7-diyne-1,12-diyl bis(toluene-p-
sulfonate) (2b) (1.00 g; 2.15 mmol) was added and the
mixture was stirred for 5 h at 60ЊC then a further 18 h at
20ЊC. Column chromatography [CH2Cl2/MeOH (95:5)
eluant] afforded the following:
4,40-bis(acetylamino)-1,10-(dodeca-5,7-diyne-1,12-diyl)dipy-
rimidin-2(1H)-one (9c): (0.47 g; 47%) as a colourless
powder, mp 220ЊC. nmax (KBr, cmϪ1): 3434, 3237 (N–H
str.), 3028 (alkene C–H str.), 2953, 2929, 2863 (aliphatic
C–H str.), 1710 (CyO str.), 1662 (N–H def.). dH
(d6-DMSO): 1.32–1.53 (m, 4H, CH2CH2–CxC), 1.58–
1.77 (m, 4H, CH2CH2N), 2.07 (s, 6H, CH3), 2.32 (t, 4H,
Jˆ6.7 Hz, CH2CxC), 3.79 (t, 4H, Jˆ6.9 Hz, CH2N), 7.13
(d, 2H, Jˆ7.2 Hz, H-5 or H-6) 8.06 (d, 2H, Jˆ7.2 Hz, H-6
or H-5), 10.79 (br s, 2H, NH). dC (d6-DMSO): 18.4, 24.7,
25.2, 28.0, 49.4, 66.0, 78.2, 95.4, 150.6, 155.7, 162.7, 171.3.
m/z (FAB, NOBA matrix): 465.2237 (100%, [Mϩ1]ϩ);
C24H29N6O4 requires: 465.2250.
4,40-Diamino-1,10-(dodeca-5,7-diyne-1,12-diyl)dipyrimi-
din-2(1H)-one (9e). Compound (9c) was stirred in 5%
ammoniacal methanol (50 cm3/100 mg) at room tempera-
ture for 18 h. The solvent was evaporated under reduced
pressure to afford the title compound (9e) (ca. 100%) as a
white powder. mp Ͼ360ЊC. nmax (KBr, cmϪ1): 3351 (N–H
str.), 3110 (alkene C–H str.), 2928, 2862 (aliphatic C–H
str.), 1659 (CyO str.), 1621 (N–H def.), 1489 (aliphatic
C–H def.). dH (d6-DMSO): 1.29–1.79 (m, 8H), 2.30 (t,
4H, Jˆ6.6 Hz, CH2CxC), 3.62 (t, 4H, Jˆ6.7 Hz, CH2N),
5.63 (br d, 2H, Jˆ7.0 Hz, H-5), 6.98 (bs, 4H, NH2), 7.55 (d,
2H, Jˆ7.0 Hz, H-6). dC (d6-DMSO): 18.4, 25.2, 28.4, 48.4,
Dodeca-5,7-diyne-1-yl-(1-(4-acetylaminopyrimidin-2(1H)-
one))-12-yloxy-(2-(4-acetylaminopyrimidine)) (10): (0.26 g;

1242
W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
65.9, 78.3, 93.5, 146.4, 156.2, 166.3. m/z (FAB, NOBA
matrix) 381.2045 (47%, [Mϩ1]ϩ); C20H25N6O2 requires:
381.2039.
at room temperature for 72 h. The solution was filtered and
the solvent was evaporated under reduced pressure to give a
yellow solid. This was pre-adsorbed on to silica gel and
purified by column chromatography [CH2Cl2/MeOH
(100:0–95:5) eluant] to afford 9-(tricosa-10,12-diynyl)-6-
chloro-9H-purin-2-amine (12d) (0.54 g; 72%) and
7-(tricosa-10,12-diynyl)-6-chloro-7H-purin-2-amine (13b)
(0.13 g; 18%).
9-(Prop-2-ynyl)-6-chloro-9H-purin-2-amine (12a) and 7-
(prop-2-ynyl)-6-chloro-7H-purin-2-amine (13a). To a
suspension of 2-amino-6-chloropurine (2.00 g; 11.79 mmol)
in DMF (50 cm3) was added anhydrous potassium carbonate
(1.64 g; 11.85 mmol). The suspension was stirred at room
temperature for 20 min, during which time a clear solution
was formed. Propargyl bromide (1.40 g; 11.79 mmol) was
added and the resulting solution was stirred for a further
44 h at room temperature. The solvent was evaporated
under reduced pressure to afford a brown powder that was
purified by column chromatography [CH2Cl2/MeOH (98:2)
eluant]. The products were 9-(prop-2-ynyl)-6-chloro-9H-
purin-2-amine (12a) (1.40 g; 57%) and 7-(prop-2-ynyl)-6-
chloro-7H-purin-2-amine (13a) (0.31 g; 12%).
Compound (12d): mp 82–86ЊC. nmax (KBr, cmϪ1): 3431,
3330, 3212 (N–H str.), 3072 (aromatic C–H str.), 2925,
2854 (aliphatic C–H str.), 1645 (N–H def.), 1607 (CyN
str.), 1560, 1523 (C–H def.). dH (CDCl3): 0.88 (t, 3H,
Jˆ6.4 Hz, CH3), 1.15–1.96 (m, 30H), 2.23 (t, 4H,
Jˆ6.7 Hz, CH2CxC), 4.08 (t, 2H, Jˆ7.2 Hz, CH2N), 5.37
(br s, 2H, NH2), 7.78 (s, 1H, H-8). dC (CDCl3): 14.0, 19.1,
22.6, 26.4, 28.1, 28.3, 28.6, 28.8, 29.0, 29.1, 29.2, 29.4,
29.4, 29.5, 31.8, 43.7, 65.1, 65.2, 77.3, 125.2, 142.3,
151.1, 153.7, 159.0. m/z (FAB, NOBA matrix): 485 (62%,
[Mϩ1]ϩ), 968 (1%, [2Mϩ1]ϩ, for MˆC28H42N535Cl).
(Found: C, 69.3; H, 8.8; N, 14.4%. C28H42N5Cl requires:
C, 69.47; H, 8.74; N, 14.47%.)
Compound (12a): mp 237ЊC. lmax MeOH (nm): 226 (e
6094), 246 (6812), 310 (8116). dH (d6-DMSO): 3.52 (t,
1H, Jˆ2.3 Hz, CxCH), 4.98 (d, 2H, Jˆ2.3 Hz, CH2CxC),
7.08 (s, 2H, NH2), 8.22 (s, 1H, H-8). dC (d6-DMSO): 32.9,
76.6, 78.4, 123.5, 142.9, 150.0, 154.0, 160.4. m/z (EI)
Compound (13b): mp 164–167ЊC. nmax: (KBr, cmϪ1): 3396,
3314, 3177 (N–H str.), 3078 (aromatic C–H str.), 2925,
2852 (aliphatic C–H str.), 1638 (N–H def.), 1616 (CyN
str.), 1542, 1505 (C–H def.). lmax MeOH (nm): 229 (e
10869), 321 (5981). dH (CDCl3): 0.88 (t, 3H, Jˆ6.4 Hz,
CH3), 1.14–2.00 (m, 30H), 2.25 (t, 4H, Jˆ6.7 Hz,
CH2CxC), 4.09 (t, 2H, Jˆ7.2 Hz, CH2N), 5.48 (br s, 2H,
NH2), 7.97 (s, 1H, H-8). dC (CDCl3): 14.0, 19.1, 22.6, 26.2,
28.1, 28.2, 28.6, 28.8, 29.0, 29.1, 29.2, 29.4, 31.3, 31.8,
47.2, 65.1, 65.2, 77.2, 77.5, 116.1, 143.3, 148.3, 159.4,
164.2. m/z (FAB, NOBA matrix): 485 (98%, [Mϩ1]ϩ),
968 (2%, [2Mϩ1]ϩ, for MˆC28H42N535Cl). Found: C,
69.3 H, 8.8, N, 14.4%. C28H42N5Cl requires: C, 69.46; H,
8.74; N, 14.47%.)
⅐ϩ
207.02927 and 209.02813 (M ); C8H6N5Cl requires:
207.03117 and 209.02822. (Found: C, 46.2; H, 2.8; N,
33.4%. C8H6N5Cl requires: C, 46.28; H, 2.91; N 33.73%.)
Compound (13a): mp 221ЊC. lmax MeOH (nm): 233 (e
8805), 322 (6472). dH (d6-DMSO) 3.61 (t, 1H, Jˆ2.4 Hz,
CxCH), 5.22 (d, 2H, Jˆ2.4 Hz, CH2CxC), 6.73 (s, 2H,
NH2), 8.48 (s, 1H, H-8). dC (d6-DMSO): 36.5, 77.6, 78.8,
⅐ϩ
115.0, 143.0, 149.4, 160.6, 164.6. m/z (EI) 207.03146 (M );
C8H6N535Cl requires: 207.03117. (Found: C, 46.0; H, 2.8; N,
33.4%. C8H6N5Cl requires: C, 46.28; H, 2.91; N, 33.73%.)
9-(Prop-2-ynyl)-6-chloro-2-acetylamino-9H-purine (12b)
and 9-(prop-2-ynyl)-6-chloro-2-(diacetylamino)-9H-purine
(12c). 9-(Prop-2-ynyl)-6-chloro-9H-purin-2-amine (110 mg;
0.53 mmol) was heated under reflux with acetic anhydride
(10 cm3) for 3 h. The solvent was evaporated under reduced
pressure and the crude product was purified by column chro-
matography [CH2Cl2/MeOH (96:4) eluant] to afford
9-(prop-2-ynyl)-6-chloro-2-acetylamino-9H-purine (12b)
(20 mg; 15%) and 9-(prop-2-ynyl)-6-chloro-2-(diacetyl-
amino)-9H-purine (12c) (50 mg; 32%).
9-(Tricosa-10,12-diynyl)-2-amino-1,9-dihydro-6H-purin-
6-one (16). This was prepared by method described above
for (15b) from 9-(tricosa-10,12-diynyl)-6-chloro-9H-purin-
2-amine (12d) (0.50 g; 1.03 mmol), dioxane (15 cm3) and
5% aqueous sodium hydroxide solution (20 cm3).
9-(Tricosa-10,12-diynyl)-2-amino-1,9-dihydro-6H-purin-6-
one (16) (0.23 g; 47%) was isolated as a white amorphous
solid which turned pink slowly on exposure to daylight, mp
191–199ЊC. nmax (KBr, cmϪ1): 3484, 3325, 3195 (N–H
str.), 2924, 2852, 2728 (C–H str.), 1724, 1689 (amide I,
II), 1627 (N–H def.). dH (d6-DMSO): 0.83 (t, 3H,
Jˆ6.7 Hz, CH3), 1.10–1.84 (m, 30H), 2.25 (t, 4H,
Jˆ6.5 Hz, CH2CxC), 3.89 (t, 2H, Jˆ7.0 Hz, CH2N), 6.42
(br s, 2H, NH2), 7.66 (s, 1H, H-8), 10.52 (br s, 1H, NHCO).
dC (d6-DMSO): 13.9, 18.3, 22.1, 25.9, 27.7, 28.2, 28.3, 28.4,
28.4, 28.7, 28.7, 28.9, 28.9, 31.3, 42.6, 48.6, 65.3, 77.9,
77.9, 116.6, 137.4, 151.1, 153.4, 156.8. m/z (FAB, NOBA
matrix): 466.3538 [Mϩ1]ϩ; [C28H43N5OϩHϩ] requires:
466.3545.
Compound (12b): mp 239–240ЊC. dH(d6-DMSO): 2.21 (s,
3H, CH3), 3.58 (t, 1H, Jˆ2.5 Hz, CxCH), 5.07 (d, 2H,
Jˆ2.5 Hz, CH2CxC), 8.59 (s, 1H, H-8), 11.85 (br s, 1H,
⅐ϩ
NH). m/z (EI): 249.042 and 251.037 (M ); C10H8N5OCl
requires: 249.042 and 251.039. Compound (12c): mp
157ЊC. dH (d6-DMSO): 2.24 (s, 6H, CH3), 3.60 (t, 1H,
Jˆ2.5 Hz, CxCH) 5.22 (d, 2H, Jˆ2.5 Hz, CH2CxC), 8.89
(s, 1H, H-8). m/z (EI) 291.0521 (M ); C12H10N5O235Cl
⅐ϩ
requires: 291.0523.
9-(Tricosa-10,12-diynyl)-6-chloro-9H-purin-2-amine (12d)
and 7-(tricosa-10,12-diynyl)-6-chloro-7H-purin-2-amine
(13b). 2-Amino-6-chloropurine (0.34 g; 2.00 mmol),
tricosa-10,12-diynyl toluene-p-sulfonate (2e) (0.75 g;
1.54 mmol) potassium carbonate (0.28 g; 2.00 mmol) and
DMF (25 cm3) were stirred under an atmosphere of nitrogen
Ethyl tricosa-10,12-diynoate (17a). Tricosa-10,12-dynoic
acid (1.00 g; 2.88 mmol), ethanol (50 cm3) and 10 drops of
conc. sulphuric acid were heated under reflux for 5 h. On
cooling, saturated sodium bicarbonate solution was added
until the solution became neutral. The mixture was

W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
1243
evaporated under reduced pressure and the resulting solid
was digested in CH2Cl2 (50 cm3) and dried (MgCl2). The
mixture was filtered and the filtrate was evaporated to give
ethyl tricosa-10,12-diynoate (17a) (0.88 g; 81%) as a clear
viscous liquid, bp 207ЊC. nmax (KBr, cmϪ1): 2927, 2854
(aliphatic C–H str.), 1737 (CyO str.), 1464, 1372 (aliphatic
C–H def.), 1181 (C–O str.). dH (CDCl3): 0.88 (t, 3H,
Jˆ6.7 Hz, CH3), 1.12–1.73 (m, 31H), 2.24 (t, 2H,
Jˆ6.9 Hz, CH2CO2 or CH2CxC), 2.27 (t, 4H, Jˆ6.8 Hz,
CH2CxC or CH2CO2), 4.13 (q, 2H, Jˆ7.1 Hz, CH2O). dC
(CDCl3): 14.0, 14.2, 19.1, 22.6, 24.8, 28.2, 28.6, 28.8, 29.0,
29.2, 29.4, 29.5, 31.8, 34.2, 60.1, 65.2, 77.3, 173.8. m/z (EI)
and the resulting solid was pre-adsorbed on silica gel and
purified by flash chromatography [CH2Cl2/MeOH (98:2)
eluant] to give 6,60-(icosa-9,11-diyne-1,20-diyl)di-1,3,5-tri-
azine-2,4-diamino (18b) (1.02 g; 21%) and methyl 21-(4,6-
diamino-1,3,5-triazin-2-yl)henicosa-10,12-diynoate (17c)
(1.27 g; 29%).
Compound (18b): mp 154ЊC. nmax (KBr, cmϪ1): 3334, 3185
(N–H str.), 2929, 2854 (aliphatic C–H str.), 1635, 1543 (N–
H def.). dH (d6-DMSO): 1.08–1.69 (m, 24H), 2.17–2.37 (m,
8H, CH2CxC and CH2-triazine), 6.55 (br s, 8H, NH2). dC
(d6-DMSO): 18.7, 27.5, 28.2, 28.7, 28.8, 29.4, 38.4, 65.8,
78.5, 167.5, 178.2. m/z (FAB, NOBA matrix): 493 (100%,
[Mϩ1]ϩ). (Found: C, 63.0; H, 8.3; N, 28.5%. C26H40N10
requires: C, 63.39; H, 8.18; N, 28.43%.)
⅐ϩ
374.3159 (M ), C25H42O2 requires: 374.3185.
6-(Docosa-9,11-diynyl)-2,4-diamino-1,3,5-triazine (17b).
Biguanide (0.24 g; 2.40 mmol) and dry methanol (50 cm3)
were heated to 40ЊC, with stirring. Ethyl tricosa-10,12-
diynoate (17a) (0.60 g; 1.60 mmol) in dry methanol
(20 cm3) was added over 10 min and the resulting solution
was stirred at 40ЊC under an atmosphere of nitrogen for
20 h. The solvent was then evaporated under reduced
pressure and the resulting solid was purified by column
chromatography [CH2Cl2/MeOH (98:2) eluant] to afford
Compound (17c): mp 124–125ЊC. nmax (KBr, cmϪ1): 3378,
3334, 3138 (N–H str.), 2930, 2854 (aliphatic C–H str.),
1722 (CyO str.) 1649, 1543 (N–H def.). dH (d6-DMSO):
1.12–1.68 (m, 24H), 2.17–2.36 (m, 8H), 3.56 (s, 3H,
CH3O–), 6.53 (br s, 4H, NH2). dC (d6-DMSO): 18.7, 24.8,
27.5, 28.2, 28.6, 28.7, 28.8, 29.0, 29.3, 33.7, 38.4, 51.6,
65.8, 78.4, 167.5, 173.8, 178.2. m/z (FAB, NOBA matrix):
443 (100%, [Mϩ1]ϩ). (Found: C, 68.5; H, 9.0; N, 15.9%.
C25H39N5O2 requires: C, 67.99; H, 8.90; N, 15.86%.
6-(docosa-9,11-diynyl)-2,4-diamino-1,3,5-triazine
(17b)
(0.39 g; 59%) as an amorphous white solid, mp 99ЊC.
lmax CHCl3 (nm): 257 (e 1054). nmax (KBr, cmϪ1): 3486,
3321, 3178 (N–H str), 2923, 2851 (aliphatic C–H str.), 1669
(CyN str.), 1636 (N–H def.), 1545 (C–H def.). dH (CDCl3):
0.88 (t, 3H, Jˆ6.4 Hz, CH3), 1.18–1.79 (m, 28H), 2.23 (t,
4H, Jˆ6.7 Hz, CH2CxC), 2.46 (t, 2H, Jˆ7.7 Hz, CH2-tri-
azine), 5.68 (br s, 4H, NH2). dC (CDCl3): 14.0, 19.1, 22.5,
27.7, 28.2, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.5,
1-(Tricosa-10,12-diynyl)pyrimidine-2,4-(1H,3H)-dione
(18c). Tricosa-10,12-diynyl toluene-p-sulfonate (2e)
(0.83 g; 1.70 mmol), uracil (0.23 g; 2.04 mmol), anhydrous
potassium carbonate (0.34 g; 2.45 mmol) and DMF
(10 cm3) were stirred under an atmosphere of nitrogen at
room temperature for 20 h. The solvent was evaporated
under reduced pressure and the residual solid was dissolved
in CH2Cl2/MeOH (90:10) and pre-adsorbed on to silica gel.
Purification by column chromatography using CH2Cl2, then
CH2Cl2/MeOH (98:2), as eluants afforded 1-(tricosa-10,12-
diynyl)pyrimidine-2,4-(1H,3H)-dione (18c) (220 mg; 30%)
as a white solid which turned purple on exposure to
daylight, mp 70–72ЊC. nmax (KBr, cmϪ1): 3162, 3053
(N–H str.), 2920, 2850 (aliphatic C–H str.), 1717, 1680
(amide I, II), 1463, 1392 (aliphatic C–H def.). dH
(CDCl3): 0.89 (t, 3H, Jˆ6.4 Hz, CH3), 1.16–1.81 (m,
30H), 2.26 (t, 4H, Jˆ7.0 Hz, CH2CxC), 3.73 (t, 2H,
Jˆ7.3 Hz, CH2N), 5.72 (dd, 1H, Jˆ7.9 Hz, 2.1, H-5), 7.16
(d, 1H, Jˆ7.9 Hz, H-6), 9.36 (br s, 1H, NH). dC (CDCl3):
14.0, 19.1, 22.6, 26.3, 28.2, 28.3, 28.6, 29.0, 29.2, 29.4,
29.5, 31.8, 48.8, 65.2, 77.3, 102.0, 144.4, 150.8, 163.8.
⅐ϩ
31.8, 38.7, 65.2, 77.4, 167.0, 179.6. m/z (EI) 411 (M ).
(Found: C, 72.9; H, 10.2; N 17.0%. C25H41N5 requires: C,
72.95; H, 10.04; N, 17.01%.)
Diethyl docosa-10,12-diyne dioate (18a). Docosa-10,12-
diyne dioic acid (4.73 g; 13.05 mmol), ethanol (150 cm3)
and conc. sulfuric acid (0.5 cm3) were heated under reflux
for 4 h. On cooling, saturated aqueous sodium bicarbonate
solution was added until no more carbon dioxide evolved.
The mixture was evaporated under reduced pressure and the
residue was partitioned between dichloromethane and water
(100 cm3/100 cm3). The organic layer was separated and
dried (CaCl2). Diethyl docosa-10,12-diyne dioate (18a)
(5.35 g; 98%) was isolated as a colourless solid after purifi-
cation by column chromatography [CH2Cl2 eluant], mp
24ЊC. nmax liq. film (cmϪ1): 2979, 2931, 2856 (aliphatic
C–H str.), 1736 (CyO str.). dH (CDCl3): 1.18–1.83 (m,
24H), 1.26 (t, 6H, Jˆ7.2 Hz, CH3), 2.24 (t, 4H, Jˆ6.9 Hz,
CH2), 2.29 (t, 4H, Jˆ7.3 Hz, CH2), 4.12 (q, 4H, Jˆ7.2 Hz,
CH2O). dC (CDCl3): 14.2, 19.1, 24.8, 28.2, 28.7, 28.8, 29.0,
34.3, 60.1, 65.1, 77.4, 173.8. m/z (EI): 373.2747
⅐ϩ
m/z (EI): 426.3231 (M ); C27H42N2O2 requires: 426.3246.
N-Succinimidyl-10,12-pentacosadiynate (18e). A solution
of N-hydroxysuccinimide (0.70 g, 6.03 mmol), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(1.19 g, 6.20 mmol) and 10,12-pentacosadiynoic acid
(2.10 g, 5.63 mmol) in dichloromethane (25 cm3) was
stirred at room temperature for 2 h. The solvent was evapo-
rated under reduced pressure and the residue was triturated
with diethyl ether (3×30 cm3). The ether extract was washed
with water (30 cm3), dried (MgSO4), then filtered and the
solvent was evaporated under reduced pressure to give the
title compound as a colourless solid (2.46 g, 93%), mp 66ЊC.
nmax (KBr, cmϪ1) 1743 (CyO str). dH (CDC13) 0.90 (t, 3H,
Jˆ6.7 Hz, CH3), 1.35–1.80 (m, 32H, CH2), 2.25 (t, 4H,
Jˆ6.8 Hz, CH2CxC), 2.60 (t, 2H, Jˆ7.7 Hz, CH2CONR),
⅐ϩ
(M ϪC2H5O); C24H37O3 requires: 373.2743.
6,60-(Icosa-9,11-diyne-1,20-diyl)di-1,3,5-triazine-2,4-dia-
mino (18b) and methyl 21-(4,6-diamino-1,3,5-triazin-2-
yl)henicosa-10,12-diynoate (17c). Biguanide (2.41 g;
23.85 mmol) was heated in dry methanol (50 cm3) to 40ЊC
under an atmosphere of nitrogen with stirring. Diethyl
docosa-10,12-diyne dioate (18a) (4.19 g; 10.00 mmol) in
dry methanol (20 cm3) was slowly added over 10 min with
stirring. The solvent was evaporated under reduced pressure

1244
W. E. Lindsell et al. / Tetrahedron 56 (2000) 1233–1245
2.85 (s, 4H, CH2CH2). dC (CDC13) 14.0, 19.1, 22.6, 24.4,
25.5, 28.2, 28.3, 28.6, 28.8, 29.0, 29.2, 29.4, 29.5, 30.8,
31.8, 65.1 (CxC), 168.6 (CyO), 169.1 (CyO). m/z (EI)
357.3155 (MϪNOCOCH2CH2CO)ϩ⅐, C25H41O requires
357.3157.
99–101ЊC. Found: C, 73.9; H, 9.1; N, 5.9%; C44H64N3O3Cl
requires C, 73.6; H, 9.0; N, 5.9%. nmax (KBr, cmϪ1) 1643
(CyO str.). dH (CDC13) 0.83 (t, 3H, Jˆ6.0 Hz, CH3) 1.20–
1.65 (br. s, 32H, CH2), 2.21 (m, 6H, CH2CxC,
CH2CONHR), 3.41 (m, 2H, CH2), 3.53 (t, 2H, Jˆ5.2 Hz,
CH2), 3.62 (dd, 2H, Jˆ5.7, 2.7 Hz, CH2), 3.73 (dd, 2H,
Jˆ5.8, 2.6 Hz, CH2), 4.03 (t, 2H, Jˆ5.1 Hz, CH2), 4.23 (t,
2H, Jˆ5.1 Hz, CH2), 6.45 (br. s, 1H, NH), 7.20 (t, 2H,
Jˆ7.6 Hz, ArH), 7.45 (t, 2H, Jˆ7.5 Hz, ArH), 7.90 (d,
2H, Jˆ8.6 Hz, ArH), 8.27 (d, 2H, Jˆ8.6 Hz, ArH), 9.5
(br. s, 1H, NϩHClϪ). dC (CDC13) 14.0, 19.1, 22.6, 25.6,
28.2, 28.7, 28.7, 28.8, 29.0, 29.1, 29.2, 29.4, 29.5, 31.8,
36.5, 39.1, 48.7, 65.1, 69.0, 70.0, 70.2, 70.5, 77.4, 112.8,
119.4, 123.2, 124.6, 133.6, 140.7, 156.4, 173.9. m/z (FAB,
NOBA matrix) 682.3 (100%) (MϩϪHCl).
10,80-Bis-(10,12-pentacosadiynamido)-30,60-dioxaoctane
(18f). A solution of 1,8-diamino-3,6-dioxaoctane (0.93 cm3,
6.36 mmol) in dichloromethane (25 cm3) was added drop-
wise over 30 min to a solution of N-succinimidyl-10,12-
pentacosadiynate (18e) (1.00 g, 2.12 mmol) in dichloro-
methane (20 cm3). The reaction mixture was stirred for an
additional 30 min, then the solvent was evaporated under
reduced pressure. The residue was dissolved in ethyl acetate
(30 cm3) and the extract was washed with water (2×30 cm3).
The organic layer was dried (MgSO4) and the solvent was
evaporated under reduced pressure. The residue was
chromatographed (silica gel, dichloromethane/methanol
[95:5] eluant) to afford the title compound (Rfˆ0.36) as a
colourless solid (1.56 g, 85%) which turned blue rapidly in
ambient light, mp 100–102ЊC. nmax (KBr, cmϪ1) 1641
(CyO str.). Found: C, 78.2; H, 11.2; N, 3.2%; C56H96N2O4
requires C, 78.1; H, 11.2; N, 3.3%. dH (CDC13) 0.85 (t, 6H,
Jˆ6.9 Hz, CH3), 1.30–1.43 (br.s, 48H, CH2), 1.43–1.70 (br.
m, 16H, CH2), 2.18 (t, 4H, Jˆ7.5 Hz, CH2CONHR), 2.25(t,
8H, J6.7, CH2CxC), 3.48 (t, 4H, Jˆ4.9 Hz, CH2O), 3.56 (m,
4H, CH2NHCOR), 3.61 (s, 4H, OCH2CH2O), 5.98 (br. s,
2H, NH). dC (CDC13) 14.0, 19.1, 22.6, 25.6, 28.2, 28.8,
29.0, 29.1, 29.2, 29.4, 29.5, 30.8, 31.8, 36.6, 39.0, 65.1,
69.9, 70.1, 77.5, 173.0 (CyO).
10-(6-Chloro-2-methoxy-9-acridinylamino)-80-(100,120-pen-
tacosadiynyl-amido)-30,60-dioxaoctane (19b). This com-
pound was prepared as described above for (19a) from
6,9-dichloro-2-methoxyacridine
(0.50 g,
1.90 mmol),
N-(80-amino-30,60-dioxaoctyl)-10,12-pentacosadiyne-1-amide
(18g) (0.94 g, 1.87 mmol) and phenol (20 g). The title
compound was a yellow solid (1.05 g, 72%), mp 144–
146ЊC. Found: C, 67.5; H, 8.6; N, 5.3%;
C45H65N3O4Cl2·H2O requires C, 67.5; H, 8.4; N, 5.3%.
nmax (KBr, cmϪ1) 3300, 3080, 2918, 2848, 1647, 1560,
1467. dH (CDC13) 0.88 (t, 3H, Jˆ6.2 Hz, CH3), 1.20–1.65
(br. s, 32H, CH2), 2.21 (m, 6H, CH2CxC, CH2CONHR),
3.45 (t, 2H, Jˆ5.1 Hz, CH2), 3.52 (t, 2H, Jˆ4.9 Hz, CH2),
3.65 (dd, 2H, Jˆ5.9, 3.6 Hz, CH2), 3.78 (dd, 2H, Jˆ5.3,
3.0 Hz, CH2), 3.95 (s, 3H, CH3O), 4.10 (m, 2H, CH2),
4.31 (m, 2H, CH2), 6.40 (br. t, 1H, NH), 7.13 (d, 2H,
Jˆ9.1 Hz, ArH), 7.55 (s, 1H, ArH), 7.80 (d, 1H,
Jˆ9.3 Hz, ArH), 7.90 (s, 1H, ArH), 8.23 (d, 1H,
Jˆ9.3 Hz, ArH). dC (CDC13) 14.0, 19.1, 22.6, 25.9, 28.2,
28.8, 29.0, 29.1, 29.2, 29.4, 29.5, 31.8, 35.9, 39.6, 48.8,
56.4, 65.1, 69.6, 70.4, 77.3, 109.8, 113.7, 117.7, 120.4,
123.8, 126.8, 134.3, 139.4, 140.1, 156.0, 174.8. m/z (FAB,
NOBA matrix, for free base) 746.6 (68%, Mϩ⅐),
C45H6435ClN3O4 requires: 746.5.
N-(80-Amino-30,60-dioxaoctyl)-10,12-pentacosadiynamide
(18g). A solution of N-succinimidyl-10,12-pentacosadiy-
nate (18e) (1.5 g, 3.18 mmol) in dichloromethane (25 cm3)
was added over 16 h by syringe pump to a stirred solution of
1,8-diamino-3,6-dioxaoctane (1.88 g, 12.7 mmol) in
dichloromethane (25 cm3) at room temperature. The solu-
tion was stirred for an additional 1 h and then evaporated to
a low volume under reduced pressure. The residual slurry
was chromatographed (silica gel, using a gradient of chloro-
form/methanol [25:1–8:1] as eluant) to yield the title
compound (0.61 g, 38%). nmax (KBr, cmϪ1) 3297, 3085
(NH str.), 2952 (CH str.), 1642 (CyO str.). dH (CDC13/
CD3OD [1:1]) 0.89(t, 3H, Jˆ6.3 Hz, CH3), 1.20–1.70 (m,
32H, CH2), 2.20 (t, 2H, Jˆ7.9 Hz, CH2), 2.25 (t, 4H,
Jˆ6.5 Hz, CxCCH2), 2.85 (t, 2H, Jˆ4.9 Hz, CH2), 3.40
(t, 4H, Jˆ5.1 Hz, CH2), 3.56 (t, 4H, Jˆ5.3 Hz, CH2O),
3.65 (s, 4H, OCH2CH2O) [NH not observed]. dC (CDC13)/
CD3OD [1:1]) 15.3, 20.4, 24.0, 27.2, 29.7, 30.1, 30.3, 30.4,
30.6, 30.7, 30.8, 31.0, 33.3, 37.7, 40.5, 42.2, 66.6, 71.1,
71.5, 71.6, 73.5, 78.6, 176.3. m/z (FAB, NOBA matrix)
505.4373 (MϩH)ϩ⅐, C31H57N2O3 requires m/z 505.4369.
Acknowledgements
We thank the Engineering and Physical Sciences Research
Council for a grant (to T. A. J. W.) and for access to the
CPMAS NMR service at the University of Durham, UK.
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